ASH1L inhibitors and treatment methods using same

Abstract

Provided are small molecule inhibitors of ASH1L activity and small molecules that promote the degradation of ASH1L, and methods of using same in the treatment of diseases including acute leukemia, solid cancers, and other diseases that depend on the activity of ASH1L. The present invention relates to a compound of the following formula: TIFF2022137128000334.tif62169 (wherein X is S, O, NH, or CH; L is composed of 0 to 3 C, S, O, and / or N, and when the number of components of L is 0, there is no bond at the position of L.)

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit to U.S. Provisional Patent Application No. 62 / 335,160, filed May 12, 2016, which is incorporated herein by reference in its entirety.

[0002] Provided herein are small molecule inhibitors of ASH1L activity and small molecules that promote the degradation of ASH1L, as well as methods of using same in the treatment of diseases including acute leukemia, solid cancers, and other diseases that depend on the activity of ASH1L. [Background technology]

[0003] ASH1L (Absent small and homeotic disc protein 1 homolog; EC:2.1.1.43) is a histone-lysine N-methyltransferase (KMTase) that methylates histone 3, lysine 36 (H3K36). ASH1L is essential for chromatin binding of MLL fusion proteins at key leukemia target genes and for MLL fusion protein-mediated oncogenic transformation, suggesting that ASH1L is a therapeutic target for MLL leukemia and possibly other leukemias with high HOX expression (Reference 1; incorporated by reference in its entirety). ASH1L is also overexpressed in various solid tumors, including thyroid and breast cancers (References 2 and 3; incorporated by reference in their entireties). In thyroid cancer, ASH1L is overexpressed in a tumor-specific truncated form. The tumor suppressor microRNA, miR-142-3p, inhibits ASH1L protein expression by binding to the 3'UTR of ASH1L, an effect that correlates with the inhibition of colony formation and delayed proliferation of thyroid cancer cells (Reference 2; incorporated by reference in its entirety). Furthermore, the ASH1L gene frequently undergoes copy number amplification in aggressive basal-like breast cancer, and high ASH1L mRNA expression is associated with shortened lifespan in breast cancer patients (Reference 3; incorporated by reference in its entirety). Finally, structural alterations near the ASH1L gene have been observed in hepatocellular carcinoma (HCC), and knockdown of ASH1L in HCC cells delayed proliferation (Reference 4; incorporated by reference in its entirety).

[0004] ASH1L activates multiple developmentally and oncogenically relevant genes, including HOXA, HOXB, HOXC, and HOXD, as well as MEIS1 (References 5-8; incorporated by reference in their entireties). The KMTase activity of ASH1L is required for at least part of its gene activation function, as deletion of the ASH1L SET domain during differentiation of mouse embryonic stem cells results in the loss of expression of 152 genes, including members of the Hox and Wnt families (Reference 8; incorporated by reference in its entirety). These findings are highly relevant, as HOX genes are oncogenic factors in a variety of hematological and solid tumors (Reference 9; incorporated by reference in its entirety). For example, overexpression of HOXA9 is highly associated with poor prognosis in AML (Reference 10; incorporated by reference in its entirety), and HOXA9 and its cofactor MEIS1 are required for the survival of MLL-rearranged leukemia cells (References 11 and 12; incorporated by reference in their entireties). Loss of ASH1L causes a significant reduction in long-term hematopoietic stem cells (HSCs) in mouse bone marrow, but has only a limited effect on peripheral blood cell counts due to increased proliferation of progenitor cells downstream of HSCs (Ref. 5; incorporated by reference in its entirety). ASH1L-deficient HSCs also fail to recapitulate bone marrow production when transplanted into lethally irradiated mice (Ref. 5; incorporated by reference in its entirety). These findings indicate that ASH1L maintains the quiescence and self-renewal capacity of long-term HSCs.

[0005] ASH1L also plays an important role in diseases other than cancer. For example, in facioscapulohumeral muscular dystrophy, ASH1L is recruited to chromosome region 4q35 by non-coding RNA, leading to H3K36 dimethylation, chromatin remodeling, and aberrant transcription of 4q35 genes (Reference 13; incorporated by reference in its entirety). In liver fibrosis, ASH1L is upregulated during the transdifferentiation of hepatic stellate cells into fibrogenic myofibroblasts, where it binds to and activates profibrogenic genes (Reference 14; incorporated by reference in its entirety). Summary of the Invention

[0006] Provided herein are small molecule inhibitors of ASH1L activity and small molecules that promote the degradation of ASH1L, as well as methods of using same in the treatment of diseases including acute leukemia, solid cancers, and other diseases that depend on the activity of ASH1L.

[0007] In some embodiments, the compounds of formula (I) are described herein:

[0008] [ka]

[0009] The present invention provides a compound having the structure: wherein X is S, O, NH, or CH; R 1 is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl, dialkylphosphine oxide, carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused with another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof; L consists of 0-3 C, S, O, and / or N, and if L has 0 members, there is no bond at L;

[0010] [ka]

[0011] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., a cycloalkyl ring or an unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5when present, are independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof;

[0012] [ka]

[0013] is sometimes present,

[0014] [ka]

[0015] and a 4- to 7-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring that forms a ring system with R G1 -R G5 optionally substituted by a substituent; R G1 -R G5 when present, are independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof; Y is a linker consisting of 0-3 C, S, O and / or N, in which case either of the C or N components of Y may be optionally substituted, and when the Y component is 0,

[0016] [ka]

[0017] There is a covalent bond of; Z is a linker consisting of 0-3 C, S, O and / or N, in which case either of the C or N components of Z may be optionally substituted, and when the Z component is 0,

[0018] [ka]

[0019] There is no bond;

[0020] [ka]

[0021] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle, or heterocycle; R A1 -R A5 is, when present, independently selected from H, alkyl, substituted alkyl, branched alkyl, substituted branched alkyl (e.g., halogen-substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle (e.g., piperidine, tetrahydropyran, alkylsulfonyl-substituted piperidine (see Compound 263), sulfonamide-substituted piperidine (see Compound 268)), aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof;

[0022] [ka]

[0023] is sometimes present,

[0024] [ka]

[0025] and a 5- to 7-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring system, with positions 0 to 5 being R E1 -R E5 optionally substituted by a substituent; R E1 -R E5 are, when present, independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, substituted amine, alkylamine, substituted alkylamine (e.g., Compound 290), thioalkyl, halogen, ketone, amide, substituted amide, alkylamide, substituted alkylamide (e.g., Compound 289), cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof;

[0026] [ka]

[0027] is sometimes present,

[0028] [ka]

[0029] and a 4- to 7-membered carbocyclic, heterocyclic, aryl, or heteroaryl ring system, with positions 0 to 5 being R M1 -R M5 may be substituted by a substituent; and RM1 -R M5 where present, are independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof.

[0030] In some embodiments, the compound is one or more of the following:

[0031] [ka] TIFF0007604006000013.tif200169 TIFF0007604006000014.tif195169 TIFF0007604006000015.tif74169

[0032] In some embodiments, when present in a compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), R, R D1-5 , R G1-5 , R A1-5 , R E1-5 , and R M1-5The substituents may be any suitable chemical functional group selected from or including H, alkyl, alkenyl, alkynyl, cycloalkyl, aromatic carbocycle, amine, alkylamine, ether, alcohol, thioether, thiol, sulfonamide, sulfonyl, thioamide, carbamate, carbamide, amide, cyano, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, alkyl group with halo substituents at multiple positions, heterocycle, heteroaryl, ring systems containing 2-3 rings (selected from cycloalkyl rings, aromatic carbocycles, heterocycles, and / or heteroaryl rings), where any of the above functional groups may be combined and / or further substituted (e.g., multiple times) to produce suitable substituents, including, but not limited to, the substituents of Compounds 1-324.

[0033] In some embodiments, when present in a compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), R, R D1-5 , R G1-5 , R A1-5 , R E1-5 , and R M1-5 Any of the substituents may be selected from the group consisting of the formulas (IIa-IIq):

[0034] [ka] TIFF0007604006000017.tif233169 TIFF0007604006000018.tif193169

[0035] is one of; In the formula, J, Q 1 , or J 1 is attached to one of the D, G, A, E, or M rings, if present; J.J. 1 , J 2 , J 3 , and J 4are, if present, a covalent bond, H, alkyl 1-15 , alkenyl 1-6 , alkynyl 1-6 , (CH2) 0-6 C(S)NH2, (CH2) 0-6 C(O)NH2, O, S, NH, (CH2) 0-6 C(O)NH(CH2) 1-6 , (CH2) 0-6 NHC(O)(CH2) 1-6 , alkylsulfonyl, sulfonamide, alkylsulfonamide, (CH2) 0-6 C(S)NH(CH2) 1-6 , (CH2) 0-6 O(CH2) 1-6 , (CH2) 0-6 OH, (CH2) 0-6 S(CH2) 1-6 , (CH2) 0-6 SH, (CH2) 0-6 NH(CH2) 1-6 , (CH2) 0-6 N(CH2) 1-6 (CH2) 1-6 (See, for example, compound 80), (CH2) 0-6 NH2, (CH2) 0-6 SO2(CH2) 1-6 , (CH2) 0-6 NHSO2(CH2) 1-6 , (CH2) 0-6 SO2NH2, halogen (e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH2) 0-6 CH2F, (CH2) 0-3 CHF(CH2) 0-2 CH3, or the like with Br, Cl, or I), dihaloalkyl (e.g., (CH2) 0-6 CF2H, (CH2) 0-3 CF2(CH2) 0-2 CH3, or the like with Br, Cl, or I), trihaloalkyl (e.g., (CH2) 0-6CF3, or the like with Br, Cl, or I), alkyl with 1 to 3 halogens at two or more positions along the chain (see, for example, compounds 126, 144, 194, 195, 200, 207, 245, 251, etc.), (CH2) 1-4 SP(Ph) = S (see, for example, compound 52), (CH) 0-6 NH(CH2) 1-5 OH, (CH2) 0-6 NH(CH2) 1-5 NH2, (CH2) 0-6 NH(CH2) 1-5 SH, (CH2) 0-6 O(CH2) 1-5 OH, (CH2) 0-6 O(CH2) 1-5 NH2, (CH2) 0-6 O(CH2) 1-5 SH, (CH2) 0-6 S(CH2) 1-5 OH, (CH2) 0-6 S(CH2) 1-5 NH2, (CH2) 0-6 S(CH2) 1-5 SH, (CH2) 0-6 O(CH2) 1-6 NH(CH2) 1-5 OH, (CH2) 0-6 O(CH2) 1-6 NH(CH2) 1-5 NH2, (CH2) 0-6 O(CH2) 1-6 NH(CH2) 1-5 SH, (CH2) 0-6 O(CH2) 1-6 O(CH2) 1-5 OH, (CH2) 0-6 O(CH2) 1-6 O(CH2) 1-5 NH2, (CH2) 0-6 O(CH2) 1-6 O(CH2) 1-5 SH, (CH2) 0-6 O(CH2) 1-6 S(CH2) 1-5 OH, (CH2) 0-6 O(CH2) 1-6 S(CH2) 1-5 NH2, (CH2)0-6 O(CH2) 1-6 S(CH2) 1-5 SH、(CH2) 0-6 S(CH2) 1-6 NH(CH2) 1-5 OH、(CH2) 0-6 S(CH2) 1-6 NH(CH2) 1-5 NH2、(CH2) 0-6 S(CH2) 1-6 NH(CH2) 1-5 SH、(CH2) 0-6 S(CH2) 1-6 O(CH2) 1-5 OH、(CH2) 0-6 S(CH2) 1-6 O(CH2) 1-5 NH2、(CH2) 0-6 S(CH2) 1-6 O(CH2) 1-5 SH、(CH2) 0-6 S(CH2) 1-6 S(CH2) 1-5 OH、(CH2) 0-6 S(CH2) 1-6 S(CH2) 1-5 NH2、(CH2) 0-6 S(CH2) 1-6 S(CH2) 1-5 SH、(CH2) 0-6 NH(CH2) 1-6 NH(CH2) 1-5 OH、(CH2) 0-6 NH(CH2) 1-6 NH(CH2) 1-5 NH2、(CH2) 0-6 NH(CH2) 1-6 NH(CH2) 1-5 SH、(CH2) 0-6 NH(CH2) 1-6 O(CH2) 1-5 OH、(CH2) 0-6 NH(CH2) 1-6 O(CH2) 1-5 NH2、(CH2) 0-6 NH(CH2) 1-6 O(CH2) 1-5 SH、(CH2) 0-6 NH(CH2) 1-6 S(CH2)1-5 OH、(CH2) 0-6 NH(CH2) 1-6 S(CH2) 1-5 NH2、(CH2) 0-6 NH(CH2) 1-6 S(CH2) 1-5 SH、(CH2) 0-3 C(O)O(CH2) 0-3 、(CH2) 0-3 C(S)O(CH2) 0-3 、(CH2) 0-3 C(O)S(CH2) 0-3 、(CH2) 0-3 C(S)S(CH2) 0-3 、(CH2) 0-3 C(O)NH(CH2) 0-3 、(CH2) 0-3 C(S)NH(CH2) 0-3 、(CH2) 0-3 NHC(O)(CH2) 0-3 、(CH2) 0-3 NHC(S)(CH2) 0-3 、(CH2) 0-3 OC(O)(CH2) 0-3 、(CH2) 0-3 OC(S)(CH2) 0-3 、(CH2) 0-3 SC(O)(CH2) 0-3 、(CH2) 0-3 SC(S)(CH2) 0-3 、(CH2) 0-3 NHC(O)NH(CH2) 0-3 、(CH2) 0-3 NHC(S)NH(CH2) 0-3 、(CH2) 0-3 OC(O)NH(CH2) 0-3 、(CH2) 0-3 OC(S)NH(CH2) 0-3 、(CH2) 0-3 SC(O)NH(CH2) 0-3 、(CH2) 0-3 SC(S)NH(CH2) 0-3 、(CH2) 0-3 NHC(O)O(CH2) 0-3 、(CH2) 0-3 NHC(S)O(CH2) 0-3, (CH2) 0-3 OC(O)O(CH2) 0-3 , (CH2) 0-3 OC(S)O(CH2) 0-3 , (CH2) 0-3 SC(O)O(CH2) 0-3 , (CH2) 0-3 SC(S)O(CH2) 0-3 , (CH2) 0-3 NHC(O)S(CH2) 0-3 , (CH2) 0-3 NHC(S)S(CH2) 0-3 , (CH2) 0-3 OC(O)S(CH2) 0-3 , (CH2) 0-3 OC(S)S(CH2) 0-3 , (CH2) 0-3 SC(O)S(CH2) 0-3 , (CH2) 0-3 SC(S)S(CH2) 0-3 , (CHO) 1-6 and trimethylmethane; Q, Q 1 , and Q 2respectively, when present, represent furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, naphthalene, pyridine, quinolone, isoquinoline, pyrazine, quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, thalidomide, triazine (e.g., 1,2,3-triazine; 1,2,4-triazine; 1,3,5-triazine), thiadiazole, aziridine, thiirane (episulfides), oxirane (ethylene oxides, epoxides), o oxaziridine, dioxirane, azetidine, oxetane, thietane, diazetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, oxane, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, trioxane, trithiane, azepane, oxepane, thiepane, homopiperazine, azocane, tetrahydropyran, cyclobutene, cyclopentene, cyclohexene, cycloheptene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclooctadiene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, any suitable C 3 ~C 7 independently selected from the group consisting of cycloalkyl groups and any of the ring structures shown in Tables 1a, 1b, 2, 3, 4, or 5; Q, Q 1 , and Q 2 each, when present, may have one or more additional J groups present at any position on the Q ring; Any of the above alkyl groups or (CH2) x-y The group may be linear or branched (see, e.g., compounds 103, 104, 138, 245, etc.); Any of the above alkyl groups or (CH2) x-yThe group may further include OH, ═O, NH, CN, dihaloalkyl (e.g., CFH), trihaloalkyl (e.g., CF), or halogen (e.g., F) substituents on one or more carbons; The number of hydrogen atoms at the terminal position of the above group may be adjusted depending on whether the group is bonded to an additional group (e.g., CH3 is adjusted to CH2, OH is adjusted to O, etc.) or whether the group is terminal (e.g., CH2 is adjusted to CH3, O is adjusted to OH, etc.); and Any of Formulas (IIa-q) may further comprise a terminal fluorophore (e.g., fluorescein), a solid surface, an enzyme ligand (e.g., thalidomide (e.g., Compounds 198, 199, 301, 286, 291), or a VHL ligand (e.g., (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (e.g., Compound 302)), or an affinity tag.

[0036] In some embodiments, any of Formulas (IIa-q) may represent a bifunctional compound comprised of an ASH1L inhibitor and an E3 ubiquitin ligase ligand linked by a linker, which functions to bind to ASH1L, recruit an E3 ubiquitin ligase (e.g., cereblon, VHL ligase) complex for ubiquitination, and induce proteosome-mediated degradation of ASH1L (e.g., compounds 198, 199, 301, 302, 286, 291). Exemplary compounds that induce target protein degradation through the involvement of ubiquitin ligase are described, for example, in U.S. Publication Nos. 2015 / 0291562; 2016 / 0235731, both of which are incorporated by reference in their entireties.

[0037] In some embodiments, when present in a compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), R, R D1-5 , R G1-5, R A1-5 , R E1-5 , and R M1-5 The substituents are independently any of the substituents present in compounds 1 to 324 shown in Table 6 or Table 7, and the positions thereof are not limited to the positions of the substituents in compounds 1 to 324.

[0038] In some embodiments, the compound is selected from the compounds shown in Table 6 or Table 7 (eg, compounds 1-324).

[0039] In some embodiments, provided herein is a pharmaceutical composition comprising any one of the aforementioned compounds claimed herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for injection.

[0040] In some embodiments, provided herein are methods for inhibiting the activity of ASH1L, comprising contacting ASH1L with an effective amount of a compound described herein, in some embodiments, the contacting comprises contacting with a cell that expresses ASH1L.

[0041] In some embodiments, provided herein are methods for degrading ASH1L by a bifunctional compound that functions to recruit both ASH1L and proteins of an E3 ubiquitin ligase complex (e.g., cereblon, VHL ligase, etc.), resulting in ubiquitination and proteasome-mediated degradation of ASH1L.

[0042] In some embodiments, provided herein are methods for treating a disease, comprising administering to a subject a pharmaceutical composition described herein in an amount effective to inhibit the activity of ASH1L or degrade ASH1L. In some embodiments, the disease is cancer. In some embodiments, the disease is a proliferative disorder. In some embodiments, the pharmaceutical composition is co-administered with an additional cancer therapeutic agent. In some embodiments, the subject is human.

[0043] In some embodiments, provided herein are uses of the compounds described herein. In some embodiments, provided herein are uses of the compounds described herein for inhibiting ASH1L activity or degrading ASH1L. In some embodiments, provided herein are uses of the compounds described herein for treating diseases (e.g., cancer). [Brief explanation of the drawings]

[0044] [Figure 1] Biochemical characterization of ASH1L inhibitors. Comparison of the activity of ASH1L inhibitors (compounds 89, 90, 95, 115, and 126) in the ASH1L in vitro KMTase assay. IC50 values ​​are shown. [Figure 2] Binding of compound 126 to the ASH1L SET domain measured by isothermal titration calorimetry (ITC). [Figure 3] Cellular activity of compounds 126 and 69 (negative control compounds). Figure 3A shows the inhibition of cell proliferation in mouse bone marrow cells transformed with MLL-AF9 (MA9) induced by compound 126 on day 8 of treatment. Figure 3B shows the inhibition of cell proliferation in mouse bone marrow cells transformed with Hoxa9 / Meis1 (HM-2, negative control cell line) induced by compound 126 on day 8 of treatment. Figure 3C shows that compound 126 induces differentiation of MLL-AF9 cells but not the negative control cell line HM-2. Figure 3D shows that compound 126 down-regulates the expression of MLL fusion target genes (Hoxa family, Meis1) but does not affect the expression of these genes in the control cell line HM-2. The negative control compound 69 does not affect gene expression in either cell line. Gene expression data are normalized based on β-actin. [Figure 4] Activity of 126 in human leukemia cell lines. Figure 4A shows the inhibition of cell proliferation in MV4;11 cells (expressing MLL-AF4) after 4 days of treatment with compounds 126 and 69. Figure 4B shows the inhibition of cell proliferation in MOLM13 cells expressing MLL-AF9 after 4 days of treatment with compounds 126 and 69. GI50 values ​​for 126 and the negative control compound 69 are shown. [Figure 5] Activity of 260 in leukemia cells. Figure 5A shows that compound 260 downregulates the expression of MLL-fusion target genes (Hoxa9, Hoxa10, and Meis1) in MLL-AF9-transformed murine leukemia cells. Figure 5B shows that compound 260 inhibits cell proliferation in a panel of human acute leukemia cells harboring various MLL translocations. [Figure 6] 301-induced degradation of ASH1L in HeLa cells. The concentrations of 301 are shown (0.05–50 μM). DETAILED DESCRIPTION OF THE INVENTION

[0045] [Definition] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the embodiments described herein, certain preferred methods, compositions, devices, and materials are described herein. However, in describing the materials and methods of the present invention, it is to be understood that the invention is not limited to the particular molecules, compositions, methodologies, or protocols described herein, as these may vary according to routine experimentation and optimization. It is also to be understood that the terminology used herein is for the purpose of describing particular variations or embodiments only, and is not intended to limit the scope of the embodiments described herein.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. However, in case of conflict, the present specification, including definitions, will control. Therefore, the following definitions apply in connection with the embodiments described herein:

[0047] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an ASH1L inhibitor" is a reference to one or more ASH1L inhibitors and equivalents thereof known to those skilled in the art, and so forth.

[0048] As used herein, the term "comprising" and linguistic variations thereof mean the presence of the recited feature(s), element(s), method step(s), etc., but do not exclude the presence of other feature(s), element(s), method step(s), etc. Conversely, the term "consisting of" and linguistic variations thereof mean the presence of the recited feature(s), element(s), method step(s), etc., but excludes any unrecited feature(s), element(s), method step(s), etc., except for impurities ordinarily associated therewith. The phrase "consisting essentially of" means the recited feature(s), element(s), method step(s), etc., plus any other feature(s), element(s), method step(s), etc. that do not materially affect the basic nature of the composition, system, or method. Many of the embodiments herein are described using the open-ended "comprising" phrase. Such embodiments encompass multiple embodiments of the closed phrase "consisting of" and / or "consisting essentially of" and may alternatively be claimed or described using such language.

[0049] All chemical names of substituents should be construed according to the IUPAC system and / or according to the revised system, with the functional groups in the substituents being presented in the order in which they branch off from the scaffold or main structure. For example, under the revised nomenclature, methyl-sulfonyl-propanol is CH2SO2CH2CH2CH2OH or:

[0050] [ka]

[0051] Refers to...

[0052] As another example, according to the revised nomenclature, the methyl-amine substituent is

[0053] [ka]

[0054] However, The amino-methyl substituent is

[0055] [ka]

[0056] is.

[0057] All chemical names of substituents should be construed with reference to the chemical structures as described and / or depicted herein in light of IUPAC nomenclature and / or revised nomenclature.

[0058] As used herein, the term "subject" refers broadly to any animal, including, but not limited to, humans and non-human animals (e.g., dogs, cats, cows, horses, sheep, poultry, fish, crustaceans, etc.). As used herein, the term "patient" generally refers to a subject being treated for a disease or condition.

[0059] As used herein, the term "subject at risk of disease," e.g., "subject at risk of cancer," refers to a subject who has one or more risk factors for developing a disease (e.g., cancer). Depending on the specific disease, risk factors may include, but are not limited to, gender, age, genetic predisposition, environmental exposure, infectious disease, and medical history of the disease, lifestyle, etc.

[0060] As used herein, the term "effective amount" refers to an amount of a composition sufficient to produce beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or doses, and is not intended to be limited to a particular formulation or route of administration.

[0061] As used herein, the terms "administration" and "administering" refer to the act of providing a drug, prodrug, or other agent or therapeutic treatment to a subject, or to cells, tissues, and organs in vivo, in vitro, or ex vivo. Exemplary routes of administration to the human body can be via the subarachnoid region of the brain or spinal cord (intraceutical), eye (intral), mouth (oral), skin (topical or transdermal), nose (intranasal), lung (inhalation), oral mucosa (buccal), ear, rectum, vagina, by injection (e.g., intravenous, subcutaneous, intratumoral, intraperitoneal, etc.), etc.

[0062] As used herein, the terms "co-administration" and "co-administering" refer to the administration of at least two agent(s) or therapies (e.g., an ASH1L inhibitor and one or more additional therapeutic agents) or therapies to a subject. In some embodiments, co-administration of two or more agents or therapies is simultaneous. In other embodiments, a first agent / therapy is administered before a second agent / therapy. Those of skill in the art will appreciate that the formulations and / or routes of administration of the various agents or therapies used may vary. Appropriate dosages for co-administration can be readily determined by those of skill in the art. In some embodiments, when agents or therapies are co-administered, each agent or therapy is administered at a lower dose than would be appropriate if administered alone. Thus, co-administration is particularly desirable in embodiments in which co-administration of agents or therapies reduces the required dosage of a potentially harmful (e.g., toxic) agent(s) and / or in embodiments in which co-administration of two or more agents sensitizes the subject to the beneficial effects of one of the agents due to co-administration of the other agent.

[0063] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with a carrier, inert or inactive, such that the composition is particularly suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.

[0064] As used herein, the terms "pharmaceutically acceptable" or "pharmacologically acceptable" refer to a composition that does not substantially produce an adverse reaction, such as a toxic, allergic, or immune response, when administered to a subject.

[0065] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, including, but not limited to, phosphate buffered saline, water, emulsions (e.g., oil / water emulsions or water / oil emulsions), and various types of wetting agents, any solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975), the entire contents of which are incorporated herein by reference.

[0066] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that, upon administration to a subject, can provide the compound of the present invention or its active metabolite or residue. As known to those skilled in the art, "salts" of the compounds of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, which are not themselves pharmaceutically acceptable, may be used in the preparation of salts that are useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0067] Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of formula NW4 + where W is C 1-4 alkyl, etc.)

[0068] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.+ , NH4 + , and NW4 + (Wherein W is C 1-4 Examples of suitable anions of the compounds of the present invention include anions of the compounds of the present invention that are compounded with a suitable cation, such as an alkyl group.

[0069] For therapeutic uses, the salts of the compounds herein are intended to be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0070] As used herein, the term "instructions for administering the compound to a subject" and its grammatical equivalents include instructions for treating a condition using the compositions contained in the kit (e.g., providing a physician with dosages, routes of administration, and decision trees that correlate patient-specific characteristics with therapeutic courses of action).

[0071] "Amino" refers to an -NH2 moiety.

[0072] "Carbonyl" refers to a moiety of the formula -C(=O)-.

[0073] "Carboxy" or "carboxyl" refers to a -CO2H moiety.

[0074] "Cyano" refers to a -CN moiety.

[0075] "Hydroxy" or "hydroxyl" refers to an --OH moiety.

[0076] "Imino" refers to an =NH moiety. Unless stated otherwise in the specification, an imino group may be optionally substituted.

[0077] "Nitro" refers to the -NO2 moiety.

[0078] "Oxo" refers to the =O moiety.

[0079] "Thioxo" refers to the =S moiety.

[0080] "Acyl" refers to the group -C(=O)R a (In the formula, R a is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), heteroalkyl, and heterocyclylalkyl. Unless stated otherwise in the specification, an acyl group may be optionally substituted.

[0081] "Alkyl" refers to an alkyl group that is saturated or unsaturated (i.e., contains one or more double and / or triple bonds) and has 1 to 12 carbon atoms (C1 to C 12 "Alkyl" refers to a straight- or branched-chain hydrocarbon moiety consisting solely of carbon and hydrogen atoms, preferably having 1 to 8 carbon atoms (C1-C8 alkyl) or 1 to 6 carbon atoms (C1-C6 alkyl), attached to the remainder of the molecule by single bonds, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkyl includes alkenyl (one or more carbon-carbon double bonds) and alkynyl (one or more carbon-carbon triple bonds). Unless otherwise specified in the specification, alkyl groups may be optionally substituted.

[0082] "Alkoxy" means a group of the formula -OR a (In the formula, R a is an alkyl group as defined herein containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkoxy group may be optionally substituted.

[0083] "Alkylamino" means a group of the formula -NHR a or -NR a R b (In the formula, R a and R band each independently represent an alkyl group, as defined herein, containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkylamino group may be optionally substituted.

[0084] "Alkylaminoalkyl" refers to an alkyl moiety containing at least one alkylamino substituent. The alkylamino substituent may be located on a tertiary, secondary, or primary carbon. Unless otherwise specified in the specification, alkylaminoalkyl groups may be optionally substituted.

[0085] An "amide" or "amido" is a group of the formula -C(=O)NR a R b or -NR a C(=O)R b (In the formula, R a and R b are each independently a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), heteroalkyl, and heterocyclylalkyl, each of which may itself be optionally substituted. In some embodiments, a C1-C4 amide group, in which case the total number of carbon atoms in the amide group includes the amide carbonyl. The -NR of an amide a R b R a R b may optionally form a 4-, 5-, 6-, or 7-membered ring together with the nitrogen to which it is attached. Unless stated otherwise in the specification, an amide group may be optionally substituted.

[0086] "Aminoalkyl" refers to an alkyl moiety containing at least one amino substituent. The amino substituent may be located at a tertiary, secondary, or primary carbon. Unless otherwise specified in the specification, aminoalkyl groups may be optionally substituted.

[0087] "Aminocarbonyl" means a group of amino acids having the formula -C(=O)NR a R b (In the formula, R a and Rb and each independently is H or alkyl. Unless stated otherwise in the specification, an aminocarbonyl group may be optionally substituted.

[0088] "Aryl" refers to a hydrocarbon ring system moiety containing 6 to 18 carbon atoms and at least one aromatic ring. For purposes of the present invention, an aryl moiety is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl moieties include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, priaden, pyrene, and triphenylene. Unless otherwise stated herein, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include aryl groups that may be substituted.

[0089] "Aralkyl" means a group of the formula -R b -R c (In the formula, R b is an alkylene chain as defined herein, and R c is one or more aryl moieties as defined herein, e.g., benzyl, diphenylmethyl, etc. Unless stated otherwise in the specification, an aralkyl group may be optionally substituted.

[0090] "Aralkylamino" means aralkyl-NR a -part (in the formula, R a is H or alkyl). Unless stated otherwise in the specification, aralkylamino may be optionally substituted.

[0091] "Aralkyloxy" refers to an aralkyl-O- moiety. Unless stated otherwise in the specification, an aralkyloxy may be optionally substituted.

[0092] "Arylamino" means -NR a- an aryl moiety (wherein R a is H or alkyl). Unless stated otherwise in the specification, an arylamino may be optionally substituted.

[0093] "Aryloxy" refers to an -O-aryl moiety. Unless stated otherwise in the specification, an aryloxy may be optionally substituted.

[0094] "Bicycloalkyl" refers to a moiety having two cycloalkyl moieties that share two or more atoms. When the cycloalkyl moieties share exactly two adjacent atoms, it is referred to as "fused." Examples include, but are not limited to, bicyclo[3.1.0]hexyl, perhydronaphthyl, and the like. When the cycloalkyl moieties share three or more atoms, it is referred to as "bridged." Examples include, but are not limited to, adamantyl, bicyclo[3.2.1]heptyl ("norbornyl"), bicyclo[2.2.2]octyl, and the like. Unless stated otherwise in this specification, a bicycloalkyl may be optionally substituted.

[0095] "Carboxyalkyl" means a group of the formula -R b -R c (In the formula, R b is an alkylene chain as defined herein, and R c is a carboxy group as defined herein. Unless stated otherwise in the specification, a carboxyalkyl group may be optionally substituted.

[0096] "Cyanoalkyl" means a group of the formula -R b -R c (In the formula, R b is an alkylene chain as defined herein, and R c is a cyano group as defined herein. Unless stated otherwise in the specification, a cyanoalkyl group may be optionally substituted.

[0097] "Carbocycle" or "carbocyclic ring" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic hydrocarbon moiety having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, which may contain fused or bridged ring systems, including cycloalkyl, cycloalkenyl, and the like. "Cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic hydrocarbon moiety having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, which may contain fused or bridged ring systems. Examples of monocyclic cycloalkyl moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl moieties include adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. "Cycloalkenyl" refers to a cycloalkyl group containing one or more carbon-carbon double bonds within the ring, such as cyclopentenyl and cyclohexenyl. Unless stated otherwise in the specification, a cycloalkyl group may be optionally substituted.

[0098] "Cycloalkylalkyl" means a group of the formula -R b R d (In the formula, R b is an alkylene chain as defined herein, and R d is a cycloalkyl moiety as defined herein. Unless stated otherwise in the specification, a cycloalkylalkyl group may be optionally substituted.

[0099] "Cycloalkylalkylamino" means cycloalkylalkyl-NR a -part (in the formula, R a is H or alkyl), where the cycloalkylalkyl moiety is attached to the nitrogen through a carbon atom, and the nitrogen acts as a linker attaching the moiety to the rest of the molecule. Unless stated otherwise in the specification, cycloalkylalkylamino may be optionally substituted.

[0100] "Cycloalkylalkyloxy" refers to an -O-cycloalkylalkyl moiety, where the cycloalkylalkyl moiety is attached via a carbon atom to an oxygen, which acts as a linker attaching the moiety to the remainder of the molecule. Unless stated otherwise in the specification, the cycloalkylalkyloxy may be optionally substituted.

[0101] "Cycloalkylamino" means -NR a - a cycloalkyl moiety, where R a is H or alkyl). Unless stated otherwise in the specification, a cycloalkylamino may be optionally substituted.

[0102] "Cycloalkyloxy" refers to an -O-cycloalkyl moiety. Unless stated otherwise in the specification, a cycloalkyloxy may be optionally substituted.

[0103] "Halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0104] "Haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more halo atoms, as defined herein, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, -CHCF, -CHCHF, -CHCHF, -CHFCF, -CHFCHF, -CHFCHF, -CHFCH, -CFCF, -CFCHF, -CFCHF, -CFCH, -CHCFCH, -CHCHFCH, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise in the specification, a haloalkyl group may be optionally substituted.

[0105] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include any element other than carbon or hydrogen. Preferred heteroatoms are oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0106] "Heteroalkyl," unless otherwise stated, alone or in combination with another term, means a straight or branched chain containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S); a monocyclic or polycyclic moiety that may include fused or bridged ring systems; or a combination thereof, in which one or more heteroatoms may be optionally oxidized. The heteroatom(s) may be located within the alkyl portion (e.g., -CH-O-CH-), at the point of attachment to the remainder of the molecule (e.g., -SOCH(CH)CH-), or a combination thereof (e.g., -NHCHCHSOCH-). Unless stated otherwise herein, heteroalkyl groups may be optionally substituted.

[0107] "Heteroaryl" refers to a 5- to 14-membered ring system moiety containing 1 to 13 carbon atoms; 1 to 6 heteroatoms, such as nitrogen, oxygen, and sulfur; and mono- or polycyclic rings in which at least one ring is aromatic. For purposes of this invention, a heteroaryl group may be a mono-, bi-, tri-, or tetracyclic ring system, may include fused or bridged ring systems, and may have one or more heteroatoms oxidized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and indophenyl. Examples of phenyl include, but are not limited to, linyl, isoindolinyl, isoquinonyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl group may be optionally substituted.

[0108] "Heteroarylalkyl" means a group of the formula -R b R f (In the formula, Rb is an alkylene chain as defined herein, and R f is a heteroaryl group, as defined herein. Unless stated otherwise in the specification, a heteroarylalkyl group may be optionally substituted.

[0109] "Heteroarylalkylamino" refers to heteroarylalkyl-NR a -part (in the formula, R a is H or alkyl). Unless stated otherwise in the specification, heteroarylalkylamino may be optionally substituted.

[0110] "Heteroarylalkyloxy" refers to a heteroarylalkyl-O- moiety. Unless stated otherwise in the specification, a heteroarylalkyloxy may be optionally substituted.

[0111] "Heteroarylamino" refers to -NR a - a heteroaryl moiety, where R a is H or alkyl). Unless stated otherwise in the specification, heteroarylamino may be optionally substituted.

[0112] "Heteroaryloxy" refers to an -O-heteroaryl moiety. Unless stated otherwise in the specification, heteroaryloxy may be optionally substituted.

[0113] "Heterobicycloalkyl" refers to a bicycloalkyl structure in which at least one carbon atom is replaced with a heteroatom, such as oxygen, nitrogen, or sulfur. Unless stated otherwise in the specification, a heterobicycloalkyl may be optionally substituted.

[0114] "Heterocyclyl" or "heterocycle" refers to a 3- to 18-membered non-aromatic ring which consists of 2 to 12 carbon atoms and 1 to 6 heteroatoms, such as nitrogen, oxygen, and sulfur. Unless stated otherwise in the specification, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, can include fused or bridged ring systems, the heteroatoms can be optionally oxidized, and the heterocyclyl can be unsaturated or saturated. Examples of such heterocyclyl moieties 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-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise in the specification, heterocyclyl groups are optionally substituted.

[0115] A "heterocyclylalkyl" or "heterocycloalkyl" is a heterocyclyl group of the formula -R b -R e (In the formula, R b is an alkylene chain as defined herein, and R e is a heterocyclyl moiety as defined herein), and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl moiety at the nitrogen atom. Unless stated otherwise in the specification, heterocyclylalkyl groups may be optionally substituted.

[0116] "Heterocyclylalkylamino" means heterocyclylalkyl-NR a -part (in the formula, R ais H or alkyl), where the heterocyclylalkyl moiety is attached to the nitrogen through a carbon atom, and the nitrogen functions as a linker attaching the moiety to the rest of the molecule. Unless stated otherwise in the specification, a heterocyclylalkylamino may be optionally substituted.

[0117] "Heterocyclylalkyloxy" refers to an -O-heterocycloalkyl moiety, where the heterocyclylalkyl moiety is attached via a carbon atom to an oxygen, which acts as a linker attaching the moiety to the remainder of the molecule. Unless stated otherwise in the specification, the heterocyclylalkyloxy may be optionally substituted.

[0118] "Heterocyclylamino" means -NR a -heterocyclyl moiety, where R a is H or alkyl), where the heterocyclyl moiety is attached to the nitrogen through a carbon atom, and the nitrogen functions as a linker attaching the moiety to the rest of the molecule. Unless stated otherwise in the specification, a heterocyclylamino may be optionally substituted. "Heterocyclyloxy" refers to an -O-heterocyclyl moiety, where the heterocyclyl moiety is attached via a carbon atom to an oxygen, which acts as a linker attaching the moiety to the remainder of the molecule. Unless stated otherwise in the specification, a heterocyclyloxy may be optionally substituted.

[0119] "Hydroxyalkyl" or "hydroxylalkyl" refers to an alkyl group that contains at least one hydroxyl substituent. The -OH substituent may be on a primary, secondary, or tertiary carbon. Unless otherwise specified herein, a hydroxylalkyl group may be optionally substituted.

[0120] "N-heteroaryl" refers to a heteroaryl moiety, as defined herein, containing at least one nitrogen and wherein the point of attachment to the rest of the molecule is through a nitrogen atom of the heteroaryl ring. Unless stated otherwise in the specification, an N-heteroaryl group may be optionally substituted.

[0121] "N-heterocyclyl" refers to a heterocyclyl moiety, as defined herein, containing at least one nitrogen and wherein the point of attachment to the rest of the molecule is through a nitrogen atom of the heterocyclyl ring. Unless stated otherwise in the specification, an N-heterocyclyl group may be optionally substituted.

[0122] "Thioalkyl" means a group of the formula -SR a (In the formula, R a is an alkyl moiety as defined herein containing 1 to 12 carbon atoms. Unless stated otherwise in the specification, a thioalkyl group may be optionally substituted.

[0123] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting two groups within a molecule, which may be saturated or unsaturated (i.e., containing one or more double and / or triple bonds) and has 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms (C1-C8 alkylene) or 1 to 6 carbon atoms (C1-C6 alkylene), such as methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single or double bond. The alkylene chain can be attached to the rest of the molecule through a single carbon (e.g., methylene) or through any two carbons within the chain (e.g., -CH2CH(CH3)CH2CH2-). Unless stated otherwise in the specification, the alkylene chain may be optionally substituted.

[0124] "Alkylenecarbonyl" means a group of the formula -C(=O)R a -(In the formula, R a is an alkylene chain as defined herein. Unless stated otherwise in the specification, an alkylenecarbonyl may be optionally substituted.

[0125] "Alkenylene" refers to an unsaturated alkylene, as defined herein, containing one or more carbon-carbon double bonds. Unless stated otherwise in the specification, an alkenylene may be optionally substituted.

[0126] "Alkenylenecarbonyl" refers to an unsaturated alkylenecarbonyl, as defined herein, containing one or more carbon-carbon double bonds. Unless otherwise specified in the specification, the alkenylenecarbonyl may be optionally substituted.

[0127] "Arylene" refers to a divalent aryl group that links one portion of the molecule to another portion of the molecule. Unless otherwise specified, an arylene may be optionally substituted.

[0128] "Heteroalkylene" refers to an alkylene group containing at least one heteroatom (e.g., N, O, or S). In some embodiments, the heteroatom is within the alkylene chain (i.e., the heteroalkylene contains at least one carbon-heteroatom-carbon bond). In other embodiments, the heteroatom is at the end of the alkylene, connecting it to the rest of the molecule (e.g., M1-HA-M2, where M1 and M2 are part of the molecule, H is a heteroatom, and A is an alkylene). Heteroalkylene can have both internal and terminal heteroatoms (e.g., -OCH2CHOCH2CHO-). Unless stated otherwise in the specification, heteroalkylene can be substituted.

[0129] "Heteroalkylenecarbonyl" means a group of the formula -C(=O)R a -(In the formula, R a is a heteroalkylene chain as defined herein. Unless stated otherwise in the specification, a heteroalkylenecarbonyl may be optionally substituted.

[0130] "Heteroarylene" refers to a divalent heteroaryl group that links one portion of a molecule to another portion of the molecule. Unless otherwise specified, heteroarylene may be optionally substituted.

[0131] "Heteroarylenecarbonyl" means a group of the formula -C(=O)R a -(In the formula, R a is heteroarylene, as defined herein. Unless otherwise specified, the heteroarylenecarbonyl may be optionally substituted.

[0132] "Heterocyclylalkylene" refers to a divalent heterocyclyl group that links one portion of the molecule to another portion of the molecule. Unless otherwise specified, a heterocycloalkylene may be optionally substituted.

[0133] "Heterocyclylalkylenecarbonyl" means a group of the formula -C(=O)R a -(In the formula, R a is heterocycloalkylene as defined herein. Unless otherwise specified, a heterocycloalkylenecarbonyl may be optionally substituted.

[0134] As used herein, the term "substituted" means that at least one hydrogen atom has been replaced with one of the groups described above (e.g., amino, carboxy, hydroxyl, imino, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl, amido, aminoalkyl, aminocarbonyl, aryl, aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl, N-heterocyclyl, thioalkyl, aryloxy ...aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryloxy, aryl and / or heterocyclylalkylenecarbonyl), wherein at least one hydrogen atom is substituted with any one of: a halogen atom such as F, Cl, Br, and I; an oxygen atom in a group such as a hydroxyl group, an alkoxy group, or an ester group; a sulfone group such as a thiol group, a thioalkyl group, or an alkylsulfone group; a sulfo group; sulfur atoms in groups such as sulfonyl groups such as amide groups, sulfonylalkyl groups such as sulfonylmethane, and sulfoxide groups such as alkylsulfoxide groups; nitrogen atoms in groups such as amino, amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and phosphorus atoms in groups such as dialkylphosphine oxide groups.and other heteroatoms in various other groups. "Substituted" also means that one or more hydrogen atoms in any of the above groups are replaced by a higher bond (e.g., a double or triple bond) to a carbon atom or heteroatom, such as the oxygen of an oxo group, a carbonyl group, a carboxyl group, and an ester group; and the nitrogen of groups such as imines, oximes, hydrazones, and nitriles. "Substituted" also includes any other group in which one or more hydrogen atoms are replaced by a bond such as -NR; g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , -SO2NR g R h , -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , or -CH2SO2NR g R h (In the formula, R g and R hare independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" includes the replacement of one or more hydrogen atoms in any of the above groups with amino, carbonyl, carboxy, cyano, hydroxyl, imino, nitro, oxo, thioxo, acyl, alkyl, alkoxy, alkylamino, alkylaminoalkyl, amido, aminoalkyl, aminocarbonyl, aryl, aralkyl, aralkylamino, aralkyloxy, arylamino, aryloxy, bicycloalkyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkylamino, cycloalkylalkyloxy, cycloalkylamino, cycloalkyloxy, halo, haloalkyl, heteroatom, heteroalkyl, heteroaryl, heteroarylalkyl. aryl, heteroarylalkylamino, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterobicycloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkylamino, heterocyclylalkyloxy, heterocyclylamino, heterocyclyloxy, hydroxyalkyl, N-heteroaryl, N-heterocyclyl, thioalkyl, alkylene, alkylenecarbonyl, alkenylene, alkenylenecarbonyl, arylene, heteroalkylene, heteroalkylenecarbonyl, heteroarylene, heteroarylenecarbonyl, heterocyclylalkylene, heterocyclylalkylenecarbonyl, trimethylsilanyl, dialkylphosphine oxide, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a)C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t N(R a )2 (wherein t is 1 or 2), -PO(R a )2, or -PO(OR a ) 2 units (each R a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl group. In addition, each of the foregoing substituents may be optionally substituted with one or more of the above substituents.

[0135] As used herein, the term "optionally substituted" means that the referenced group (e.g., alkyl, cycloalkyl, etc.) may or may not be substituted with one or more additional group(s).

[0136] As used herein, the term "absent" in reference to a functional group or substituent, particularly in reference to the chemical structure of a compound, means that the particular functional group or substituent is not present in the compound being described. When used in reference to a substituent (e.g., a pendant group rather than a linking group), the absence of a substituent typically means that there is no bond to the substituent, and that the absence of a bond is compensated for by an H atom. When used in reference to a position within a chain or ring (e.g., a linking group rather than a pendant group), the absence of that position typically means that the two positions that would otherwise be connected by the absent position are (1) directly linked by a covalent bond or (2) not linked, whether this is apparent from the structure or is explicitly shown.

[0137] As used herein, the terms "ring system" and "polycyclic ring system" refer to a chemical structure or moiety that contains two or more rings that share at least one bond (and two or more atom positions). For example, a polycyclic ring system containing cyclohexane and cyclopentane is:

[0138] [ka]

[0139] When an aryl or heteroaryl ring is included in a polycyclic ring system, the aromaticity of the ring is maintained unless otherwise specified, for example, a polycyclic ring system containing benzene and cyclohexane is:

[0140] [ka]

[0141] Detailed Description Provided herein are small molecule inhibitors of ASH1L activity and small molecules that promote the degradation of ASH1L, as well as methods of using same in the treatment of diseases including acute leukemia, solid cancers, and other diseases that depend on the activity of ASH1L.

[0142] In some embodiments, provided herein are small molecule inhibitors that directly target the SET domain of ASH1L and block its catalytic activity. Experiments conducted during the development of embodiments herein demonstrated that small molecule inhibitors of ASH1L exhibited antiproliferative effects in MLL leukemia cells, and knockdown of ASH1L inhibited the growth of ASH1L-overexpressing breast cancer cells and downregulated the expression of target genes, including Hoxa9 and Meis1, in an MLL leukemia model.

[0143] In some embodiments, the compounds described herein are used to treat or prevent a disease (e.g., cancer (e.g., leukemia, breast cancer, ovarian cancer, melanoma, prostate cancer, thyroid cancer, or metastases thereof), muscular dystrophy, liver fibrosis, etc.) and / or alleviate symptoms associated therewith. In some embodiments, provided herein are pharmaceutical compositions comprising a compound described herein and / or within the scope herein. In some embodiments, a pharmaceutical composition comprising a compound described herein and / or within the scope herein is administered to a subject to treat a disease condition (e.g., cancer (e.g., leukemia, breast cancer, ovarian cancer, melanoma, prostate cancer, thyroid cancer, or metastases thereof), muscular dystrophy, liver fibrosis, etc.).

[0144] In certain embodiments, the compounds of formula (I) are described herein:

[0145] [ka]

[0146] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein; L consists of 0 to 3 C, S, O, and / or N. When L has 0 components, there is no bond at the L position (e.g., N and

[0147] [ka]

[0148] there is no bond directly connecting the

[0149] [ka]

[0150] , 0th to 5th place are RD1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0151] [ka]

[0152] is sometimes present,

[0153] [ka]

[0154] and a 4- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R G1 -R G5 may be substituted by a substituent, R G1 -R G5 is selected from any suitable substituent (e.g., pendant group) described herein; Y is a linker comprised of 0-3 C, S, O, and / or N, where either the C or N component of Y is optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Y is 0, then Y (i.e.,

[0155] [ka]

[0156] There is a covalent bond between Z is a linker consisting of 0-3 C, S, O and / or N, where either the C or N component of Z can be optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Z has 0 components, the Z position (i.e.,

[0157] [ka]

[0158] There is no bond between

[0159] [ka]

[0160] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0161] [ka]

[0162] is sometimes present,

[0163] [ka]

[0164] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -RE5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0165] [ka]

[0166] is sometimes present,

[0167] [ka]

[0168] and a 4- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R M1 -R M5 may be substituted by a substituent, R M1 -R M5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0169] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R G1 -R G5 , R A1 -R A5 , R E1 -R E5 , R M1 -R M5 , R 1etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, aromatic ring, substituted aromatic ring, aromatic heterocycle, substituted aromatic heterocycle, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or aromatic heterocycle fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof; D1 -R D5 , R G1 -R G5 , R A1 -R A5 , R E1 -R E5 , R M1 -R M5 are respectively

[0170] [ka]

[0171] The nucleotide sequence may be in any suitable position.

[0172] In some embodiments, compounds of formula (IA) are described herein:

[0173] [ka]

[0174] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein; L consists of 0 to 3 C, S, O, and / or N. When L has 0 components, there is no bond at the L position (e.g., N and

[0175] [ka]

[0176] there is no bond directly connecting the

[0177] [ka]

[0178] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein; Y is a linker comprised of 0-3 C, S, O, and / or N, where either the C or N component of Y is optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Y is 0, then Y (i.e.,

[0179] [ka]

[0180] There is a covalent bond between Z is a linker consisting of 0-3 C, S, O and / or N, where either the C or N component of Z can be optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Z has 0 components, the Z position (i.e.,

[0181] [ka]

[0182] There is no bond between

[0183] [ka]

[0184] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0185] [ka]

[0186] is sometimes present,

[0187] [ka]

[0188] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -R E5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0189] [ka]

[0190] is sometimes present,

[0191] [ka]

[0192] and a 4- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R M1 -R M5 may be substituted by a substituent, R M1 -R M5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0193] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R E1 -R E5 , R M1 -R M5 , R 1 etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof.

[0194] In some embodiments, compounds of formula (IB) are described herein:

[0195] [ka]

[0196] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R1 is any suitable substituent (e.g., pendant group) described herein; L consists of 0 to 3 C, S, O, and / or N. When L has 0 components, there is no bond at the L position (e.g., N and

[0197] [ka]

[0198] there is no bond directly connecting the

[0199] [ka]

[0200] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0201] [ka]

[0202] is sometimes present,

[0203] [ka]

[0204] and a 4- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R G1 -R G5 may be substituted by a substituent, R G1 -R G5is selected from any suitable substituent (e.g., pendant group) described herein; Y is a linker comprised of 0-3 C, S, O, and / or N, where either the C or N component of Y is optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Y is 0, then Y (i.e.,

[0205] [ka]

[0206] There is a covalent bond between Z is a linker consisting of 0-3 C, S, O and / or N, where either the C or N component of Z can be optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Z has 0 components, the Z position (i.e.,

[0207] [ka]

[0208] There is no bond between

[0209] [ka]

[0210] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0211] [ka]

[0212] is sometimes present,

[0213] [ka]

[0214] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -R E5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0215] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R G1 -R G5 , R A1 -R A5 , R E1 -R E5 , R 1 etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen-substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen-substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, aromatic heterocycle, substituted aromatic heterocycle, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or aromatic heterocycle fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof; in which case R6 is present in any suitable position, e.g.,

[0216] [ka]

[0217] can and may be present in one or more positions.

[0218] In certain embodiments, compounds of formula (IC) are described herein:

[0219] [ka]

[0220] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein; L consists of 0 to 3 C, S, O, and / or N. When L has 0 components, there is no bond at the L position (e.g., N and

[0221] [ka]

[0222] there is no bond directly connecting the

[0223] [ka]

[0224] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein; Y is a linker comprised of 0-3 C, S, O, and / or N, where either the C or N component of Y is optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Y is 0, then Y (i.e.,

[0225] [ka]

[0226] There is a covalent bond between Z is a linker consisting of 0-3 C, S, O and / or N, where either the C or N component of Z can be optionally substituted with any suitable substituent (e.g., pendant group) described herein, and when Z has 0 components, the Z position (i.e.,

[0227] [ka]

[0228] There is no bond between

[0229] [ka]

[0230] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0231] [ka]

[0232] is sometimes present,

[0233] [ka]

[0234] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -R E5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0235] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R E1 -R E5 , R 1 etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen-substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen-substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, aromatic heterocycle, substituted aromatic heterocycle, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or aromatic heterocycle fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof; in which case R6 is present in any suitable position, e.g.,

[0236] [ka]

[0237] can and may be present in one or more positions.

[0238] In certain embodiments, compounds of formula (ID) are described herein:

[0239] [ka]

[0240] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein; L consists of 0 to 3 C, S, O, and / or N. When L has 0 components, there is no bond at the L position (e.g., N and

[0241] [ka]

[0242] there is no bond directly connecting the

[0243] [ka]

[0244] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0245] [ka]

[0246] , 0th to 5th place are R A1 -R A5an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0247] [ka]

[0248] is sometimes present,

[0249] [ka]

[0250] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -R E5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0251] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R E1 -R E5 , R 1etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen-substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen-substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, aromatic heterocycle, substituted aromatic heterocycle, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or aromatic heterocycle fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof; in which case R6 is present in any suitable position, e.g.,

[0252] [ka]

[0253] can and may be present in one or more positions.

[0254] In certain embodiments, compounds of formula (E) are described herein:

[0255] [ka]

[0256] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein;

[0257] [ka]

[0258] , 0th to 5th place are R D1 -R D5an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0259] [ka]

[0260] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0261] [ka]

[0262] is sometimes present,

[0263] [ka]

[0264] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -R E5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0265] In some embodiments, suitable substituents described herein (e.g., RD1 -R D5 , R A1 -R A5 , R E1 -R E5 , R 1 etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof.

[0266] In certain embodiments, compounds of formula (IF) are described herein:

[0267] [ka]

[0268] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein;

[0269] [ka]

[0270] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5is selected from any suitable substituent (e.g., pendant group) described herein;

[0271] [ka]

[0272] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0273] [ka]

[0274] is sometimes present,

[0275] [ka]

[0276] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -R E5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0277] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R E1 -R E5 , R 1etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen-substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen-substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, aromatic heterocycle, substituted aromatic heterocycle, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or aromatic heterocycle fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof; in which case R6 is present in any suitable position, e.g.,

[0278] [ka]

[0279] can and may be present in one or more positions.

[0280] In certain embodiments, compounds of formula (IG):

[0281] [ka]

[0282] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein; L consists of 0 to 3 C, S, O, and / or N. When L has 0 components, there is no bond at the L position (e.g., N and

[0283] [ka]

[0284] there is no bond directly connecting the

[0285] [ka]

[0286] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0287] [ka]

[0288] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0289] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R 1etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof.

[0290] In certain embodiments, compounds of formula (IH) are described herein:

[0291] [ka]

[0292] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein;

[0293] [ka]

[0294] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0295] [ka]

[0296] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0297] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R 1 etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof.

[0298] In certain embodiments, the compounds of formula (II) are described herein:

[0299] [ka]

[0300] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein;

[0301] [ka]

[0302] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0303] [ka]

[0304] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0305] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R 1etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof.

[0306] In certain embodiments, compounds of formula (IJ) are described herein:

[0307] [ka]

[0308] or a salt thereof, During the ceremony: X=S, O, NH, or CH2; R 1 is any suitable substituent (e.g., pendant group) described herein;

[0309] [ka]

[0310] , 0th to 5th place are R D1 -R D5 an optionally substituted 4- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R D1 -R D5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0311] [ka]

[0312] is sometimes present,

[0313] [ka]

[0314] and a 4- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R G1 -R G5 may be substituted by a substituent, R G1 -R G5 is selected from any suitable substituent (e.g., pendant group) described herein;

[0315] [ka]

[0316] , 0th to 5th place are R A1 -R A5 an optionally substituted 5- to 7-membered aryl, heteroaryl, carbocycle (e.g., cycloalkyl ring or unsaturated non-aromatic carbocycle), or heterocycle; R A1 -R A5 is selected from any suitable substituent (e.g., pendant group) described herein; and

[0317] [ka]

[0318] is sometimes present,

[0319] [ka]

[0320] and a 5- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring that forms a ring system with R E1 -R E5 may be substituted by a substituent, R E1 -R E5 is selected from any suitable substituent (e.g., pendant group) described herein.

[0321] In some embodiments, suitable substituents described herein (e.g., R D1 -R D5 , R A1 -R A5 , R 1 etc.) are each independently selected from H, alkyl, substituted alkyl (e.g., halogen substituted alkyl), branched alkyl, substituted branched alkyl (e.g., halogen substituted branched alkyl), hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, carbocycle, substituted carbocycle, aromatic ring, substituted aromatic ring, heteroaromatic ring, substituted heteroaromatic ring, substituted or unsubstituted non-aromatic heterocycle, aromatic carbocycle or heteroaromatic ring fused to another aromatic ring, hydrogen bond donor, hydrogen bond acceptor, and combinations thereof.

[0322] In some embodiments, any of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0323] [ka]

[0324] is a 4-7 membered aryl, heteroaryl, carbocycle (e.g., a cycloalkyl ring or an unsaturated non-aromatic carbocycle), or heterocycle.

[0325] [ka]

[0326] is selected from an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered aryl, an optionally substituted 6-membered heteroaryl, an optionally substituted 5-membered cycloalkyl, an optionally substituted 6-membered cycloalkyl, an optionally substituted 5-membered carbocycle, an optionally substituted 6-membered carbocycle, an optionally substituted 5-membered non-aromatic heterocycle, or an optionally substituted 6-membered non-aromatic heterocycle.

[0327] In some embodiments, any of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0328] [ka]

[0329] teeth,

[0330] [ka]

[0331] In some embodiments,

[0332] [ka]

[0333] X 1 , X 2 , X 11 , X 12 , X 13 (if present), and X 14 are each independently selected from C, N, O, and S. In other embodiments, X 1 , X 2 , X 11 , X 12 , X13 (if present), and X 14 is C unless specified to be O, N, or S. In other embodiments, X 1 , X 2 , X 11 , X 12 , X 13 (if present), and X 14 are each independently C, N, O, or S, even if another position is specified to be O, N, or S. In some embodiments,

[0334] [ka]

[0335] is selected from the structures listed in Table 1a.

[0336] [ka]

[0337] may not be one or more of the structures listed in Table 1a.

[0338] [Table 1a] TIFF0007604006000110.tif111169

[0339] In some embodiments,

[0340] [ka]

[0341] is selected from the structures listed in Table 1b.

[0342] [ka]

[0343] may not be one or more of the structures listed in Table 1b.

[0344] [Table 1b] TIFF0007604006000114.tif242169 TIFF0007604006000115.tif242169 TIFF0007604006000116.tif88169

[0345] of a compound having one of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ), as shown in Tables 1a and 1b.

[0346] [ka]

[0347] may contain one or more heteroatoms.

[0348] [ka]

[0349] may contain 0, 1, 2, 3, or 4 ring heteroatoms.

[0350] [ka]

[0351] However, it may contain 2, 3, 4, 5, or 6 ring carbon atoms.

[0352] In some embodiments, R D1 , R D2 , R D3 , R D4, and / or R D5 (

[0353] [ka]

[0354] R (if present and depending on the ring size) is independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. D1-5 The base is

[0355] [ka]

[0356] R D1-5 The base is

[0357] [ka]

[0358] It may also be attached to a ring carbon of R D1-5 The base is

[0359] [ka]

[0360] It may also be attached to a ring heteroatom of R D1-5 The base is

[0361] [ka]

[0362] In some cases, two R D1-5 The base is

[0363] [ka]

[0364] In some cases, R D1-5 The base is

[0365] [ka]

[0366] may be bonded to each ring atom of

[0367] In some embodiments, X is CH 2 , O, NH 2 , or S.

[0368] In some embodiments, R 1is H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.

[0369] In some embodiments, L is a linear chain of 0 to 3 (e.g., 0, 1, 2, 3) members (e.g., C, S, O, and / or N) in length. In some embodiments, when L is absent,

[0370] [ka]

[0371] and N. In some embodiments, L is

[0372] [ka]

[0373] and N. In some embodiments, L is selected from O, NH, S, CH, (CH), (CH), OCH, SCH, NHCH, CHOCH, CHSCH, CHNHCH, O(CH), S(CH), NH(CH), CH=CH, NCH, and CHCH=CH, in any suitable orientation. In some embodiments, L is a linker of any suitable combination of S, C, O, and N-containing moieties. In some embodiments, any component C or N of the L bond may be substituted with a group selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.

[0374] In some embodiments, any of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0375] [ka]

[0376] is an optionally present 3- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring;

[0377] [ka]

[0378] In some embodiments,

[0379] [ka]

[0380] is not present. In some embodiments,

[0381] [ka]

[0382] is selected from an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered aryl, an optionally substituted 6-membered heteroaryl, an optionally substituted 5-membered cycloalkyl, an optionally substituted 6-membered cycloalkyl, an optionally substituted 5-membered carbocycle, an optionally substituted 6-membered carbocycle, an optionally substituted 5-membered non-aromatic heterocycle, or an optionally substituted 6-membered non-aromatic heterocycle. In some embodiments,

[0383] [ka]

[0384] is selected from the structures listed in Table 2.

[0385] [ka]

[0386] may not be one or more of the structures listed in Table 2.

[0387] [Table 2] TIFF0007604006000136.tif232169TIFF0007604006000137.tif242169TIFF0007604006000138.tif178169

[0388] As shown in Table 1a, compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0389] [ka]

[0390] may contain one or more heteroatoms.

[0391] [ka]

[0392] may contain 0, 1, 2, 3, or 4 ring heteroatoms.

[0393] [ka]

[0394] However, it may contain 2, 3, 4, 5, or 6 ring carbon atoms.

[0395] In some embodiments,

[0396] [ka]

[0397] teeth

[0398] [ka]

[0399] In some embodiments,

[0400] [ka]

[0401] shares a bond and an atom pair. In some embodiments,

[0402] [ka]

[0403] Any suitable bond and atom pair may be shared between to form a polycyclic ring system.

[0404] In some embodiments, R G1 , R G2 , R G3 , R G4 , and / or R G5 (

[0405] [ka]

[0406] R (if present and depending on the ring size) is independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. G1-5 The base is

[0407] [ka]

[0408] R G1-5 The base is

[0409] [ka]

[0410] It may also be attached to a ring carbon of R G1-5 The base is

[0411] [ka]

[0412] It may also be attached to a ring heteroatom of R G1-5 The base is

[0413] [ka]

[0414] In some cases, two R G1-5 The base is

[0415] [ka]

[0416] In some cases, R G1-5 The base is

[0417] [ka]

[0418] may be bonded to each ring atom of

[0419] In some embodiments, Z may or may not be present in a compound of one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ). When Z is absent, there is no bond or atom in Z. In some embodiments, Z is 0-3 elements linked in a linear chain (when Z=0,

[0420] [ka]

[0421] (There are no bonds, atoms, or connections in Z between). In some embodiments, Z is a linear chain of 0-3 members O, C, N, and / or S. In some embodiments, Z is

[0422] [ka]

[0423] and a direct bond between O, NH, S, CH, (CH), (CH), OCH, SCH, NHCH, CHOCH, CHSCH, CHNHCH, O(CH), S(CH), NH(CH), CH=CH, NCH, and CHCH=CH, in any suitable orientation. In some embodiments, Z is a linker of any suitable combination of S, C, O, and N-containing moieties. In some embodiments, any component C or N of the Z bond may be substituted with a group selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.

[0424] In some embodiments, Y may or may not be present in a compound of one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ). When Y is absent,

[0425] [ka]

[0426] In some embodiments, Y is a linear bond of 0 to 3 elements (when Y=0,

[0427] [ka]

[0428] (There is no direct covalent bond between in Y.) In some embodiments, Y is a linear chain of 0-3 members O, C, N, and / or S. In some embodiments, Y is

[0429] [ka]

[0430] and a direct bond between O, NH, S, CH, (CH), (CH), OCH, SCH, NHCH, CHOCH, CHSCH, CHNHCH, O(CH), S(CH), NH(CH), CH=CH, NCH, and CHCH=CH, in any suitable orientation. In some embodiments, Y is a linker of any suitable combination of S, C, O, and N-containing moieties. In some embodiments, any component C or N of the Y bond may be substituted with a group selected from halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino.

[0431] In some embodiments, any of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0432] [ka]

[0433] is a 5-7 membered aryl, heteroaryl, carbocycle (e.g., a cycloalkyl ring or an unsaturated non-aromatic carbocycle), or heterocycle.

[0434] [ka]

[0435] is selected from an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered aryl, an optionally substituted 6-membered heteroaryl, an optionally substituted 5-membered cycloalkyl, an optionally substituted 6-membered cycloalkyl, an optionally substituted 5-membered carbocycle, an optionally substituted 6-membered carbocycle, an optionally substituted 5-membered non-aromatic heterocycle, or an optionally substituted 6-membered non-aromatic heterocycle.

[0436] In some embodiments, any of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0437] [ka]

[0438] teeth,

[0439] [ka]

[0440] In some embodiments,

[0441] [ka]

[0442] X 1 , X 2 , X 11 , X 12 , X 13 (if present), and X 14 are each independently selected from C, N, O, and S. In other embodiments, X 1 , X 2 , X 11 , X 12 , X 13 (if present), and X 14 is C unless specified to be O, N, or S. In other embodiments, X 1 , X 2 , X 11 , X 12 , X 13 (if present), and X 14 are each independently C, N, O, or S, even if another position is specified to be O, N, or S. In some embodiments,

[0443] [ka]

[0444] is selected from the structures listed in Table 3a.

[0445] [ka]

[0446] may not be one or more of the structures listed in Table 3a.

[0447] [Table 3a] TIFF0007604006000166.tif160169 In some embodiments,

[0448] [ka]

[0449] is selected from the structures listed in Table 3b.

[0450] [ka]

[0451] may not be one or more of the structures listed in Table 3b.

[0452] [Table 3b] TIFF0007604006000170.tif242169 TIFF0007604006000171.tif242169 of a compound having one of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ), as shown in Tables 3a and 3b.

[0453] [ka]

[0454] may contain one or more heteroatoms.

[0455] [ka]

[0456] may contain 0, 1, 2, 3, or 4 ring heteroatoms.

[0457] [ka]

[0458] However, it may contain 2, 3, 4, 5, or 6 ring carbon atoms.

[0459] In some embodiments, R A1 , R A2 , R A3 , R A4 , and / or R A5 (

[0460] [ka]

[0461] R (if present and depending on the ring size) is independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. A1-5 The base is

[0462] [ka]

[0463] R A1-5 The base is

[0464] [ka]

[0465] It may also be attached to a ring carbon of R A1-5 The base is

[0466] [ka]

[0467] It may also be attached to a ring heteroatom of R A1-5 The base is

[0468] [ka]

[0469] In some cases, two R A1-5 The base is

[0470] [ka]

[0471] In some cases, R A1-5 The base is

[0472] [ka]

[0473] may be bonded to each ring atom of

[0474] In some embodiments, any of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0475] [ka]

[0476] is an optionally present 3- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring;

[0477] [ka]

[0478] In some embodiments,

[0479] [ka]

[0480] is not present. In some embodiments,

[0481] [ka]

[0482] is selected from an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered aryl, an optionally substituted 6-membered heteroaryl, an optionally substituted 5-membered cycloalkyl, an optionally substituted 6-membered cycloalkyl, an optionally substituted 5-membered carbocycle, an optionally substituted 6-membered carbocycle, an optionally substituted 5-membered non-aromatic heterocycle, or an optionally substituted 6-membered non-aromatic heterocycle. In some embodiments,

[0483] [ka]

[0484] is selected from the structures listed in Table 4.

[0485] [ka]

[0486] may not be one or more of the structures listed in Table 4.

[0487] [Table 4] TIFF0007604006000189.tif242169 TIFF0007604006000190.tif242169 TIFF0007604006000191.tif178169

[0488] As shown in Table 4, a compound having one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0489] [ka]

[0490] may contain one or more heteroatoms.

[0491] [ka]

[0492] may contain 0, 1, 2, 3, or 4 ring heteroatoms.

[0493] [ka]

[0494] However, it may contain 2, 3, 4, 5, or 6 ring carbon atoms.

[0495] In some embodiments,

[0496] [ka]

[0497] teeth

[0498] [ka]

[0499] In some embodiments,

[0500] [ka]

[0501] shares a bond and an atom pair. In some embodiments,

[0502] [ka]

[0503] Any suitable bond and atom pair may be shared between to form a polycyclic ring system.

[0504] In some embodiments, R E1 , R E2 , R E3 , R E4 , and / or R E5 (

[0505] [ka]

[0506] R (if present and depending on the ring size) is independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. E1-5 The base is

[0507] [ka]

[0508] R E1-5 The base is

[0509] [ka]

[0510] It may also be attached to a ring carbon of R E1-5 The base is

[0511] [ka]

[0512] It may also be attached to a ring heteroatom of R E1-5 The base is

[0513] [ka]

[0514] In some cases, two R E1-5 The base is

[0515] [ka]

[0516] In some cases, R E1-5 The base is

[0517] [ka]

[0518] may be bonded to each ring atom of

[0519] In some embodiments, any of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0520] [ka]

[0521] is an optionally present 3- to 7-membered carbocyclic (e.g., cycloalkyl or unsaturated non-aromatic carbocyclic), heterocyclic, aryl, or heteroaryl ring;

[0522] [ka]

[0523] In some embodiments,

[0524] [ka]

[0525] is not present. In some embodiments,

[0526] [ka]

[0527] is selected from an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered aryl, an optionally substituted 6-membered heteroaryl, an optionally substituted 5-membered cycloalkyl, an optionally substituted 6-membered cycloalkyl, an optionally substituted 5-membered carbocycle, an optionally substituted 6-membered carbocycle, an optionally substituted 5-membered non-aromatic heterocycle, or an optionally substituted 6-membered non-aromatic heterocycle. In some embodiments,

[0528] [ka]

[0529] is selected from the structures listed in Table 5.

[0530] [ka]

[0531] may not be one or more of the structures listed in Table 5.

[0532] [Table 5] TIFF0007604006000213.tif242169 TIFF0007604006000214.tif242169 TIFF0007604006000215.tif185169

[0533] As shown in Table 5, a compound having one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ)

[0534] [ka]

[0535] may contain one or more heteroatoms.

[0536] [ka]

[0537] may contain 0, 1, 2, 3, or 4 ring heteroatoms.

[0538] [ka]

[0539] However, it may contain 2, 3, 4, 5, or 6 ring carbon atoms.

[0540] In some embodiments,

[0541] [ka]

[0542] teeth

[0543] [ka]

[0544] In some embodiments,

[0545] [ka]

[0546] shares a bond and an atom pair. In some embodiments,

[0547] [ka]

[0548] Any suitable bond and atom pair may be shared between to form a polycyclic ring system.

[0549] In some embodiments, R M1 , R M2 , R M3 , R M4 , and / or R M5 (

[0550] [ka]

[0551] R (if present and depending on the ring size) is independently selected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl, cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl, aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, and heteroarylalkylamino. M1-5 The base is

[0552] [ka]

[0553] R M1-5 The base is

[0554] [ka]

[0555] It may also be attached to a ring carbon of R M1-5 The base is

[0556] [ka]

[0557] It may also be attached to a ring heteroatom of R M1-5 The base is

[0558] [ka]

[0559] In some cases, two R M1-5 The base is

[0560] [ka]

[0561] In some cases, R M1-5 The base is

[0562] [ka]

[0563] may be bonded to each ring atom of

[0564] As described above, when present in a compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), R, R D1-5 , R G1-5 , R A1-5 , R E1-5 , and R M1-5 The substituents can be any suitable chemical functionality, such as: Single atoms: H, Cl, Br, F, or I; Alkyl group: methyl, ethyl, propyl, butyl, pentyl, hexyl, or any suitable straight or branched chain C 1 ~C 10 alkyl groups; Alkenyl: ethenyl, propenyl, butenyl, pentenyl, hexenyl, or any suitable C 1 ~C 10 alkenyl groups; Alkynyl: ethynyl, propynyl, butynyl, pentynyl, hexynyl, or any suitable C 1 ~C 10 alkenyl groups; Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or any suitable C 3 ~C 7 Cycloalkyl groups, which may be further substituted (e.g., compounds 186-190); Cycloalkenyl: cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclooctadiene; optionally further substituted; Aryl or heteroaryl: furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, naphthalene, pyridine, quinolone, isoquinoline, pyrazine, quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, triazine (e.g., 1,2,3-triazine; 1,2,4-triazine; 1,3,5-triazine, etc.), thiadiazole, etc.; optionally further substituted; Non-aromatic heterocycles: aziridine, thiirane (episulfides), oxirane (ethylene oxides, epoxides), oxaziridine, dioxirane, azetidine, oxetane, thietane, diazetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, oxane, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, trioxane, trithiane, azepane, oxepane, thiepane, homopiperazine, azocane, tetrahydropyran, etc.; Haloalkanes: halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethanes, 2-haloethanes, 1,2-dihaloethanes, 1-halopropanes, 2-halopropanes, 3-halopropanes, 1,2-dihalopropanes, 1,3-dihalopropanes, 2,3-dihalopropanes, 1,2,3-trihalopropanes, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.), as well as branched-chain haloalkanes (e.g., compounds 195-200); Alcohol: OH, methanol, ethanol, propanol, butanol, pentanol, hexanol, cyclic alcohols (e.g., cyclohexanol), aromatic alcohols (e.g., phenol), or any other suitable combination of an OH moiety and a second moiety, branched chain alcohols (e.g., compounds 123 and 151); Ketones: methyl methyl ketone (acetone), methyl ethyl ketone (butanone), propyl ethyl ketone (pentanone), or any other suitable combination of alkyl chain and =O; Aldehydes: methanal, ethanal, propanal, butanal, pentanal, hexanal, or any other suitable combination of alkyl chain and =O; Carboxylate: methanoate, ethanoate, propanoate, butanoate, pentanoate, hexanoate, or alkyl chain and OO - any other suitable combination with; Carboxylic acids: methanoic acid, ethanoic acid, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, or any other suitable combination of alkyl chains and OOH; Ether: methoxy, ethoxy, methylmethoxy, ethylmethoxy, or any other suitable combination of alkyl chains around the O; Amides: Methanamide (CONH2), Ethanamide (CH2CONH2), Propanamide ((CH2)2CONH2), Alkanes n Amide ((CH2) n CONH2), n-methylalkanes n Amide ((CH2) n CONHCH3), c-methylalkane n Amide ((CH2) n NHCOCH3), n-alkylalkane n Amide ((CH2) n CONH(CH2) m CH3), c-methylalkanes n Amide ((CH2) n NHCO(CH2) m CH3), etc.; Primary amines: NH2, methylamine, ethylamine, cyclopropylamine, etc.; Secondary amines: aminomethyl (NHCH3), aminoethyl (NHCH2CH3), methyl-aminomethyl (CH2NHCH3; also known as methylamine-methane), alkyl n -Aminomethane ((CH2) n NHCH3), etc.; Tertiary amines: dimethylamine (N(CH3)2), dimethylamine (N(CH3)2), methyl-ethyl-amine (NCH3CH2CH3), methane-diethylamine (CH2N(CH2CH3)2; also known as methylamine-diethane), etc.; Azides: Methyl azide (CH2NNN), ethyl azide ((CH2)2NNN), alkyl n Azide ((CH2) n NNN) etc.; Cyanates: Methyl cyanate (CH2OCN), ethyl cyanate ((CH2)2OCN), alkyl n Cyanate ((CH2) n OCN), etc.; Cyano: cyano (-CN), methylcarbonitrile (CHCN), ethylcarbonitrile ((CH)CN), alkyl n Carbonitrile ((CH2) n CN), etc. Thiols: methanethiol (CH2SH), ethanethiol ((CH2)2SH), alkanes n Thiol ((CH2) n SH), etc. Sulfides: dimethyl sulfide (CH2SCH3), methyl-ethyl sulfide (CH2SCH2CH3), alkyl n -Alkyl m Sulfide ((CH2) n S(CH2) m-1 CH3), etc.; Sulfoxides: dimethyl sulfoxide (CH2SOCH3), methyl-ethyl sulfoxide (CH2SOCH2CH3), alkyl n -Alkyl m Sulfoxide ((CH2) n SO(CH2) m-1 CH3), etc.; Sulfones: dimethyl sulfone (CH2SO2CH3; also known as methyl-sulfone-methyl), methyl-ethyl sulfone (CH2SO2CH2CH3; also known as methyl-sulfone-ethyl), alkyl n -Alkyl m Sulfone ((CH2) n SO2(CH2) m-1 CH3; also known as alkyl n -sulfone-alkyl m ), R x SO2R y wherein Rx and Ry are independently selected from any of the moieties set forth in this list or combinations thereof; Sulfonamides: SO2NH2, methylsulfonamide (CH2SO2NH2), ethylsulfonamide ((CH2)2SO2NH2), alkyl n Sulfonamide ((CH2) n SO2NH2), methyl methyl sulfonamide (CH2SO2NHCH3), alkyl n Alkyl m Sulfonamide ((CH2) n SO2NH(CH2) m CH3 etc.; Sulfinic acids: SO2H, methylsulfinic acid (CH2SO2H), ethylsulfinic acid ((CH2)2SO2H), alkyl n Sulfinic acid ((CH2) n SO2H), etc.; Thiocyanate: SCN, methyl thiocyanate (CH2SCN), ethyl thiocyanate ((CH2)2SCN), alkyl n Thiocyanate ((CH2)nSCN), etc.; Phosphates: OP(=O)(OH)2, methyl phosphate (CH2OP(=O)(OH)2), ethyl phosphate ((CH2)2OP(=O)(OH)2), alkyl n Phosphate ((CH2) n OP(=O)(OH)2), etc.; and suitable combinations thereof. For example, in some embodiments, R 1 , R D1-5 , R G1-5 , R A1-5 , RE1-5 , and R M1-5 The substituents, if present, are independently selected from H, alkyl groups (e.g., straight chain alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), branched chain alkyl groups (e.g., isopropyl, 2-methyl-hexyl, 3-methyl, 2-propyl-octyl, etc.), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), branched chain cyclic alkyl (e.g., methylcyclohexyl, ethylcyclobutyl, propylcyclohexyl, etc.)), substituted alkyl groups (e.g., halogen-substituted alkyl groups (e.g., trihalobutane (e.g., trifluorobutane), dihalogenated alkyl groups (e.g., methylcyclohexyl, ethylcyclobutyl, propylcyclohexyl, etc.)), and the like. chlorobutane (e.g., difluorobutane), monohalobutane (e.g., monofluorobutane), trihalopropane (e.g., trifluoropropane), dihalopropane (e.g., difluoropropane), monohalopropane (e.g., monofluoropropane), trihaloethane (e.g., trifluoroethane), dihaloethane (e.g., difluoroethane), haloethane (e.g., fluoroethane), halomethane (e.g., fluoromethane), dihalomethane (e.g., difluoromethane), trihalomethane (e.g., trifluoromethane), alkyl groups in which multiple carbons are substituted with halogen (e.g., 3-fluoro,4-trifluoroisobutane (e.g., R in compound 245) A See Substituents), 2-difluoro, 3-fluoropropane, etc.), alkenes (e.g., CH=CH2, CH2CH=CH2, CH=CHCH3, etc.), alkynes (e.g., C≡CH, C≡CCH3, CH2C≡CH, etc.), alkoxy groups (e.g., hydroxyl (e.g., (CH2) 0-6 OH, ether ((CH2) 0-6 O(CH2) 0-6)), halogen-substituted alkoxy (4-trifluoro,3-isobutanol (see, e.g., Compound 252), 3-difluoro,2-propanol, etc.), amines (e.g., NH2), alkylamines (e.g., primary amines (e.g., ethylamine, isobutylamine), n-propylamine, sec-butylamine, isopropylamine, isoamylamine, methylamine, dimethylamine, n-amylamine, etc.), secondary amines (e.g., dimethylamine, methylethanolamine, diphenylamine, etc.), tertiary amines (e.g., trimethylamine, triphenylamine, etc.), thioalkyl (e.g., thiols (e.g., (CH2) 0-6 -SH), thioethers (e.g., (CH2) 0-6 -S-(CH2) 0-6 ), substituted ethers and thioethers (see, e.g., Compound 266), combinations thereof, and the like), substituted cycloalkyl groups (e.g., halogen-substituted cycloalkyl groups, cycloalkoxy groups, cycloalkylamines, and the like), halogen-substituted alkylamines (e.g., trifluoromethylamine, trifluoroethylamine (see, e.g., Compound 248), trifluorobutylamine, and the like), halogens (e.g., F, Cl, Br, I, and At), ketones, amides, alkylamides, cyano groups, methylcarbonitriles (e.g., CHCN), -SOCH groups, -SONH groups, sulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl), substituted alkylsulfonyl groups (e.g., trifluoroethylsulfonyl), and the like), sulfoamines (e.g., (CH) 0-6 SO2NH2 (see, for example, compound 268), (CH2) 0-6 NHSO2, (CH2) 0-6 NHSO2(CH2) 0-6 (See, for example, compound 309), (CH2) 0-6 SO2NH(CH2) 0-6etc.), dialkylphosphine oxides (e.g., -PO(CH3)2)), carbocycles (substituted or unsubstituted), heterocycles (substituted (e.g., see Compound 274) or unsubstituted), aromatic rings, substituted aromatic rings (e.g., branched aromatic rings (e.g., ethylbenzene, methylbenzene, etc.), halobenzenes (e.g., chlorobenzene, fluorobenzene, etc.)), carbocyclic (substituted or unsubstituted), carbocyclic aryl (substituted or unsubstituted), heteroaryl (substituted (e.g., sulfonyl-substituted (e.g., see Compound 263), halo-substituted, etc.) or unsubstituted), alkyl-bonded carbons alkyl-linked heterocycles (substituted or unsubstituted), alkyl-linked aromatic rings (substituted or unsubstituted), alkyl-linked substituted aromatic rings, alkyl-linked halobenzenes (e.g., chlorobenzene, fluorobenzene, etc.), alkyl-linked carbocyclic rings (substituted (e.g., halo-substituted (e.g., see Compound 258), trihalo-alkyl-substituted (e.g., see Compound 257)) or unsubstituted), alkyl-linked carbocyclic aryls (substituted or unsubstituted), alkyl-linked heteroaryls (substituted or unsubstituted), amine-linked carbocyclic rings (substituted or unsubstituted), amine-linked aryl ... amine-linked heterocycles (substituted or unsubstituted), amine-linked aromatic rings (substituted or unsubstituted), amine-linked substituted aromatic rings, amine-linked halobenzenes, amine-linked carbocyclic (substituted or unsubstituted), amine-linked carbocyclic aryl (substituted or unsubstituted), amine-linked heteroaryl (substituted (see, for example, Compound 271) or unsubstituted), alkylamine-linked carbocyclic (substituted or unsubstituted), alkylamine-linked heterocyclic (substituted or unsubstituted), alkylamine-linked aromatic rings (substituted or unsubstituted), alkylamine-linked substituted aromatic rings, alkylamine-linked halobenzenes, alkylamines ether-linked carbocyclic (substituted or unsubstituted), alkylamine-linked carbocyclic aryl (substituted or unsubstituted), alkylamine-linked heteroaryl (substituted or unsubstituted), ether-linked carbocyclic (substituted or unsubstituted), ether-linked heterocyclic (substituted or unsubstituted), ether-linked aromatic ring (substituted or unsubstituted), ether-linked substituted aromatic ring, ether-linked halobenzene, ether-linked carbocyclic (substituted or unsubstituted), ether-linked carbocyclic aryl (substituted or unsubstituted), ether-linked heteroaryl (substituted or unsubstituted), thioether-linked carbocyclic (substituted or unsubstituted),Thioether-linked heterocycle (substituted or unsubstituted), thioether-linked aromatic ring (substituted or unsubstituted), thioether-linked substituted aromatic ring, thioether-linked halobenzene, thioether-linked carbocycle (substituted or unsubstituted), thioether-linked carbocyclic aryl (substituted or unsubstituted), thioether-linked heteroaryl (substituted or unsubstituted), sulfonyl-linked carbocycle (substituted or unsubstituted), sulfonyl-linked heterocycle (substituted or unsubstituted), sulfonyl-linked aromatic ring (substituted or unsubstituted), sulfonyl-linked substituted aromatic ring, sulfonyl-linked halobenzene, sulfonyl-linked carbocycle (substituted or unsubstituted), sulfonyl-linked carbocyclic aryl (substituted or unsubstituted), sulfonyl-linked heteroaryl (substituted or unsubstituted), sulfonamido-linked carbocyclic (substituted or unsubstituted), sulfonamido-linked heterocyclic (substituted or unsubstituted), sulfonamido-linked aromatic ring (substituted or unsubstituted), sulfonamido-linked substituted aromatic ring, sulfonamido-linked halobenzene, sulfonamido-linked carbocyclic (substituted or unsubstituted), sulfonamido-linked carbocyclic aryl (substituted or unsubstituted), sulfonamido-linked heteroaryl (substituted or unsubstituted), amido-linked carbocyclic (substituted substituted or unsubstituted), amide-linked heterocycle (substituted or unsubstituted), amide-linked aromatic ring (substituted or unsubstituted), amide-linked substituted aromatic ring, amide-linked halobenzene, amide-linked carbocyclic (substituted or unsubstituted), amide-linked carbocyclic aryl (substituted or unsubstituted), amide-linked heteroaryl (substituted (e.g., alkylpyrrole (see, e.g., Compound 293), pyrrole amine (see, e.g., Compound 296), pyrrole ether (see, e.g., Compound 297), etc.) or unsubstituted (e.g., imidazole (see, e.g., Compound 273), indole (see, e.g., See Compounds 293 and 294), alkylamide-linked carbocycles (substituted or unsubstituted), alkylamide-linked heterocycles (substituted or unsubstituted), alkylamide-linked aromatic rings (substituted or unsubstituted), alkylamide-linked substituted aromatic rings (substituted or unsubstituted), alkylamide-linked halobenzenes, alkylamide-linked carbocycles (substituted or unsubstituted), alkylamide-linked carbocyclic aryls (substituted or unsubstituted), alkylamide-linked heteroaryls (substituted or unsubstituted), carbamide-linked carbocycles (substituted or unsubstituted), carbamide-linked heterocycles (substituted or unsubstituted),Carbamido-linked aromatic rings (substituted or unsubstituted), carbamido-linked substituted aromatic rings, carbamido-linked halobenzenes, carbamido-linked carbocyclic rings (substituted or unsubstituted), carbamido-linked carbocyclic aryls (substituted or unsubstituted), carbamido-linked heteroaryls (substituted or unsubstituted (see, e.g., Compound 314)), bridged carbocyclic rings (substituted or unsubstituted), bridged heterocyclic rings (substituted (see, e.g., Compound 272) or unsubstituted), bridged aromatic rings (substituted or unsubstituted), bridged substituted aromatic rings, bridged halobenzenes, bridged carbocyclic rings (substituted or unsubstituted), bridged carbocyclic aryls (substituted or unsubstituted), bridged heteroaryls (substituted or unsubstituted), and / or combinations thereof.

[0565] In some embodiments, when present in a compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), R, R D1-5 , R G1-5 , R A1-5 , R E1-5 , and R M1-5 Any of the substituents may be represented by the formula (IIa to IIq):

[0566] [ka] TIFF0007604006000231.tif242169 TIFF0007604006000232.tif94169

[0567] is one of; In the formula, J, Q 1 , or J 1 is attached to one of the D, G, A, E, or M rings, if present; J.J. 1 , J 2 , J 3 , and J 4 are, if present, a covalent bond, H, alkyl 1-15 , alkenyl 1-6 , alkynyl 1-6, (CH2) 0-6 C(S)NH2, (CH2) 0-6 C(O)NH2, O, S, NH, (CH2) 0-6 C(O)NH(CH2) 1-6 , (CH2) 0-6 C(S)NH(CH2) 1-6 , (CH2) 0-6 O(CH2) 1-6 , (CH2) 0-6 OH, (CH2) 0-6 S(CH2) 1-6 , (CH2) 0-6 SH, (CH2) 0-6 NHC(O)(CH2) 1-6 , alkylsulfonyl, sulfonamide, alkylsulfonamide, (CH2) 0-6 NH(CH2) 1-6 , (CH2) 0-6 N(CH2) 1-6 (CH2) 1-6 (See, for example, compound 80), (CH2) 0-6 NH2, (CH2) 0-6 SO2(CH2) 1-6 , (CH2) 0-6 NHSO2(CH2) 1-6 , (CH2) 0-6 SO2NH2, halogen (e.g., F, Cl, Br, or I), haloalkyl (e.g., (CH2) 0-6 CH2F, (CH2) 0-3 CHF(CH2) 0-2 CH3, or the like with Br, Cl, or I), dihaloalkyl (e.g., (CH2) 0-6 CF2H, (CH2) 0-3 CF2(CH2) 0-2 CH3, or the like with Br, Cl, or I), trihaloalkyl (e.g., (CH2) 0-6 CF3, or the like with Br, Cl, or I), alkyl with 1 to 3 halogens at two or more positions along the chain (see, for example, compounds 126, 144, 194, 195, 200, 207, 245, 251, etc.), (CH2) 1-4 SP(Ph) = S (see, for example, compound 52), (CH) 0-6 NH(CH2)1-5 OH、(CH2) 0-6 NH(CH2) 1-5 NH2、(CH2) 0-6 NH(CH2) 1-5 SH、(CH2) 0-6 O(CH2) 1-5 OH、(CH2) 0-6 O(CH2) 1-5 NH2、(CH2) 0-6 O(CH2) 1-5 SH、(CH2) 0-6 S(CH2) 1-5 OH、(CH2) 0-6 S(CH2) 1-5 NH2、(CH2) 0-6 S(CH2) 1-5 SH、(CH2) 0-6 O(CH2) 1-6 NH(CH2) 1-5 OH、(CH2) 0-6 O(CH2) 1-6 NH(CH2) 1-5 NH2、(CH2) 0-6 O(CH2) 1-6 NH(CH2) 1-5 SH、(CH2) 0-6 O(CH2) 1-6 O(CH2) 1-5 OH、(CH2) 0-6 O(CH2) 1-6 O(CH2) 1-5 NH2、(CH2) 0-6 O(CH2) 1-6 O(CH2) 1-5 SH、(CH2) 0-6 O(CH2) 1-6 S(CH2) 1-5 OH、(CH2) 0-6 O(CH2) 1-6 S(CH2) 1-5 NH2、(CH2) 0-6 O(CH2) 1-6 S(CH2) 1-5 SH、(CH2) 0-6 S(CH2) 1-6 NH(CH2) 1-5 OH、(CH2) 0-6 S(CH2) 1-6 NH(CH2) 1-5NH2、(CH2) 0-6 S(CH2) 1-6 NH(CH2) 1-5 SH、(CH2) 0-6 S(CH2) 1-6 O(CH2) 1-5 OH、(CH2) 0-6 S(CH2) 1-6 O(CH2) 1-5 NH2、(CH2) 0-6 S(CH2) 1-6 O(CH2) 1-5 SH、(CH2) 0-6 S(CH2) 1-6 S(CH2) 1-5 OH、(CH2) 0-6 S(CH2) 1-6 S(CH2) 1-5 NH2、(CH2) 0-6 S(CH2) 1-6 S(CH2) 1-5 SH、(CH2) 0-6 NH(CH2) 1-6 NH(CH2) 1-5 OH、(CH2) 0-6 NH(CH2) 1-6 NH(CH2) 1-5 NH2、(CH2) 0-6 NH(CH2) 1-6 NH(CH2) 1-5 SH、(CH2) 0-6 NH(CH2) 1-6 O(CH2) 1-5 OH、(CH2) 0-6 NH(CH2) 1-6 O(CH2) 1-5 NH2、(CH2) 0-6 NH(CH2) 1-6 O(CH2) 1-5 SH、(CH2) 0-6 NH(CH2) 1-6 S(CH2) 1-5 OH、(CH2) 0-6 NH(CH2) 1-6 S(CH2) 1-5 NH2、(CH2) 0-6 NH(CH2) 1-6 S(CH2) 1-5 SH、(CH2) 0-3 C(O)O(CH2)0-3 、(CH2) 0-3 C(S)O(CH2) 0-3 、(CH2) 0-3 C(O)S(CH2) 0-3 、(CH2) 0-3 C(S)S(CH2) 0-3 、(CH2) 0-3 C(O)NH(CH2) 0-3 、(CH2) 0-3 C(S)NH(CH2) 0-3 、(CH2) 0-3 NHC(O)(CH2) 0-3 、(CH2) 0-3 NHC(S)(CH2) 0-3 、(CH2) 0-3 OC(O)(CH2) 0-3 、(CH2) 0-3 OC(S)(CH2) 0-3 、(CH2) 0-3 SC(O)(CH2) 0-3 、(CH2) 0-3 SC(S)(CH2) 0-3 、(CH2) 0-3 NHC(O)NH(CH2) 0-3 、(CH2) 0-3 NHC(S)NH(CH2) 0-3 、(CH2) 0-3 OC(O)NH(CH2) 0-3 、(CH2) 0-3 OC(S)NH(CH2) 0-3 、(CH2) 0-3 SC(O)NH(CH2) 0-3 、(CH2) 0-3 SC(S)NH(CH2) 0-3 、(CH2) 0-3 NHC(O)O(CH2) 0-3 、(CH2) 0-3 NHC(S)O(CH2) 0-3 、(CH2) 0-3 OC(O)O(CH2) 0-3 、(CH2) 0-3 OC(S)O(CH2) 0-3 、(CH2) 0-3 SC(O)O(CH2) 0-3 、(CH2) 0-3 SC(S)O(CH2) 0-3, (CH2) 0-3 NHC(O)S(CH2) 0-3 , (CH2) 0-3 NHC(S)S(CH2) 0-3 , (CH2) 0-3 OC(O)S(CH2) 0-3 , (CH2) 0-3 OC(S)S(CH2) 0-3 , (CH2) 0-3 SC(O)S(CH2) 0-3 , (CH2) 0-3 SC(S)S(CH2) 0-3 , (CHO) 1-6 and trimethylmethane; Q, Q 1 , and Q 2respectively, when present, represent furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, naphthalene, pyridine, quinolone, isoquinoline, pyrazine, quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, thalidomide, triazine (e.g., 1,2,3-triazine; 1,2,4-triazine; 1,3,5-triazine), thiadiazole, aziridine, thiirane (episulfides), oxirane (ethylene oxides, epoxides), o oxaziridine, dioxirane, azetidine, oxetane, thietane, diazetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, oxane, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, trioxane, trithiane, azepane, oxepane, thiepane, homopiperazine, azocane, tetrahydropyran, cyclobutene, cyclopentene, cyclohexene, cycloheptene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclooctadiene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, any suitable C 3 ~C 7 independently selected from the group consisting of cycloalkyl groups and any of the ring structures shown in Tables 1a, 1b, 2, 3, 4, or 5; Q, Q 1 , and Q 2 each, when present, may have one or more additional J groups present at any position on the Q ring; Any of the above alkyl groups or (CH2) x-y The group may also be linear or branched (see, e.g., compounds 103, 104, 138, 245, etc.); Any of the above alkyl groups or (CH2) x-yThe group may also further include OH, =O, NH2, CN, dihaloalkyl (e.g., CF2H), trihaloalkyl (e.g., CF3), or halogen (e.g., F) substituents on one or more carbons; The number of hydrogen atoms at the terminal position of the above group may be adjusted depending on whether the group is bonded to an additional group (e.g., CH3 is adjusted to CH2, OH is adjusted to O, etc.) or whether the group is terminal (e.g., CH2 is adjusted to CH3, O is adjusted to OH, etc.); and Any of Formulas (IIa-q) may further comprise a terminal fluorophore (e.g., fluorescein), a solid surface, an enzyme ligand (e.g., thalidomide (e.g., Compounds 198, 199, 301, 286, 291), or a VHL ligand (e.g., (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (e.g., Compound 302)), or an affinity tag.

[0568] In some embodiments, any of Formulas (IIa-q) may represent a bifunctional compound comprised of an ASH1L inhibitor and an E3 ubiquitin ligase ligand linked by a linker, which functions to bind to ASH1L, recruit an E3 ubiquitin ligase (e.g., cereblon, VHL ligase) complex for ubiquitination, and induce proteosome-mediated degradation of ASH1L (e.g., compounds 198, 199, 301, 302, 286, 291). Exemplary compounds that induce target protein degradation through the involvement of ubiquitin ligase are described, for example, in U.S. Publication Nos. 2015 / 0291562; 2016 / 0235731, both of which are incorporated by reference in their entireties.

[0569] In some embodiments, the compound is one of formulas (IA)-(IG) or (IJ), where the ring

[0570] [ka]

[0571] together form an indole ring, where the indole nitrogen (position 1) is substituted with a heterocycle (e.g., piperidine, bridged piperidine, alkyl-substituted piperidine, etc.), which heterocycle is further substituted with an alkylsulfonyl (e.g., see Compound 318) or sulfonamide (e.g., see Compound 268); and the 6-position of the indole ring is substituted with an alkylamine (e.g., (CH) 0-3 NH(CH2) 0-3 ) linked heteroaryl groups (see, for example, compound 319) or alkylamides (e.g., (CH2) 0-3 NHC(O)(CH2) 0-3 )-linked heteroaryl group (see, e.g., compound 318). In certain embodiments, the compound is of formula (IE), X is S, and R 1 is H and the ring

[0572] [ka]

[0573] together form an indole ring, where the indole nitrogen (position 1) is substituted with a piperidine (bridged or unbridged), which in turn is substituted with an alkylsulfonyl (see, e.g., Compound 318) or sulfonamide (see, e.g., Compound 268); and the 6-position of the indole ring is substituted with an alkylamine (e.g., (CH) 0-3 NH(CH2) 0-3 ) linked heteroaryl groups (see, for example, compound 319) or alkylamides (e.g., (CH2) 0-3 NHC(O)(CH2) 0-3 ) linked heteroaryl groups (see, for example, compound 318).

[0574] In some embodiments, when present in a compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), R, R D1-5 , RG1-5 , R A1-5 , R E1-5 , and R M1-5 The substituents may include any of the aforementioned substituents (or combinations thereof), a biologically active or functional small molecule moiety, such as a fluorophore (see, e.g., compounds 287 and 288), a drug or drug-like moiety (e.g., thalidomide (see, e.g., compounds 198, 199, 286, 291, etc.)), an affinity moiety (e.g., biotin), etc. In some embodiments, the substituent includes a ligand for an enzyme of interest (e.g., a ubiquitin ligase ligand (e.g., thalidomide), a von Hippel-Lindau tumor suppressor ligand (see, e.g., compound 302, etc.)).

[0575] In some embodiments, when present in a compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), R, R D1-5 , R G1-5 , R A1-5 , R E1-5 , and R M1-5 The substituent may be attached to a solid surface.

[0576] The compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ) may be selected from compounds 1-324 listed in Table 6. Compounds of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ) that are not listed in Table 6 are also within the scope of the present specification.

[0577] [Table 6] TIFF0007604006000236.tif242169 TIFF0007604006000237.tif242169 TIFF0007604006000238.tif242169 TIFF0007604006000239.tif242169 TIFF0007604006000240.tif242169 TIFF0007604006000241.tif242169 TIFF0007604006000242.tif242169 TIFF0007604006000243.tif242169 TIFF0007604006000244.tif242169 TIFF0007604006000245.tif242169 TIFF0007604006000246.tif162169 TIFF0007604006000247.tif242169 TIFF0007604006000248.tif242169 TIFF0007604006000249.tif242169 TIFF0007604006000250.tif242169 TIFF0007604006000251.tif242169 TIFF0007604006000252.tif242169 TIFF0007604006000253.tif194169 TIFF0007604006000254.tif98169 TIFF0007604006000255.tif242169 TIFF0007604006000256.tif242169 TIFF0007604006000257.tif242169 TIFF0007604006000258.tif242169 TIFF0007604006000259.tif242169 TIFF0007604006000260.tif242169 TIFF0007604006000261.tif242169 TIFF0007604006000262.tif242169 TIFF0007604006000263.tif242169 TIFF0007604006000264.tif242169 TIFF0007604006000265.tif242169 TIFF0007604006000266.tif242169 TIFF0007604006000267.tif242169 TIFF0007604006000268.tif242169 TIFF0007604006000269.tif213169 TIFF0007604006000270.tif242169 TIFF0007604006000271.tif242169 TIFF0007604006000272.tif242169 TIFF0007604006000273.tif242169 TIFF0007604006000274.tif242169 TIFF0007604006000275.tif242169 TIFF0007604006000276.tif242169 TIFF0007604006000277.tif209169 TIFF0007604006000278.tif215169 TIFF0007604006000279.tif180169 TIFF0007604006000280.tif198169 TIFF0007604006000281.tif203169 TIFF0007604006000282.tif189169 TIFF0007604006000283.tif242169 TIFF0007604006000284.tif242169 TIFF0007604006000285.tif200169 TIFF0007604006000286.tif242169 TIFF0007604006000287.tif242169 TIFF0007604006000288.tif242169 TIFF0007604006000289.tif242169 TIFF0007604006000290.tif242169 TIFF0007604006000291.tif242169 TIFF0007604006000292.tif242169 TIFF0007604006000293.tif242169 TIFF0007604006000294.tif242169 TIFF0007604006000295.tif242169 TIFF0007604006000296.tif242169 TIFF0007604006000297.tif242169 TIFF0007604006000298.tif242169 TIFF0007604006000299.tif242169 TIFF0007604006000300.tif242169 TIFF0007604006000301.tif242169 TIFF0007604006000302.tif242169 TIFF0007604006000303.tif242169 TIFF0007604006000304.tif109169

[0578] In some embodiments, the substituents and functional groups of the compounds in Table 6 may be incorporated into formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ) to obtain compounds within the scope herein.

[0579] The compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ) may be selected from compounds 319-324 listed in Table 7. Compounds of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and / or (IJ) that are not listed in Table 7 are also within the scope of the present specification.

[0580] [Table 7] TIFF0007604006000306.tif242169

[0581] In some embodiments, the substituents and functional groups of the compounds in Table 7 may be incorporated into formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ) to obtain compounds within the scope herein.

[0582] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers may be carried out by chromatography, or by forming diastereomers and separating them by recrystallization, chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, the disclosure of which is incorporated herein by reference.) Stereoisomers may also be obtained by stereoselective synthesis.

[0583] In some embodiments, compounds may exist as tautomers, and all tautomers are included in the formulas described herein.

[0584] Unless otherwise specified, divalent variables or groups depicted herein may be attached in the orientation in which they are depicted, or in the opposite orientation.

[0585] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may also be in the form of pharmaceutically acceptable salts. Similarly, active metabolites of these compounds with similar activity are also encompassed within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0586] In some embodiments, the compounds or salts described herein may be prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they can be administered more easily than the parent drug. For example, a prodrug may be orally bioavailable, while the parent drug is not. A prodrug may also improve the solubility of a pharmaceutical composition over the parent drug. A non-limiting example of a prodrug is a compound described herein administered as an ester ("prodrug") that facilitates penetration across cell membranes, where water solubility is detrimental for transport but beneficial upon metabolic hydrolysis to the carboxylic acid, the active component, and entry into the cell. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, which is metabolized to release the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to the biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[0587] In producing a prodrug, a pharmaceutically active compound is modified so that the active compound is regenerated upon in vivo administration. Prodrugs can be designed to alter the metabolic stability or transport properties of a drug, block side effects or toxicity, improve the taste of a drug, or change other characteristics or properties of a drug. In some embodiments, a prodrug of a compound is designed after determining a pharmaceutically active compound, using knowledge of pharmacodynamic processes and in vivo drug metabolism. (For example, 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, Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol.4,p.1985;Rooseboom et al.,Pharmacological Reviews,56:53-102,2004;Miller et al.,J.Med.Chem.Vol.46,no.24,5097-5116,2003;Aesop Cho,“Recent Advances in Oral Prodrug Discovery”,Annual Reports in Medicinal Chemistry, Vol. 41, 395-407, 2006).

[0588] The compounds described herein can be labeled isotopically (e.g., with radioisotopes) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, photoactivatable or chemiluminescent labels, affinity labels (e.g., biotin), degradation tags (e.g., thalidomide, conjugates (e.g., compounds 198, 199, etc.), VHL ligand conjugates (e.g., compound 302), etc.).

[0589] The compounds and salts described herein include isotopically labeled compounds.Generally, isotopically labeled compounds are identical to those listed in the various formulas and structures presented herein, except that one or more atoms are replaced with atoms that have atomic mass or mass number different from the atomic mass or mass number that is most commonly found in nature.The examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Certain isotopically labeled compounds according to the present invention, such as 3 H and 14 Incorporation of a radioactive isotope such as C is useful for drug and / or substrate tissue distribution assays. 2 Substitution with isotopes such as H may afford certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0590] In additional or further embodiments, the compounds described herein, when administered to an organism in need thereof, are metabolized to produce metabolic products which are then used to achieve a desired effect, including a desired therapeutic effect.

[0591] The compounds described herein may be formed as and / or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include: (1) salts of a compound in free base form with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid, or the like; or an organic acid, such as 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]octo- (2) acid addition salts formed by reaction with 2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylbutyric 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.; (3) salts formed by replacing an acidic proton present in the parent compound 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. Optionally, the compounds described herein may be coordinated with an organic base, 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, etc. 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, etc.

[0592] Reference to a pharmaceutically acceptable salt should be understood to include its solvent addition forms or crystalline forms, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and can be formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein can exist in both solvated and unsolvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0593] In some embodiments, compounds described herein, such as compounds having any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein, are in various forms, including, but not limited to, amorphous, milled, and nanoparticulate forms. Additionally, compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include compounds with the same elemental composition but different crystal packing arrangements. Polymorphs typically differ in X-ray diffraction patterns, melting points, densities, hardnesses, crystal shapes, optical properties, stability, and solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, may result in the predominance of a single crystalline form.

[0594] Screening and characterization of pharmaceutically acceptable salts, polymorphs, and / or solvates can be performed using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods correspond to thermochemical decomposition or thermophysical processes, including but not limited to polymorphic transitions. Such methods are used to analyze polymorphic relationships, determine weight loss, detect glass transition temperatures, or test excipient compatibility. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric analysis with infrared (TG / IR). X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy with EDX (in a gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0595] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0596] Pharmaceutical Composition In certain embodiments, a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, is combined with one or more additional agents to form a pharmaceutical composition. Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, that facilitate processing of the active compound into a pharmaceutically usable formulation. Appropriate formulations will vary depending on the selected route of administration. For further details regarding suitable excipients for the pharmaceutical compositions described herein, see, for example, 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.

[0597] As used herein, a pharmaceutical composition refers to a mixture of a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, and other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. Pharmaceutical compositions facilitate administration of a compound to an organism. In practicing the methods of treatment or use provided herein, a therapeutically effective amount of a compound described herein is administered as a pharmaceutical composition to a mammal having the disease, disorder, or condition being treated. In some embodiments, the mammal is a human. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. Compounds or salts of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein, can be used alone or in combination with one or more therapeutic agents as components of mixtures (as combination therapy).

[0598] The pharmaceutical formulations described herein can be administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal. Furthermore, the pharmaceutical compositions described herein, including a compound of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein, can be formulated into any suitable dosage form, including, but not limited to, aqueous oral dispersions, solutions, gels, syrups, elixirs, slurries, suspensions, aerosols, fast-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, and capsules.

[0599] The compounds and / or compositions may be administered locally rather than systemically, for example, by direct injection of the compound into an organ or tissue, often as a depot or sustained-release formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Furthermore, the drug may be administered in a targeted drug delivery system, for example, a liposome coated with an organ-specific antibody. The liposome is selectively taken up by the targeted organ. Furthermore, the drug may be provided in the form of a fast-release formulation, a sustained-release formulation, or an intermediate-release formulation.

[0600] Pharmaceutical compositions containing the compounds described herein can be manufactured in a conventional manner using conventional processes, such as, by way of example only, mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing.

[0601] The pharmaceutical compositions include as an active ingredient at least one compound of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ) in free acid or free base form or in pharmaceutically acceptable salt form, having any suitable substituents and functional groups as disclosed herein.

[0602] In certain embodiments, the compositions provided herein may also include one or more preservatives that inhibit microbial activity. Suitable preservatives include quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0603] Oral pharmaceutical preparations can be prepared by mixing one or more compounds or salts of any one of Formulae (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, with one or more solid excipients, optionally milling the resulting mixture and optionally adding suitable auxiliary agents before processing the granular mixture into tablets, pills, or capsules. Suitable excipients include, for example, bulking agents, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and other excipients, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0604] The dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings to distinguish or characterize different combinations of active compound doses.

[0605] Orally usable pharmaceuticals include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added.

[0606] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet (including a suspension tablet, a fast-dissolving tablet, a chewable tablet, a fast-disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile-packed powder, a sachet powder, or an effervescent powder), a capsule (including both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, i.e., "sprinkle capsules"), a solid dispersion, a solid solution, a biodegradable dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In yet other embodiments, the pharmaceutical formulation is in the form of a tablet, including, but not limited to, a fast-dissolving tablet. Furthermore, the pharmaceutical formulation of the compounds described herein may be administered as a single capsule or in a multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, or four capsules or tablets.

[0607] In some embodiments, solid dosage forms, such as tablets, effervescent tablets, and capsules, are prepared by mixing particles of a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, with one or more pharmaceutical excipients to form a bulk blend composition. A homogeneous bulk blend composition means that the particles of a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, are uniformly dispersed throughout the composition so that the composition can be subdivided into unit dosage forms of equal potency, such as tablets, pills, and capsules. Individual unit doses may also include a film coating that disintegrates upon oral ingestion or contact with a diluent. These formulations may be prepared by conventional pharmaceutical techniques.

[0608] The pharmaceutical solid dosage forms described herein may comprise a compound of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, and one or more pharmaceutically acceptable excipients, such as a compatible carrier, binder, filler, suspending agent, flavoring agent, sweetener, disintegrant, dispersant, surfactant, lubricant, colorant, diluent, solubilizer, humectant, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, or one or more combinations thereof. In yet another aspect, a film coating is applied around a formulation of a compound described herein using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000). In one embodiment, some or all of the particles of a compound described herein are coated. In another embodiment, some or all of the particles of a compound described herein are microencapsulated. In yet another embodiment, the particles of the compounds described herein are not microencapsulated or coated.

[0609] Carriers suitable for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol, and the like.

[0610] Bulking agents suitable for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[0611] Disintegrants are often used in formulations to maximize the release of a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, from a solid dosage form base, particularly when the dosage form is compressed with a binder. Disintegrants facilitate the rupture of the dosage form base by swelling or capillary action when moisture is absorbed by the dosage form. Disintegrants suitable for use in the solid dosage forms described herein include natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, wood products, methyl crystalline cellulose (e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming), and the like. cross-linked starches such as sodium starch glycolate; cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone; alginates such as alginic acid or alginates such as sodium alginate; clays such as Veegum HV (magnesium aluminum silicate); gums such as agar, guar, carob, karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; natural sponge; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; combinations of sodium lauryl sulfate and starch;

[0612] Binders impart cohesiveness to solid oral dosage form formulations; in powder-filled capsule formulations, they facilitate plug formation that allows filling into soft or hard shell capsules; and in tablet formulations, they ensure tablet integrity after compression and help ensure blend uniformity prior to the compression or filling process. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate®), and hydroxypropyl methylcellulose acetate stearate (Aqoate®). HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g., Dipac®), glucose, dextrose , molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as acacia, tragacanth, gum ghatti, isapol husk gum solution, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and the like.

[0613] Typically, 20-70% binder is used in the formulation of powder-filled gelatin capsules. The amount of binder used in a tablet formulation varies depending on the method used, such as direct compression, wet granulation, roller compaction, or the use of other excipients, such as fillers, which can act as modest binders themselves. In some embodiments, the amount of binder used in the formulation is determined by the formulator, but binder usage of up to 70% is common in tablet formulations.

[0614] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali metal and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate or sodium lauryl sulfate, and the like.

[0615] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrins), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins, and the like.

[0616] Suitable humectants for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, docusate sodium, triacetin, vitamin E TPGS, and the like.

[0617] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and the like.

[0618] Suitable suspending agents for use in the solid dosage forms described herein include polyvinylpyrrolidone, such as polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol (e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000), vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone / vinyl acetate copolymer (S630), ... These include, but are not limited to, resorbate 80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth gum and acacia gum, guar gum, xanthans including xanthan gum, sugars, cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and the like.

[0619] Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0620] There is considerable overlap among the excipients used in the solid dosage forms described herein, and therefore the above excipients should be considered merely exemplary, and not limiting, of the types of excipients that can be included in solid dosage forms of the pharmaceutical compositions described herein.

[0621] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, plasticizers are generally high-boiling solids or liquids. Suitable plasticizers can be added at about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearates, and castor oil.

[0622] Compressed tablets are solid dosage forms prepared by compressing a bulk blend of the above formulations. In various embodiments, compressed tablets designed to dissolve in the mouth contain one or more flavoring agents. In other embodiments, compressed tablets contain a film surrounding the final compressed tablet. In some embodiments, the film coating has an effect on patient compliance (e.g., Opadry® coating or sugar coating). Film coatings, including Opadry®, typically range from about 1% to about 3% of the tablet weight. In other embodiments, compressed tablets contain one or more excipients.

[0623] Capsules can be prepared, for example, by placing a bulk blend formulation of the above compounds inside a capsule. In some embodiments, the formulation (non-aqueous suspension and solution) is placed in a soft gelatin capsule. In other embodiments, the formulation is placed in a standard gelatin capsule or a non-gelatin capsule, such as a capsule containing HPMC. In other embodiments, the formulation is placed in a sprinkle capsule. In this case, the capsule can be swallowed whole, or the capsule can be opened and the contents sprinkled on food before eating. In some embodiments, the therapeutic dose is divided into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in capsule form.

[0624] In various embodiments, particles of a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, and one or more excipients are dry mixed and compressed into a mass, such as a tablet, of sufficient hardness to obtain a pharmaceutical composition that substantially disintegrates and releases the formulation into gastrointestinal fluids in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes after oral administration.

[0625] In another aspect, the dosage form may contain a microencapsulated formulation.In some embodiments, one or more other compatible materials are present in the microencapsulated material.Exemplary materials include, but are not limited to, pH adjusters, erosion promoters, antifoaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrating agents, bulking agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[0626] Materials useful for microencapsulation as described herein include substances that are compatible with the compounds described herein and that sufficiently isolate the compounds from other incompatible excipients.

[0627] In yet another embodiment, effervescent powders are also prepared according to the present disclosure. Effervescent salts are used to disperse pharmaceutical agents in water for oral administration. Effervescent salts are granules or coarse powders containing a pharmaceutical agent in a dry mixture, usually consisting of sodium bicarbonate, citric acid, and / or tartaric acid. When such salts are added to water, the acid and base react to release carbon dioxide gas, thereby producing "effervescence." Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid, and / or tartaric acid. Any acid-base combination that results in the release of carbon dioxide can be used in place of the combination of sodium bicarbonate, citric acid, and tartaric acid, as long as the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or greater.

[0628] In other embodiments, the formulations described herein, comprising a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, are solid dispersions. Methods for making such solid dispersions include, but are not limited to, those described in U.S. Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Patent Publication No. 2004 / 0013734. In yet other embodiments, the formulations described herein are solid solutions. Solid solutions incorporate materials together with an active agent and other excipients; the mixture is heated to dissolve the drug, and the resulting composition is cooled to obtain a solid blend that can be further formulated, added directly to capsules, or compressed into tablets. Methods for preparing such solid solutions include, but are not limited to, those described in US Pat. Nos. 4,151,273, 5,281,420, and 6,083,518.

[0629] In some embodiments, there is provided a pharmaceutical formulation comprising particles of a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, and at least one dispersing or suspending agent for oral administration to a subject. The formulation may be a powder and / or granules for suspension, which upon mixing with water will provide a substantially uniform suspension.

[0630] The liquid pharmaceutical dosage form for oral administration may be an aqueous suspension selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).

[0631] The aqueous suspensions and dispersions described herein can maintain a homogeneous state as defined in the USP Pharmacists' Pharmacopeia (2005 Edition, Chapter 905) for at least 4 hours. For determining the homogeneity of the entire composition, homogeneity should be determined by consistent sampling methods. In one embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 1 minute. In another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, the aqueous suspension can be resuspended into a homogeneous suspension by physical agitation lasting less than 30 seconds. In yet another embodiment, the homogeneous aqueous dispersion is maintained without the need for agitation.

[0632] The pharmaceutical compositions described herein may contain any of the following: acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarois, berry, blackcurrant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cilamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinic acid, licorice syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidin DC, neotame, orange, pear, peach, peppermint , peppermint cream, Prosweet® powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talc, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, oil of wintergreen, xylitol, or any combination of these flavoring ingredients, such as anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[0633] In some embodiments, the pharmaceutical formulations described herein may be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase within another, usually in the form of droplets. Generally, emulsions are generated by vigorous mechanical dispersion. In contrast to emulsions or microemulsions, SEDDSs spontaneously form emulsions when added to excess water without external mechanical dispersion or agitation. The advantage of SEDDSs is that only gentle mixing is required to disperse the droplets throughout the solution. Furthermore, water or an aqueous phase can be added immediately prior to administration, thereby maintaining the stability of unstable or hydrophobic active ingredients. Therefore, SEDDSs provide an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDSs can improve the bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms include, but are not limited to, those described in US Pat. Nos. 5,858,401, 6,667,048, and 6,960,563.

[0634] Because different practitioners in the art often categorize a given additive differently, or because a given additive is commonly used for several different functions, overlap exists among the additives listed above for use in the aqueous dispersions or suspensions described herein, and therefore the additives listed above should be considered merely exemplary and not limiting of the types of additives that can be included in the formulations described herein.

[0635] Promising excipients for intranasal formulations include, for example, U.S. Patent Nos. 4,476,116, 5,116,817, and 6,391,452. Solutions of formulations in saline using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents are also disclosed. See, e.g., Ansel, H.C. et al., Pharmaceutical Dosage Forms and Drug See Delivery Systems, Sixth Ed. (1995). Preferably, these compositions and formulations are prepared using suitable non-toxic pharmaceutically acceptable ingredients. The selection of a suitable carrier largely depends on the exact nature of the desired nasal dosage form, such as a solution, suspension, ointment, or gel. Nasal dosage forms generally contain a large amount of water in addition to the active ingredient. Small amounts of other ingredients, such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffers, and other stabilizers and solubilizers, may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.

[0636] For administration by inhalation, the compounds described herein can be in the form of aerosol, mist or powder.The pharmaceutical compositions described herein are advantageously delivered in the form of aerosol spray from a pressurized pack or nebulizer, using suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.In the case of pressurized aerosol, dosage units can be determined by providing a valve that delivers a metered amount.Capsules and cartridges, such as gelatin, for example, that are used in inhalers or insufflators can be formulated to contain a powder mixture of the compounds described herein and suitable powder base, such as lactose or starch.

[0637] Buccal formulations containing the compounds described herein can be administered using a variety of formulations, including, but not limited to, those described in U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. Furthermore, the buccal dosage forms described herein can further comprise a biodegradable (hydrolyzable) polymer carrier, which also functions to adhere the dosage form to the buccal mucosa. The buccal dosage form is manufactured to gradually degrade over a predetermined period of time, essentially delivering the compound throughout that time. Buccal drug delivery avoids the disadvantages of oral drug administration, such as delayed absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and / or inactivation due to the first-pass effect in the liver. With regard to biodegradable (hydrolyzable) polymer carriers, virtually any such carrier can be used, as long as the desired drug release profile is not compromised and the carrier is compatible with the compounds described herein and any other components that may be present in the buccal dosage unit. Generally, the polymeric carrier comprises a hydrophilic (water-soluble and water-swellable) polymer that adheres to the moist surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and copolymers, such as those known as "carbomers" (Carbopol®, available from BFGoodrich, is one such polymer). Other ingredients can also be incorporated into the buccal dosage forms described herein, including, but not limited to, disintegrants, diluents, binders, lubricants, flavoring agents, coloring agents, preservatives, etc. For buccal or sublingual administration, the composition can take the form of a tablet, lozenge, or gel formulated in a conventional manner.

[0638] The transdermal formulations described herein are not limited to the compositions disclosed in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, and 4,069,307. The compositions can be administered using a variety of devices, including, but not limited to, those described in US Pat. Nos. 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801, and 6,946,144.

[0639] The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients common in the art. In one embodiment, the transdermal formulations described herein comprise at least three components: (1) a compound or salt formulation of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein; (2) a penetration enhancer; and (3) an aqueous adjuvant. Furthermore, the transdermal formulations may include additional components, such as, but not limited to, gelling agents, creams, and ointment bases. In some embodiments, the transdermal formulations may further comprise a woven or nonwoven backing material to facilitate absorption and prevent removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein may maintain a saturated or supersaturated state to facilitate diffusion into the skin.

[0640] Formulations suitable for transdermal administration of the compounds described herein may use transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in polymers or adhesives. Such patches may be manufactured to deliver pharmaceutical agents continuously, in pulses, or on demand. Furthermore, transdermal delivery of the compounds described herein may be achieved by iontophoretic patches, etc. Furthermore, transdermal patches can provide controlled delivery of the compounds described herein. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. The absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to facilitate passage through the skin. For example, a transdermal device may be in the form of a bandage containing a backing member, a reservoir containing the compound and optionally a carrier, optionally a rate-controlling barrier that delivers the compound to the recipient's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0641] Formulations suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders to be reconstituted into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0642] For intravenous injection, the compounds described herein may be formulated in aqueous solution, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation.Such penetrants are generally recognized in the art.For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably physiologically compatible buffers or excipients.Such excipients are generally recognized in the art.

[0643] Parenteral injections may include bolus injections or continuous infusions. Injectable formulations may be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The pharmaceutical compositions described herein may be in a form suitable for parenteral injection, such as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation additives such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compound may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0644] In certain embodiments, delivery systems for pharmaceutical compounds such as, for example, liposomes and emulsions may be used. In certain embodiments, the compositions provided herein also comprise a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran, among others.

[0645] In some embodiments, the compounds described herein can 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. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity agents, buffers, and preservatives.

[0646] The compounds described herein may also be formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In a suppository form of a composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally combined with cocoa butter, is first melted.

[0647] In general, agents such as compounds of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein, are administered in an amount effective to ameliorate or prevent the onset of a disease or disorder (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that can at least partially prevent or reverse a disease or disorder. The dosage required to achieve an effective amount may vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered.

[0648] Determining an effective amount may also involve in vitro assays in which various doses of the drug are administered to cells in culture to determine the concentration of the drug effective to ameliorate some or all of the symptoms, in order to calculate the concentration required in vivo. Effective amounts may also be based on in vivo animal studies.

[0649] The agent can be administered before, concurrently with, and after the appearance of symptoms of a disease or disorder. In some embodiments, the agent is administered to a subject who has a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to the disease or disorder, or who has a genotype that predisposes the subject to the disease or disorder.

[0650] In some embodiments, the compositions described herein are provided as pharmaceutical and / or therapeutic compositions. The pharmaceutical and / or therapeutic compositions of the present invention can be administered in several ways, depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be topical (including intraocular and transmucosal, including vaginal and rectal delivery), pulmonary (e.g., by inhalation or inhalation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epithelial, and transdermal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional carriers; aqueous, powder, or oily bases; thickeners, and the like, may be required or desirable. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids, or binders may be desirable. Compositions and formulations for parenteral, intrathecal, or intracerebroventricular administration may include sterile aqueous solutions, which may contain buffers, diluents, and other suitable additives, such as, but not limited to, permeation enhancers, carrier compounds, and other pharmaceutically acceptable carriers or excipients. Pharmaceutical and / or therapeutic compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions can be generated from a variety of components, including, but not limited to, preformed liquids, self-emulsifying solids, and self-emulsifying semisolids.

[0651] Pharmaceutical and / or therapeutic formulations, which may be conveniently provided in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical / nutrition industries. Such techniques include the step of admixing the active ingredient with the pharmaceutical carrier(s) or excipient(s). Generally, the formulations are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. The compositions of the present invention may be formulated into any of many possible dosage forms, including, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous, oily, or mixed media. Suspensions may further contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. Suspensions may also contain stabilizers. In one embodiment of the present invention, the pharmaceutical compositions may be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies, and liposomes, which are essentially similar in nature but differ in the ingredients and consistency of the final product.

[0652] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of a precise dose. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit doses may be in the form of packages containing different amounts of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be contained in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is common to include a preservative in the composition. By way of example only, parenteral injection preparations may be provided in unit dosage forms, including, but not limited to, ampoules or multiple-dose containers, with an added preservative.

[0653] Dosage and administration regimens are tailored by clinicians or those skilled in the art of pharmacology based on well-known pharmacological and therapeutic considerations, including, but not limited to, the desired level of therapeutic effect and the practical level of therapeutic effect achieved. It is generally recommended to administer chemotherapeutic agents according to well-known pharmacological principles (e.g., it is generally recommended not to change the dose by more than 50% at a time and only every 3-4 drug half-lives). For compositions where maximum efficacy is desired, with relatively little or no consideration of dose-related toxicity, it is not uncommon for the dose to exceed the average required dose. This approach is commonly referred to as a "maximum dose" strategy. In certain embodiments, the compound is administered to a subject at a dose of about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with other agents (e.g., sensitizers), the effective amount may be less than when the agent is used alone. Dosing can be once daily or multiple times daily for one or more consecutive days.

[0654] [Treatment method] The present disclosure provides compounds and methods for inhibiting the activity of ASH1L. In certain embodiments, the present disclosure provides compounds that bind to and / or inhibit the activity of ASH1L.

[0655] The inhibition of ASH1L activity can be evaluated and demonstrated by a variety of methods known in the art.Non-limiting examples include: (a) directly reducing ASH1L activity; (b) reducing cell proliferation and / or cell viability; (c) increasing cell differentiation; (d) reducing the level of downstream target of ASH1L activity; and (e) measuring tumor volume and / or tumor volume growth rate.Can use kit and commercially available assay to determine one or more of the above.

[0656] The present disclosure provides compounds and methods for treating a subject suffering from a disease, the methods including administering to the subject a compound or salt described herein, e.g., a compound or salt of any of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein. In certain embodiments, the disease is selected from diseases associated with ASH1L expression (e.g., aberrant expression, overexpression, etc.) and / or activity (e.g., cancer). In certain embodiments, the disease is mediated by ASH1L activity and / or expression (e.g., aberrant expression, overexpression, etc.). In certain embodiments, the disease is leukemia, hematological malignancy, solid tumor cancer, glioma, other cancer, muscular dystrophy, liver fibrosis, etc.

[0657] In some embodiments, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a compound or salt described herein, e.g., a compound or salt of any of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein. In some embodiments, the cancer is mediated by the expression (e.g., aberrant expression, overexpression, etc.) and / or activity of ASH1L. In certain embodiments, the cancer is leukemia, breast cancer, prostate cancer, pancreatic cancer, lung cancer, thyroid cancer, liver cancer, skin cancer, or brain cancer.

[0658] In certain embodiments, the present disclosure provides a method of treating a disease in a subject, the method comprising determining whether the subject has an ASH11-mediated condition (e.g., cancer), and administering to the subject a therapeutically effective amount of a compound or salt described herein, for example, a compound or salt having any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein.

[0659] In some embodiments, ASH1L expression (e.g., aberrant expression, overexpression, etc.) and / or activity has been identified in hematological malignancies, such as cancers affecting the blood, bone marrow, and / or lymph nodes. Accordingly, certain embodiments are directed to administering a compound or salt described herein, e.g., a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein, to a subject with a hematological malignancy. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds disclosed herein can be used to treat diseases such as ALL, AML, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), hairy cell leukemia, and / or other leukemias. In certain embodiments, the compounds or salts of the present disclosure can be used to treat lymphoma, such as any subtype of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

[0660] Whether a tumor or cancer expresses ASH1L (e.g., overexpressed, abnormally expressed, etc.) can be determined by evaluating the nucleotide sequence encoding ASH1L or by evaluating the amino acid sequence of ASH1L. Methods for detecting ASH1L nucleotide sequences are known to those skilled in the art. Such methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting curve analysis, and microarray analysis. Methods for detecting ASH1L protein are known to those skilled in the art. Such methods include, but are not limited to, detection using ASH1L-specific binding agents (e.g., antibodies), protein electrophoresis, and Western blotting, as well as direct peptide sequencing.

[0661] A variety of samples can be used in the methods of determining whether a tumor or cancer expresses (e.g., overexpresses, aberrantly expresses, etc.) ASH1L or is mediated by ASH1L activity. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is taken from a cancer or a subject with a tumor. In some embodiments, the sample is a fresh sample of tumor / cancer. In some embodiments, the sample is a frozen sample of tumor / cancer. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0662] In certain embodiments, the present disclosure provides a method for inhibiting ASH1L activity in a sample, the method comprising administering a compound or salt described herein to said sample containing ASH1L.

[0663] The present disclosure provides methods for treating a disease by administering to a subject suffering from the disease a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, wherein the compound binds to ASH1L and / or inhibits ASH1L activity. In certain embodiments, the compound binds to ASH1L covalently. In certain embodiments, the compound binds to ASH1L non-covalently.

[0664] The present disclosure also relates to a method of treating a hyperproliferative disorder in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or salt of any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein.In some embodiments, the method is directed to treating acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder (CMD), or a combination of these. Harm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, uterine cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, throat cancer Head cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma with occult primary lesions, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, breast cancer The present invention relates to the treatment of cancers such as craniomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach / gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, specific cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, the present invention relates to the treatment of non-cancerous hyperproliferative disorders such as skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)).In some cases, the method relates to the treatment of leukemia, hematological malignancies, solid tumor cancer, prostate cancer (e.g., castration-resistant prostate cancer), breast cancer, Ewing's sarcoma, osteosarcoma, primary osteosarcoma, T-cell prolymphocytic leukemia, glioma, glioblastoma, liver cancer (e.g., hepatocellular carcinoma), or diabetes.

[0665] Subjects that can be treated with the compounds of the invention, or pharmaceutically acceptable salts, esters, prodrugs, solvates, tautomers, stereoisomers, isotopologues, hydrates, or derivatives thereof, according to the methods of the invention, include, for example, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonal tumor, germ cell tumor, Primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumor, CNS cancer, uterine cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma melanoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma with occult primary lesions, midline lining of the lung, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasia, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer , oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, pediatric specific cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, virus-induced cancer, leukemia, hematological malignancies, solid tumor cancer, prostate cancer, castration-resistant prostate cancer, breast cancer, Ewing's sarcoma,Subjects diagnosed with osteosarcoma, primary osteosarcoma, T-cell prolymphocytic leukemia, glioma, glioblastoma, hepatocellular carcinoma, liver cancer, or diabetes mellitus are included. In some embodiments, subjects treated with the compounds of the present invention include subjects diagnosed with non-cancerous hyperproliferative disorders such as skin (e.g., psoriasis), restenosis, or benign hyperplasia of the prostate (e.g., benign prostatic hyperplasia (BPH)).

[0666] The present invention further provides methods for inhibiting the activity of ASH1L by contacting ASH1L (e.g., contacting a cell, tissue, or organ expressing ASH1L) with an effective amount of a compound or salt having any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein. In some embodiments, the present invention provides methods for inhibiting the activity of ASH1L in a subject, including, but not limited to, a rodent and a mammal, such as a human, by administering to the subject an effective amount of a compound or salt having any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein. In some embodiments, the percent inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0667] In some embodiments, the present disclosure provides methods for inhibiting the activity of ASH1L in a cell by contacting the cell with a compound of the present invention in an amount sufficient to inhibit the activity. In some embodiments, the present disclosure provides methods for inhibiting the activity of ASH1L in a tissue by contacting the tissue with a compound or salt having any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), in an amount sufficient to inhibit ASH1L activity in the tissue. In some embodiments, the present disclosure provides methods for inhibiting the activity of ASH1L in an organism (e.g., a mammal, a human, etc.) by contacting the organism with a compound or salt having any one of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), in an amount sufficient to inhibit ASH1L activity in the organism.

[0668] The composition comprising the compound or its salt described herein can be administered for preventive and / or therapeutic treatment.For therapeutic use, the composition is administered to a patient who already suffers from a disease in an amount sufficient to cure or at least partially prevent the symptoms of the disease.The effective amount for this use depends on the severity and course of the disease, existing therapy, the patient's health condition, weight, and response to drugs, and the judgment of the treating clinician.

[0669] For prophylactic applications, compositions containing the compounds described herein or salts thereof are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this application, the precise amount also depends on the patient's health, weight, and the like. When used in a patient, the effective amount for this application depends on the severity and course of the disease, disorder, or condition, existing therapy, the patient's health and response to the drugs, and the judgment of the treating clinician.

[0670] If the patient's condition does not improve, then at the discretion of the clinician, the compound may be administered chronically, i.e., for an extended period of time, including for the life of the patient, so as to improve or, if not improve, inhibit or limit the symptoms of the patient's disease.

[0671] If the patient's condition improves, at the clinician's discretion, administration of the compound may continue, or the administered drug dose may be temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary from 2 days to 1 year, and includes, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during the drug holiday period can be from about 10% to about 100%, including, by way of example only, 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%.

[0672] Once improvement in the patient's condition has occurred, a maintenance dose is administered as needed. Thereafter, the dose and / or frequency of administration may be reduced, depending on symptoms, to a level that maintains improvement in the disease, disorder, or condition. However, upon recurrence of symptoms, the patient may require long-term intermittent therapy.

[0673] The amount of a given drug that would correspond to such an amount will vary depending on factors such as the particular compound, the disease and its severity, and the identity (e.g., body weight) of the subject or host requiring treatment, but can be determined in an art-recognized manner based on the individual circumstances surrounding each case, including, for example, the specific drug being administered, the route of administration, the condition being treated, and the subject or host being treated. However, in general, doses employed for adult treatment will usually range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. For convenience, the desired dose may be administered in a single dose or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, e.g., two, three, four, or more times per day.

[0674] The toxicity and therapeutic efficacy of such treatment regimens are evaluated in cell cultures or experimental animals using LD 50 (lethal dose for 50% of the population) and ED 50 The LD (the dose therapeutically effective in 50% of the population) can be determined by standard pharmaceutical procedures, including, but not limited to, determining the LD (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Compounds that exhibit large therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in deriving a dosage range for use in humans. The dose of such compounds can be determined based on the ED4000 dose that results in minimal toxicity. 50 The dose can vary within this range depending on the dosage form employed and the route of administration utilized.

[0675] [Combination therapy] Provided herein are methods of combination therapy using agents known to modulate other pathways, or other components of the same pathway, or even a set of overlapping target enzymes, in combination with a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups disclosed herein. In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of the invention with chemotherapeutic agents, targeted agents, therapeutic antibodies, and radiation therapy, resulting in a synergistic or additive therapeutic effect.

[0676] Generally, in embodiments using combination therapy, the compositions described herein and other agents need not be administered in the same pharmaceutical composition, and may require administration by different routes due to differences in physical and chemical properties. When possible, determining the mode of administration and the suitability of administration in the same pharmaceutical composition is well within the knowledge of the clinician. Initial administration can be performed according to established protocols recognized in the art, and then the dose, mode of administration, and time of administration can be modified by the clinician based on the observed effects.

[0677] In some cases, it may be appropriate to administer at least one compound described herein in combination with another therapeutic agent. By way of example only, if nausea is one of the side effects experienced by a patient when receiving any one of the compounds described herein, such as a compound or salt of any one of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, it may be appropriate to administer an anti-nausea agent in combination with the first therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., an adjuvant alone may have minimal therapeutic effect, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit received by a patient may be increased by administering another therapeutic agent (including a treatment regimen) that also has a therapeutic benefit in addition to one of the compounds described herein. In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the sum of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0678] The specific selection of compounds to be used is determined by the diagnosis and determination of the patient's condition and the appropriate treatment protocol. Depending on the nature of the disease, disorder, or condition, the patient's condition, and the actual selection of compounds to be used, the compounds may be administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially. The order of administration and the number of administration repetitions of each therapeutic agent during a treatment protocol can be determined within the knowledge of a clinician after evaluating the disease being treated and the patient's condition.

[0679] When drugs are used in combination therapy, the therapeutically effective dose may vary. Methods for experimentally determining the therapeutically effective dose of drugs and other agents used in combination therapy regimens have been described in the literature. For example, the use of metronomic dosing, i.e., giving low doses frequently to minimize toxic side effects, has been widely described in the literature. Combination therapy also includes cyclical therapy with varying start and stop times to aid in the clinical management of patients.

[0680] In the combination therapy described herein, the dosage of the co-administered compound will, of course, vary depending on the type of co-administered drug used, the specific drug used, the disease being treated, etc. Furthermore, when co-administered with one or more biologically active agents, the compounds provided herein may be administered simultaneously with the biologically active agent(s) or sequentially. When administered sequentially, the attending physician will determine the appropriate order for administering the protein together with the biologically active agent(s).

[0681] In any event, the multiple therapeutic agents, one of which is a compound or salt of any one of Formulae (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, may be administered in any order, or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, integrated form or in multiple forms (by way of example only, either a single pill or two separate pills). Multiple doses of one of the therapeutic agents may be administered, or multiple doses of both therapeutic agents may be administered. If not simultaneously, the time period between multiple doses may vary from more than zero weeks to less than four weeks. Furthermore, combination methods, compositions, and formulations are not limited to the use of only two agents; multiple combinations of agents in a treatment are also envisioned.

[0682] It is understood that the dosage regimen for treating, preventing, or ameliorating the condition(s) for which relief is sought can be modified according to various factors. These factors include the disorder or condition suffered by the subject, as well as the subject's age, weight, sex, diet, and health status. Therefore, the dosage regimen actually used may vary significantly and may therefore deviate from the dosage regimen described herein.

[0683] The pharmaceutical compositions constituting the combination therapy disclosed herein may be in a single dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical compositions constituting the combination therapy may also be administered sequentially, in which case each therapeutic compound is administered in a two-step administration regimen. A two-step administration regimen may require sequential administration of the active agents or spaced-apart administration of separate active agents. The duration between administration steps may range from minutes to hours, depending on the properties of each agent, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. The optimal administration interval may also be determined by circadian fluctuations in target molecule concentrations.

[0684] Additionally, the compounds described herein may also be used in combination with procedures that may provide additive or synergistic benefit to the patient. By way of example only, pharmaceutical compositions of the compounds disclosed herein and / or combinations with other therapeutic agents may be combined with genetic testing to determine whether an individual is a carrier of a mutant gene known to be correlated with a certain disease or condition, thereby predicting which patients will benefit therapeutically and / or prophylactically from the methods described herein.

[0685] The compounds and combination therapies described herein can be administered before, during, or after the onset of disease, and the timing of administration of compositions containing the compounds may vary. Thus, for example, to prevent the onset of disease, the compounds can be used as prophylactic agents and administered continuously to subjects prone to developing a condition or disease. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of symptoms. Administration of the compounds can begin within the first 48 hours of the onset of symptoms, preferably within the first 48 hours, more preferably within the first 6 hours, and most preferably within 3 hours of the onset of symptoms. Initial administration can be by any practical route, such as intravenous injection, bolus injection, infusion over about 5 minutes to about 5 hours, pill, capsule, transdermal patch, buccal delivery, or a combination thereof. The compounds are preferably administered as soon as practicable after the onset of disease is detected or suspected, for the period required to treat the disease, for example, from one day to about three months. The length of treatment can vary from subject to subject, and can be determined using known criteria. For example, the compound or a formulation containing the compound can be administered for at least two weeks, preferably for about one month to about five years.

[0686] In particular, when the compounds and pharmaceutical compositions herein are used to treat cancer, they may be co-administered with one or more chemotherapeutic agents. Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds herein. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, protein-protein interaction inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0687] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules, such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as numerous other chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metuledopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine. Nitrogen mustards such as chlorambucil, chlornaphazine, clofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquin, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinomycin, and an Thromycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin Antibiotics such as benzodiazepine, benzodiazepine, benzocaine ...Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calucelone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucide; and gallium nitrate ;hydroxyurea;lentinan;lonidamine;mitoguazone;mitoxantrone;mopidamol;nitracrine;pentostatin;phenamet;pirarubicin;podophyllic acid;2-ethylhydrazide;procarbazine;PSK.RTM.;razoxane;sizofiran;spirogermanium;tenuazonic acid;triaziquone;2,2',2''-trichlorotriethylamine;urethane;vindesine;dacarbazine;mannomustine;mitobronitol;mitolactol;pipobroman;gacytosine;arabinoside ("Ara-C");cyclophosphamide;thiotepa;taxanes, such as paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Suitable chemotherapeutic cell modulating agents also include antihormonal drugs that act to regulate or inhibit hormone action on tumors, such as antiestrogens including tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000;If necessary, the compound or pharmaceutical composition of the present invention may be administered with a commonly prescribed anticancer drug, such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agent, antitumor active herb, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW. 2992, biricodal, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, Imexo It can be used in combination with fluticasone, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar;

[0688] Embodiments herein further relate to methods of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal by using a compound or salt of any of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), having any suitable substituents and functional groups as disclosed herein, or a pharmaceutical composition provided herein, in combination with radiation therapy. Techniques for administering radiation therapy are known in the art, and such techniques can be used in the combination therapy described herein. The administration of the compounds of the invention in this combination therapy can be determined as described herein.

[0689] Radiation therapy can be administered by one of several methods, or a combination of methods, including, but not limited to, external beam radiation therapy, internal beam radiation therapy, interstitial beam radiation therapy, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by inserting a space-sealed radioactive material into the body at or near the site of a tumor or other proliferative tissue disease. This term is intended to include, but is not limited to, the emission of radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Radiation sources suitable for use as cell modulators in the present invention include both solid and liquid sources. By way of non-limiting example, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, solid-source Ir-192, solid-source I-125, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material can also be a fluid made from a solution of any radionuclide(s), such as a solution of I-125 or I-131, or a radioactive fluid can be made using a slurry of a suitable fluid containing small particles of a solid radionuclide, such as Au-198, Y-90, etc. Additionally, the radionuclide(s) can be contained within a gel or radioactive microspheres.

[0690] The compounds or pharmaceutical compositions herein are also used in combination with an amount of one or more substances selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor.

[0691] Antiangiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used in combination with the compounds of the present invention and the pharmaceutical compositions described herein. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include those disclosed in WO96 / 33172 (published October 24, 1996), WO96 / 27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO98 / 07697 (published February 26, 1998), WO98 / 03516 (published February 26, 1998), and WO98 / 03516 (published March 7, 1996). WO98 / 34918 (published January 29, 1998), WO98 / 34915 (published August 13, 1998), WO98 / 33768 (published August 6, 1998), WO98 / 30566 (published July 16, 1998), European Patent Publication No. 606,046 (published July 13, 1994), European Patent Publication No. 931,788 (published July 28, 1999), WO90 / 0 5719 (published May 31, 1990), WO99 / 52910 (published October 21, 1999), WO99 / 52889 (published October 21, 1999), WO99 / 29667 (published June 17, 1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 99129 No. 61.1, filed June 3, 1999, U.S. Provisional Application No. 60 / 148,464, filed August 12, 1999, U.S. Pat. No. 5,863,949, issued January 26, 1999, U.S. Pat. No. 5,861,510, issued January 19, 1999, and European Patent Publication No. 780,386, published June 25, 1997, all of which are incorporated herein by reference in their entireties.Preferred MMP-2 and MMP-9 inhibitors have little or no inhibitory activity against MMP-1. More preferably, they include those that selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO32-3555, and RS13-0830.

[0692] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibitory phycotoxins that inhibit protein phosphatase type 2A or type 1, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA inhibitors that inhibit the expression of proteins (involved in autophagy), including, but not limited to, ATG5, may be used.

[0693] In some embodiments, the compounds described herein are formulated and administered in combination with a liquid or solid tissue barrier, also known as a lubricant. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, Seprafilm, Interceed, and hyaluronic acid.

[0694] In some embodiments, the pharmaceutical agent administered in conjunction with a compound described herein may be any suitable drug useful for delivery by inhalation, for example, an analgesic such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine, an antianginal agent such as diltiazem; an antiallergic agent such as cromoglycate, ketotifen, or nedocromil; an antiinfective such as a cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, or pentamidine; an antihistamine such as methapyrilene; an anti-inflammatory agent such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone; an antitussive such as noscapine; a bronchodilator such as ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, or the like. diuretics such as amiloride; anticholinergics such as ipratropium, atropine, or oxitropium; hormones such as cortisone, hydrocortisone, or prednisolone; xanthines such as aminophylline, choline theophyllinate, lysine theophyllinate, or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. It will be apparent to those skilled in the art that, where necessary, pharmaceutical agents may be used in the form of a salt (e.g., as an alkali metal salt or amine salt, or as an acid addition salt), or as an ester (e.g., a lower alkyl ester), or as a solvate (e.g., hydrate) to optimize the activity and / or stability of the pharmaceutical agent.

[0695] Other exemplary therapeutic agents useful in combination therapy include the agents listed above, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid agents, estrogens and progestins, androgens, adrenocorticotropic hormones, corticosteroids and their synthetic analogs; inhibitors of corticosteroid synthesis and action, insulin, oral hypoglycemic agents, and pancreatic endocrine pharmacology, agents affecting calcification and bone turnover, such as calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, water-soluble vitamins, etc. These include, but are not limited to, vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase drugs; agents acting on the neuromuscular junction and / or autonomic ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

[0696] Other suitable therapeutic agents for co-administration with the compounds herein also include agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances produced by the biotransformation of products of selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory drugs, analgesics and antipyretics, agents that inhibit the synthesis of prostaglandins and thromboxanes, and agents that inhibit the synthesis of induced schizophrenia. These include selective inhibitors of cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, beta-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors.

[0697] Additional therapeutic agents contemplated for co-administration with the compounds and compositions herein include diuretics, vasopressin, agents that affect renal water retention, renin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, beta-adrenergic receptor antagonists, agents to treat hypercholesterolemia, and agents to treat dyslipidemia.

[0698] Other therapeutic agents contemplated for co-administration with the compounds and compositions herein include agents used to regulate gastric acid secretion, agents for treating peptic ulcers, agents for treating gastroesophageal reflux disease, agents for improving gastrointestinal function, antiemetics, agents used for irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary tract disease, agents used for pancreatic disease, therapeutic agents used to treat protozoal infections, drugs used to treat malaria, amebiasis, giardiasis, trichomoniasis, trypanosomiasis, and / or leishmaniasis, and / or drugs used in chemotherapy for helminthiasis. Other therapeutic agents include antibacterial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and drugs for urinary tract infections, penicillins, cephalosporins, and other beta-lactam antibiotics, drugs containing aminoglycosides, protein synthesis inhibitors, drugs used in chemotherapy for tuberculosis, Mycobacterium avium complex disease, and leprosy, antifungals, and antivirals, including nonretrovirals and antiretrovirals.

[0699] Examples of therapeutic antibodies that can be used in combination with the compounds herein include, but are not limited to, anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.

[0700] Additionally, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressants, tolerogens, and immunostimulants, are contemplated by the methods herein. Additionally, therapeutic agents acting on the blood and blood-forming organs, hematopoietic agents, growth factors, minerals, and vitamins, anticoagulants, thrombolytic agents, and antiplatelet agents.

[0701] For the treatment of kidney cancer, the compounds of the present invention can be combined with sorafenib and / or Avastin. For the treatment of endometriosis, the compounds of the present invention can be combined with doxorubicin, taxotere (taxol), and / or cisplatin (carboplatin). For the treatment of ovarian cancer, the compounds of the present invention can be combined with cisplatin (carboplatin), taxotere, doxorubicin, topotecan, and / or tamoxifen. For the treatment of breast cancer, the compounds of the present invention can be combined with taxotere (taxol), gemcitabine (capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901, Avastin, Herceptin, OSI-906, and / or OSI-930. For the treatment of lung cancer, the compounds of the present invention may be combined with taxotere (taxol), gemcitabine, cisplatin, pemetrexed, tarceva, PD0325901, and / or avastin.

[0702] Additional therapeutic agents that can be used in combination with the compounds herein are described in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

[0703] The compounds described herein can be used in combination with other suitable agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds described herein are co-administered with other agents such as those described above. When used in combination therapy, the compounds described herein are administered simultaneously with the second agent or separately. This combination administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any of the agents described above can be administered simultaneously, with both agents present in separate formulations. Alternatively, the compounds of the present invention can be administered immediately after any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present invention and any of the agents described above are administered within minutes, hours, or days of each other.

[0704] In some embodiments, the compounds described herein are co-administered with another therapeutic agent effective in the treatment of leukemia and / or other cancers. In some embodiments, the compounds described herein are administered in combination with one or more therapeutic agents approved for the treatment of acute lymphoblastic leukemia (ALL), such as, for example, ABITREXATE (methotrexate), ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), ARRANON (nelarabine), asparaginase Erwinia chrysanthemi, CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), CLOFARABINE, CLOFAREX (clofarabine), CLOLAR (clofarabine), cyclophosphamide, cytarabine, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), dasatinib, daunorubicin hydrochloride, doxorubicin hydrochloride, Erwinase (asparaginase Erwinia chrysanthemi), It is co-administered with folate (methotrexate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GLEEVEC (imatinib mesylate), ICLUSIG (ponatinib hydrochloride), imatinib mesylate, MARQIBO (vincristine sulfate liposome), methotrexate, METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate), nelarabine, NEOSAR (cyclophosphamide), ONCASPAR (peguaspargase), pegaspargase, ponatinib hydrochloride, RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib), TARABINE PFS (cytarabine), VINCASAR PFS (vincristine sulfate), vincristine sulfate, etc.

[0705] In some embodiments, the compounds described herein are co-administered with one or more therapeutic agents approved for the treatment of acute myeloid leukemia (AML), such as, for example, ADRIAMYCIN PFS (doxorubicin hydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), arsenic trioxide, CERUBIDINE (daunorubicin hydrochloride), CLAFEN (cyclophosphamide), cyclophosphamide, cytarabine, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), daunorubicin hydrochloride, doxorubicin hydrochloride, NEOSAR (cyclophosphamide), RUBIDOMYCIN (daunorubicin hydrochloride), TARABINE PFS (cytarabine), TRISENOX (arsenic trioxide), VINCASAR PFS (vincristine sulfate), vincristine sulfate, etc.

[0706] In some embodiments, the compounds described herein are co-administered with one or more therapeutic agents approved for the treatment of chronic lymphocytic leukemia (CLL), such as alemtuzumab, AMBOCHLORIN (chlorambucil), AMBOCLORIN (chlorambucil), ARZERRA (ofatumumab), bendamustine hydrochloride, CAMPATH (alemtuzumab), CHLORAMBUCILCLAFEN (cyclophosphamide), cyclophosphamide, CYTOXAN (cyclophosphamide), FLUDARA (fludarabine phosphate), fludarabine phosphate, LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), NEOSAR (cyclophosphamide), ofatumumab, TREANDA (bendamustine hydrochloride), etc.

[0707] In some embodiments, the compounds described herein are co-administered with one or more therapeutic agents approved for the treatment of chronic myeloid leukemia (CML), such as BOSULIF (bosutinib), bosutinib, CLAFEN (cyclophosphamide), cyclophosphamide, cytarabine, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), dasatinib, GLEEVEC (imatinib mesylate), ICLUSIG (ponatinib hydrochloride), imatinib mesylate, NEOSAR (cyclophosphamide), nilotinib, omacetaxine mepesuxinate, ponatinib hydrochloride, SPRYCEL (dasatinib), SYNRIBO (omacetaxine mepesuxinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), etc.

[0708] In some embodiments, the compounds described herein are co-administered with one or more therapeutic agents approved for the treatment of meningeal leukemia, such as CYTARABINE, CYTOSAR-U (cytarabine), TARABINE PFS (cytarabine), etc.

[0709] In some embodiments, a compound described herein is co-administered with one or more alkylating agents (e.g., for the treatment of cancer) selected from, for example, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine, apaziquone, brostallicin, bentamstine, carmustine, estramustine, fotemustine, glufosfamide, mafosfamide, bendamustine, mitolactol, cisplatin, carboplatin, epplatin, lobaplatin, nedaplatin, oxaliplatin, and satraplatin.

[0710] In some embodiments, a compound described herein is co-administered with one or more antimetabolites (e.g., for the treatment of cancer) selected from, e.g., methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine, fludarabine, 5-azacytidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethinylcytidine, cytosine arabinoside, hydroxyurea, melphalan, nelarabine, nolatrexed, ocfosfate, premetrexed disodium, pentostatin, peritrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, and vinorelbine.

[0711] In some embodiments, a compound described herein is co-administered with one or more hormone therapy agents (e.g., for treating cancer) selected from, e.g., exemestane, lupron, anastrozole, doxercalciferol, fadrozole, formestane, abiraterone acetate, finasteride, epristeride, tamoxifen citrate, fulvestrant, trelstar, toremifene, raloxifene, lasofoxifene, letrozole, sagopilone, ixabepilone, epothilone B, vinblastine, vinflunine, docetaxel, and paclitaxel.

[0712] In some embodiments, the compounds described herein are co-administered with one or more cytotoxic topoisomerase inhibitors (e.g., for the treatment of cancer) selected from, for example, aclarubicin, doxorubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan, topotecan, edotecarin, epimbicin, etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirumbicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and the like.

[0713] In some embodiments, the compounds described herein are co-administered with one or more anti-angiogenic compounds (e.g., for the treatment of cancer) selected from, for example, acitretin, aflibercept, angiostatin, aplidine, asental, axitinib, resentin, bevacizumab, brivanib alaninate, cilengutide, combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, levimastat, removab, revlimid, sorafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, ukrain, and vitaxin.

[0714] In some embodiments, a compound described herein is co-administered with one or more antibodies (e.g., for treating cancer) selected from, for example, trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, oregovomab, and alemtuzumab.

[0715] In some embodiments, the compounds described herein are co-administered with one or more VEGF inhibitors (e.g., for the treatment of cancer) selected from, for example, sorafenib, DAST, bevacizumab, sunitinib, resentin, axitinib, aflibercept, telatinib, brivanib alaninate, vatalanib, pazopanib, and ranibizumab.

[0716] In some embodiments, the compounds described herein are co-administered with one or more EGFR inhibitors (e.g., for the treatment of cancer) selected from, for example, cetuximab, panitumumab, vectibix, gefitinib, erlotinib, and zactima.

[0717] In some embodiments, the compounds described herein are co-administered with one or more HER2 inhibitors (e.g., for the treatment of cancer) selected from, for example, lapatinib, trastuzumab, and pertuzumab. The CDK inhibitor is selected from roscovitine and flavopiridol.

[0718] In some embodiments, the compounds described herein are co-administered with one or more proteasome inhibitors (eg, for the treatment of cancer) selected from, for example, bortezomib and carfilzomib.

[0719] In some embodiments, the compounds described herein are co-administered with one or more serine / threonine kinase inhibitors (e.g., for the treatment of cancer) selected from, for example, MEK inhibitors and Raf inhibitors, such as sorafenib.

[0720] In some embodiments, a compound described herein is co-administered with one or more tyrosine kinase inhibitors (e.g., for treating cancer) selected from, for example, dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate, brivanib alaninate, pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix, gefitinib, erlotinib, lapatinib, trastuzumab, and pertuzumab.

[0721] In some embodiments, the compounds described herein are co-administered with one or more androgen receptor antagonists (e.g., for the treatment of cancer) selected from, for example, nandrolone decanoate, fluoxymesterone, android, prostoid, andromustine, bicalutamide, flutamide, apocyproterone, apoflutamide, chlormadinone acetate, androcur, tabi, cyproterone acetate, and nilutamide.

[0722] In some embodiments, the compounds described herein are co-administered with one or more aromatase inhibitors (e.g., for the treatment of cancer) selected from, for example, anastrozole, letrozole, testolactone, exemestane, aminoglutethimide, and formestane.

[0723] In some embodiments, the compounds described herein are co-administered with one or more other anti-cancer agents, including, for example, alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotene, velcade, gallium nitrate, canfosfamide, darinaparsin, and tretinoin. In preferred embodiments, the compounds of the present disclosure can be used in combination with chemotherapy (e.g., cytotoxic agents), antihormonal therapy, and / or targeted therapy, such as other kinase inhibitors, mTOR inhibitors, and angiogenesis inhibitors.

[0724] In embodiments in which the compounds and pharmaceutical compositions herein are used to treat or prevent non-cancer diseases and / or conditions, the compounds and pharmaceutical compositions herein may be co-administered with therapeutic agents and / or therapies known to those of skill in the art that are appropriate for treating such diseases and / or conditions.

[0725] 〔kit〕 Kits and articles of manufacture for use in the therapeutic applications described herein are also provided. In some embodiments, such kits include a carrier, package, or container compartmentalized to contain one or more containers, such as vials, tubes, etc., each container(s) containing one of the individual components used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be made from a variety of materials, such as glass or plastic.

[0726] The articles of manufacture provided herein include packaging materials. Packaging materials used to package pharmaceuticals include, for example, those described in U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended administration and treatment method. For example, the container(s) contain a compound or salt of any of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (II), and (IJ), optionally in a composition or in combination with another agent disclosed herein, and having any suitable substituents and functional groups as disclosed herein. The container(s) optionally have a sterile access port (for example, the container is an IV bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise, in addition to the compound, an identifying description or label or instructions relating to the use of the compound in the methods described herein.

[0727] For example, kits typically include one or more additional containers, each containing one or more of the various materials (e.g., reagents, which may be in concentrated form, and / or devices) desirable from a commercial and user perspective when using the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; labels for the carrier, package, container, vial, and / or tube indicating the contents and instructions for use, and package inserts describing the instructions for use. A set of instructions is also typically included. A label may be present on the container or associated with the container. For example, a label is present on the container if the letters, numbers, or other characters comprising the label are attached, molded, or etched into the container itself, and is associated with the container if they are present in a container or carrier that also holds the container, e.g., as a package insert. Furthermore, labels are used to indicate that the contents should be used for a particular therapeutic application. Furthermore, the label indicates the direction in which the contents should be used, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is present in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack may comprise, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device may be accompanied by instructions for administration. Alternatively, the pack or dispenser may be accompanied by a notice affixed to the container in a form prescribed by a governmental authority regulating the manufacture, use, or sale of pharmaceuticals, which notice indicates approval by that authority of the drug form for human or veterinary administration. Such notice may be, for example, labeling approved by the U.S. Food and Drug Administration for prescription drugs, or an approved package insert. In some embodiments, compositions containing a compound provided herein formulated with a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of a designated condition. [Example]

[0728] The following examples and preparations further describe and illustrate the compounds provided herein and methods for preparing such compounds. It should be understood that the scope of the present invention is not limited in any way to the scope of the following examples and preparations.

[0729] [I. Chemical synthesis] Scheme 1 - General synthetic strategy for compounds of formula IE

[0730] [ka]

[0731] The first step in the general procedure for synthesizing compounds having formula IE is to introduce a halogen atom (i.e., bromine) as a substituent on ring A. Selected compounds used commercially available starting materials containing bromine as IE.2. Compound IE.2 is then coupled with IE.3, which contains a boronic acid (or boronic ester) moiety suitable for coupling reactions catalyzed by palladium complexes. Optionally, the substituent R A1- R A5 , R D1- R D5 , R E1- R E5 can be modified as shown in Examples 2-7. After the appropriate modifications, structure IE.4 is further converted to thioamide or amide IE. Thioamides (X=S) can be obtained by treating IE.4 with sodium hydrosulfide, and amides (X=O) can be obtained by treatment with hydrogen peroxide.

[0732] Example 1. Synthesis of 3-(1H-indol-4-yl)benzothioamide (81)

[0733] [ka]

[0734] 3-(1H-indol-4-yl)benzonitrile (81-1). 3-Bromobenzonitrile (46 mg, 0.25 mmol) and (1H-indol-4-yl)boronic acid (60 mg, 0.37 mmol) were dissolved in THF (20 mL) and water (2 mL). Pd(dppf)Cl2 (80 mg) was added along with cesium carbonate (300 mg). The mixture was refluxed for 30 min. THF was evaporated, and the crude product was purified using column chromatography (silica gel, hexane, ethyl acetate). 156 mg of compound was isolated (71% yield). 1 H NMR (600 MHz, CDCl3) δ ppm 6.61 - 6.68 (m, 1H) 7.16 (dd, J=7.3, 0.7 Hz, 1H) 7.27 - 7.33 (m, 2H) 7.46 (d, J=8.4 Hz, 1H) 7.55- 7.60 (m, 1H) 7.65 (dt, J=7.7, 1.3 Hz, 1H) 7.93 (dt, J=7.7, 1.5 Hz, 1H) 7.98 (d, J=1.47Hz, 1H) 8.38 (br. s., 1H); 13 C NMR (150 MHz, CDCl3) δ 111.3, 112.6, 119.1, 119.9, 122.4, 125.1, 125.9, 129.3, 130.4, 131.9, 132.2,133.1, 136.3, 142.6.

[0735] 3-(1H-indol-4-yl)benzothioamide (81). 3-(1H-indol-4-yl)benzonitrile (40 mg, 0.2 mmol) was dissolved in ethanol (2 mL) and NaHS (100 mg, 1.8 mmol) was added. The mixture was stirred overnight. The solvent was evaporated and the compound was purified using column chromatography (silica gel, hexane, ethyl acetate). 42 mg of material was obtained (94% yield). 1H NMR (600MHz, acetonitrile-d3) δ ppm 6.65-6.71 (m, 1H) 7.16 - 7.32 (m, 2H) 7.35 - 7.41 (m, 1H) 7.47 - 7.62 (m, 2H) 7.84 - 7.91 - 7.98 (m, 2H) 8.20(br. s., 1H) 8.21 - 8.24 (m, 1H) 8.37 (br. s., 1H) 9.49-9.54 (m, 1H); 13 C NMR (150 MHz,CDCl3) δ 100.13, 113.8, 118.9, 121.5, 125., 125.5, 126.7, 128.2, 131.2, 132.3, 136.2,139.5, 140.9, 202.1;[M+H] + HRMS(ESI) calculated value: 252.07, found value: 253.0795.

[0736] Example 2. Synthesis of 3-(6-(hydroxymethyl)-1-(4,4,4-trifluorobutyl)-1H-indol-3-yl)benzothioamide (124)

[0737] [ka]

[0738] 3-Bromo-1H-indole-6-carbaldehyde (124-1). To a solution of 1H-indole-6-carbaldehyde (2.0 g, 13.8 mmol) in DMF (20 mL) was added a solution of NBS (2.9 g, 15.2 mmol) in DMF (15 mL) over 20 min at -20 °C. The mixture was stirred and allowed to warm slowly to room temperature over 5 h. The DMF was removed under reduced pressure, and the residue was purified by silica gel flash chromatography using hexane and ethyl acetate (0–50%) to give compound 124-1 (2.9 g, 94%). 1 H NMR (400 MHz, CD3OD) δ 9.99 (s, 1H), 7.98 (s, 1H), 7.67 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (m, 2H).

[0739] 3-(6-Formyl-1H-indol-3-yl)benzonitrile (124-2). 3-Bromo-1H-indole-6-carbaldehyde (0.95 g, 4.26 mmol), (3-cyanophenyl)boronic acid (1.26 g, 8.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.58 g, 0.63 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.37 g, 1.27 mmol), anhydrous KF (0.74 g, 12.83 mmol), and anhydrous THF (24 mL) were mixed under a nitrogen atmosphere and stirred at 40 °C overnight. The mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography with hexane and ethyl acetate (0-60%) to give compound 124-2 (0.76 g, 72%). 1 H NMR (400 MHz, CD3OD) δ 10.0 (s, 1H), 8.02 (m, 4H), 7.91 (m,1H), 7.72 (dd, J = 8.0, 1.3 Hz, 1H), 7.62 (m, 2H).

[0740] 3-(6-Formyl-1-(4,4,4-trifluorobutyl)-1H-indol-3-yl)benzonitrile (124-3). To a solution of 3-(6-formyl-1H-indol-3-yl)benzonitrile (0.70 g, 2.85 mmol) in anhydrous DMF (11 mL) was added NaH (0.22 g, 9.20 mmol) at 0 °C under N2 atmosphere and stirred for 30 min. 4-Bromo-1,1,1-trifluorobutane (490 μL, 4.00 mmol) was added to the mixture via syringe, and the resulting mixture was stirred and gradually warmed to room temperature over 2 h. The mixture was worked up with ethyl acetate (40 mL) and water (10 mL, 3 times). The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography using hexane and ethyl acetate (0–40%) to give compound 124-3 (0.98 g, 97%). 1 H NMR (400 MHz, CD3CN) δ 10.1 (s, 1H), 7.94 (m, 2H), 7.85 (m, 2H), 7.71 (dd, J = 8.0, 1.3 Hz, 1H), 7.55 (m, 3H), 4.35 (t, J = 6.4 Hz, 2H), 2.20 (m, 4H).

[0741] 3-(6-(hydroxymethyl)-1-(4,4,4-trifluorobutyl)-1H-indol-3-yl)benzonitrile (124-4). To a solution of 3-(6-formyl-1-(4,4,4-trifluorobutyl)-1H-indol-3-yl)benzonitrile (30 mg, 0.084 mmol) in methanol (5 mL) was added NaBH4 (10 mg, 0.26 mmol) at 0 °C and stirred for 1 h. Methanol was removed under reduced pressure, and the residue was worked up with ethyl acetate (30 mL) and water (8 mL, 3 times). The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography using hexane and ethyl acetate (0-40%) to give compound 124-4 (25 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 1H), 7.80 (m, 2H), 7.47 (m, 2H), 7.37 (s, 1H), 7.19 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.80 (s, 2H), 4.21 (t, J = 4.0 Hz, 2H), 2.09 (m, 4H). [M-OH] + LCMS (ESI) calculated value 341, found value 341.

[0742] 3-(6-(hydroxymethyl)-1-(4,4,4-trifluorobutyl)-1H-indol-3-yl)benzothioamide (124). 3-(6-Formyl-1-(4,4,4-trifluorobutyl)-1H-indol-3-yl)benzonitrile (25 mg, 0.070 mmol), NaHS (78 mg, 1.40 mmol), MgCl (130 mg, 1.40 mmol), and anhydrous DMF (4 mL) were mixed and stirred at room temperature for 3 h. The mixture was worked up with ethyl acetate (40 mL) and saturated NaHCO solution (8 mL x 3). The ethyl acetate layer was concentrated under reduced pressure to give a crude residue, which was purified by silica gel flash chromatography using DCM and 5% NHOH in methanol (methanol: 0-5%) to give compound 124 (15 mg, 55%). 1 H NMR (600 MHz, CDCl3) δ 8.18 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 (d, J =8.0 Hz, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.33 (s, 1H), 7.21 (d, J = 4.0 Hz, 1H), 4.28 (t,J = 4.0 Hz, 2H), 2.18 (m, 4H). 13C NMR (150 MHz, CDCl3) δ 204.1, 139.9, 136.8, 135.8, 135.7, 130.6, 124.9 (q, J =276 Hz), 120.0, 116.4, 108.1, 65.9, 45.0, 31.1 (q, J =28.5 Hz),22.9 (q, J =3.0 Hz). [M+H] + HRMS(ESI) calculated value 393.1243, found value 393.1241.

[0743] Example 3. Synthesis of 3-(6-amino-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-3-yl)benzothioamide (126)

[0744] [ka]

[0745] Methyl (2,2-dimethyl-1,3-dioxan-5-yl)methanesulfonate (126-1). (2,2-Dimethyl-1,3-dioxan-5-yl)methanol (50 mg, 0.34 mmol) was dissolved in DCM (0.4 mL). The mixture was cooled to -78 °C. Triethylamine (143 μL, 1 mmol) and methanesulfonyl chloride (32 μL, 0.4 mmol) were added sequentially. The reaction mixture was stirred at -78 °C to 0 °C. After 3 h, the reaction mixture was transferred to a separatory funnel, diluted with DCM, and washed with sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated. 1 H NMR (600 MHz, acetone-d6) δ ppm 1.35 (d, J = 2.5 Hz, 3H) 1.42 (d, J = 2.9 Hz, 3H) 2.03 (td, J=7.2, 3.3 Hz, 1 H) 3.14 (d, J = 3.3 Hz, 3H) 3.74 - 3.83 (m, 2H) 4.04 - 4.15 (m, 2H) 4.39 (dd, J=7.2, 3.1 Hz, 2H).

[0746] 3-(6-Nitro-1H-indol-3-yl)benzonitrile (126-2). (3-Cyanophenyl)boronic acid (805 mg, 5.5 mmol), 3-bromo-6-nitro-1H-indole (660 mg, 2.7 mmol), Pd2(dba)3 (512 mg, 0.6 mmol), tri-t-butylphosphonium tetrafluoroborate (157 mg, 0.5 mmol), and KF (477 mg, 8.2 mmol) were mixed in THF. The mixture was degassed. The reaction was kept under a stream of argon and heated to 40 °C. The reaction mixture was cooled to room temperature and filtered through a Celite pad, washing with ethyl acetate (60 mL). The filtrate was concentrated to give a dark red solid. Purification was performed by column chromatography. 1 H NMR (600 MHz, acetonitrile-d3) δ ppm 7.63 - 7.71 (m, 2 H), 7.93 - 7.96 (m, 1 H), 7.99 - 8.05 (m, 2 H), 8.05 - 8.09 (m, 2 H), 8.47 - 8.50 (m, 1 H), 10.00 - 10.40 (bs, 1 H).

[0747] 3-(1-((2,2-Dimethyl-1,3-dioxan-5-yl)methyl)-6-nitro-1H-indol-3-yl)benzonitrile (126-3). 3-(6-Nitro-1H-indol-3-yl)benzonitrile (540 mg) and cesium carbonate were mixed in dry DMF (4 mL). The dark red reaction mixture was stirred at room temperature for several minutes. A suspension of mesylate 126-1 in DMF (3 mL) was added. The flask was stirred under argon and heated to 60 °C. Water was added and the compound was extracted with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over sodium sulfate. After evaporation, the crude compound was purified using column chromatography (silica gel, hexane-ethyl acetate). 470 mg (50%) of a yellow solid was obtained. 1H NMR (600 MHz, CDCl3) δ ppm 1.51 (s, 3H) 1.55 (s, 3H) 2.06 - 2.13 (m, 1H) 3.59 (d, J = 11.4 Hz, 2H) 4.13 (dd, J = 12.3, 2.8 Hz, 2H) 4.61 (d, J=8.4 Hz, 2H) 7.55 - 7.67(m, 3H) 7.86 (d, J = 7.7 Hz, 1H) 7.88 - 7.95 (m, 2H) 8.12 (dd, J = 8.8, 2.2 Hz, 1H) 8.46 (d, J = 1.5 Hz, 1H); 13 C NMR (150 MHz, CDCl3) δppm 19.6, 28.3, 34.8, 46.1, 61.0, 98.9, 107.2, 113.3, 116.1, 116.1, 118.7, 119.6, 129.8, 130.1, 130.2, 130.8, 131.6, 132.0, 135.4, 135.8, 143.7.

[0748] 3-(1-(3-Hydroxy-2-(hydroxymethyl)propyl)-6-nitro-1H-indol-3-yl)benzonitrile (126-4). 3-(1-((2,2-Dimethyl-1,3-dioxan-5-yl)methyl)-6-nitro-1H-indol-3-yl)benzonitrile (350 mg, 0.9 mmol) was dissolved in THF (4.5 mL) and 3 M HCl (aq, 0.6 mL) was added. The reaction mixture was stirred at room temperature for 1.5 h. The mixture was concentrated to remove THF, diluted with water, and extracted with several portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a light orange solid (280 mg, 89% yield). 1H NMR (600 MHz, acetonitrile-d3) δ ppm 2.23 (td, J=12.0, 6.1 Hz, 1H) 2.96 (br. s., 2H) 3.51 - 3.63 (m, 4H) 4.45 (d, J = 7.0 Hz, 2H) 7.62 - 7.72 (m, 2H) 7.96 (m, 1H) 7.99 -8.11 (m, 4H) 8.60 (d, J = 1.8 Hz, 1H); 13 C NMR (150 MHz, acetonitrile-d3) δ ppm 45.5, 46.2, 61.7, 109.1, 114.2, 116.4, 116.7, 120.2, 120.8, 131.1, 131.2, 131.8, 132.9, 135.3, 136.9 137.4, 144.7.

[0749] 3-(1-(3-Fluoro-2-(fluoromethyl)propyl)-6-nitro-1H-indol-3-yl)benzonitrile (126-5). To a solution of TEA.HF (93 uL, 0.57 mmol) in dry DCM (0.9 mL) was added Xtalfluor E (97 mg, 0.42 mmol) at 0 °C. Then, a solution of 3-(1-(3-hydroxy-2-(hydroxymethyl)propyl)-6-nitro-1H-indol-3-yl)benzonitrile (50 mg, 0.14 mmol) in DCM (0.5 mL) was added dropwise at 0 °C. This mixture was stirred at 0 °C for 30 min and at room temperature for 2 h. The reaction was then quenched with saturated NaHCO3, the aqueous phase was extracted with DCM, and the organic phase was dried over sodium sulfate. The volatiles were evaporated, and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate) to give 29 mg of product (57% yield). 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.71 - 2.87 (m, 1H) 4.45 - 4.52 (m, 1H) 4.53 - 4.59 (m, 4H) 4.60 - 4.66 (m, 1H) 7.68 - 7.73 (m, 1H) 7.78 (d, J = 7.7 Hz, 1H) 8.05 (dd, J = 8.8, 1.8 Hz, 1H) 8.09 (d, J = 8.1 Hz, 1H) 8.13 - 8.19 (m, 2H) 8.37 (m, 1H) 8.66 (d, J = 1.8 Hz, 1H).

[0750] 3-(6-Amino-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-3-yl)benzonitrile (126-6). To a solution of 3-(1-(3-fluoro-2-(fluoromethyl)propyl)-6-nitro-1H-indol-3-yl)benzonitrile (29 mg, 0.082 mmol) in acetone (1.6 mL) was added water (320 μL), followed by ammonium chloride (176 mg) and zinc powder (106 mg). The mixture was stirred for 60 minutes. The acetone was evaporated and the residue was partitioned between ethyl acetate and concentrated ammonia solution. The mixture was filtered through Celite and the organic phase was dried over MgSO4 and evaporated. The compound was used in the next step without further purification. [M+H+AcCN] + LR-MS calculated value: 367, observed value 367.10.

[0751] 3-(6-amino-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-3-yl)benzothioamide (126). To a solution of 3-(6-amino-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-3-yl)benzonitrile (23 mg, 0.072 mmol) in DMF (0.2 mL) was added sodium hydrosulfite (60 mg, 1 mmol) and magnesium chloride (101 mg, 0.5 mmol) at room temperature. The mixture was stirred for 2 hours. Water (0.4 mL) was added, and the product was extracted with ethyl acetate (3 × 5 mL). The organic phase was dried over sodium sulfate and evaporated. The yellow residue was purified using column chromatography (silica gel, hexane-ethyl acetate) to give 10 mg (39%) of the thioamide. 1H NMR (600 MHz, DMSO-d6) δ ppm 2.50 - 2.64 (m, 1H) 4.10 (d, J =7.7 Hz, 2H) 4.35 - 4.53 (m, 4H) 4.88 (s, 2H)6.48 (dd, J = 8.6, 1.7 Hz, 1H) 6.54 (d, J=1.1 Hz, 1H) 7.33 - 7.39 (m, 2H) 7.53 (d, J = 8.4Hz, 1H) 7.62 (d, J = 8.1 Hz, 1H) 7.66 (d, J =8.1 Hz, 1H) 8.05 (m, 1H) 9.47 (br. s., 1H) 9.81 (br. s., 1H); 13 C NMR (150 MHz, DMSO-d6)δ ppm 40.7 (J = 18 Hz), 42.2, 80.7, 81.8, 93.4, 110.7, 115.0, 117.0, 119.8, 124.0, 124.2, 124.9, 128.3, 128.6, 135.4, 138.6, 140.1, 144.8, 200.6 C 19 H 19 HR-MS of F2N3S [ESI, M+H + ]Calculated value: 360.1346, measured value: 360.1341.

[0752] Example 4. Synthesis of 3-(6-amino-1-cyclopentyl-1H-indol-3-yl)benzothioamide (127)

[0753] [ka]

[0754] 3-(1-Cyclopentyl-6-nitro-1H-indol-3-yl)benzonitrile (127-1). Under a stream of N2, a solution of DIAD (90 μL, 0.34 mmol) in anhydrous DCM (0.1 mL) was added dropwise over 15 min to a suspension of 3-(6-nitro-1H-indol-3-yl)benzonitrile (50 mg, 0.19 mmol), Ph3P (90 mg, 0.34 mmol), cyclopentanol (36 μL, 0.34 mmol), and anhydrous DCM (3 mL) at 0 °C. The mixture was allowed to warm slowly to room temperature and continued stirring overnight. The mixture was purified by silica gel flash chromatography using hexane and ethyl acetate (0 to 50% ethyl acetate) to give compound 127-1 (52 mg, 83%). [M+H] + LCMS (ESI) calculated value 332, found value 332.

[0755] 3-(6-Amino-1-cyclopentyl-1H-indol-3-yl)benzonitrile (127-2). 3-(1-Cyclopentyl-6-nitro-1H-indol-3-yl)benzonitrile (50 mg, 0.14 mmol), Zn (200 mg, 3.2 mmol), NH₄Cl (200 mg, 3.8 mmol), acetone (8 mL), and water (1.5 mL) were mixed in a round-bottom flask and stirred at room temperature for 2 h. The mixture was worked up with ethyl acetate (40 mL) and saturated NaHCO₃ (10 mL, twice). The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography using DCM and 5% NH₄OH in methanol (methanol: 0-15%) to give compound 127-2 (33 mg, 76%). 1 H NMR (600 MHz, CD3OD) δ 7.94(m, 2H), 7.63 (d, J =6.0 Hz, 1H), 7.52 (m, 2H), 7.44 (m, 1H), 6.87 (d, J = 6.0 Hz, 1H), 6.72 (d, J =6.0 Hz, 1H), 4.74 (m, 1H), 2.23 (m, 2H), 1.95 (m, 4H), 1.95 (m, 2H). [M+H] + LCMS (ESI) calculated value 302, found value 302.

[0756] 3-(6-Amino-1-cyclopentyl-1H-indol-3-yl)benzothioamide (127). 3-(6-Amino-1-cyclopentyl-1H-indol-3-yl)benzonitrile (30 mg, 0.1 mmol), NaHS (200 mg, 3.6 mmol), MgCl (200 mg, 2.1 mmol), and anhydrous DMF (5 mL) were mixed and stirred at room temperature for 3 h. The mixture was worked up with ethyl acetate (40 mL) and saturated NaHCO solution (8 mL x 3). The ethyl acetate layer was concentrated under reduced pressure to give the crude residue, which was purified by silica gel flash chromatography using DCM and 5% NHOH in methanol (methanol: 0-5%) to give compound 127 (19 mg, 56%). 1 H NMR (600 MHz, CD3OD) δ 8.20 (s, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.71 (m, 2H), 7.42 (t, J = 6.0 Hz, 2H), 6.93 (s, 1H), 6.74 (d, J = 6.0 Hz, 1H), 4.80 (m, 1H), 2.23 (m, 2H), 1.95 (m, 4H), 1.95 (m, 2H). 13 C NMR (150 MHz, CD3OD) δ204.1, 142.6, 141.7, 139.9, 137.7, 134.5, 130.6, 130.2, 129.9, 126.9, 124.8, 122.4, 121.2, 116.9, 112.8, 58.1, 33.3, 30.6, 27.7. [M+H] + HRMS(ESI) calculated value 336.1529, found value 336.1529.

[0757] Example 5. Synthesis of 3-(6-amino-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-3-yl)benzamide (194)

[0758] [ka]

[0759] 3-(6-amino-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-3-yl)benzamide (194). To a stirred solution of 3-(6-amino-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-3-yl)benzonitrile (15 mg, 0.04 mmol) and potassium carbonate (15 mg) in DMSO, hydrogen peroxide (30%, 15 μL) was added at 0° C. The solid mixture was allowed to warm to room temperature. After 20 minutes, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, evaporated, and purified on a column (silica gel, hexane-ethyl acetate). The crude product 194.1 was dissolved in acetone (0.8 mL), and water (0.15 mL) was added. Then, ammonium chloride (86 mg) and zinc powder (52 mg) were added, and the mixture was stirred at room temperature for 40 minutes. The mixture was filtered through Celite and washed with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The compound was purified by column chromatography (silica gel, hexane-ethyl acetate). 10 mg of a colorless oil was obtained (yield 76%). 1 H NMR (600 MHz, acetonitrile-d3) δ ppm 2.56 - 2.73 (m, 1H) 4.20 (d, J=7.7 Hz, 2H) 4.39 - 4.64 (m, 4H) 6.01 (bs, 1H) 6.56 - 6.65 (m, 1H) 6.68 - 6.75 (m, 1H) 6.83 (bs, 1H) 7.31 (m, 1H) 7.46 - 7.54 (m, 1H) 7.63 - 7.72 (m, 2H) 7.78 - 7.86 (m, 1H) 8.02 - 8.09 (m, 1H); 13 C NMR (150 MHz, CDCl 3, HSQC) δ ppm 40.4, 41.7, 80.2, 81.3, 93.8, 110.2, 119.6, 123.7, 123.7, 124.8, 128.2, 129.0;C 19 H 20 HR-MS of F2N3O [ESI, M+H +]Calculated value: 344.1574, measured value: 344.1567.

[0760] Example 6. Synthesis of 3-(1-(3-fluoro-2-(fluoromethyl)propyl)-6-(hydroxymethyl)-1H-indol-3-yl)benzothioamide (236)

[0761] [ka]

[0762] 3-(1-((2,2-Dimethyl-1,3-dioxan-5-yl)methyl)-6-formyl-1H-indol-3-yl)benzonitrile (236-1). 3-(6-Formyl-1H-indol-3-yl)benzonitrile (150 mg, 0.6 mmol), (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate (125-1) (204 mg, 0.9 mmol), and cesium carbonate (596 mg, 1.8 mmol) were stirred in DMF (0.6 mL) at 60 °C for 18 h. Water was added, and the compound was extracted with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over sodium sulfate. After evaporation, the crude compound was purified using column chromatography (silica gel, hexane-ethyl acetate). 50 mg (33%) of a yellow solid was obtained. 1 H NMR (600 MHz, CDCl3) δ ppm 1.50 (s, 3H) 1.53 (s, 3H)2.08 - 2.14 (m, 1H) 3.59 - 3.65 (m, 2H) 4.07- 4.13 (m, 2H) 4.59 (d, J=8.1 Hz, 2H) 7.53 -7.62 (m, 3H) 7.76 (dd, J=8.2, 0.9 Hz, 1H) 7.88 (d, J = 7.7 Hz, 1H) 7.92 (m, 1H) 7.98 (d, J=8.1 Hz, 1H) 8.01 - 8.05 (m, 2H) 10.11 (s, 1H).

[0763] Methyl 3-(3-cyanophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1H-indol-6-yl)acetate (236-3). To a stirred solution of 3-(1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-6-formyl-1H-indol-3-yl)benzonitrile (110 mg, 0.29 mmol) in MeOH / THF (6 mL, 1:1 v / v) was added sodium borohydride (16 mg, 0.44 mmol) at 0 °C. The mixture was stirred at 0 °C for an additional 30 min. The solvent was evaporated, and water, followed by ethyl acetate, was added. The organic phase was dried over sodium sulfate, and the solvent was evaporated. The residue was then dissolved in DCM (2 mL), and triethylamine (76 μL, 0.58 mmol) was added, followed by acetic anhydride (56 μL, 0.58 mmol). The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated. The crude mixture was purified by column chromatography (silica gel, hexane-ethyl acetate). 104 mg (85%) of a colorless oil was obtained. 1 H NMR (600 MHz, CDCl3) δ ppm 1.49 (s, 3H)1.52 (s, 3H) 2.06 - 2.11 (m, 1H) 2.11 - 2.14(m, 3H) 3.62 (dd, J = 12.1, 1.8 Hz, 2H) 4.02- 4.16 (m, 2H) 4.48 (d, J=8.1 Hz, 2H) 5.26 (s, 2H) 7.25 (d, J=8.1 Hz, 1H) 7.39 (m, 1H) 7.45 (m, 1H) 7.51 - 7.57 (m, 2H) 7.87 (d, J = 8.4 Hz, 2H) 7.91 (m, 1H); 13 C NMR (150 MHz, CDCl3) δ ppm 20.1, 21.2, 27.8, 34.7, 45.8, 61.3, 67.0, 98.5, 98.7, 110.5, 112.9, 115.0, 119.1, 119.7, 121.5, 125.8, 127.6, 129.2, 129.6, 130.5, 131.4, 136.7, 136.9, 171.0.

[0764] Methyl (3-(3-cyanophenyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)-1H-indol-6-yl)acetate (236-4). To a solution of methyl 3-(3-cyanophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1H-indol-6-yl)acetate (40 mg, 0.096 mmol) in 0.4 mL of THF was added HCl (3 M aqueous solution, 64 μL) and the mixture was stirred for 15 min. The THF was evaporated and the residue was partitioned between acetyl acetate and water. The aqueous phase was extracted with additional ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. Used in the next step without further purification.

[0765] Methyl (3-(3-cyanophenyl)-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-6-yl)acetate (236-5). To a solution of TEA.HF (33 uL, 0.2 mmol) in dry DCM (0.3 mL) was added Xtalfluor E (35 mg, 0.15 mmol) at 0 °C. Then, a solution of methyl (3-(3-cyanophenyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)-1H-indol-6-yl)acetate (19 mg, 0.05 mmol) in DCM (0.5 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 30 minutes and at room temperature for 4 hours. The reaction was then quenched with saturated NaHCO3, the aqueous phase was extracted with DCM, and the organic phase was dried over sodium sulfate. The volatiles were evaporated and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate) to give 10 mg of product (55% yield). 1 H 1 H NMR (600 MHz, CDCl3) δ ppm 2.14 (s, 3H) 2.59 - 2.75 (m, 1H) 4.39 (d, J = 7.3 Hz, 2H) 4.45 - 4.53(m, 2H) 4.53 - 4.61 (m, 2H) 5.28 (s, 2H) 7.28 (m, 1H) 7.37 (m, 1H) 7.45 (m, 1H) 7.53 - 7.60 (m, 2H) 7.86 - 7.91 (m, 2H) 7.92 (m, 1H) 13 C NMR (150 MHz, CDCl3) δ ppm 21.0, 41.7 (J =18Hz), 42.9, 66.9, 80.2, 81.3, 110.0, 113.0, 115.6, 119.0, 121.7, 125.8, 127.2, 129.4, 129.6, 130.5, 131.4, 136.4, 136.9, 170.9.

[0766] 3-(1-(3-Fluoro-2-(fluoromethyl)propyl)-6-(hydroxymethyl)-1H-indol-3-yl)benzothioamide (236, SKA-174). To a solution of methyl (3-(3-cyanophenyl)-1-(3-fluoro-2-(fluoromethyl)propyl)-1H-indol-6-yl)acetate (10 mg, 0.026 mmol) in MeOH:DCM (2:1 v / v) was added 2 M potassium carbonate solution (26.5 μL) and the mixture was sonicated for 60 min. The volatiles were evaporated, and the residue was dissolved in DCM, dried over sodium sulfate, and evaporated. DMF (100 μL) was added, followed by sodium hydrosulfide (50 mg) and magnesium chloride (100 mg). After 30 min, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and purified using preparative TLC (silica gel, hexane:ethyl acetate 1:1 v / v). 1 H NMR (600 MHz, AcCN-d3) δ ppm 2.66 - 2.80 (m, 1H) 4.39 (d, J = 7.7Hz, 2H) 4.46 - 4.67 (m, 4H) 4.75 (d, J = 5.1 Hz, 2H) 7.19 - 7.24 (m, 1H) 7.52 (s, 2H) 7.59(s, 1H) 7.77 - 7.82 (m, 1H) 7.86 - 7.90 (m, 1H) 7.92 - 7.99 (m, 1H) 8.11 - 8.19 (m, 1H) 8.20 - 8.23 ​​(m, 1H) 8.31 - 8.42 (m, 1H);13 C NMR (150 MHz, AcCN-d3) δ ppm 41.7, 42.7, 44.2,65.8, 82.2, 83.3, 109.7, 117.1, 120.9, 121.3, 125.9, 126.4, 126.8, 128.6, 130.1, 131.2, 136.9, 138.1, 138.7, 141.6, 204.1;C 20 H 21 HR-MS [ESI, M+H + ]Calculated value: 375.1343, measured value: 375.1335.

[0767] Example 7. Synthesis of 3-(1-(3,3-difluoropropyl)-6-(hydroxymethyl)-1H-indol-3-yl)benzothioamide (131)

[0768] [ka]

[0769] 3-Bromo-1H-indole-6-carboxylate (131-1). To a solution of methyl 1H-indole-6-carboxylate (1.00 g, 5.71 mmol) in anhydrous DMF (10 mL) was added dropwise over 20 min at −60 °C, stirred, and allowed to warm slowly to room temperature over 3 h under N2 atmosphere. The reaction mixture was worked up with ethyl acetate (100 mL) and water (20 mL x 3). The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography using hexane and ethyl acetate (EA: 0-40%) to give the product (1.41 g, 98%). 1 H NMR (600 MHz, CD3OD) δ 8.15 (s, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.50 (m, 2H), 3.94 (s, 3H).

[0770] Methyl 3-(3-cyanophenyl)-1H-indole-6-carboxylate (131-2). Methyl 3-bromo-1H-indole-6-carboxylate (1.12 g, 4.43 mmol), (3-cyanophenyl)boronic acid (1.30 g, 8.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (608 mg, 0.66 mmol), tri-tert-butylphosphonium tetrafluoroborate (385 mg, 1.32 mmol), anhydrous KF (769 mg, 13.30 mmol), and anhydrous THF (20 mL) were mixed under a nitrogen atmosphere and stirred at 40 °C overnight. The mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using hexane and ethyl acetate (0-60%) to give the product (1.05 g, 86%). 1 H NMR (600 MHz, CD3OD) δ 8.20 (S, 1H), 8.02 (brs, 2H), 7.93 (d, J = 12.0 Hz, 1H), 7.84 (m, 2H), 7.62 (m, 2H), 3.95 (s, 3H).

[0771] Methyl 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-(3-cyanophenyl)-1H-indole-6-carboxylate (131-3). To a solution of methyl 3-(3-cyanophenyl)-1H-indole-6-carboxylate (100 mg, 0.36 mmol) in anhydrous DMF (2.0 mL) was added NaH (40 mg, 1.67 mmol) at 0 °C under N2 atmosphere and stirred for 30 min. 2-(2-Bromoethyl)-1,3-dioxolane (126 μL, 1.08 mmol) was added to the above mixture via syringe, and the resulting mixture was stirred and gradually warmed to room temperature over 2 h. The mixture was worked up with ethyl acetate (40 mL) and water (10 mL, 3 times). The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using hexane and ethyl acetate (0-50%) to give the product (120 mg, 89%). 1H NMR (600 MHz, CD3OD) δ 8.24 (s, 1H), 8.06 (s, 1H), 8.01 (m, 2H), 7.86 (d, J = 6.0 Hz, 1H), 7.83 (s, 1H), 7.64 (m, 2H), 4.92 (t, J = 6.0 Hz, 1H), 4.45 (t,J = 6.0 Hz, 2H), 3.98 (m, 2H), 3.95 (s, 3H),3.86 (m, 2H), 2.24 (m, 2H).

[0772] Methyl 3-(3-cyanophenyl)-1-(3-oxopropyl)-1H-indole-6-carboxylate (131-4). Methyl 1-(2-(1,3-dioxolan-2-yl)ethyl)-3-(3-cyanophenyl)-1H-indole-6-carboxylate (120 mg, 0.32 mmol), THF (8 mL), and aqueous HCl (3.5 M, 2 mL) were mixed and stirred at 0 °C until no further progress was observed by TLC analysis. The THF was removed by blowing air through the mixture, and the remaining mixture was extracted with EA (25 mL). The EA layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the product (100 mg, 94%).

[0773] Methyl 3-(3-cyanophenyl)-1-(3,3-difluoropropyl)-1H-indole-6-carboxylate (131-5). To a solution of EtNHF (120 μL, 0.74 mmol) and XtalFluor-E (130 mg, 0.57 mmol) in DCM (4 mL) was added methyl 3-(3-cyanophenyl)-1-(3-oxopropyl)-1H-indole-6-carboxylate (100 mg, 0.30 mmol). The mixture was stirred at 0 °C for 1 h and then allowed to warm gradually to room temperature overnight. The DCM was removed under reduced pressure, and the residue was worked up with ethyl acetate (25 mL) and saturated NaHCO (8 mL x 2). The ethyl acetate layer was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography using hexanes and ethyl acetate (0-40%) to give the title compound (30 mg, 28%) with some impurity. 1H NMR (600 MHz, CD3OD) δ 8.23 ​​(s, 1H),8.03 (s, 1H), 7.98 (m, 2H), 7.80 (m, 2H), 7.64 (m, 2H), 6.03 (tt, J = 60.0, 6.0 Hz, 1H),4.49 (t, J = 6.0 Hz, 2H), 2.48 (m, 2H).

[0774] Methyl 3-(3-carbamothioylphenyl)-1-(3,3-difluoropropyl)-1H-indole-6-carboxylate (131-6). 3-(3-Cyanophenyl)-1-(3,3-difluoropropyl)-1H-indole-6-carboxylate (30 mg, 0.08 mmol), NaHS (230 mg, 4.1 mmol), MgCl (220 mg, 2.3 mmol), and anhydrous DMF (2.5 mL) were mixed and stirred at room temperature for 3 hours. The mixture was worked up with ethyl acetate (40 mL) and saturated NaHCO solution (10 mL, 3 times). The ethyl acetate layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (25 mg, 81%). 1 H NMR (600 MHz, CD3OD) δ 8.11 (d, J = 12.0 Hz, 2H), 7.98 (s, 1H), 7.80 (m, 4H), 7.45 (d, J = 6.0 Hz, 1H), 5.98 (tt, J= 60.0, 6.0 Hz, 1H), 4.47 (t, J = 6.0 Hz, 2H), 2.43 (m, 2H).

[0775] 3-(1-(3,3-Difluoropropyl)-6-(hydroxymethyl)-1H-indol-3-yl)benzothioamide (131). To a solution of methyl 3-(3-carbamothioylphenyl)-1-(3,3-difluoropropyl)-1H-indole-6-carboxylate (25 mg, 0.06 mmol) in anhydrous THF (2.0 mL) was added a 1 M THF solution of DIBAL (0.55 mL, 0.55 mmol) at −78 °C under N2 atmosphere and allowed to warm gradually to room temperature over 2 h. The mixture was worked up with ethyl acetate (15 mL) and aqueous HCl (1 M, 10 mL). The ethyl acetate layer was concentrated and purified by silica gel flash chromatography using hexane and ethyl acetate (EA: 0–80%) to give the product (10 mg, 46%). 1 H NMR (600 MHz, CD3OD) δ 8.26 (s, 1H), 7.93 (d, J = 12.0 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 7.75 (d, J = 6.0 Hz, 1H), 7.59 (m, 1H), 7.51 (m, 1H), 7.47 (t, J = 6.0 Hz, 1H), 7.21 (d, J = 12.0 Hz, 1H), 5.95 (tt, J = 60.0, 6.0 Hz, 1H), 4.47 (t, J = 6.0 Hz, 2H), 2.43 (m, 2H). 13 C NMR (150 MHz, CD3OD) δ 204.5, 141.8, 138.3, 137.1, 130.9, 129.5, 127.5, 127.3, 126.9, 125.1, 121.1, 120.8, 117.5, 117.4 (t, J = 237.0 Hz), 65.9, 40.8 (t, J = 6.0 Hz), 35.8 (t, J = 21.0 Hz). [M+H] + HRMS(ESI) calculated value 361.1181, found value 361.1175.

[0776] II. Experimental Procedure [Protein purification] The ASH1L SET protein was expressed as a MOCR fusion protein in E. coli BL21(DE3)T1R cells at 22°C. Transformed cells were lysed in Buffer A containing 50 mM Tris (pH 7.5), 500 mM NaCl, 1 mM tris(2-carboxyethyl)phosphine (TCEP), and 20 mM imidazole. Cell debris was pelleted by centrifugation, and the supernatant was loaded onto a column packed with nickel-nitrilotriacetic acid beads. The column was washed with Buffer A, and the protein was eluted with a 100 mL linear gradient to Buffer A containing 500 mM imidazole. The MOCR tag was cleaved with tobacco etch virus (TEV) protease during overnight dialysis against 50 mM Tris (pH 7.5), 100 mM NaCl, and 1 mM TCEP. Cleaved ASH1L was isolated from MOCR by repeated nickel column purification and collection of ASH1L in the flow-through and low-imidazole fractions. ASH1L was further purified by gel filtration chromatography using a Superdex-75 column equilibrated with buffer B containing 50 mM Tris (pH 7.5), 100 mM NaCl, and 1 mM TCEP. ASH1L SET-PHD and SET-BAH proteins were purified similarly, with the following differences: expression was performed at 18°C. TEV cleavage and the second nickel column were omitted to maintain protein stability, and gel filtration was performed on a Superdex-200 column.

[0777] [ASH1L histone methyltransferase assay (KMTase assay)] Chicken mono- / dinucleosomes (HMT-35-179), chicken oligo-nucleosomes (HMT-35-177), and HeLa nucleosomes (HMT-35-123) were purchased from Reaction Biology. For test compounds, 0.25 μM of ASH1L SET-BAH construct (amino acids 2069-2833) was diluted with 0.7 μM SAM, 0.2 μM chicken mono- / dinucleosomes, and HMTase buffer (50 mM Compounds were incubated in a concentration range of 500-0.2 μM in Tris (pH 8.5), 25 mM NaCl, 2 mM MgCl2, and 1 mM DTT in a total volume of 15 μL at 30°C for 1 h. The reaction was terminated by spotting 5 μL of the reaction mixture onto a P81 cellulose cube (Reaction Biology). The P81 cube was dried for 45 min and washed five times with 50 mM sodium bicarbonate (pH 9.0), for 10 min each. The P81 cube was then dried for 1 h, added to 10 mL of Ultima Gold scintillation cocktail (PerkinElmer), and analyzed using a Beckman scintillation counter.

[0778] [Isothermal titration calorimetry] ASH1L SET was diluted with ITC buffer (50 mM sodium phosphate pH 7.5, 50 mM The compound was extensively dialyzed at 4 °C against ASH1L (NaCl, 1 mM TCEP). Compound 126 was dissolved in DMSO and diluted with ITC buffer to a final concentration of 0.1 mM in 5% DMSO. The protein solution was adjusted to a final DMSO concentration of 5%. To maintain the stability of ASH1L, both protein and compound solutions were adjusted to 50 μM SAM. Titrations were performed at 25 °C using a VP-ITC titration calorimetry system (MicroCal). A calorimetric cell containing ASH1L (10 μM) was titrated with compound (0.1 mM) injected in a 10 μl volume. Data were analyzed using Origin 7.0 (OriginLab) to obtain thermodynamic parameters.

[0779] [Cell viability assay] MA9 (MLL-AF9 transformed), HM2 (Hoxa9 / Meis1 transformed) mouse bone marrow cells (BMC), MV4;11, and MOL13 human leukemia cells were cultured in 24-well plates at 1 × 10 5 Cells were seeded at 1 × 10 cells / ml, treated with 0.25% DMSO or compounds, and cultured at 37°C for 12 days. Every 4 days, 1 × 10 cells were cultured at 37°C for 12 days. 5A volume equivalent to 100 cells was spun down and resuspended in fresh medium supplemented with fresh compound. On day 0 and at 4-day intervals, 100 μl aliquots of the cell suspension were transferred to quadruplicate 96-well plates. Quadruplicate samples were incubated at 37°C for 4 days, after which viable cells were measured using an MTT cell proliferation assay kit (Roche). Absorbance was read at 570 nm using a PHERAstar (BMG) microplate reader.

[0780] [Quantitative RT-PCR] Total RNA was extracted from cells using the RNeasy Mini Kit (QIAGEN), and 100–2000 ng of total RNA was reverse transcribed using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems) according to the manufacturer's protocol. Real-time PCR was performed using a CFX96 Real-Time PCR Detection System (Biorad). TaqMan Gene Expression Master Mix and TaqMan Gene Expression Assays for mouse Gapdh (Mm99999915), mouse Ash1l (Mm00467322), mouse Hoxa7 (Mm00657963), mouse Hoxa9 (Mm00439364), mouse Hoxa10 (Mm00433966), mouse Meis1 (Mm00487664), and mouse B-actin (Mm00607939) were purchased from Thermo Fisher Scientific. Relative quantification of each gene transcript was performed using ΔΔC as described in the Biorad Real-Time PCR Applications Guide. t This was carried out using the method.

[0781] [Cytospin / Wright-Giemsa staining] 1 x 10 treated with compound 5 MA9 mouse BMCs were collected and placed in a Shandon EZ Single Cytofunnel (Thermo Fisher). Samples were centrifuged at 600 rpm for 5 minutes. Slides were air-dried and then stained with the Hema-3 kit (Thermo Fisher).

[0782] Various modifications and variations of the described methods and compositions of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the appended claims.

[0783] [References] The following references, some of which are cited above by number / letter, are incorporated herein by reference in their entirety: 1.Li Zhu,Qin Li2,Stephen HKWong,Min Huang,Brianna J.Klein,Jinfeng Shen,Larissa Ikenouye,Masayuki Onishi,Dominik Schneidawind,Corina Buechele,Loren Hansen,Jesus Duque-Afonso,Fangfang Zhu,Gloria Mas Martin,Or Gozani,Ravindra Majeti, Tatiana G. Kutateladze, and Michael L. Cleary, (2016), ASH1L Links Histone H3 Lysine 36 di-methylation to MLL Leukemia. Cancer Discovery, in press. 2.Colamaio, M.,Puca,F.,Ragozzino,E.,Gemei,M.,Decaussin-Petrucci,M.,Aiello,C.,Bastos,AU,Federico,A.,Chiappetta,G.,Vecchio,L.Del,Torregrossa,L.,Battista,S.,and Fusco,A.(2014)Downregulation of miR-142-3p contributes to thyroid follicular tumorigenesis by targeting ASH1L and MLL1.J.Clin.Endocrinol.Metab.100,E59-E69. [ PMC free article ] [ PubMed ] 3. Liu, L., Kimball, S., Liu, H., Holowatyj, A., and Yang, Z.-Q their significance in breast cancer.Oncotarget.6,2466-2482. 4.Fujimoto, A., Furuta, M., Totoki, Y., Tsunoda, T., Kato, M., Shiraishi, Y., Tanaka, H., Taniguchi, H., Kawakami, Y., Ueno, M., Gotoh, K., Ariizumi, S., Ward ell , CP , Hayami , S. , Nakamura , T. , Aikata , H. , Arihiro , K. , Boroevich , KA , Abe , T. , Nakano , K. , Maejima , K. , Sasaki-Oku , A. , Ohsawa , A. , Shibuya , T. , Nakamura ,H.,Hama,N.,Hosoda,F.,Arai,Y.,Ohashi,S.,Urushidate,T.,Nagae,G.,Yamamoto,S.,Ueda,H.,Tatsuno,K.,Ojima,H.,Hiraoka,N.,Okusaka,T.,Kubo,M.,M arubashi , S. , Yamada , T. , Hirano , S. , Yamamoto , M. , Ohdan , H. , Shimada , K. , Ishikawa , O. , Yamaue , H. , Chayama , K. , Miyano , S. , Aburatani , H. , Shibata , T. , and Nakagawa,H.(2016)Whole-genome mutational landscape and characterization of noncodi...

Claims

1. A compound of the following formula or a salt thereof: 【Chemistry 1】 [In the formula, R Ｄ１ -R Ｄ４ is substituted for a substitutable hydrogen atom on the benzene ring, R Ｄ１ -RD4 is H, OH, methoxy, methyl, F, NHCH ３ and N.H. ２ is selected from R Ａ１ and RE1 is represented by the formula (IIa to IIq): 【Chemistry 2】 【change】 【change】 is one of; In the formula, J, Q １ , or J １ is attached to one of the indole rings; J.J. １ , J ２ , J ３ , and J ４ Each represents, when present, a covalent bond, H, alkyl １－１５ , alkenyl １－６ , alkynyl １－６ , (CH ２ ) ０－６ C(S)NH ２ , (CH ２ ) ０－６ C(O)NH ２ ,O,S,NH,(CH ２ ) ０－６ C(O)NH(CH ２ ) １－６ , (CH ２ ) ０－６ NHC(O)(CH ２ ) １－６ , alkylsulfonyl, sulfonamide, alkylsulfonamide, (CH ２ ) ０－６ C(S)NH(CH ２ ) １－６ , (CH ２ ) ０－６ O (CH ２ ) １－６ , (CH ２ ) ０－６ OH, (CH ２ ) ０－６ S (CH ２ ) １－６ , (CH ２ ) ０－６ S.H., (C.H. ２ ) ０－６ NH (CH ２ ) １－６ , (CH ２ ) ０－６ N (CH ２ ) １－６ (CH ２ ) １－６ , (CH ２ ) ０－６ N.H. ２ , (CH ２ ) ０－６ SO ２ (CH ２ ) １－６ , (CH ２ ) ０－６ N.H.S.O. ２ (CH ２ ) １－６ , (CH ２ ) ０－６ SO ２ N.H. ２ , halogen, haloalkyl, dihaloalkyl, trihaloalkyl, alkyl having 1 to 3 halogens at 2 or more positions along the chain, (CH ２ ) １－４ SP (Ph) ２ = S, (CH ２ ) ０－６ NH (CH ２ ) １－５ OH, (CH ２ ) ０－６ NH (CH ２ ) １－５ N.H. ２ , (CH ２ ) ０－６ NH (CH ２ ) １－５ S.H., (C.H. ２ ) ０－６ O (CH ２ ) １－５ OH, (CH ２ ) ０－６ O (CH ２ ) １－５ N.H. ２ , (CH ２ ) ０－６ O (CH ２ ) １－５ S.H., (C.H. ２ ) ０－６ S (CH ２ ) １－５ OH, (CH ２ ) ０－６ S (CH ２ ) １－５ N.H. ２ , (CH ２ ) ０－６ S (CH ２ ) １－５ S.H., (C.H. ２ ) ０－６ O (CH ２ ) １－６ NH (CH ２ ) １－５ OH, (CH ２ ) ０－６ O (CH ２ ) １－６ NH (CH ２ ) １－５ NH ２ 、(CH ２ ) ０－６ O(CH ２ ) １－６ H ２ ) １－５ H. ２ ) ０－６ O(CH ２ ) １－６ O(CH ２ ) １－５ Hmm, Hmm ２ ) ０－６ O(CH ２ ) １－６ O(CH ２ ) １－５ NH ２ 、(CH ２ ) ０－６ O(CH ２ ) １－６ O(CH ２ ) １－５ H. ２ ) ０－６ O(CH ２ ) １－６ H ２ ) １－５ Hmm, Hmm ２ ) ０－６ O(CH ２ ) １－６ H ２ ) １－５ NH ２ 、(CH ２ ) ０－６ O(CH ２ ) １－６ H ２ ) １－５ H. ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ Hmm, Hmm ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ NH ２ 、(CH ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ H. ２ ) ０－６ H ２ ) １－６ O(CH ２ ) １－５ Hmm, Hmm ２ ) ０－６ H ２ ) １－６ O(CH ２ ) １－５ NH ２ 、(CH ２ ) ０－６ H ２ ) １－６ O(CH ２ ) １－５ H. ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ Hmm, Hmm ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ NH ２ 、(CH ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ H. ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ Hmm, Hmm ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ NH ２ 、(CH ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ H. ２ ) ０－６ H ２ ) １－６ O(CH ２ ) １－５ Hmm, Hmm ２ ) ０－６ H ２ ) １－６ O(CH ２ ) １－５ NH ２ 、(CH ２ ) ０－６ H ２ ) １－６ O(CH ２ ) １－５ H. ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ Hmm, Hmm ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ NH ２ 、(CH ２ ) ０－６ H ２ ) １－６ H ２ ) １－５ H. ２ ) ０－３ C(O)O(CH ２ ) ０－３ 、(CH ２ ) ０－３ C(S)O(CH ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ C(S)S(CH ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ I'm sorry ２ ) ０－３ 、(CH ２ ) ０－３ I'm sorry ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ H.E. ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ I'm sorry ２ ) ０－３ 、(CH ２ ) ０－３ I'm sorry ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ HUNTER ２ ) ０－３ 、(CH ２ ) ０－３ SC(S)NH(CH ２ ) ０－３ 、(CH ２ ) ０－３ I'm sorry ２ ) ０－３ 、(CH ２ ) ０－３ I'm sorry ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ P.S. ２ ) ０－３ 、(CH ２ ) ０－３ SC(O)O(CH ２ ) ０－３ , (CH ２ ) ０－３ SC(S)O(CH ２ ) ０－３ , (CH ２ ) ０－３ NHC(O)S(CH ２ ) ０－３ , (CH ２ ) ０－３ NHC(S)S(CH ２ ) ０－３ , (CH ２ ) ０－３ O.C. (O) S (CH ２ ) ０－３ , (CH ２ ) ０－３ OC(S)S(CH ２ ) ０－３ , (CH ２ ) ０－３ SC(O)S(CH ２ ) ０－３ , (CH ２ ) ０－３ SC(S)S(CH ２ ) ０－３ , (CH ２ O) １－６ and trimethylmethane; Q, Q １ , and Q ２ respectively, when present, for furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, naphthalene, pyridine, quinolone, isoquinoline, pyrazine, quinoxaline, pyrimidine, quinazoline, pyridazine, cinnoline, phthalazine, thalidomide, triazine, thiadiazole, aziridine, thiirane, oxirane, oxaziridine, dioxirane, azetidine, oxetane, thietane, di Azetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, oxane, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, trioxane, trithiane, azepane, oxepane, thiepane, homopiperazine, azocane, tetrahydropyran, cyclobutene, cyclopentene, cyclohexene, cycloheptene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, 1,5-cyclooctadiene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, any C ３ ~C ７ cycloalkyl groups; Q, Q １ , and Q ２ each, when present, may have one or more additional J groups present at any position on the Q ring; Any of the above alkyl groups or (CH ２ ) ｘ－ｙ The group may also be linear or branched; Any of the above alkyl groups or (CH ２ ) ｘ－ｙ The group may also have OH, ═O, NH ２ , CN, dihaloalkyl, trihaloalkyl, or halogen substituents; The number of hydrogens at the terminal positions of the above groups may be adjusted depending on whether the group is attached to an additional group or whether the group is terminal.

2. A compound or a salt thereof selected from the group consisting of: 【Chemistry 3】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

3. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a salt thereof, and a pharma- ceutically acceptable carrier.

4. The pharmaceutical composition of claim 3 , wherein the pharmaceutical composition is formulated for oral administration or injection.

5. 5. A pharmaceutical composition according to claim 3 or 4, in an amount effective to inhibit the activity of ASH1L, for use in treating a disease in a subject.

6. The pharmaceutical composition according to claim 5 , wherein the disease is cancer.

7. 7. The pharmaceutical composition of claim 6, wherein the disease comprises leukemia, hematological malignancies, solid tumor cancer, breast cancer, prostate cancer, liver cancer, or thyroid cancer.

8. 8. The pharmaceutical composition of claim 7, wherein the disease comprises AML, ALL, mixed lineage leukemia, or leukemia with partial tandem duplication of MLL.

9. 3. A therapeutically effective amount of the compound or salt thereof according to claim 1 or 2 for use in a method of treatment of a disorder mediated by chromosomal rearrangement of chromosome 11q23 in a subject in need of such treatment.

10. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is co-administered with an additional therapeutic agent.

11. The pharmaceutical composition of claim 9 , wherein the subject is a human.

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