Targeted heterobifunctional small molecule proteolysis targeting chimeras

Abstract

Provided herein are compounds having a structure of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 as disclosed herein and methods of using the disclosed compounds to inhibit MAP3K1 activity. For example, the compounds of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 as disclosed herein are useful for methods of treating diseases and disorders including, without limitation, cancer.

Description

TARGETED HETEROBIFUNCTIONAL SMALL MOLECULE PROTEOLYSIS TARGETING CHIMERASSTATEMENT OF U.S. GOVERNMENT SUPPORT

[0001] This invention was made with U.S. government support under Grant Nos. R21 CA251151 and P20 GM121316, awarded by the National Institutes of Health. The U.S. government has certain rights in the invention.BACKGROUND

[0002] Krasmutationis associated with ~30% of all cancers, with ~90% in pancreatic cancer (PC). PC is a deadly disease with a median 5-year survival of —10%, indicating a need for novel therapeutic options for Krasmutalionassociated cancers. Constitutive activation (ca) of I KKp enables tumor growth and metastasis in the presence of Krasmutation,(4) which is consistent with higher levels of p-IKK observed in tumors when compared to adjacent normal tissue. (3,24) Several ATP-competitive I KKp inhibitors were developed and four were advanced to clinical trials. However, none were approved by the FDA due to unfavorable safety profile, lack of efficacy or portfolio repositioning. This considerably reduced enthusiasm for the clinical development of ATP-competitive IKKp inhibitors. (25-30)

[0003] MAP3K1 is an upstream kinase that phosphorylates IKKp and inhibition of MAP3K1 results in reduced p- I KKp levels, reduced tumor growth and metastasis in Krasmutationdriven pancreatic cancer.(3,31 ,32) Analyses of MAP3K1 transcript levels in PC patients shows that higher MAP3K1 is associated with poorer 5-year survival (FIG.1 A). Since drugs target the corresponding proteins, in FIG. 1 B the transcript and the protein levels of MAP3K1 were compared. Pearson and spearman values suggest that MAP3K1 protein levels correlate with the MAP3K1 transcript levels, making MAP3K1 protein an attractive target.

[0004] Thus, a need exists for MAP3K1 inhibitors and methods of treating MAP3K1 -mediated disorders, such as cancer.SUMMARY

[0005] In various aspects, the present disclosure provides compounds, and pharmaceutically acceptable salts thereof, having the structure of X’-Y1’-ZT, wherein X’ is a MAP3K1 warhead moiety, Y’ is a linker moiety (“L”), and Z’ is an E3 ligase binding moiety (“E”). In various aspects, the MAP3K1 warhead moiety binds to MAP3K1 (for example, the MAP3K1 warhead moiety may be a quinoxaline-based small molecule fragment). In various aspects, the E3 ligase binding moiety is a small molecule, a peptide, an antibody, or a fragment thereof (for example, the E3 ligase binding moiety may be a thalidomide analog).

[0006] In various other aspects, the present disclosure provides compounds, and pharmaceutically acceptable salts thereof, having a structure of Formula 0:(0), wherein X is O, NRN, or S; Y and Z are each independently O, NRN, O, S, or CH2; each RNis independently H or C1-3 alkyl; R1and R2are each independently H or 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from O, S, and N, and the heteroaryl is optionally substituted with 1-4 R3; each R3is independently halogen, Ci^ alkyl, or Ce-w aryl, whereineach Ci-6 alkyl and Cg-io aryl is optionally substituted with 1-3 R4; each R4is independently halogen, OH,CN, C1.6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CO2H, or CO2C1.6 alkyl; ring A is C6-10 aryl, 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N, or 5- to 8-membered heterocycloalkyl having 1-4 ring heteroatoms selected from 0, S, and N, and the Ce-io aryl, 5-7 membered heteroaryl, and 5- to 8-membered heterocycloalkyl are optionally substituted; L is a linker moiety; and E is an E3-ligase binding moiety. In various aspects, the compound or salt has

[0008] In various other aspects, provided are pharmaceutical compositions comprising a compound or salt disclosed herein and a pharmaceutically acceptable carrier or excipient.

[0009] In various other aspects, provided are methods of inhibiting MAP3K1 signaling comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt disclosed herein. Also provided are methods of treating or preventing a disease or disorder capable of being modulated by MAP3K1 signaling inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt disclosed herein. In various aspects, the disease or disorder capable of being modulated by MAP3K1 signaling inhibition is cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGs. 1 A and 1 B show characteristics of MAP3K1 expression. FIG. 1 A shows a Kaplan-Meier plot ofMAP3K1 expression and survival probability of PC patients (log-rank P value = 0.011), and FIG. 1B shows a correlation plot between MAP3K1 expression and MAP3K1 protein levels.

[0011] FIG. 2 shows the domain architecture of MAP3K1 along with the binding sites of MAPK signaling molecules The K1272M and C443A are inactivating mutations of the kinase and E3 ligase domains, respectively. D878 is a caspase cleavage site. K1371 is a feedback auto-ubiquitination site.

[0012] FIGs. 3A-3F show the results of efficacy studies with IKAM-1 in animal models of pancreatic cancer.FIGs. 3A and 3B: IKAM-1 inhibits PC tumor growth. T3M4 cells (3*105 cells) were orthotopically implanted into the pancreas of athymic nude mice (n = 6). Tumors were treated with vehicle control and IKAM-1 (40 mg / Kg. p.o. for 28 days). Tumor volume and weight were measured at the time of sacrifice. FIGs. 3C and 3D: Average histoscore of p- IKKp IHC in vehicle and IKAM-1 treated tumor-bearing animals (n = 5). Data represented as average ± SEM (n = 5), p-value determined by unpaired student’s t-test. Representative tumors are shown. FIGs. 3E and 3F: KPC1245 primary cell line derived from a murine KPC tumor was implanted into the pancreas of C57BL / 6 mice. Six days post implantation the mice were randomly distributed into 3 groups viz., the control group (n = 3), the gemcitabine treatment group (n = 4) and IKAM-1 treatment group (n = 9). The mice in the gemcitabine group were treated (100 mg / kg) i.p every 4 days. The mice in the IKAM-1 group were orally dosed at 40 mg / kg in 100 L every day. The mice were monitored for 4-weeks. The final tumor weights and tumor volumes were determined at necropsy.

[0013] FIG. 4 shows the binding mode of IKAM-1 and Sorafenib in MAP3K1 generated using Schrodinger GLIDE. MAP3K1 is shown as a cartoon with the ATP binding site shown in surface rendering. Sorafenib and IKAM-1 are shown as sticks.

[0014] FIGs. 5A and 5B show validation of IKAM-1 binding mode in MAP3K1. FIG. 5A: Chemical structures of IKAM-1, 45-019 (also called 1) and 51-106 (also called 2). The anticipated effects associated with the changes are also summarized. FIG. 5B: Kinome profiling (KiNativTM) at equimolar concentrations of 51-106 (triangles), IKAM-1 (circles) and 45-019 (squares) in PANC1 cells. This kinome dataset is the result of an analysis of duplicate treated and control samples. The % changes in MS signals being reported are statistically significant (p-value < 0.04, Student’s t-test).

[0015] FIG. 6 shows the results of treating HCT116 wild type (WT) and HCT116 CRBN- / - (generated by the UNMC CRISPR core) cells with 1 pM (n = 6) of the quinoxaline based PROTACs. The cells were incubated for 72 h and the cell growth were assessed using Presto Blue assay.

[0016] FIGs. 7A-7E show the results of follow up studies in colorectal cancer cells and colon tumor organoids. FIG. 7A: Western blot with HCT116 wild type (WT) and HCT116 CRBN(- / -) (generated by the UNMC CRISPR core) cell lysates showing CRISPR mediated CRBN knock out. FIG. 7B: A 3-day growth inhibition dose response assay with HCT116 WT and HCT116 CRBN(- / -) cells subjected to 50-008 (n = 3). FIG. 7C: Chemical structures of 50-008 and the control compound 50-074 (also called 17). FIG. 7D: A 3-day growth inhibition dose response assay in HCT 116 WT cells with 50-008 and 50-074 (n=3). FIG. 7E: A 3-day dose-response study in colon tumor organoid (Q20-70T) with 50-008 and 50-074 (n=3). Cell growth and organoid growth were assessed using Presto Blue assay. Dose response curves were fitted by Sigmoidal 4 parameter logistic cure using Graph pad Prism 9.4.

[0017] FIGs. 8A-8C show cell cycle analyses and apoptosis studies with 50-008 in HCT116 cells. FIG. 8A: HCT116 wild type (WT) and HCT116 CRBN(- / -) cells were treated with 50-008 or 50-074 (also called compound 17) (1 pM). Following a 24h incubation they were subjected to cell cycle analyses by flow cytometry. FIG. 8B: A dose response study with 50-008 in HCT116 WT cells, the % change in S-phase cells were plotted against the concentration of 50-008. Dose response curve was fitted by Sigmoidal 4 parameter logistic cure using Graph pad Prism 9.4. FIG. 8C: HCT116 wild type (WT) and HCT116 CRBN(- / -) cells were treated with 50-008 (1 pM).Following a 24h incubation they were subjected to caspase 3 / 7 assay, the data was normalized to cell growth which was measured by Alamar blue.

[0018] FIGs. 9A and 9B show predictive modeling with 50-008 viability and available cell line proteomics data. FIG. 9A: Histogram of 50-008 IC50 values in the panel of 869 cancer cell lines. FIG. 9B: Predictive modeling using available cell line proteomics data.

[0019] FIGs. 10A-10C show the results of mechanism of action studies with 50-008. FIG. 10A: T47D cells were subjected to 0.1 pM (n = 6) of the quinoxaline based PROTACs. The cells were incubated for 72 h and the cell growth were assessed using Presto Blue assay. FIG. 10B: Dose-response studies with 50-008 in T47D cells, the IC50 value (0.56 nM) was derived through curve fitting using Sigmoidal 4 parameter logistic cure using Graph pad Prism 9.4. FIG. 10C: T47D (4 x 104 cells / well) were subjected to 0.1 pM of 50-008 or 0.1 pM of bortezomib and monitored for the induction of apoptosis (pSIVA-IANBD, Kinetic apoptosis kit, Abeam) every 2h by live cell imaging (Incucyte®). The plots show average fold change (n = 3) of green (apoptosis) I phase.

[0020] FIGs. 11 A and 11B show the effect of 50-008 on MAP3K1 mediated signaling. FIG. 11A: oncogenic signaling pathways regulated by MAP3K1. FIG. 11 B: T47D cells were treated with 0.1 pM of 50-008 for 12h and the resulting lysates were subjected Western blot analyses and probed with the indicated antibodies.

[0021] FIGs. 12A and 12B show histograms summarizing the IC50 values of 50-008 and FIG. 12A: Trametinib and FIG. 12B: Dabrafenib in large panels of cancer cell lines.

[0022] FIGs. 13A-13D show a comparison of the effects of 50-008, Trametinib, and Dabrafenib in the subset of BRAFV600X mutant cell lines. Correlation plots are shown for the growth inhibitory effects (IC50 values) of 50-008and (FIG. 13A) Trametinib and (FIG. 13B) Dabrafenib in BRAF mutant cell lines. The IC50 values indicated by squares are cell lines that are more sensitive to 50-008 when compared to either Trametinib or Dabrafenaib. The IC50 values indicated in circles are cell lines that are more sensitive to Trametinib or Dabrafenib. The IC50 values shown in triangles are those cell lines that are equally sensitive to 50-008 or Trametinib or Darbrafenib. FIG. 13C: Dose-response curves that reflect the efficacy of 50-008 (circles), T rametinib (squares) and Dabrafenib (diamonds) in COLO783 cells (skin cancer). FIG. 13D: Dose-response curves that reflect the efficacy of 50-008 (circles), Trametinib (squares) and Dabrafenib (diamonds) in A673 cells (bone cancer).

[0023] FIGs. 14A-14C show the results of PK studies with 50-008. FIG. 14A: Standard curve from the study, FIG. 14B: Plots of the IP and IV data from the PK study (n = 3). FIG. 14C: Summary ofthe PK parameters estimated by non-compartmental model using WinNonlin 8.3.

[0024] FIG. 15 shows lung, breast and pancreas cancer cell lines that are most sensitive to 50-008 (IC50 < 10 nM).

[0025] FIG. 16 shows linkers for exploring efficacy as a function of conformational flexibility.

[0026] FIG. 17 shows a schema for a dose-escalating toxicity study.

[0027] FIG. 18 shows a 3-day growth inhibition dose response assay in HCT116 WT, HCT116 MAP3K1-KO and HCT116 CRBN-KO cells.

[0028] FIG. 19 shows that BRCA_MUT cell lines are more sensitive to 50-008 treatment compared to BRCA_WT cell lines.

[0029] FIGs. 20A-20F show the inhibitory effects of 50-008 in breast cancer models. FIG. 20A: baseline levels of MAP3K1 and CRBN, the two proteins targeted by 50-008 or PROTAC 8 in breast cancer cells (two lines shown: MCF7 and T47D). FIG. 20B: In a 3-day growth inhibition assay, potent inhibition of cell growth (IC50 = 2 nM) was observed in T47D cells, and ~650-fold lower activity in MCF7 cells was observed, correlating well with the MAP3K1 levels shown in FIG. 20A. FIG. 20C: dose dependent decrease of MAP3K1 levels in T47D cells with a DC50 value of 314 nM. FIG. 20D: 50-008 mediated degradation of MAP3K1 is blocked in a competitive inhibition setting with the MAP3K1 inhibitor 51 -106 or CRBN binder pomalidomide (Pom). FIG. 20E: a loss of MAP3K1 degradation was observed in a combination treatment setting with MLN492, a neddylation inhibitor that blocks the formation of a stable ternary complex between MAP3K1:50-008:CRBN. FIG. 20F: 50-008 was observed to mediate proteasomal degradation of MAP3K1.

[0030] FIG. 21 shows the inhibitory effect of constrained PROTACs in a breast cancer model.DETAILED DESCRIPTION

[0031] The MAPK pathway involves a series of three kinases that sequentially phosphorylate and activate their substrates. The 24 MAP3Ks are RAF1, BRAF, ARAF and MAP3K1-MAP3K21 that phosphorylate MAP2Ks which in turn phosphorylate MAPKs to regulate an array of cellular processes including proliferation and differentiation. MAP3K1 is a 1512 amino acid protein with two zinc finger domains (SWIM-type338-366and RING-type443492), a tumor overexpressed gene (TOG542-888) domain and a kinase domain (1243-1508) at its C-terminus (FIG. 2).(33) Amongthe 24 MAP3Ks, only MAP3K1 contains both a kinase domain and an E3-ubiquitin ligase domain. The presence of these two enzymatic domains uniquely positions MAP3K1 at the interface between phosphorylation and ubiquitin mediated signaling pathways.

[0032] Several proteins in the MAPK signaling pathway and other pathways bind to MAP3K1. These binding interactions have been characterized by overexpression studies. For example, JNK1 / 2 (MAPK8 / 9), MEK1 (MAP2K1), RAF1 and ERK2 (MAPK1) bind to the N-terminus of MAP3K1.(34-36) These interactions facilitate the transfer of extracellular signals to intracellular targets. MAP3K1 also constitutively associates with non-MAPK signaling molecules such as the cullin-RING ligase (CRL) 4 to regulate DNA-damage response and tubulin to regulate cell migration.(33,37) Without wishing to be bound by any particular theory, perturbing MAP3K1 using selective small molecules (inhibitors and / or PROTACs) is believed to impact not just MAP3K1 but the associated proteins as well, thus making MAP3K1 an attractive therapeutic target.

[0033] The compounds disclosed herein (e.g., compounds of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof) bind to MAP3K1 and cause degradation of the bound MAP3K1 protein. Compounds disclosed herein (e.g., compounds of Formula (0), Formula (I), Formula (la), and as disclosed in Table 1 , and pharmaceutically acceptable salts thereof) may also cause degradation or inhibition of other proteins that associate and / or bind with MAP3K1 including but not limited to RAD51 AP1 , MEK, ERK, IKK-beta, and JNK.Compounds of the Disclosure

[0034] Quinoxaline analogs have been shown to inhibit IKK ,(1 ), and hit-to-lead optimization, and lead compound optimization in tumor models have led to the discovery of compounds useful in the treatment of diseases or disorders, such as cancer.(1-13) A small molecule inhibitor (IKAM-1) has been discovered that selectively binds to and inhibits MAP3K1 to reduce pS177 181-IKKp levels.(3) Elevated levels of p-IKKp in tumors and metastasis derived from pancreatic cancer patients has been observed. This is consistent with reports that showed expression of a constitutively active (ca) I KKps177E-S181Ein the presence of KRASmutationresulted in early onset of cancer and a dramatic reduction in the survival of mice.(4) Moreover, reduced p-IKKp levels in pancreatic tumors have been observed in mice treated with IKAM-1 compared to vehicle treated mice. Lastly, IKAM-1 analogs have been shown to be orally bioavailable and to inhibit tumor growth in orthotopic xenograft and orthotopic syngeneic pancreatic tumor models.(2,3)

[0035] To improve efficacy, the instant disclosure provides an IKAM-1 based proteolysis targeting chimera (PROTAC). With 12 PROTACs in clinical trials as of Mar 2022, the PROTAC approach is rapidly emerging as a mainstream strategy in drug discovery. In addition to the improved potency observed with PROTACs, the catalytic nature of PROTACs allows dosing at sub-stoichiometric concentrations that minimize dose-limiting toxicities, a known complication associated with classical reversible inhibitors such as IKAM-1.(14,15).

[0036] In some cases, compounds of the present disclosure are heterofunctional bispecific molecules, also called proteolysis targeting chimeras (PROTACs). The compositions of the present disclosure contains a warhead moiety, a linker moiety, and a proteolysis targeting group (e.g, an E3 ligase binding moiety).

[0037] In some cases, compounds of the present disclosure are of the general design:

[0038] The warhead moiety can target and bind to (and inhibit) MAP3K (also known as MEKK1). The MAP3K1 warhead moiety may be selected from a small molecule, a peptide, and an antibody or fragment thereof. In one embodiment the MAP3K1 warhead group is a quinoxaline based small molecule as described in US20210002258 and WO2022192341 (incorporated by reference herein). In one embodiment the general structure of the MAP3K1 warhead group is:

[0039] In other embodiments, the general structure of the MAP3K1 warhead group is:wherein R1and R2can be H, a 5-7 membered heteroaryl having 1-4 ring heteroatoms independently selected from N, 0, and S, and optionally substituted with 1-4 R6; Ar can be any substituted aromatic ring; and HetAr can be any heterocyclic ring structure.

[0040] In one embodiment the proteolysis targeting group is an E3 ligase binding molecule. The E3 ligase binding molecule can be selected from a small molecule, a peptide, or an antibody or fragment thereof. In one embodiment the E3 ligase binding molecule includes but is not limited to an iKBa-derived motif (such as a phosphopeptide motif), a HIF-1 a derived motif (such as a HIF-1 a pentapeptide or octopeptide motif), nutlin, bestatin, methyl-bestatin, thalidomide, pomalidomide, lenalidomide, thalidomide analogs, VHL binding molecules (including ones described in Galdeano et al, J. Med Chem 2014, 57 (20): 8657-8663) which is herein incorporated by reference). The E3 ligase binding molecules are capable of binding to and / or recruiting an E3 ligase including butnot limited to VHL, cereblon, MDM2, clAP1, and APC / CCDH-1In one embodiment the E3 ligase binding molecule binds to and / or recruits the E3 ligase cereblon.

[0041] In one embodiment the linker includes but is not limited to an alkyl, a substituted alkyl, alkanes, substituted alkanes, an ester, a polyether, substituted polyether, an amine, an amide, a sulfide, a thiol ester, and a thiol or combinations thereof. In one embodiment the linker contains between 1 and 30 carbons. Said carbons may be substituted with nitrogen, oxygen and other groups. In one embodiment the linkers include but are not limited to polyethylene glycol, polyethylene glycol-amide, alkanes, and alkane-amides. In one embodiment the polyethylene glycol linker contains between 2-30 carbons. In one embodiment the alkane linker contains between 1 -30 carbons.Linkers of the present disclosure include but are not limited to:

[0042] In some embodiments, contemplated are linkers based on the above with ketones, amides, cyclopropyl, epoxides and aziridine moieties at different positions to access additional conformations.

[0043] In one embodiment compounds of the disclosure have the structure:wherein the Linker group is selected from one of the linkers described above, and wherein Z can be NH, O, or S; and wherein X can be CH2 or a carbonyl group.

[0044] Provided herein are compounds, and a pharmaceutically acceptable salts thereof, having the structure of X’-YI’-Zr, wherein X’ is a MAP3K1 warhead moiety, Y' is a linker moiety (“L”), and Z’ is an E3 ligase binding moiety (“E”). In some cases, the MAP3K1 warhead moiety binds to MAP3K1. In some cases, the MAP3K1 warhead moiety comprises a small molecule, a peptide, an antibody, ora fragment thereof. In some cases, the MAP3K1 warhead moiety comprises a fragment of a small molecule. In some cases, the MAP3K1 warhead moiety is a quinoxalinebased small molecule fragment. In some cases, the E3 ligase binding moiety is a small molecule, a peptide, anantibody, or a fragment thereof. In some cases, the E3 ligase binding moiety comprises a small molecule-based fragment. In some cases, the E3 ligase binding moiety is an IxBa-derived motif (such as a phosphopeptide motif), a H IF-1 a derived motif (such as a HIF-1 a pentapeptide or octopeptide motif), nutlin, bestatin, methyl-bestatin, thalidomide, pomalidomide, lenalidomide, thalidomide analogs, or a VHL binding molecule fragment. In some cases, the E3 ligase binding moiety comprises a thalidomide-based fragment.

[0045] In some cases, provided herein are compounds and pharmaceutically acceptable salts thereof having the structure of Formula 0:whereinX is 0, NRN, orS;Y and Z are each independently 0, NRN, 0, S, or CFfe; each RNis independently H or C1.3 alkyl;R1and R2are each independently H or 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N, and the heteroaryl is optionally substituted with 1-4 R3; each R3is independently halogen, C1-6 alkyl, or Cs-io aryl, wherein each C1.6 alkyl and Ce-io aryl is optionally substituted with 1-3 R4; each R4is independently halogen, OH,CN, C1.6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CO2H, or CO2C1-6 alkyl; ring A is Ce-io aryl, 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N, or 5- to 8-membered heterocycloalkyl having 1-4 ring heteroatoms selected from 0, S, and N, and the Ce-io aryl, 5-7 membered heteroaryl, and 5- to 8-membered heterocycloalkyl are optionally substituted;L is a linker moiety; andE is an E3-ligase binding moiety.

[0046] In some cases, ring A is optionally substituted Cs-io aryl. In some cases, ring A is optionally substituted phenyl. It will be understood that when ring A is optionally substituted, the optional substituents are in addition to the L-E moiety.

[0047] In some cases, provided herein are compounds and pharmaceutically acceptable salts thereof having the structure of Formulawherein one of R5, R6, and R7is C(O)NH-L-E, C(O)B-L-E, or C(O)NH-L-B-E, wherein B is a 4- to 8-membered nitrogen-containing heterocycloalkyl, and two of R5, R6, and R7are each independently H, halogen, Ci-e alkyl, C1-6 haloalkyl, Ci^ alkoxy, C1.6 haloalkoxy, C2.6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, CB-IO aryl optionally substituted with 1-3 R8, or 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N; andR8is halogen, OH, CN, alkyl, C1.6 haloalkyl, Ci-e alkoxy, CO2H, or CO2C1.6 alkyl.

[0048] In some cases, R1is H.

[0049] In some cases, R2is 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N. In some cases, R2is 5-membered heteroaryl having 1-4 ring heteroatoms selected from O, S, and N. In some cases, R2is 5- to 7-membered heteroaryl having 1-4 ring N heteroatoms. In some cases, R2is 5-membered heteroaryl having 1-4 ring N heteroatoms. In some cases, the heteroaryl is pyrazolyl. In some cases, the heteroaryl is substituted with 1-4 R3. In some cases, the heteroaryl is substituted with 1 R3. In some cases, the heteroaryl is substituted with 1 R3. In some cases, R3is Ci-e alkyl. In some cases, R2is pyrazolyl substituted with methyl. In some cases, R2is. In some cases, R2is

[0050] In some cases, X is O.

[0051] In some cases, at least one of Y and Z is NRN. In some cases, at least one of Y and Z is CH2. In some cases, Y is NRN. In some cases, Y is CH2. In some cases, Z is NRN. In some cases, Z is CH2. In some cases, both Y and Z are NRN. In some cases, at least one RNis H. In some cases, each RNis H. In some cases, both Y and Z are NH.

[0052] In some cases, R5is H.

[0053] In some cases, R7is C(O)NH-L-E. In some cases, R7is C(O)B-L-E, orC(O)NH-L-B-E. In some cases, R7is C(O)B-L-E. In some cases, R7is C(O)NH-L-B-E.

[0054] In some cases, E has the structure:wherein Q is CH2 or C(O). In some cases, RNis H. In some cases, RNis CH3. In some cases, E has the structure:is CH2. In some cases, Q is C(O). In some cases, E has the structure:In some cases, E has the structure:In some cases, E has the structure:cases, E has the structure:some cases, E has the structure:

[0055] In some cases, provided herein are compounds and pharmaceutically acceptable salts thereof having the structure of Formula la:some cases, R6is Ci^ haloalkyl. In some cases, R6is CF3. In some cases, R6is halogen. In some cases, R6is Br.

[0056] In some cases, provided herein are compounds and pharmaceutically acceptable salts thereof having the structure of Formula lb or Ic:me cases, the compound or salt has the structure of Formula lb. In some cases, the compound or salt has the structure of Formula lb.

[0057] In some cases, B is a 4- to 6-membered nitrogen-containing heterocycloalkyl. In some cases, B is a 4- membered nitrogen-containing heterocycloalkyl. In some cases, B is a 5-membered nitrogen-containing heterocycloalkyl. In some cases, B is a 6-membered nitrogen-containing heterocycloalkyl. In some cases, B has the, ,. In some cases, B has the structure

[0058] In some cases, L is C2-10 alkylene, C2-10 alkenylene, or C2-10 polyalkoxy, each optionally interrupted by one NHC(O)CH2, C(O), orcyclopropanyl. In some cases, L is C2-10 alkylene, C2-10 alkenylene, or Cwo polyalkoxy. Insome cases, L is C2.10 alkylene or C2-10 polyalkoxy. In some cases, L is C2.10 alkylene. In some cases, C2-10 alkenylene. In some cases, L is C2-10 polyalkoxy. In some cases, L is interrupted by one NHC(O)CH2, C(O), or cyclopropanyl. In some cases, L is interrupted by one NHC(O)CH2. In some cases, L is interrupted by one C(O). In. , . In some cases, L is. In some cases, L is. In some cases, L is. In some cases, L Is. In some cases, L is. In some cases, L is. In some cases, L is. In some cases, L is. In some cases, L is. In some cases, L is.0.. In some cases, L is. In some cases, L is. In some cases, L is. In some cases, L isO. , .

[0059] Specifically contemplated compounds of the disclosed Formula I include the compounds having a structure shown in Table 1.Table 1

[0060] In some cases, the compound is compound 50-008 or a pharmaceutically acceptable salt thereof. In some cases, the compound is selected from Compound 50-008, Compound 58-136, Compound 58-140, Compound 58- 145, and Compound 58-149, or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 50-008, or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 58- 136, or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 58-140, or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 58-145, or a pharmaceutically acceptable salt thereof. In some cases, the compound is Compound 58-149, or a pharmaceutically acceptable salt thereof.

[0061] As used herein, the term “alkyl” refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms. The term Cnmeans the alkyl group has “n” carbon atoms. For example, C4 alkyl refers to an alkyl group that has 4 carbon atoms. The term Cre alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1 to 6 carbon atoms), as well as all subgroups (e.g., 1-5, 2-6, 1-4, 3-6, 1, 2, 3, 4, 5, and 6 carbon atoms). Nonlimiting examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), f-butyl (1,1 -dimethylethyl), and hexyl. Unless otherwise indicated, an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.

[0062] As used herein, the term “alkylene” refers to an alkyl group that is substituted with at least two nonhydrogen substituents (i.e., is at least disubstituted).

[0063] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more halogen atoms. Specifically contemplated is an alkenyl group with one or more fluorine atoms, e.g., trifluoromethyl. The alkenyl group can be perhalogenated.

[0064] The term “halogen” refers to heteroatoms selected from F, Cl, Br, and I.

[0065] As used herein, the term “alkenyl” is defined identically as “alkyl” except for containing at least one carboncarbon double bond, and having two to thirty carbon atoms. The term Cnmeans the alkenyl group has “n” carbon atoms. For example, C4 alkenyl refers to an alkenyl group that has 4 carbon atoms. C2-6 alkenyl refers to an alkenyl group having a number of carbon atoms encompassing the entire range (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms). Specifically contemplated alkenyl groups include ethenyl, 1 -propenyl, 2-propenyl, and butenyl. Unless otherwise indicated, an alkenyl group can be an unsubstituted alkenyl group or a substituted alkenyl group.

[0066] As used herein, the term “alkenylene” refers to an alkenyl group that is substituted with at least two nonhydrogen substituents (i.e., is at least disubstituted).

[0067] As used herein, the term “haloalkenyl” refers to an alkenyl group substituted with one or more halogen atoms. Specifically contemplated is an alkenyl group with one or more fluorine atoms. The alkenyl group can be perhalogenated.

[0068] As used herein, the term “alkynyl” is defined identically as “alkyl” except for containing at least one carboncarbon triple bond, and having two to six carbon atoms. The term Cnmeans the alkynyl group has “n” carbon atoms.For example, C4 alkynyl refers to an alkynyl group that has 4 carbon atoms. C2-6 alkynyl refers to an alkynyl group having a number of carbon atoms encompassing the entire range (e.g., 2 to 6 carbon atoms), as well as all subgroups (e.g., 2-5, 2-4, 3-6, 2, 3, 4, 5, and 6 carbon atoms). Specifically contemplated alkynyl groups include ethynyl, 1 -propynyl, 2-propynyl, and butynyl. Unless otherwise indicated, an alkynyl group can be an unsubstituted alkenyl group or a substituted alkenyl group.

[0069] As used herein, the term “haloalkynyl” refers to an alkynyl group substituted with one or more halogen atoms. Specifically contemplated is an alkynyl group with one or more fluorine atoms. The alkynyl group can be perhalogenated.

[0070] As used herein, the term "aryl" refers to a cyclic aromatic group, such as a monocyclic aromatic group, e.g., phenyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups as described herein. A Ce-w aryl group is an aryl group that has 6-10 ring carbon atoms. Aryl groups can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl, anthracenyl). Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0071] As used herein, the term “heteroaryl” refers to a cyclic aromatic ring having five to seven total ring atoms (e.g., a monocyclic aromatic ring with 5-7 total ring atoms), and containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur atoms in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four, substituents as described herein. In some cases, the heteroaryl group is substituted with one or more alkyl groups, such as methyl groups. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, pyrazolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

[0072] The term "heterocycloalkyl" as used herein refers to a non-aromatic monocyclic, fused, spiro or bridged ring system which can be saturated or contain one or more units of unsaturation, having five to eight ring atoms in which one to four (e.g., one to four, or one, two, three, or four) ring atoms is a heteroatom selected from, N, S, and O. Examples of heterocycles include, but are not limited to, quinuclidinyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino (including, for example, 3-morpholino, 4-morpholino), 2- thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, pyrrolidin-2-one, 1- tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 1- pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2- thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1 -imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzodithianyl, 3-(1-alkyl)-benzimidazol-2- onyl, and 1,3-dihydro-imidazol-2-onyl. A heterocycloalkyl is unsubstituted or substituted as described herein.

[0073] As used herein, the term “substituted," when used to modify a chemical functional group, unless noted otherwise, refers to the replacement of at least one hydrogen radical on the functional group with a substituent.Substituents can include, but are not limited to, alkyl, cycloalkyl, alkynyl, heterocycloalkyl, thioether, polythioether, aryl, heteroaryl, hydroxyl, oxy, alkoxy, heteroalkoxy, aryloxy, heteroaryloxy, ester, thioester, carboxy, cyano, nitro, amino, amido, acetamide, and halogen (e.g., fluoro, chloro, bromo, or iodo). When a chemical functional group includes more than one substituent, the substituents can be bound to the same carbon atom or to two or more different carbon atoms.

[0074] The term “alkoxy” used herein refers to an — O-alkyl group. The term “haloalkoxy” used herein refers to an — O-haloalkyl group.

[0075] As used herein, the term “polyalkoxy” refers to an alkylene group (e.g., a disubstituted C2-10 alkyl chain) interrupted by one or more non-adjacent 0 atoms. In particular embodiments, a “polyalkoxy” group as used herein has the structure (CH2CH2O)n(CH2CH2), where n is an integer from 1 to 4. In cases where the polyalkoxy group is interrupted as described herein (i.e., with one NHC(O)CH2, C(O), or cyclopropylene), the polyalkoxy group can have the structure (CH2CH2O)n(CH2)-W or (CH2CH2O)n-W-(CH2), where W is the interrupting group (i.e., NHC(O)CH2, C(O), or cyclopropylene).Pharmaceutically Acceptable Salts

[0076] The compounds disclosed herein (i.e., compounds of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1) may also exist in the form of pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable. The salts, i.e., pharmaceutically acceptable salts, may be prepared by reacting an appropriate base or acid with a stoichiometric equivalent of a compound disclosed herein (i.e., compounds of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1).

[0077] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include anions, for example sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1 ,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, O- hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, and mandelate. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0078] Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of compounds may also be prepared with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium, or ferric, and the like. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.Dosing and Pharmaceutical Formulations

[0079] The term “therapeutically effective amount,” as used herein, refers to an amount of a compound sufficient to treat, ameliorate, or prevent the identified disease or condition, or to exhibit a detectable therapeutic, prophylactic, or inhibitory effect. The effect can be detected by, for example, an improvement in clinical condition, reduction in symptoms, or by any of the assays or clinical diagnostic tests described herein or known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0080] Dosages of the therapeutic can alternately be administered as a dose measured in mg / kg. Contemplated mg / kg doses of the disclosed therapeutics include about 0.001 mg / kg to about 1000 mg / kg. Specific ranges of doses in mg / kg include about 0.1 mg / kg to about 500 mg / kg, about 0.5 mg / kg to about 200 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, and about 5 mg / kg to about 30 mg / kg.

[0081] A compound or salt of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 used in a method described herein can be administered in an amount of about 0.005 to about 750 milligrams per dose, about 0.05 to about 500 milligrams per dose, or about 0.5 to about 250 milligrams per dose. For example, a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 can be administered, per dose, in an amount of about 0.005, 0.05, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, or750 milligrams, including all doses between 0.005 and 750 milligrams.

[0082] The compounds described herein may be formulated in pharmaceutical compositions with a pharmaceutically acceptable excipient, carrier, or diluent. The compound or composition comprising the compound is administered by any route that permits treatment of the disease or condition. One route of administration is oral administration. Additionally, the compound or composition comprising the compound may be delivered to a patient using any standard route of administration, including parenterally, such as intravenously, intraperitoneally, intrapulmonary, subcutaneously or intramuscularly, intrathecally, topically, transdermally, rectally, orally, nasally or by inhalation. Slow release formulations may also be prepared from the agents described herein in order to achieve a controlled release of the active agent in contact with the body fluids in the gastro intestinal tract, and to provide asubstantial constant and effective level of the active agent in the blood plasma. The crystal form may be embedded for this purpose in a polymer matrix of a biological degradable polymer, a water-soluble polymer or a mixture of both, and optionally suitable surfactants. Embedding can mean in this context the incorporation of micro-particles in a matrix of polymers. Controlled release formulations are also obtained through encapsulation of dispersed microparticles or emulsified micro-droplets via known dispersion or emulsion coating technologies.

[0083] Administration may take the form of single dose administration, or a compound as disclosed herein can be administered over a period of time, either in divided doses or in a continuous-release formulation or administration method (e.g., a pump). However the compounds of the embodiments are administered to the subject, the amounts of compound administered and the route of administration chosen should be selected to permit efficacious treatment of the disease condition.

[0084] In an embodiment, the pharmaceutical compositions are formulated with one or more pharmaceutically acceptable excipient, such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form. The pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11 , preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, the pH is adjusted to a range from about pH 5.0 to about pH 8. More particularly, the pharmaceutical compositions may comprise a therapeutically or prophylactically effective amount of at least one compound as described herein, together with one or more pharmaceutically acceptable excipients. Optionally, the pharmaceutical compositions may comprise a combination of the compounds described herein, or may include a second active ingredient useful in the treatment or prevention of a disorder as disclosed herein (e.g., an anticancer agent or an anti-inflammatory agent).

[0085] Formulations, e.g., for parenteral or oral administration, are most typically solids, liquid solutions, emulsions or suspensions, while inhalable formulations for pulmonary administration are generally liquids or powders. A pharmaceutical composition can also be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration. Alternative pharmaceutical compositions may be formulated as syrups, creams, ointments, tablets, and the like.

[0086] The term “pharmaceutically acceptable excipient” refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity.

[0087] Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions (see, e.g., Remington's Pharmaceutical Sciences).

[0088] Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Other exemplary excipients include antioxidants (e.g., ascorbic acid), chelating agents (e.g., EDTA), carbohydrates (e.g., dextrin, hydroxyalkylcellulose, and / or hydroxyalkylmethylcellulose), stearic acid, liquids(e.g., oils, water, saline, glycerol and / or ethanol) wetting or emulsifying agents, pH buffering substances, and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

[0089] The pharmaceutical compositions described herein are formulated in any form suitable for an intended method of administration. When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.

[0090] Pharmaceutically acceptable excipients particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.

[0091] Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0092] Formulations for oral use may be also presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

[0093] In another embodiment, pharmaceutical compositions may be formulated as suspensions comprising a compound of the embodiments in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension.

[0094] In yet another embodiment, pharmaceutical compositions may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.

[0095] Excipients suitable for use in connection with suspensions Include suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia); dispersing or wetting agents (e.g., a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate)); and thickening agents (e.g., carbomer, beeswax, hard paraffin or cetyl alcohol). The suspensions may also contain one or more preservatives (e.g., acetic acid, methyl or n-propyl p-hydroxy-benzoate); one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

[0096] The pharmaceutical compositions may also be in the form of oil-in water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

[0097] Additionally, the pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. This emulsion or suspension may be formulated by a person of ordinary skill in the art using those suitable dispersing or wetting agents and suspending agents, including those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,2-propane-diol.

[0098] The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids (e.g., oleic acid) may likewise be used in the preparation of injectables.

[0099] To obtain a stable water-soluble dose form of a pharmaceutical composition, a pharmaceutically acceptable salt of a compound described herein may be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M solution of succinic acid, or more preferably, citric acid. If a soluble salt form is not available, the compound may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from about 0 to about 60% of the total volume. In one embodiment, the active compound is dissolved in DMSO and diluted with water.

[0100] The pharmaceutical composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle, such as water or isotonic saline or dextrose solution. Also contemplated are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, payability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.

[0101] In some embodiments, the compounds described herein may be formulated for oral administration in a lipid-based formulation suitable for low solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds.

[0102] As such, pharmaceutical compositions comprise a therapeutically or prophylactically effective amount of a compound described herein, together with at least one pharmaceutically acceptable excipient selected from the group consisting of medium chain fatty acids and propylene glycol esters thereof (e.g., propylene glycol esters ofedible fatty acids, such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polyoxyl 40 hydrogenated castor oil.

[0103] In some embodiments, cyclodextrins may be added as aqueous solubility enhancers. Exemplary cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of a-, 0-, and y- cyclodextrin. A specific cyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC), which may be added to any of the above-described compositions to further improve the aqueous solubility characteristics of the compounds of the embodiments. In one embodiment, the composition comprises about 0.1% to about 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% to about 15% hydroxypropyl-o-cyclodextrin, and even more preferably from about 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound described herein.Therapeutic Methods

[0104] The compounds of the present disclosure (i.e., compounds of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1, and pharmaceutically acceptable salts thereof) can be used for the treatment of disease. In one embodiment diseases include but are not limited to cancer, inflammatory diseases, and neurological disorders and diseases. In one embodiment cancer includes but is not limited to leukemia (ex. Acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia), lymphoma (ex. Hodgkin lymphoma, Non-Hodgkin lymphoma), multiple myeloma, breast cancer, prostate cancer, pancreatic cancer, colon cancer, thyroid cancer, bladder cancer, liver cancer, neuroblastoma, brain cancers (gliomas, meningiomas, pituitary adenomas etc.), lung cancer, ovarian cancer, stomach cancer, skin cancer (melanoma), cervical cancer, testicular cancer, kidney cancer, carcinoid tumors, and bone cancer. In another embodiment inflammatory diseases include but are not limited to arthritis, atherosclerosis, inflammatory bowel disease, rheumatoid arthritis, colitis, pancreatitis, hepatitis, thyroiditis, Crohn’s disease, asthma, and pelvic inflammatory disease. In another embodiment neurological disorders and diseases include but are not limited to Alzheimer’s disease, Parkinson's disease, traumatic brain injury, stroke, Amyotrophic Lateral Sclerosis, Huntington’s disease, ischemia, attention deficit disorders, and epilepsy.

[0105] In another embodiment it is envisioned that the compounds of the present disclosure (i.e., compounds ofFormula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof) can be used in combination with other drugs including but not limited to additional anti-cancer drugs, antiinflammatory drugs, or immune modulatory drugs.

[0106] Provided herein are MAP3K1 inhibitors, as exemplified by compounds of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1, and pharmaceutically acceptable salts thereof, for the treatment of a variety of diseases and conditions wherein inhibition of MAP3K1 has a beneficial effect. In one embodiment, provided is a method of inhibiting MAP3K1 signaling activity in cells comprising contacting the cell with a compound disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof) in an amount effective to decrease MAP3K1 signaling. In some cases, provided herein are methods of treating diseases and disorders capable of being modulated by MAP3K1 signalinginhibition in a subject comprising administering to the subject a therapeutically effective amount of a compound disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1, and pharmaceutically acceptable salts thereof). In some cases, the disease or disorder is cancer, an autoimmune disease, an inflammatory disease, diabetes, a cardiovascular disease, or a neurological disease.

[0107] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat," "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof) to an individual in need of such treatment.

[0108] The term "treatment" also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and / or malfunctions. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

[0109] The compounds described herein therefore can be used to treat a variety of diseases and conditions where modulation (e.g., inhibition) of the MAP3K1 signaling pathway provides a benefit. Examples of such diseases and conditions include, but are not limited to cancer, autoimmune diseases, inflammatory diseases, diabetes, cardiovascular diseases, and neurological diseases.

[0110] The disclosed methods are useful for treating cancer, for example, inhibiting cancer growth, including complete cancer remission, for inhibiting cancer metastasis, and for promoting cancer resistance. The term “cancer growth” generally refers to any one of a number of indices that suggest change within the cancer to a more developed form. Thus, indices for measuring an inhibition of cancer growth include but are not limited to a decrease in cancer cell survival, a decrease in tumor volume or morphology (for example, as determined using computed tomographic (CT), sonography, or other imaging method), a delayed tumor growth, a destruction of tumor vasculature, improved performance in delayed hypersensitivity skin test, an increase in the activity of cytolytic T- lymphocytes, and a decrease in levels of tumor-specific antigens.

[0111] The term “cancer resistance” refers to an improved capacity of a subject to resist cancer growth, in particular growth of a cancer already had. In other words, the term “cancer resistance” refers to a decreased propensity for cancer growth in a subject.

[0112] In some aspects, the cancer comprises a solid tumor, for example, a carcinoma and a sarcoma. Carcinomas include malignant neoplasms derived from epithelial cells which infiltrate, for example, invade, surrounding tissues and give rise to metastases. Adenocarcinomas are carcinomas derived from glandulartissue, or from tissues that form recognizable glandular structures. Another broad category of cancers includes sarcomas and fibrosarcomas, which are tumors whose cells are embedded in a fibrillar or homogeneous substance, such as embryonic connective tissue. In another aspect, methods of treatment are presented herein to treat cancers of myeloid or lymphoid systems, including leukemias, lymphomas, and other cancers that typically are not present as a tumor mass, but are distributed in the vascular or lymphoreticular systems. Further contemplated are methods for treatment of adult and pediatric oncology, growth of solid tumors / malignancies, myxoid and round cell carcinoma, locally advanced tumors, cancer metastases, including lymphatic metastases. The cancers listed herein are not intended to be limiting. Age (child and adult), sex (male and female), primary and secondary, pre- and post- metastatic, acute and chronic, benign and malignant, anatomical location cancer embodiments and variations are contemplated targets. Cancers are grouped by embryonic origin (e.g., carcinoma, lymphomas, and sarcomas), by organ or physiological system, and by miscellaneous grouping. Particular cancers may overlap in their classification, and their listing in one group does not exclude them from another.

[0113] Carcinomas that may be targeted include adrenocortical, acinar, acinic cell, acinous, adenocystic, adenoid cystic, adenoid squamous cell, cancer adenomatosum, adenosquamous, adnexel, cancer of adrenal cortex, adrenocortical, aldosterone-producing, aldosterone-secreting, alveolar, alveolar cell, ameloblastic, ampullary, anaplastic cancer of thyroid gland, apocrine, basal cell, basal cell, alveolar, comedo basal cell, cystic basal cell, morphea-like basal cell, multicentric basal cell, nodulo-ulcerative basal cell, pigmented basal cell, sclerosing basal cell, superficial basal cell, basaloid, basosquamous cell, bile duct, extrahepatic bile duct, intrahepatic bile duct, bronchioalveolar, bronchiolar, bronchioloalveolar, bronchoalveolar, bronchoalveolar cell, bronchogenic, cerebriform, cholangiocelluarl, chorionic, choroids plexus, clear cell, cloacogenic anal, colloid, comedo, corpus, cancer of corpus uteri, cortisol-producing, cribriform, cylindrical, cylindrical cell, duct, ductal, ductal cancer of the prostate, ductal cancer in situ (DCIS), eccrine, embryonal, cancer en cuirasse, endometrial, cancer of endometrium, endometroid, epidermoid, cancer ex mixed tumor, cancer ex pleomorphic adenoma, exophytic, fibrolamellar, cancer fibro'sum, follicular cancer of thyroid gland, gastric, gelatinform, gelatinous, giant cell, giant cell cancer of thyroid gland, cancer gigantocellulare, glandular, granulose cell, hepatocellular, Hurthle cell, hypemephroid, infantile embryonal, islet cell carcinoma, inflammatory cancer of the breast, cancer in situ, intraductal, intraepidermal, intraepithelial, juvenile embryonal, Kulchitsky-cell, large cell, leptomeningeal, lobular, infiltrating lobular, invasive lobular, lobular cancer in situ (LCIS), lymphoepithelial, cancer medullare, medullary, medullary cancer of thyroid gland, medullary thyroid, melanotic, meningeal, Merkel cell, metatypical cell, micropapillary, mucinous, cancer muciparum, cancer mucocellulare, mucoepidermoid, cancer mucosum, mucous, nasopharyngeal, neuroendocrine cancer of the skin, noninfiltrating, non-small cell, non-small cell lung cancer (NSCLC), oat cell, cancer ossificans, osteoid, Pagefs, papillary, papillary cancer of thyroid gland, periampullary, preinvasive, prickle cell, primary intrasseous, renal cell, scar, schistosomal bladder, Schneiderian, scirrhous, sebaceous, signet-ring cell, cancer simplex, small cell, small cell lung cancer (SCLC), spindle cell, cancer spongiosum, squamous, squamous cell, terminal duct, anaplastic thyroid, follicular thyroid, medullary thyroid, papillary thyroid, trabecular cancer of the skin, transitional cell, tubular, undifferentiated cancer of thyroid gland, uterine corpus, verrucous, villous, cancer villosum, yolk sac, squamous cell particularly of the head and neck, esophageal squamous cell, and oral cancers and carcinomas.

[0114] Sarcomas that may be targeted include adipose, alveolar soft part, ameloblastic, avian, botryoid, sarcoma botryoides, chicken, chloromatous, chondroblastic, clear cell sarcoma of kidney, embryonal, endometrial stromal, epithelioid, Ewing's, fascial, fibroblastic, fowl, giant cell, granulocytic, hemangioendothelial, Hodgkin's, idiopathic multiple pigmented hemorrhagic, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T cells, Jensen's, Kaposi's, kupffer cell, leukocytic, lymphatic, melanotic, mixed cell, multiple, lymphangio, idiopathic hemorrhagic, multipotential primary sarcoma of bone, osteoblastic, osteogenic, parosteal, polymorphous, pseudo-kaposi, reticulum cell, reticulum cell sarcoma of the brain, rhabdomyosarcoma, rous, soft tissue, spindle cell, synovial, telangiectatic, sarcoma (osteosarcoma) / malignant fibrous histiocytoma of bone, and soft tissue sarcomas.

[0115] Lymphomas that may be targeted include AIDS-related, non-Hodgkin's, Hodgkin's, T-cell, T-cell leukemia / lymphoma, African, B-cell, B-cell monocytoid, bovine malignant, Burkit's, centrocytic, lymphoma cutis, diffuse, diffuse, large cell, diffuse, mixed small and large cell, diffuse, small cleaved cell, follicular, follicular center cell, follicular, mixed small cleaved and large cell, follicular, predominantly large cell, follicular, predominantly small cleaved cell, giant follicle, giant follicular, granulomatous, histiocytic, large cell, immunoblastic, large cleaved cell, large nocleaved cell, Lennert's, lymphoblastic, lymphocytic, intermediate; lymphocytic, intermediately differentiated, plasmacytoid; poorly differentiated lymphocytic, small lymphocytic, well differentiated lymphocytic, lymphoma of catle; MALT, mantle cell, mantle zone, marginal zone, Mediterranean lymphoma mixed lymphocytic-histiocytic, nodular, plasmacytoid, pleomorphic, primary central nervous system, primary effusion, small b-cell, small cleaved cell, small concleaved cell, T-cell lymphomas; convoluted T-cell, cutaneous t-cell, small lymphocytic T-cell, undefined lymphoma, u-cell, undifferentiated, aids-related, central nervous system, cutaneous T-cell, effusion (body cavity based), thymic lymphoma, and cutaneous T cell lymphomas.

[0116] Leukemias and other blood cell malignancies that may be targeted include acute lymphoblastic, acute myeloid, acute lymphocytic, acute myelogenous leukemia, chronic myelogenous, hairy cell, erythroleukemia, lymphoblastic, myeloid, lymphocytic, myelogenous, leukemia, hairy cell, T-cell, monocytic, myeloblastic, granulocytic, gross, hand mirror-cell, basophilic, hemoblastic, histiocytic, leukopenic, lymphatic, Schilling's, stem cell, myelomonocytic, monocytic, prolymphocytic, promyelocytic, micromyeloblastic, megakaryoblastic, megakaryoctyic, heder cell, bovine, aleukemic, mast cell, myelocytic, plamsa cell, subleukemic, multiple myeloma, nonlymphocytic, chronic myelogenous leukemia, chronic lymphocytic leukemia, polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and high grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, myelodysplasia and chronic myelocytic leukemias.

[0117] Brain and central nervous system (CNS) cancers and tumors that may be targeted include astrocytomas (including cerebellar and cerebral), brain stem glioma, brain tumors, malignant gliomas, ependymoma, glioblastoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic gliomas, primary central nervous system lymphoma, ependymoma, brain stem glioma, visual pathway and hypothalamic glioma, extracranial germ cell tumor, medulloblastoma, myelodysplastic syndromes, oligodendroglioma, myelodysplastic / myeloproliferative diseases, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorders, neuroblastoma, plasma cell neoplasm / multiple myeloma, central nervous systemlymphoma, intrinsic brain tumors, astrocytic brain tumors, gliomas, and metastatic tumor cell invasion in the central nervous system.

[0118] Gastrointestimal cancers that may be targeted include extrahepatic bile duct cancer, colon cancer, colon and rectum cancer, colorectal cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastronintestinal carcinoid tumors, gastrointestinal stromal tumors, bladder cancers, islet cell carcinoma (endocrine pancreas), pancreatic cancer, islet cell pancreatic cancer, prostate cancer rectal cancer, salivary gland cancer, small intestine cancer, colon cancer, and polyps associated with colorectal neoplasia.

[0119] Lung and respiratory cancers that may be targeted include bronchial adenomas / carcinoids, esophagus cancer esophageal cancer, esophageal cancer, hypopharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, lung carcinoid tumor, non-small cell lung cancer, small cell lung cancer, small cell carcinoma of the lungs, mesothelioma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngeal cancer, oral cancer, oral cavity and lip cancer, oropharyngeal cancer; paranasal sinus and nasal cavity cancer, and pleuropulmonary blastoma.

[0120] Urinary tract and reproductive cancers that may be targeted include cervical cancer, endometrial cancer, ovarian epithelial cancer, extragonadal germ cell tumor, extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, spleen, kidney cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, penile cancer, renal cell cancer (including carcinomas), renal cell cancer, renal pelvis and ureter (transitional cell cancer), transitional cell cancer of the renal pelvis and ureter, gestational trophoblastic tumor, testicular cancer, ureter and renal pelvis, transitional cell cancer, urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, ovarian carcinoma, primary peritoneal epithelial neoplasms, cervical carcinoma, uterine cancer and solid tumors in the ovarian follicle), superficial bladder tumors, invasive transitional cell carcinoma of the bladder, and muscle-invasive bladder cancer.

[0121] Skin cancers and melanomas (as well as non-melanomas) that may be targeted include cutaneous t-cell lymphoma, intraocular melanoma, tumor progression of human skin keratinocytes, basal cell carcinoma, and squamous cell cancer. Liver cancers that may be targeted include extrahepatic bile duct cancer, and hepatocellular cancers. Eye cancers that may be targeted include intraocular melanoma, retinoblastoma, and intraocular melanoma Hormonal cancers that may be targeted include: parathyroid cancer, pineal and supratentorial primitive neuroectodermal tumors, pituitary tumor, thymoma and thymic carcinoma, thymoma, thymus cancer, thyroid cancer, cancer of the adrenal cortex, and ACTH-producing tumors.

[0122] Miscellaneous other cancers that may be targeted include advanced cancers, AIDS-related, anal cancer adrenal cortical, aplastic anemia, aniline, betel, buyo cheek, cerebriform, chimney-sweeps, clay pipe, colloid, contact, cystic, dendritic, cancer a deux, duct, dye workers, encephaloid, cancer en cuirasse, endometrial, endothelial, epithelial, glandular, cancer in situ, kang, kangri, latent, medullary, melanotic, mule-spinners', non-small cell lung, occult cancer , paraffin, pitch workers', scar, schistosomal bladder, scirrhous, lymph node, small cell lung, soft, soot, spindle cell, swamp, tar, and tubular cancers.

[0123] Miscellaneous other cancers that may be targeted also include carcinoid (gastrointestinal and bronchal) Castleman's disease chronic myeloproliferative disorders, clear cell sarcoma of tendon sheaths, Ewing's family of tumors, head and neck cancer, lip and oral cavity cancer, Waldenstrom's macroglobulinemia, metastatic squamous neck cancer with occult primary, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, Wilms' tumor, mycosis fungoides, pheochromocytoma, sezary syndrome, supratentorial primitive neuroectodermal tumors, unknown primary site, peritoneal effusion, malignant pleural effusion, trophoblastic neo-plasms, and hemangiopericytoma.

[0124] Specific cancers contemplated include acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, Kaposi sarcoma, lymphoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain stem glioma, brain tumor, astrocytoma, brain and spinal cord tumor, brain stem glioma, CNS atypical teratoid / rhabdoid tumor, CNS embryonal tumor, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, pineal parenchymal tumor, supratentorial primitive neuroectodermal tumor, pineoblastoma, breast cancer, bronchial tumor, Burkitt lymphoma, non-Hodgkin lymphoma, carcinoid tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular (liver) cancer, histiocytosis, langerhans cell, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, renal cell cancer, langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LOIS), lung cancer, lymphoma, macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoide, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor, pituitary tumor, plasma cell neoplasm, pleuropulomary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, uterine sarcoma, soft tissue sarcoma, skin cancer, small cell lung cancer, small intestines cancer, squamous cell carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma, thymic cancer, thyroid cancer, gestational trophoblastic cancer, vaginal cancer, vulvar cancer, Wilms tumor, and Waldenstrom macroglobulinemia. Specific cancers contemplated include pancreatic cancer, lymphoma, leukemia, colon cancer, colorectal cancer, familial adenomatous polyposis (FAP), hereditary non-polyposis cancer (HNPCC), colitis-associated cancer, gastric cancer, and breast cancer. Specific inflammatory diseases contemplated include arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuritis, asthma, inflammatorybowel disease, helicobacter pylori-associated gastritis, Crohn’s disease, ulcerative colitis, and systemic inflammatory response syndrome.

[0125] The term "autoimmune disease" is used throughout the specification to refer to a pathogenic condition in which the patient’s immune system results in disease from a self antigen (autoimmunity) or a foreign antigen (immune dysfunction / dysregulation or immune inflammatory disease). Autoimmunity is present in everyone to some extent. It is usually harmless and probably a universal phenomenon of vertebrate life. However, autoimmunity can be the cause of a broad spectrum of human illnesses, known as autoimmune diseases. This concept of autoimmunity as the cause of human illness is relatively new, and it was not accepted into the mainstream of medical thinking until the 1950s and 1960s. Autoimmune diseases are, thus, defined when the progression from benign autoimmunity to pathogenic autoimmunity occurs. This progression is determined by both genetic influences and environmental triggers. The concept of autoimmunity as the actual cause of human illness (rather than a consequence or harmless accompaniment) can be used to establish criteria that define a disease as an autoimmune disease. Autoimmune diseases or diseases which are characterized as involving immune dysfunction or disregulation (immune inflammatory disease), which may be treated by the present disclosure include systemic lupus erythematosis (SLE), diabetes mellitus (type I), asthma, ulcerative cholitis, Grave's disease, arthritis, including rheumatoid arthritis and osteoarthritis, pernicious anemia, and multiple sclerosis, among numerous others. Numerous autoimmune diseases may be treated using the method of the present disclosure including autoimmune blood diseases, including pernicious anemia, autoimmune hemolytic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, ankylosing spondilitis; autoimmune diseases of the musculature including polymyositis and dermatomyositis, autoimmune diseases of the ear including autoimmune hearing loss and Meniere's syndrome, autoimmune eye diseases, including Mooren's disease, Reiter's syndrome and Vogt-Koyanagi-Harada disease, autoimmune diseases of the kidney including glomerulonephritis and IgA nephropathy; diabetes mellitus (type I); autoimmune skin diseases including pemphigus (autoimmune bullous diseases), such as pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, vitiligo, epidermolysis bullosa acquisita, psoriasis and alopecia greata; cardiovascular autoimmune diseases, including autoimmune myocarditis, vasculitis including Churg-Strauss syndrome, giant cells arteritis, Kawasaki's disease, polyarteritis nodosa, Takayasu's arteritis and Wegener's granulomatosis; endocrine autoimmune diseases, including Addison's disease, autoimmune hypoparathyroidism, autoimmune hypophysitis, autoimmune oophoritis, autoimmune orchitis, Grave's Disease, Hashimoto's thyroiditis, polyglandular autoimmune syndrome type 1 (PAS-I) polyglandular autoimmune syndrome type 2 (PAS-2), and polyglandular autoimmune syndrome type 3 (PAS-3); autoimmune gastroenteric diseases including autoimmune hepatitis, primary biliary cirrhosis, inflammatory bowel disease, celiac disease, Crohn's disease; autoimmune nervous diseases, including multiple sclerosis, myasthenia gravis, Guillan-Barre syndrome and chronic inflammatory demyelinating neuropathy; and systemic autoimmune diseases including systemic lupus erythematosus, antiphospholid syndrome, autoimmune lymphoproliferative disease, autoimmune polyendocrinopathy, Bechet's disease, Goodpasture's disease, arthritis, including rheumatoid arthritis, osteoarthritis and septic arthritis, sarcoidosis, scleroderma and Sjogren's syndrome and psoriasis among others.

[0126] As used herein, "inflammatory diseases" refers to diseases, disorders and conditions, that are mediated by VCAM-1 and / or IL-6. Exemplary inflammatory diseases, include, but are not limited to, arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemic-reperfusion injury, postangioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina, and small artery disease.

[0127] As used herein, “cardiovascular disease” (CVD) is used to classify numerous conditions that affect the heart, heart valves, blood, and vasculature of the body, including coronary artery disease (CAD). Cardiovascular diseases include, but are not limited to, endothelial dysfunction, coronary artery disease, carotid artery disease, angina pectoris, myocardial infarction, atherosclerosis, congestive heart failure, hypertension, cerebrovascular disease, stroke, transient ischemic attacks, deep vein thrombosis, peripheral artery disease, cardiomyopathy, arrhythmias, aortic stenosis, and aneurysm. Such diseases frequently involve atherosclerosis.

[0128] Particularly contemplated are methods of treating and / or preventing diseases including but not limited to cancer, autoimmune diseases, inflammatory diseases, diabetes, cardiovascular diseases, and neurological diseases. Cancer includes but is not limited to ovarian cancer, breast cancer, prostate cancer, colon cancer, liver cancer, brain cancer, kidney cancer, lung cancer, leukemia, lymphoma, multiple myeloma, thyroid cancer, bone cancer, esophageal cancer, and pancreatic cancer. Inflammatory diseases include but are not limited to arthritis, rheumatoid arthritis, atherosclerosis, multiple sclerosis, asthma, inflammatory bowel disease, Crohn’s disease, gastritis, pancreatitis, systemic inflammatory response syndrome, and chronic inflammatory demyelinating polyradiculoneuritis.

[0129] In particular embodiments, provided herein are methods of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof). In some cases, the cancer is skin cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, brain cancer, kidney cancer, lung cancer, leukemia, lymphoma, multiple myeloma, thyroid cancer, bone cancer, esophageal cancer, or pancreatic cancer. In some cases, the cancer is colorectal cancer, breast cancer, ovarian cancer, skin cancer, bone cancer, lung cancer, or pancreatic cancer. In some cases, the cancer is colorectal cancer. In some cases, the cancer is breast cancer. In some cases, the cancer is ovarian cancer. In some cases, the cancer is skin cancer. In some cases, the cancer is bone cancer. In some cases, the cancer is lung cancer. In some cases, the cancer is pancreatic cancer.

[0130] Presented herein are methods of administering compounds disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof) as the neat compound or as a pharmaceutical composition orally, intravenously, or parenterally. In some cases, the compound or salt is administered orally. Administration of a pharmaceutical composition, or neat compound of a compound disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof), can be performed during or after the onset of the disease orcondition of interest. Typically, the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered. Further provided are kits comprising a compound disclosed herein (i.e., a compound of Formula 0, Formula I, Formula la, Formula lb, Formula Ic, or Table 1 , and pharmaceutically acceptable salts thereof) and, optionally, a second therapeutic agent useful in the treatment of diseases and conditions wherein inhibition of IKK£ provides a benefit, packaged separately or together, and an insert having instructions for using these active agents.General Synthesis of Compounds

[0131] The compounds disclosed herein can be synthesized through any means available to the synthetic chemist and in view of the guidance of general Scheme 1 below. Non-limiting examples for preparing compounds disclosed herein is provided below.Scheme 1

[0132] Example reagents and conditions for reactions of Scheme 1 are: (i) Acetic acid, cone. HNO3, rt, 24 h; (ii) PCI5, POCI3, reflux; (iii) heteroarylborane or heteroarylborate, Pd(PPh3)4, aqueous Na2CO3, DMF:Dioxane (1 :1), 100° C; (iv) Pt / C, H2, EtOH, room temperature; (v) BTC, toluene, reflux; (vi) NaOH, MeOH:THF (1:1), 50 °C, 16h. Further derivatization with an amine-bearing E3-ligase binding moiety-Linker moiety conjugate (E-L-NH2) yields compounds of Formula (I). Compounds as disclosed herein can be prepared by the method noted in the above scheme.

[0133] Further examples are provided below. They should, however, not be construed as limiting the scope. All citations throughout the disclosure are hereby expressly incorporated by reference.EXAMPLES

[0134] The examples provided herein demonstrate several features of the disclosed compounds.

[0135] Building on expertise in developing PROTACs,(6,9, 13, 16-18), a set of IKAM-1 based PROTACs was developed to identify compound 50-008, which inhibited colon tumor organoid growth (Q20-70T; IC50 = 29 nM). Compound 50-008 has been profiled against a panel of 869 cancer cell lines (PRISM). (19) This study identified 131 cell lines that were resistant to 50-008 (IC50 value > 1 OjiM), and 267 cells lines that were sensitive to 50-008 (IC50 value < 0.1 iM). Mechanistic studies and predictive modeling revealed that 50-008 activity requires cereblon (CRBN), a component of the cullin (CUL) 4 E-3 ligase. Moreover, 50-008 reduced p-l KK and p-ERK, but not p-Akt levels. In head-to-head studies of > 330 cancer cell lines, 50-008 exhibited comparable potencies to FDA approved MEK (Trametinib) and BRAF (Dabrafenib) inhibitors. Preliminary pharmacokinetic (PK) studies revealed that intraperitoneal administration (30 mg / kg) of 50-008 resulted in a 62% bioavailability, which as comparable to IKAM- 1.(3) It is thought that 50-008 perturbs MAP3K1 associated signaling to inhibit cancer cell growth.Characterization of the mechanism of action of 50-008

[0136] Of the 267 sensitive cancer cell lines, 10 of 31 derived from breast (HCC38, T47D, MDAMB175VII, and HCC1937), lung (NCIH1048, NCIH1581 , ABC1 , and DV90), and pancreas (PATU8988S and PATU8902) were selected and were highly sensitive with IC50 < 10 nM. Consistent with clinical data that shows 30% of all cancers are associated with Krasmutation, 3 / 10 cell lines above have a Krasmuta,ion. The instant examples demonstrate the sensitivity of these cell lines to + 50-008 and investigate the mechanism of action using proteome-wide profiling using mass spectrometry (MS) and RNA-seq. Western blot (WB) analyses are used to validate the findings. The above cell lines (± 50-008) are also subjected to cell cycle analyses, invasion, migration, and apoptosis.Conducting linker optimization and assess efficacy as a function of linker conformation

[0137] In 50-008, a quinoxaline analog (QA) is conjugated to thalidomide (TH) that binds to CRBN through a flexible linker. The instant examples investigate linker rigidity between QA and TH to improve membrane permeability and bioavailability, by reducing exposed polar surfaces and lowering entropic penalty, respectively.(20,21) These analogs provide structural information regarding the binding mode, mechanism of action and efficacy as a function of linker conformation. The analogs with IC50 < 29 nM in Q20-70T are subjected to PRISM screen followed by solubility, metabolic stability, permeability, and PK studies.Conducting pharmacodynamics (PD) studies with 50-008 or an improved analog in tumor models

[0138] A 3+3 dose-escalation toxicity study is conducted to determine the optimal dose of 50-008 and an improved analog for PD studies.(22,23) Changes in body weight, CBC, CMP, TNFa and IL-6 are used to assess toxicity. Since 3 / 10 highly sensitive cell lines (IC50 < 10 nM) in Aim 1 carry a PI3K3CA mutation, 50-008 and / or analogs are evaluated in both a Krasmutationand PI3K3CAmutationdriven tumor models. These studies lay the foundation for investigation new drug (IND) enabling toxicity studiesExample 1 : Preliminary MAP3K1 Inhibition StudiesMAP3K1 knockout mouse models

[0139] Other than the failure of eyelid closure, Map3k1 null mice are viable and exhibit normal phenotype. Transforming growth factor (TGF) a in the advancing eyelid tip facilitate the migration of epithelial cells to cover the cornea. Consistently, deletion of TGFa leads to mice born with open eyes, suggesting defective cell migration as the cause of eyelid closure in Map3k1 null mice. Single cell tracking studies with Map3k1-'- mouse embryo fibroblasts (MEFs) confirmed defective motility. Since the Map3k1 null mice are normal except for the eyelid closure defect, most migratory processes during embryonic development are compensated for in Map3k1 null mice.(38)

[0140] In a second mouse model (Map3k1DKD), the Map3k1 kinase domain (KD) was replaced with bacterial LacZ gene, which expressed a MAP3K1-0-galactosidase fusion protein. Like Map3k1+mice, Map3 fDKD®KDwere normal except the failure of eyelid closure, while MAP3K1+ / DKDexhibited normal development including closed eyelids at birth. Mechanistic studies with keratinocytes, the major constituent of eyelid epidermis, from Map3k1+IDKDand Map3 1DKD / DKDrevealed that Map3k1 specifically transduces signals from TGF- / activin receptors, but not from TGFa, to JNK to regulate F-actin mediated epidermal keratinocyte migration but not fibroblasts. (39) Together these studies suggest that transient inhibition of MAP3K1 kinase activity is likely to have minimal effects on normal cellular functions.

[0141] Nearly 2 / 3 of cancer deaths are associated with metastases.(40) Mammary-targeted expression of polyoma-virus middle T antigen (PyMT) in mice leads to the development of mammary tumors that rapidly metastasizes to the lungs.(41) Map3k1-’-, PyMT mice exhibited a significant delay in developing lung metastases when compared to Map3k1* , PyMT mice due to improved basement membrane integrity of the primary tumor. Since Map3k1 null mice develop normally, this suggests MAP3K1 targeted therapies could be effective in treating pathologies associated with destructive tissue remodeling.(42)Discovery of IKAM-1 as a selective MAP3K1 inhibitor- In vitro kinase assays and cell-based kinase assays (KiNativ)

[0142] Although in vitro kinase assays are routinely used to guide SAR, it is increasingly acknowledged that the correlation between the activity I selectivity exhibited by an inhibitor in the in vitro kinase assays and cell-based kinase assays are poor. For example, profiling the FDA approved kinase inhibitor, Sorafenib in an in vitro kinase assay (KinomeScan of 442 kinases) identified 65 kinases with sub-jiM potency and 6 (DDR1 , HIPK4, FLT3K663Q, MLTK, DDR2 and RETM918T) of these 65 kinases exhibited single digit nM activities. (43) Remarkably, profiling Sorafenib in a cell-based KiNativ screen (215 kinases) identified only 2 kinases, MLTK (MAP3K20) and MAP3K1, that exhibited IC50 values of 170nM and 270nM, respectively. Sorafenib was inactive (>1 OpM) against remaining 213 kinases that were quantified in the KINativ screen.(44) This lack of correlation between cell-free kinome profiling and cell-based kinome profiling is consistent with our findings with IKAM-1 (Table 1).(3) Selective inhibition of MAP3K1 by IKAM-1 was observed in the KiNativ screen but not in in vitro kinase assays. The KiNativ screen preferentiallyprofiles kinases in the their active states.(45) The structural similarity between Sorafenib and IKAM-1 suggests that both Sorafenib and IKAM-1 target activated full length MAP3K1 which is not recapitulated in the in vitro setting.00143] Chemical structures of I KAM-1 and Sorafenib are shown in the above table. The IC50 or Kd values ofIKAM-1 and Sorafenib in cell-free and cell-based kinase profiling studies. The effect of IKAM-1 on the kinase activities were measured in the in vitro kinase assays. The in vitro kinase assays with Sorafenib measured binding affinity. The IKAM-1 KiNativ screen was conducted with PANC1 lysates while the Sorafenib KiNativ screen was conducted with A375 lysates.IKAM-1 inhibits pancreatic tumor growth and metastasis:

[0144] An orthotopic xenograft model was used to test the efficacy of IKAM-1 on pancreatic tumors derived from human cell lines to mimic late-stage pancreatic tumors in patients. 14 days post orthotopic implantation of PC cells(T3M4 with Kras06™), mice were treated orally with either IKAM-1 (40 mg / kg) or vehicle. In IKAM-1 treated mice reduced tumor volume and tumor weight was observed (FIGs. 3A and 3B) when compared to vehicle treated mice. Reduced expression of p-IKKp in the IKAM-1 treated tumors was observed when compared to vehicle treated tumors (FIGs. 3C and 3D) indicating in vivo target perturbation. Reduced Ki-67 and CD31 positive tumor cells were also observed in IKAM-1 treated tumors as compared to vehicle treated tumors. Consistent with reduced CD31 staining reduced metastasis was observed compared to the peritoneum and liver, no metastasis to lung and diaphragm in IKAM-1 as compared to vehicle treated tumor bearing animals.(3)

[0145] The efficacy of IKAM-1 in an immunocompetent syngeneic orthotopic model was also assessed. C57BL / 6 mice were orthotopically challenged with KrasG12D / Trp53R172H / Pdx1Cre (KPC1245) tumor cells (5 x 104) derived from a primary culture of spontaneously generated murine KPC tumor. 6 days post challenge, treatment cohorts began receiving daily oral administration of IKAM-1 (40 mg / kg) for four weeks. IKAM-1 was formulated as previously described, (46) and 100 pL of IKAM-1 solution was dosed daily by oral gavage. In parallel, mice were treated with gemcitabine at 100 mg / kg every 4 days by Intraperitoneal administration. Animal necropsies were generally unremarkable, with the exception of periodic gastric gas accumulation, IKAM-1 treated mice showed no apparent signs of toxicity. The final tumor volumes and weights from mice from the various groups are summarized in FIGs. 3E and 3F. These results demonstrate that IKAM-1 does not exhibit any adverse effect in pancreatic tumor bearing mice with an intact immune system. Together, these results show that oral dosing of IKAM-1 reduced p-IKKD levels in tumors, reduced PC tumor growth and metastasis with no obvious toxicities.(3)

[0146] The lead IKAM-1 reduced tumor growth in PC models by ~50-65% . The lack of tumor regression in these models suggests our current lead compound does not have adequate potency.(47)PROTACs vs. Inhibitors

[0147] Conventional non-covalent small molecule inhibitors (SMIs) typically bind to the active site of the target protein to inactivate its function. The efficacy of the SMI is therefore proportional to the residence time of the SMI on the target protein .(48,49) This requires high in vivo concentrations of the SMI to ensure adequate occupancy of the target protein (occupancy driven model), which contributes off target effects.(14) Proteolytic targeting chimeras (PROTACs)(50) effectively address the above problems. PROTACs are heterobifunctional molecules where in one end of the PROTAC binds to the protein of interest (POI) while the other end binds to an E3-ligase. In cells, the productive formation of a ternary complex in which the PROTAC is sandwiched by the POI and the E3-ligase allows the E3-ligase to polyubiquitinate the POI (event driven model). The ubiquitinated POI is then recognized by the cellular ubiquitin proteosome machinery resulting in the proteolysis of the POI.(18) The chemically induced degradation of the POI results in the release of the PROTAC and E3-ligase to initiate the next iteration of binding- ubiquitination-proteolysis of the POI.(13) Thus, the catalytic nature of the PROTAC mediated degradation alleviates the need for high drug concentrations. Since the POI is degraded the need for the POI targeted ligand to bind to the active site is not required thus expanding the drug target space.(14) As of Mar 2022, 12 PROTACs that target 8 different cellular targets have advanced to clinical trials, thus providing critical proof of concept for this strategy.(47)Example 2: Validation of IKAM-1 binding mode

[0148] Other than an AlphaFold structure, there are no known crystal or NMR structures of MAP3K1.(51 -53) IKAM-1 and Sorafenib exhibited MAP3K1 binding only in the KiNativ screen, which profiles kinases in their native and activated state. Using Schrodinger GLIDE and the AlphaFold MAP3K1 structure a model was generated that describes the binding mode of Sorafenib and IKAM-1 (FIG. 4). The GLIDE scores show that Sorafenib binds to MAP3K1 with ~16-fold (-5.37 vs. -4.30) higher affinity compared to IKAM-1, which is consistent with the KiNativ data that shows Sorafenib is ~12-fold (0.27 vs. 4.2 pM) more efficacious than IKAM-1. The improved efficacy of Sorafenib when compared to IKAM-1 can be attributed to (i) the acetamide that occupies a hydrophobic pocket (L1321, 11323) deep in the ATP binding site, (ii) the hydrogen bonding distance of the urea moiety with the hinge region residue (Met1326) is shorter (2.1 vs. 3.6 A), and (iii) the orthogonal multipolar C-F ■ C=O with Gln1247.(54)

[0149] To validate the IKAM-1 binding mode, it is thought that replacing the urea -NH with -CH2 results in reduced activity due to the loss of hydrogen bonding with the hinge region residue (Met1326). It is also thought that replacing the -Br in IKAM-1 with -CF3 improves binding through the formation of orthogonal multipolar C-F- ■ -0=0 with Gin1247. To test these hypotheses, compound 1 was synthesized in which the urea -NH was replaced with -CH2, and 2 in which the -Br atom was replaced with a -CF3 (FIG. 5A) and evaluated them in a KiNativ screen.

[0150] The KiNativ screen quantified the activities of >300 kinases and dot (inhibited kinases: IKAM-1 (circles), Compound 45-019 (squares) and Compound 51-106 (triangles)) represents a quantified kinase (FIG. 5B). Replacing the urea with an amide in Compound 45-019 to disrupt the hydrogen bonding with the hinge region residue Met1326resulted in a 51% reduction in MAP3K1 inhibitory activity. On the other hand, replacing the -Br atom with a - CF3 group in Compound 51-106 to enhance binding through an orthogonal multipolar C-F - -C=O interaction resulted in a 43% increase in MAP3K1 inhibitory activity. Together these data validate the binding mode of IKAM-1.Example 3: Synthesis and screening of a focused set of quinoxaline-based PROTACs

[0151] IKAM-1 binding mode shows that the F-atom is solvent exposed. Therefore, the F-atom was replaced with a -CO2H in 2 to generate 3, which was conjugated to a set of 14 linkers with varied length and composition (Compounds 50-001, 50-002, 50-003, 50-005, 50-006, 50-007, 50-009, 50-010, 50-011, 50-012, 50-013, 50-014, and 50-025). PROTACs were generated by conjugating the above analogs to cereblon (CRBN) binding IMiDs (Scheme 2 and FIG. 6). Compound 48-069 has the structure:Scheme 2. Reagents and conditions: i) BTC, toluene, reflux, 70%; ii) NaOH, MeOH:THF (1:1), 50 °C, 16h, 80%.

[0152] The set of quinoxaline based PROTACs were screened in isogenic KRASmutHCT116 ± CRBN cells (FIG. 6). The screen identified 50-008, which inhibited the growth of HCT116 only in the presence of CRBN. The minimal SAR from this preliminary screen shows that changing the linker length from 3-carbon atoms in 50-008 to 2-carbon atoms in 5 resulted in a loss of activity, indicating the importance of linker length.

[0153] A follow up dose response study with 50-008 in HCT116 WT, MAP3K1 (- / -) and CRBN(- / -) cells (FIG. 7A) showed that MAP3K1-KO and CRBN-KO resulted in loss of activity (FIG. 7B). Methylation of the piperidinedione in the IMIDs inhibits binding to CRBN, (55) which has been used to chemically validate the mechanism of action of I MID based PROTACs.(56) To chemically validate the mechanism of action (MOA) of 50-008, analog 50-074 was prepared (also called compound 17) in which the piperidinedione nitrogen is methylated (FIG. 7C). Growth inhibition studies in HCT 116 cells (FIG. 7D) and in colon tumor organoids (Q20-70T, Dr. A. Black, the UNMC organoid core) (FIG. 7E), clearly show that CRBN binding is critical for 50-008 activity. The methylated analog 50-074 is inactive against both the HCT 116 and colon tumor organoid, Q20-70T.Example 4: 50-008 induces S-phase arrest and induces apoptosis in HCT116 cells

[0154] To elucidate the MOA of 50-008, HCT116 WT cells were subjected to 1 .M each of 50-008 and 50-074, and HCT 116 CRBN(- / -) cells were subjected to 1 jiM of 50-008. Following a 24h incubation cell cycle analyses were conducted (FIG. 8A). S-phase arrest was observed only in HCT 116 WT cells and not in either 50-074 treated HCT116 cells or 50-008 treated HCT 116 CRBN(- / -) cells (FIG. 8A). A follow up dose-response study with 50-008 in HCT116 WT cells (FIG. 8B) showed a dose-dependent S-phase arrest and curve fitting the data resulted in an IC50 value of 205 nM, which was comparable with the IC50 value derived from the growth inhibition assay (FIGs. 7B and 7D). Caspase 3 / 7 activation was also assessed (FIG. 8C), hallmark of apoptosis, which showed that 50-008 induced apoptosis only in HCT116 WT cells. Together these data reveal that the effects induced by 50-008 require CRBN.Example 5: Profiling 50-008 Against a Panel of 869 Cancer Cell Lines

[0155] A large-scale PRISM cancer cell viability profiling was conducted using DNA bar-coded cells.(19) Briefly, cells were treated with increasing concentration of 50-008 (5 nM - 10 j M) and incubated for 5-days. The cells were then lysed the mRNA isolated, and the barcode sequences were amplified by PCR and detected by a Luminex scanner. The amount of barcode correlates with the viability of the cells following treatment. This was used to generate cell line sensitivity signature for 50-008. Although 930 cancer cell lines were screened only 869 passed quality control (QC).

[0156] The histogram in FIG. 9A summarizes the growth inhibitory effects of 50-008 in the panel of 869 QC validated cancer cell lines. 131 cell line that were resistant to 50-008 (IC50 value > 10 .M) were identified, and 267 cells lines were also identified that were sensitive to 50-008 (IC50 value < 0.1 .M). The screen also identified 14 cell lines that had IC50 values of < 5 nM (highly sensitive).

[0157] Data are presented in Table 2. Compound 51-113 is a reference inhibitor compound having the structure:Table 2Example 6: Predictive Modeling with 50-008 Viability and Available Cell Line Proteomics Data

[0158] The available cancer cell line encyclopedia includes quantitative proteomics of 375 cancer cell lines. (57) CRBN protein levels were available for 801267 sensitive cell lines and 56 / 131 resistant cell lines. FIG. 9B shows that the sensitive cell lines (IC50 value < 0.1 pM) had higher CRBN levels when compared to the resistant cell lines (IC50 value > 10 .M). This is consistent with our data in HCT116 cells that shows 50-008 activity requires CRBN.

[0159] Correlation plots are generated for the > 6300 proteins that were quantified and the IC50 values of 50-008. There is a large set (> 265 cancer cell lines) of cell lines that are sensitive to 50-008, so predictive modeling leads to additional testable hypotheses that impact various cancer types.Example 7: Mechanism of Action (MOA) Studies with 50-008

[0160] One of the 14 highly sensitive cell lines is the luminal A breast cancer cell line T47D. A PROTAC screen was conducted in T47D cells to determine if there are cell type specific effects (FIG. 10A). 50-008 was the most potent inhibitor; however inhibition of growth with PROTACs 8 and 12 was also observed. Consistent with the PRISM screen 50-008 inhibited growth of T47D cells with an IC50 = 0.56 nM (highly sensitive) (FIG. 10B). Live cell imaging was used to monitor induction of apoptosis overtime (FIG. 10C).(58) In a head-to-head comparison 50-008 more potently induced apoptosis than the clinically used drug Bortezomib.

[0161] The complexity of MAP3K1 associated signaling, / .e., the number of signaling pathways influenced, has progressively increased, since its discovery nearly 3 decades ago.(3, 31-35, 37, 59-81) FIG. 11 A summarizes the major oncogenic signaling cascades regulated by MAP3K1. The pathways activated are dependent on the extracellular stimulus and on the MAP3K1 complex. For example, TNFa stimulation activates the I KKp mediated NFKB pathway, while phorbol 12-myristate 13-acetate (PMA) stimulation activates JNK mediated AP-1 pathway. Meanwhile sorbitol activates the E3-ligase domain resulting in the ubiquitination and degradation ofERK.(64,71 ,77,80-82) MAP3K1 mediated downstream signaling also relies on the composition of the MAP3K1 associated proteins. For example, in breast cancer, association of MAP3K1 with RAD51AP1 activates HER2 mediated PI3K / Akt pathway, on the other hand, association of MAP3K1 with the RAD51AP1-DYRK4 fusion protein, which is found in 9% of luminal breast cancer, rewires the signaling through the MEK-ERK pathway.(75) In BAALC (brain and acute leukemia, cytoplasmic) high AML, association of BAALC-MAP3K1 results in activation of ERK to support proliferation. (83) The ability to regulate oncogenic signaling pathways in a context dependent manner makes the unique MAP3K1 associated complexes attractive therapeutic targets.

[0162] To explore the effect of 50-008 on MAP3K1 mediated signaling, T47D cells were subjected to 50-008 and probed the pathways regulated by MAP3K1 FIG. 11 B. Reduction in p-IKKp levels was observed in 50-008 treatedsample. This is consistent with a previous study that showed MAP3K1 mediates p-licBa by activating the IKK complex, (31) and studies with IKAM-1 that showed MAP3K1 inhibition reduced p-IKK ,(3) Association of MAP3K1 with RAD51AP1 results in increased pS473-Akt, 50-008 did not affect pS473-Akt levels suggesting that the MAP3K1- RAD51AP1 complex is not perturbed. ERK associates with MAP3K1 and p-ERK is a key driver of oncogenesis.(84) 50-008 treatment results in reduced p-ERK levels and as a consequence reduced DUSP4 levels resulting in increased p-JNK and c-Jun.(79) A CRISPR paralog screen identified DUSP4 / 6 supports the growth of NRAS and BRAF mutant cells. (85) Reduction in p-ERK and DUSP4 observed with 50-008 treatment phenocopies the effects associated with BRAF and MEK inhibition, which is a therapeutic strategy for KRASmutdriven cancers. The efficacy of 50-008 was compared against the FDA approved MEK and BRAF inhibitors, Trametinib and Dabrafenib, respectively (FIGs. 12A and 12B).

[0163] Compound 50-008 and Trametinib were evaluated in 457 common cell lines while 50-008 and Dabrafenib were evaluated in 333 common cell lines (depmap database). A remarkable ~27% cancer cell lines were sensitive (IC50 value < 0.1 p.M) to 50-008 as compared to -15% that were sensitive to Trametinib (FIG. 12A) and ~3.3% were sensitive to Dabrafenib (FIG. 12B). Since Trametinib and Dabrafenib are approved for the treatment of BRAF V600E mutation driven tumors the effects of 50-008, Trametinib and Dabrafenib were compared in the subset of BRAFV600X mutant cell lines (FIGs. 13A-13D). The correlation plots show that 10 / 42 cell lines with BRAFV600E mutation were more sensitive to 50-008 when compared to Trametinib (FIG. 13A, ), while 16 / 37 cell lines with BRAFV600E mutation were more sensitive to 50-008 when compared to Dabrafenib (FIG. 13B). Interestingly, a higher percentage of non-melanoma cell lines with BRAFV600E mutation were more sensitive to 50-008 when compared to Dabrafenib or Trametinib. COLO783 is a melanoma cell line (FIG. 13C) and A673 is a cell line derived from bone cancer (FIG. 13D). In both these cell lines 50-008 was more effective when compared to either Trametinib or Dabrafenib. These head-to-head comparison studies showed that 50-008 has comparable potencies as FDA approved and currently marketed drugs Trametinib and Dabrafenib.Example 8: Pharmacokinetic (PK) Studies with Compound 50-008

[0164] To further assess the viability of 50-008 as a lead compound that is suitable for optimization, PK studies were conducted to assess among others bioavailability. Briefly, based on our experience^, 46, 86-88) and reported literature, (89-92) mice were administered with 50-008 at 30 mg / kg by both intraperitoneal (IP) and intravenous (IV) routes. Blood sampling was performed at 0.083, 0.25, 0.5, 1 , 2, 4, 8 and 24h for the IV route and at 0.25, 0.5, 1 , 2, 4, 6, 8 and 24h for the IP route. No abnormal clinical symptoms were observed during the entire experiment. An internal standard MS method was used to quantify the levels of 50-008 in the above samples.

[0165] FIGs. 14A-14C summarize the data from the preliminary PK study. The standard curve for the method of quantification yielded a high R2value indicating a good correlation between the AUC and the concentration of the 50-008. FIG. 14C summarizes the PK parameters estimated by a non-compartmental model using WinNonlin 8.3. 50-008 has a half-life of > 10h in both routes, a mean retention time (MRT) of ~24h (IP administration) and has a bioavailability of > 60%.

[0166] In summary, the development of a PROTAC (50-008) has been described starting from a selective MAP3K1 inhibitor (2, FIG. 5A). 50-008 requires CRBN for its anticancer activity. 50-008 inhibits growth of 267 / 869 cancer cell lines with IC50 < 100 nM and 11 cancer cell lines with an IC50 < 1nM. 50-008 inhibited growth of colon tumor organoids with IC50 = 29 nM, induced an S-phase cell cycle arrest and apoptosis. Without wishing to be bound by any particular theory, it is thought that 50-008 exhibited these effects by perturbing the MAP3K1-IKKP and MAP3K1-MEK-ERK-DUSP4 signaling axes. 50-008 is an ideal lead molecule as it exhibits comparable potencies to targeted FDA approved drugs Trametinib and Dabrafenib, more importantly it has excellent PK properties.Example 9: Characterization of the Mechanism of Action of 50-008

[0167] The discovery of a selective MAP3K1 inhibitor (IKAM-1) that is orally bioavailable and exhibits anticancer activity in orthotopic tumor models is innovative.(3) The development of a potent PROTAC (50-008) with broad anticancer activities (269 cancer cell lines with IC50 < 100 nM) using structure-guided modifications is innovative.

[0168] 31 / 869 cancer cell lines were sensitive to 50-008 with IC50 < 10 nM. This example focuses on 10 of the 31 cell lines that are derived from breast (HCC38, T47D, MDAMB175VII, and HCC1937), lung (NCIH1048, NCIH1581, ABC1, and DV90), and pancreas (PATU8988S and PATU8902) (FIG. 15).

[0169] Induction of S-phase arrest is observed in 50-008 treated cells and an IC50 value is derived by curve fitting S-phase cells (FIG. 8B). As observed with HCT116 cells, the cell cycle IC50 values correspond well with the IC50 value derived from the growth inhibition assay (FIG. 15). MAP3K1 has been implicated in enabling migration, therefore 50-008 treatment results in inhibition of cancer cell migration. A dose- and time-dependent induction of apoptosis is observed in the cancer cell lines. Flow cytometry was used to assess changes to the cell cycle (FIGs. 8A and 8B).Example 10: Linker Optimization and Efficacy Assessment as a Function of Conformation

[0170] The conclusion from a relatively large PROTAC dataset was that linker length, ligase binding moiety, cellular target occupancy, ternary complex formation or target expression level were at best inconsistent in predicting efficacy. (134) A variable that was not addressed in the above dataset was restricting the conformation of the linker, which impacts membrane permeability and bioavailability, by reducing exposed polar surfaces and efficacy by lowering entropic penalty. (20, 21)

[0171] Based on preliminary data that describes MAP3K1 binding and the reported data that describes thalidomide binding to CRBN, here the linker in 50-008 is defined as the 6-atom N-(3-aminopropyl)formamide. Ketones, alkenes, amides, cyclopropyl, epoxides and aziridine moieties are incorporated to restrict the rotation of the 6-atom linker. FIG. 16 summarizes a series of linkers that were designed to probe the conformational space around atoms 3 and 4 in the linker. The dihedral angle about this C3-C4 bond ranges from 0°-360°, with the most favorable free conformation as the anti, wherein the dihedral angle is 180°. Introducing an E double bond (L1, FIG. 16) between C3-C4 results in locking that dihedral angle at 180° and a Z double bond (L2, FIG. 16) locks that 0°. The bond length for the C3-C4 is reduced from -1.48 A for the sp3-sp3 single bond to ~1.34 A for the sp2-sp2 double bond. In linkers L3-L5, an extra carbon atom in the linker was introduced without altering the length. This allowsaccess to minimum energy conformations where the dihedral angle about this C3-C4 bond for L3 is -70°, L4 is -150° and L5 is ~5°, with the caveat of having an extra carbon atom.

[0172] Linkers with ketones, amides, cyclopropyl, epoxides and aziridine moieties at different positions have been designed to access additional conformations.

[0173] Scheme 3 summarizes a representative synthesis of a PROTAC with linkers L1 and L2. Briefly, fragment 4 is generated through an S Ar displacement of the F atom from a fluorothalidomide analog following methods previously reported.(9) The quinoxaline acid is coupled to the primary amine in 4 using amide coupling conditions. The double bond in the linker is generated by incubating 5 with an appropriate base to trigger dehydrohalogenation. The three components, namely the base, the solvent and the reaction temperature are optimized to access the desired analog 6. A mixture of products may be obtained, however the dramatic difference in the shape the two molecules allows chromatographic separation to generate PROTACs with linkers L1 and L2. These can be easily converted to the corresponding cyclopropyl linker (L4 and L5) containing PROTACs by a sulfur-ylide based cyclopropanation reaction following reported methods.(147)Scheme 3. Synthesis of PROTAC with linkers L1 and L2. (i) Amide coupling conditions (ii) base, solvent, rt-reflux.

[0174] Scheme 4 summarizes a representative synthesis of PROTACs with constrained linkers.Scheme 4

[0175] In Scheme 4, Ring B is a nitrogen-containing heterocyclic ring having 3 to 8 total ring members. A suitable nitrogen-containing heterocyclic compound b having a linker L as defined herein is coupled with starting compound a to yield an intermediate compound c. This intermediate compound c is deprotected, then further coupled with compound 51-115 to yield a PROTAC with a constrained linker having a structure of Formula lb.

[0176] A person of skill can adapt the synthesis shown in Scheme 4 to use an alternatively protected compound e to produce similar PROTACs having a Formula Ic, as shown in Scheme 5:Scheme 5Example 11 : Inhibitory Effects of Compounds of the Disclosure in Breast Cancer Models

[0177] Compound 50-008 was found to inhibit both T47D and MCF7 cell lines using methods known in the art and disclosed herein (see e.g., Rana S. et al. Bioorg Med Chem Lett. 2019 Jun 1 ;29(11):1375-1379). Data are presented in FIGs. 20A-20F.

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Claims

What is Claimed:

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of X’-Y1’-ZT, wherein X’ Is a MAP3K1 warhead moiety, Y' is a linker moiety (“L”), and Z' is an E3 ligase binding moiety (“E”).

2. The compound or salt of claim 1 , wherein the MAP3K1 warhead moiety binds to MAP3K1.

3. The compound or salt of claim 1 or 2, wherein the MAP3K1 warhead moiety comprises a small molecule, a peptide, an antibody, ora fragment thereof.

4. The compound or salt of claim 3, wherein the MAP3K1 warhead moiety is a quinoxaline-based small molecule fragment.

5. The compound or salt of any one of claims 1 to 4, wherein the E3 ligase binding moiety is a small molecule, a peptide, an antibody, ora fragment thereof.

6. The compound or salt of claim 5, wherein the E3 ligase binding moiety is an IxBa-derived motif (such as a phosphopeptide motif), a HIF-1 a derived motif (such as a HIF-1 a pentapeptide or octopeptide motif), nutlin, bestatin, methyl-bestatin, thalidomide, pomalidomide, lenalidomide, thalidomide analogs, or a VHL binding molecule.

7. The compound or salt of any one of claims 1 to 6, having the structure of Formula 0:RY%Ax- ER2 T X A xA7L(0), whereinX is 0, NRN, orS;Y and Z are each independently 0, NRN, 0, S, or CH2; each RNis independently H or C1.3 alkyl;R1and R2are each independently H or 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N, and the heteroaryl is optionally substituted with 1-4 R3; each R3is independently halogen, Ci-e alkyl, or Ce-io aryl, wherein each C1.6 alkyl and Ce-w aryl is optionally substituted with 1-3 R4; each R4is independently halogen, OH,CN, C1.6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CO2H, or CO2Ci-e alkyl; ring A is Ce-io aryl, 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N, or 5- to 8-membered heterocycloalkyl having 1-4 ring heteroatoms selected from 0, S, and N, and the Ce-io aryl, 5-7 membered heteroaryl, and 5- to 8-membered heterocycloalkyl are optionally substituted;L is a linker moiety; andE is an E3-ligase binding moiety.

8. The compound or salt of claim 7, wherein ring A is optionally substituted Ce-io aryl.

9. The compound or salt of claim 7 or 8, wherein ring A is optionally substituted phenyl.

10. The compound or salt of any one of claims 7 to 9, having the structure of Formula I:one of R5, R6, and R7is C(O)NH-L-E, C(O)B-L-E, or C(O)NH-L-B-E, wherein B is a 4- to 8-membered nitrogen-containing heterocycloalkyl, and two of R5, R6, and R7are each independently H, halogen, C-i-6 alkyl, C-i-e haloalkyl, C-i-6 alkoxy, C-i-6 haloalkoxy, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C6-10 aryl optionally substituted with 1-3 R8, or 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N; andR8is halogen, OH, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CO2H, or CO2C1.6 alkyl.11 . The compound or salt of any one of claims 7 to 10, wherein R1is H.

12. The compound or salt of any one of claims 7 to 11 , wherein R2is 5-7 membered heteroaryl having 1-4 ring heteroatoms selected from 0, S, and N.

13. The compound or salt of claim 12, wherein the heteroaryl is pyrazolyl.

14. The compound or salt of claim 12 or 13, wherein the heteroaryl is substituted with 1-4 R3.

16. The compound or salt of claim 14 or 15, wherein R2is pyrazolyl substituted with methyl.

17. The compound or salt of any one of claims 1 to 16, wherein X is 0.

18. The compound or salt of any one of claims 1 to 17, wherein at least one of Y and Z is NRN.

19. The compound or salt of claim 18, wherein both Y and Z are NRN.

20. The compound or salt of claim 18 or 19, wherein both Y and Z are NH.21 . The compound or salt of any one of claims 10 to 20, wherein R5is H.

22. The compound or salt of any one of claims 10 to 21 , wherein R7is C(O)NH-L-E.

23. The compound or salt of any one of claims 10 to 21 , wherein R7is C(O)B-L-E, or C(O)NH-L-B-E.

24. The compound or salt of any one of claims 1 to 23, wherein E has the structure:wherein Q is CH2or C(O).

25. The compound or salt of claim 24, wherein Q is C(O).

26. The compound or salt of claim 24, wherein E has the structure:

27. The compound or salt of any one of claims 24 to 26, wherein E has the structure:

28. The compound or salt of any one of claims 1 to 27, having the structure of Formula la:

29. The compound or salt of any one of claims 10 to 28, wherein R6is C1-6 haloalkyl.

30. The compound or salt of claim 29, wherein R6is CF3.

31. The compound or salt of any one of claims 1 to 27, having the structure of Formula lb or Ic:

32. The compound or salt of claim 31 , wherein B is B is a 4- to 6-membered nitrogen-containing heterocycloalkyl.

33. The compound or salt of any one of claims 1 to 32, wherein isalkylene,alkenylene, or C2-10 polyalkoxy, each optionally interrupted by one NHC(O)CH2, C(O), orcyclopropanyl.

35. The compound or salt of claim 34, wherein L is ' ' .

36. A compound, as recited in Table 1 , or a pharmaceutically acceptable salt thereof.

37. The compound of Table 1, which is Compound 50-008, Compound 58-136, Compound 58-140, Compound 58-145, or Compound 58-149, or a pharmaceutically acceptable salt thereof.

38. The compound of claim 36 which is Compound 50-008, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising the compound or salt of any one of claims 1 to 38 and a pharmaceutically acceptable carrier or excipient.

40. The compound or salt of any one of claims 1 to 38 or the pharmaceutical composition of claim 39 for use in inhibiting MAP3K1 signaling in a subject in need thereof.

41. The compound or salt of any one of claims 1 to 38 or the pharmaceutical composition of claim 39 for use in treating a disease or disorder capable of being modulated by MAP3K1 signaling.

42. The compound, salt, or pharmaceutical composition for use of claim 41 , wherein the disease or disorder is cancer, an autoimmune disease, an inflammatory disease, diabetes, a cardiovascular disease, or a neurological disease.

43. The compound, salt, or pharmaceutical composition for use of claim 42, wherein the disease or disorder is cancer.

44. The compound, salt, or pharmaceutical composition for use of claim 43, wherein the cancer is skin cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, brain cancer, kidney cancer, lung cancer, leukemia, lymphoma, multiple myeloma, thyroid cancer, bone cancer, esophageal cancer, or pancreatic cancer.

45. The compound, salt, or pharmaceutical composition for use of claim 43 or 44, wherein the cancer is colorectal cancer, breast cancer, ovarian cancer, skin cancer, bone cancer, lung cancer, or pancreatic cancer.

46. The compound, salt, or pharmaceutical composition for use of any one of claims 43 to 45, wherein the cancer is colorectal cancer.

47. Use of the compound or salt of any one of claims 1 to 38 or a pharmaceutical composition thereof in the manufacture of a medicament for treating a disease or disorder capable of being modulated MAP3K1 signaling.

48. The use of claim 47, wherein the disease or disorder is cancer, an autoimmune disease, an inflammatory disease, diabetes, a cardiovascular disease, or a neurological disease.

49. The use of claim 48, wherein the disease or disorder is cancer.

50. The use of claim 49, wherein the cancer is skin cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, brain cancer, kidney cancer, lung cancer, leukemia, lymphoma, multiple myeloma, thyroid cancer, bone cancer, esophageal cancer, or pancreatic cancer51. The use of claim 49 or 50, wherein the cancer is colorectal cancer, breast cancer, ovarian cancer, skin cancer, bone cancer, lung cancer, or pancreatic cancer.

52. The use of any one of claims 49 to 51 , wherein the cancer is colorectal cancer.

53. A method of inhibiting MAP3K1 signaling comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt of any one of claims 1 to 38 or the pharmaceutical composition of claim 39.

54. A method of treating or preventing a disease or disorder capable of being modulated by MAP3K1 signaling inhibition, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt of any one of claims 1 to 38 or the pharmaceutical composition of claim 39.

55. The method of claim 54, wherein the disease or disorder is cancer, an autoimmune disease, an inflammatory disease, diabetes, a cardiovascular disease, or a neurological disease.

56. The method of claim 55, wherein the disease or disorder is cancer.

57. The method of claim 56, wherein the cancer is skin cancer, ovarian cancer, breast cancer, prostate cancer, colorectal cancer, liver cancer, brain cancer, kidney cancer, lung cancer, leukemia, lymphoma, multiple myeloma, thyroid cancer, bone cancer, esophageal cancer, or pancreatic cancer.

58. The method of claim 56 or 57, wherein the cancer is colorectal cancer, breast cancer, ovarian cancer, skin cancer, bone cancer, lung cancer, or pancreatic cancer.

59. The method of any one of claims 56 to 58, wherein the cancer is colorectal cancer.

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