PCNA inhibitors

Abstract

To provide compositions of PCNA modulators, and methods for treating or preventing cancer.SOLUTION: The invention provides a compound having the following formula, and a pharmaceutical composition comprising the compound. In the formula, ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl; and ring B is a substituted or unsubstituted naphthyl, a substituted or unsubstituted quinolinyl, or a substituted or unsubstituted isoquinolinyl.SELECTED DRAWING: Figure 10A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 220,014, filed September 17, 2015, U.S. Provisional Patent Application No. 62 / 313,592, filed March 25, 2016, and U.S. Provisional Patent Application No. 62 / 340,964, filed May 24, 2016, the contents of which are incorporated herein in their entirety for all purposes.

[0002] Reference to a "Sequence Listing," table, or computer program listing annex, submitted as an ASCII file The sequence listing in file 48440-512001WO_ST25.TXT, 4,862 bytes, IBM-PC, MS-Windows operating system machine format, created on September 13, 2016, is incorporated herein by reference.

[0003] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under grants R01 CA121289, R01CA120954, and P30CA033572 awarded by the National Institutes of Health, and W81XWH-11-1-0786 awarded by the Department of Defense. The government has certain rights in this invention. [Background technology]

[0004] Neuroblastoma (NB) arises from neural crest progenitor cells in the sympathetic nervous system and accounts for approximately 15% of all childhood cancer deaths, making it one of the most common childhood lymphomas [1]. Risk stratification is the single most important factor determining treatment options and prognosis for NB patients. Survival rates are excellent for low- and intermediate-risk groups [2]. Localized perinatal adrenal tumors often regress spontaneously. Current treatment for high-risk NB consists of induction therapy, consolidation with high-dose chemotherapy and autologous stem cell transplantation (HDCT / autoSCT), and maintenance therapy with 13-cis-retinoic acid and immunotherapy to reduce recurrence from minimal residual disease [3]. Despite aggressive treatment regimens that often result in serious side effects and possibly secondary malignancies [4], approximately 50% of patients with progressive disease develop resistance to treatment or relapse. The survival outlook for high-risk NB patients is poor [5, 6]. Therefore, there is a significant medical need for new therapies to improve cancer treatment outcomes. Disclosed herein are solutions to these and other problems in the art. Summary of the Invention

[0005] Provided herein are, inter alia, ligands for proliferating cell nuclear antigen (PCNA) and methods of using same.

[0006] In one aspect, a compound is provided having the formula: [ka] During the ceremony, Ring A is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- to 6-membered heteroaryl; Ring B is a substituted or unsubstituted naphthyl, a substituted or unsubstituted quinolinyl, or a substituted or unsubstituted isoquinolinyl; R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -CN, -SOCl, -SO n1 R10 , -SO v1 NR 7 R 8 , -NHNH2, -ONR 7 R 8 , -NHC=(O)NHNH2, -NHC=(O)NR 7 R 8 , -N(O) m1 , -NR 7 R 8 , -C(O)R 9 , -C(O)-OR 9 , -C(O)NR 7 R 8 , -OR 10 , -NR 7 SO2R 10 , -NR 7 C=(O)R 9 , -NR 7 C(O)-OR 9 , -NR 7 OR 9 , -OCX 1 3. -OCHX 1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 1 The substituents may optionally be combined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R 2 are independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 2 3. -OCHX 22. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 are independently hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 3 3. -OCHX 3 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, -CX A 3. -CHX A 2. -CH2X A , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX A 3. -OCHX A 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 7 and R 8The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z1 is independently an integer of 0 to 4; m1 and v1 are independently 1 or 2; n1 is independently an integer from 0 to 4; X 1 , X 2 , X 3 , and X A are independently -Cl, -Br, -I, or -F.

[0007] In another aspect, there is provided a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In another aspect, there is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, there is provided a method of inhibiting PCNA activity in a subject in need thereof, comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0010] [Figure 1A] 1A-1E show data on the development of AOH1160, a potent PCNA modulator. Figure 1A shows the AOH1160 chemical structure. The ether oxygen in AOH1160 is indicated by the dashed box. [Figure 1B]Figures 1A-1E show data on the development of AOH1160, a potent PCNA modulator. Figure 1B is a line graph showing that human NB cell lines, SK-N-DZ (circles), SK-N-AS (squares), and SK-N-BE(2)c (triangles), were cultured in the presence of various concentrations of AOH1160. Nonmalignant 7SM0032 cells (triangles) and human PBMCs (crosses) were also cultured under the same AOH1160 treatment. Cells cultured in the absence of AOH1160 served as controls. Cell growth was measured by the CellTitor Glo assay (Promega). The mean luminescence signal of triplicates normalized to the control for each cell line is graphed + / - standard deviation. [Figure 1C] Figures 1A-1E show data from the development of AOH1160, a potent PCNA modulator. Figure 1C is a line graph showing that TRβ reporter cells were treated with various concentrations of T3, AOH39 (N-(2-((2-benzylphenyl)amino)-2-oxoethyl)-1-naphthamide), or AOH1160 for 24 h. The effect of compounds on TRβ activity was examined by measuring relative luminescence units (RLU) in a luminescence plate reader. Circles: signal from T3-treated cells; squares: overlapping signals from AOH39- or AOH1160-treated cells. [Figure 1D] Figures 1A-1E show data from the development of AOH1160, a potent PCNA modulator. Figure 1D shows a computer modeling image of the small molecule bound to PCNA. The model was initially constructed using the AAD methodology and further refined using 50 ns metadynamics simulations. The small molecule (as a stick) near the binding pocket and the PCNA surface are shown. The PCNA loop residues L126-Y133 are shown in black to gray shading. The image shows AOH1160 as various shades of gray sticks and AOH39 as a gray stick. [Figure 1E]Figures 1A-1E show data from the development of AOH1160, a potent PCNA modulator. Figure 1E shows a series of spectra from a standard NMR experiment using 1 μM PCNA. The T3 compound structure is shown at the top along with the proton label. Spectrum 1) is the T3 reference spectrum; Spectrum 2) is the saturation spectrum of 30 μM T3 complexed with PCNA in the absence of AOH1160; Spectrum 3) is the reference spectrum of 30 μM T3 and 2.9 μM AOH1160; and Spectrum 4) is the saturation spectrum of 30 μM T3 complexed with PCNA in the presence of 3.2 μM AOH1160. [Figure 2A] Figure 2A shows a series of spectra representing 7SM0032 (lower series of spectra) or SK-N-DZ (upper series of spectra) cells that were fixed, stained with PI, treated with 500 nM AOH1160 for the indicated times, and then analyzed by flow cytometry. [Figure 2B] Figure 2B shows data on the induction of cell cycle arrest, DNA damage, and apoptosis by AOH1160. Figure 2B is a series of gel images showing extracts from 7SM0032 or SK-N-DZ cells treated with 500 nM AOH1160 for the indicated times analyzed by Western analysis. Figures 2C-2D are a series of images showing TUNEL analysis. 7SM0032 or SK-N-DZ cells treated with 500 nM AOH1160 for 24 hours were fixed on slides. Cell apoptosis was analyzed by TUNEL assay. [Figure 2C] Figures 2C-2D show data on the induction of cell cycle arrest, DNA damage, and apoptosis by AOH1160. Figures 2C-2D are a series of images showing TUNEL analysis. 7SM0032 cells or SK-N-DZ cells treated with 500 nM AOH1160 for 24 hours were fixed on slides. Cell apoptosis was analyzed by TUNEL assay. Figure 2C: TMR fluorophore bound to the free end of DNA indicates cells undergoing apoptosis. DAPI-stained nuclei are observed. [Figure 2D] Figure 2C-2D shows data on the induction of cell cycle arrest, DNA damage, and apoptosis by AOH1160. Figures 2C-2D are a series of images showing TUNEL analysis. 7SM0032 or SK-N-DZ cells treated with 500 nM AOH1160 for 24 hours were fixed on slides. Cell apoptosis was analyzed by TUNEL assay. Figure 2D: The abundance of apoptotic cells relative to the total cell number in six randomly selected fields was averaged and graphed with + / - standard deviation. Light and dark bars represent the results from 7SM0032 and SK-N-DZ cells, respectively. [Figure 3A] Figure 3A shows images of individual DNA strands elongating from a DNA replication origin (DNA fiber assay). Synchronized cells were sequentially incubated in the presence of CldU and IdU before and after AOH1160 treatment, respectively. Cells sequentially incubated with the same two nucleotide analogs but treated without AOH1160 served as a control. The images in Figure 3A show representative images of labeled DNA strands from cells treated with or without AOH1160. [Figure 3B] Figure 3B is a histogram showing the inhibition of replication fork elongation by AOH1160. Synchronized cells were sequentially incubated in the presence of CldU and IdU before and after AOH1160 treatment, respectively. Cells sequentially incubated with the same two nucleotide analogs but treated without AOH1160 served as a control. Figure 3B shows the average lengths of DNA segments incorporating CldU (light gray) and IdU (dark gray), measured from over 30 independent DNA strands in cells treated with or without AOH1160, and graphed with standard deviations. [Figure 4]Figure 4 shows a line graph depicting the inhibition of HR-mediated DSB repair. DR-GFP (squares) and EJ5-GFP (circles) cell lines were transiently transfected with the pCBASce plasmid expressing l-SceI meganuclease. Three hours after transfection, cells were treated with various concentrations of AOH1160 in fresh growth medium. DMSO-treated cells served as a control. HR (homologous recombination) and EJ-mediated (end-joining) DSB double-strand break repair events were indicated by the restoration of a functional GFP gene in each cell line and quantified by measuring the relative abundance of GFP-positive cells by flow cytometry. Triplicate results for each cell line and treatment condition compared to those from the control were averaged and graphed with + / - standard deviation. [Figure 5] Figure 5 shows a line graph demonstrating the enhanced sensitivity to cisplatin by AOH1160. Human SK-N-DZ NB cells were treated with or without various concentrations of cisplatin (CPT) for 18 hours in the presence or absence of 500 nM AOH1160. Cells were washed twice with growth medium and cultured in fresh medium for 3 weeks to allow colony formation. Colony counts on dishes treated with cisplatin without AOH1160 (circles) were normalized to the colony counts on dishes without cisplatin or AOH1160 treatment. Colony counts on dishes treated with both cisplatin and AOH1160 (triangles) were normalized to the colony counts on dishes treated with 500 nM AOH1160 alone. The relative colony counts for triplicates per treatment condition were averaged and graphed with + / - standard deviation. * indicates p<0.01. [Figure 6A] Figures 6A-6B show measurements of in vivo tumor growth inhibition by AOH1160. Histogram Figure 6A shows mice bearing SK-N-BE(2)c-derived xenograft tumors that were given vehicle alone or 30 mg / kg AOH1160 for 4 weeks. Tumors were isolated from these mice at the end of the experiment. Tumor weights were measured and plotted individually. Circles represent mice treated with vehicle alone, and triangles represent mice treated with AOH1160. [Figure 6B]Figures 6A-6B show measurements of in vivo tumor growth inhibition by AOH1160. Figure 6B shows animal weight over time. Circles represent mice treated with vehicle only, and triangles represent mice treated with AOH1160. [Figure 6C] Figure 6C shows tumor volume (V = L × W × 0.5) based on tumor length (L) and width (W) at various time points after tumor implantation. Filled triangles represent tumor volumes from mice treated with 30 mg / kg AOH1160, and filled circles represent tumor volumes from mice treated with vehicle alone. * indicates p<0.01. [Figure 7] NCI-60 Panel Study. The effect of AOH1160 on the growth of the NCI-60 panel of 60 cancer cell lines representing nine major cancer types was tested in a five-dose study. Log IC50 values ​​determined for each cell line are shown. The median IC50 for the cell lines in this panel is approximately 320 nM or 3.2 x 10-7 M (this Log value corresponds to -6.5 on the graph). This study was performed at the National Cancer Institute. [Figure 8A] FIG. 8A shows the degradation profile of AOH1160 by amide cleavage in mouse plasma. [Figure 8B] Figure 8B shows the stability of AOH1160 in human and animal plasma. AOH1160 was rapidly degraded in plasma collected from wild-type Balb / c mice. Liquid chromatography-mass spectrometry (LC-MS) analysis of AOH1160 metabolites revealed that the compound was degraded by amide cleavage, as shown in the left panel. This amide cleavage was catalyzed by the carboxylesterase ES-1, which is highly expressed in rodents but not significantly expressed in the blood of higher mammalian species. AOH1160 was stable in the plasma of dogs, monkeys, and humans, as well as in the plasma of ES-1-deficient mice (Es1e / SCID). The stability of AOH1160 in Es1e / SCID mice not only demonstrated that ES-1 is involved in the rapid degradation of AOH1160, but also identified a mouse model that mimics the human enzymatic environment for pharmacological studies of AOH1160. [Figure 9]Pharmacokinetic Study of AOH1160. Pharmacokinetic studies are important to determine how much drug / compound an animal actually receives. In this study, the compound was given orally to Es1e / SCID mice at 20 mg / kg in a newly designed formulation. Plasma was collected at six time points after administration. Plasma concentrations of AOH1160 were determined by MS. [Figure 10A] Inhibition of growth xenograft tumors derived from a triple-negative breast cancer cell line (MDA-MB-436). Mice bearing xenograft tumors received either vehicle alone or 40 mg / kg AOH1160 throughout the study. Tumor volumes over the course of the study are shown (Figure 10A). Es1e / SCID mice used in this study were treated once daily with vehicle alone (diamonds) or 40 mg / kg AOH1160 (squares). AOH1160 inhibited tumor growth but did not cause significant weight loss. [Figure 10B] Inhibition of growth xenograft tumors derived from a triple-negative breast cancer cell line (MDA-MB-436). Mice bearing xenograft tumors were given either vehicle alone or 40 mg / kg AOH1160 throughout the study. Mouse weights over the course of the study are shown (Figure 10B). Es1e / SCID mice used in this study were treated once daily with vehicle alone (diamonds) or 40 mg / kg AOH1160 (squares). AOH1160 inhibited tumor growth but did not cause significant weight loss. [Figure 11] AOH1160 Stability in Liver Microsome Assay. The liver is the major organ involved in drug metabolism. The stability of AOH1160 was tested in a liver microsome assay. The major pathways involved in AOH1160 metabolism were determined by analyzing metabolites. AOH1160 was primarily metabolized by human liver microsomes via mono- and dihydroxylation in an NADPH-dependent manner. [Figure 12]Effect of AOH1160 on mouse brain tumors. The compound was administered to tumor-bearing mice once a week. The brain cancer cells used in this study contain luciferase. To measure tumor growth, luciferin was injected into each mouse. The relative growth of tumors in live mice was determined by measuring the luminescence signal with a CCD camera. The compound inhibited brain tumor growth. [Figure 13A] Identification of AOH1996, a stable analog of AOH1160. Because AOH1160 is known to be primarily metabolized via hydroxylation in the liver, several AOH1160 analogs were synthesized. [Figure 13B] Identification of AOH1996, a stable analog of AOH1160. Because AOH1160 is known to be primarily metabolized via hydroxylation in the liver, several AOH1160 analogs were synthesized, some of which mimic hydroxylated AOH1160 (Figure 13B). [Figure 13C] Identification of AOH1996, a stable analog of AOH1160. Because AOH1160 is known to be primarily metabolized via hydroxylation in the liver, several AOH1160 analogs were synthesized, some of which mimic hydroxylated AOH1160 (Figure 13C). [Figure 13D] Identification of AOH1996, a stable analog of AOH1160. Because AOH1160 is known to be primarily metabolized via hydroxylation in the liver, several AOH1160 analogs were synthesized. Other analogs have the corresponding hydroxylation site blocked by o-methylation (Figure 13D). [Figure 13E] Identification of AOH1996, a stable analog of AOH1160. Because AOH1160 is known to be primarily metabolized in the liver via hydroxylation, several AOH1160 analogs were synthesized. Other analogs have the corresponding hydroxylation site blocked by o-methylation (Figure 13E). [Figure 13F]Identification of AOH1996, a stable analog of AOH1160. Because AOH1160 is known to be primarily metabolized via hydroxylation in the liver, several AOH1160 analogs were synthesized. One o-methylated analog, AOH1996, is stable to NADPH-dependent metabolism in liver microsomal assays (Figure 13F). [Figure 14A] Like AOH1160, AOH1996 selectively kills neuroblastoma (Figure 14A) at submicromolar concentrations. This compound has minimal toxicity to non-malignant cells, including neural crest stem cells (7SM0032), human small airway epithelial cells (hSAEC), and PBMC. [Figure 14B] Like AOH1160, AOH1996 selectively kills small cell lung cancer cells (Figure 14B) at submicromolar concentrations. This compound has minimal toxicity to non-malignant cells, including neural crest stem cells (7SM0032), human small airway epithelial cells (hSAECs), and PBMCs. [Figure 15A] Like AOH1160, AOH1996 caused S / G2 cell cycle arrest in neuroblastoma cells (SH-SY5Y and SK-N-BE(2)c) but had little effect on normal cells (7SM0032). [Figure 15B] Like AOH1160, AOH1996 caused S / G2 cell cycle arrest in neuroblastoma cells (SH-SY5Y and SK-N-BE(2)c) but had little effect on normal cells (7SM0032). [Figure 15C] Like AOH1160, AOH1996 caused S / G2 cell cycle arrest in neuroblastoma cells (SH-SY5Y and SK-N-BE(2)c) but had little effect on normal cells (7SM0032). DETAILED DESCRIPTION OF THE INVENTION

[0011] Proliferating cell nuclear antigen (PCNA) plays a key role in regulating DNA synthesis and repair, making it essential for the growth and survival of cancer cells. Previously, a novel cancer-associated PCNA isoform (dubbed caPCNA) was reported to be ubiquitously expressed in a wide range of cancer cells and tumor tissues, but significantly less expressed in non-malignant cells. The caPCNA-specific antigenic site was found to be located between L126 and Y133 within the interdomain connecting loop of PCNA. By computer modeling and medicinal chemistry targeting of the binding pocket partially delineated by the L126-Y133 region of PCNA, we identified AOH1160, a potent PCNA inhibitor, which selectively kills neuroblastoma (NB) cells without significant toxicity to a wide range of non-malignant cells. Mechanistically, AOH1160 interferes with DNA replication, blocks homologous recombination-mediated DNA repair, and causes cell cycle arrest. AOH1160 induces apoptosis in NB cells and sensitizes them to cisplatin treatment. AOH1160 can be orally administered to animals and inhibits tumor growth without causing death or significant weight loss in mice. These results demonstrate the favorable pharmacological and therapeutic properties of AOH1160 and its potential as a novel therapeutic agent for treating NB.

[0012] PCNA is central to important cellular processes, including DNA replication, cell cycle control, and DNA damage repair, which are essential for cancer cell proliferation and survival.

[10] Inhibition of PCNA is seen as an effective method for suppressing tumor growth, and several attempts have been made in recent years to block various aspects of PCNA function. [13, 19, 39-42] The L126-Y133 region on PCNA is an attractive target due to the structural differences and accessibility between nmPCNA and caPCNA.

[16] As well as studies showing that cell-penetrating peptides containing the L126-Y133 octapeptide can block PCNA interaction with its interacting partners and selectively kill NB cells without causing significant toxicity to non-malignant cells.

[18]

[0013] Described herein is the successful identification of small molecule compounds, including AOH1160, that inhibit PCNA function. The compounds are chemically novel in the drug discovery space. AOH1160 possesses particularly remarkable and favorable therapeutic properties. AOH1160 is a small molecule PCNA inhibitor that is orally bioavailable and kills tumors in vivo without causing significant toxicity after systemic administration to animals. Therefore, successfully translating this compound into the clinic could usher in a new class of anticancer drugs and significantly improve NB treatment options. In addition to AOH1160's potential as an effective monotherapy, its ability to sensitize NB cells to treatment with DNA-damaging agents (e.g., platinum-containing compounds) could significantly improve the efficacy and reduce the dose-limiting side effects of conventional chemotherapy in the clinic.

[0014] A.Definition Abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0015] Where a substituent is specified by its conventional chemical formula written from left to right, this equally encompasses the chemically identical substituent that would result from writing the structure from right to left, e.g., -CHO- is equivalent to -OCH-.

[0016] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched acyclic carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which can include divalent and polyvalent groups, having the specified number of carbon atoms (i.e., C-C 10means 1 to 10 carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those containing one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated.

[0017] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited to, by -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0018] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched acyclic chain or combination thereof containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) (e.g., O, N, P, S, or Si) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heteroalkyl moiety may contain three heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heteroalkyl moiety may contain four heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heteroalkyl moiety may contain five heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heteroalkyl moiety may contain up to eight heteroatoms (e.g., O, N, S, Si, or P), which are optionally different.

[0019] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, as used herein, heteroalkyl groups include groups that are attached to the remainder of the molecule via a heteroatom, e.g., —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and / or —SOR′. When “heteroalkyl” is recited followed by a specific heteroalkyl group, e.g., —NR′R″, etc., it is understood that the terms heteroalkyl and —NR′R″ are not overlapping or mutually exclusive. Rather, the specific heteroalkyl group is recited to add clarity. Thus, the term “heteroalkyl” should not be construed herein as excluding specific heteroalkyl groups, e.g., —NR′R″, etc.

[0020] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, non-aromatic cyclic versions of "alkyl" and "heteroalkyl," respectively, in which the carbons comprising the ring or rings are not necessarily bonded to hydrogen, since all carbon valencies participate in bonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, 3-hydroxy-cyclobut-3-enyl-1,2,dione, 1H-1,2,4-triazolyl-5(4H)-one, 4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, mean divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively. A heterocycloalkyl moiety may contain one ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety may contain two ring heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heterocycloalkyl moiety may contain three ring heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heterocycloalkyl moiety may contain four ring heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heterocycloalkyl moiety may contain five ring heteroatoms (e.g., O, N, S, Si, or P), which are optionally different. A heterocycloalkyl moiety may contain up to eight ring heteroatoms (e.g., O, N, S, Si, or P), which are optionally different.

[0021] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0022] The term "acyl," unless otherwise specified, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0023] The term "aryl," unless otherwise specified, refers to a polyunsaturated aromatic hydrocarbon substituent, which may be fused together (i.e., fused-ring aryl) or covalently linked monocyclic or polycyclic rings (preferably 1 to 3 rings). Fused-ring aryl refers to multiple rings fused together, in which at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, e.g., N, O, or S, in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, in which at least one of the fused rings is an aromatic heterocyclic ring). 5,6-fused-ring heteroarylene refers to two rings fused together, in which one ring has five members and the other has six members, and at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, and at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be bonded to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2 thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of aryl and heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthalyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, Examples of heteroaryl include pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, and quinolyl. The above examples may be substituted or unsubstituted, and the divalent group of each of the above heteroaryl examples is a non-limiting example of heteroarylene. The heteroaryl moiety may contain one ring heteroatom (e.g., O, N, or S). The heteroaryl moiety may contain two ring heteroatoms (e.g., O, N, or S), which are optionally different. The heteroaryl moiety may contain three ring heteroatoms (e.g., O, N, or S), which are optionally different. The heteroaryl moiety may contain four ring heteroatoms (e.g., O, N, or S), which are optionally different. The heteroaryl moiety may contain five ring heteroatoms (e.g., O, N, or S), which are optionally different. The aryl moiety may have a single ring. The aryl moiety may have two rings, which are optionally different. The aryl moiety may have three rings, which are optionally different. The aryl moiety may have four rings, which are optionally different. The heteroaryl moiety may have one ring.The heteroaryl moiety may have two rings, which are optionally different. The heteroaryl moiety may have three rings, which are optionally different. The heteroaryl moiety may have four rings, which are optionally different. The heteroaryl moiety may have five rings, which are optionally different.

[0024] A fused-ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused-ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Each fused-ring heterocycloalkyl-aryl, fused-ring heterocycloalkyl-heteroaryl, fused-ring heterocycloalkyl-cycloalkyl, or fused-ring heterocycloalkyl-heterocycloalkyl is independently unsubstituted or substituted with one or more of the substituents described herein.

[0025] As used herein, the term "oxo" means an oxygen that is double bonded to a carbon atom.

[0026] As used herein, the term "alkylsulfonyl" means a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0027] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0028] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) include, but are not limited to, -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R, in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. , -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C=(O)NR''NR'''R'''', -CN, -NO2. R, R', R'', R''', and R'''' each preferably independently represent hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy group, or arylalkyl group. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected, as is each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0029] Similar to the substituents described for the alkyl radical, substituents on the aryl and heteroaryl groups are varied and include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′′′, —NR″C(O)2R′, —NR-C(NR′R″R′′)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)2R′, —S and R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected, as are each R', R'', R''', and R'''' groups when more than one of these groups is present.

[0030] Two or more substituents can optionally be joined to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic substructure. In one embodiment, the ring-forming substituents are attached to adjacent members of the substructure. For example, two ring-forming substituents attached to adjacent members of a cyclic substructure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the substructure. For example, two ring-forming substituents attached to a single member of a cyclic substructure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the substructure.

[0031] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be bonded to a ring of the formula -A-(CH2) r A and B can be optionally replaced with a substituent of the formula -B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring thus formed can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') dwherein s and d are independently an integer of 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R" and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0032] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0033] As used herein, substituent means a group selected from the following moieties: (A) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (i) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: (a) oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one substituent selected from the following: oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -S03H, -S04H, -SON2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHS02H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0034] As used herein, a "size-limited substituent" or "size-limited substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0035] As used herein, a "lower substituent" or "lower substituent group" means a group selected from all of the substituents described above for "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0036] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower-rank substituent.

[0037] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C-C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl; each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene; each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 The arylene and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0038] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C8 10 In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C8 10 and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a species described in the Examples section below, in a Figure, or in a Table.

[0039] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound of the present invention contains a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functionality, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galactunoric acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are suitable for the present invention. Salts tend to be more soluble in aqueous solutions or other protic solvents than the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, at a pH range of 4.5 to 5.5, which is combined with a buffer solution prior to use.

[0040] Therefore, the compounds of the present invention can exist as salts with, for example, pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

[0041] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0042] Provided herein are pharmaceutical agents (e.g., compounds, drugs, therapeutic agents) that may be in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under selected physiological conditions to provide the final pharmaceutical agent (e.g., compound, drug, therapeutic agent). Furthermore, prodrugs can be converted to pharmaceutical agents (e.g., compounds, drugs, therapeutic agents) by chemical or biochemical methods in an ex vivo environment. Prodrugs described herein include compounds that readily undergo chemical changes under selected physiological conditions to provide pharmaceutical agents (e.g., compounds, drugs, therapeutic agents) in a biological system (e.g., in a subject, in cancer cells, in the extracellular space near cancer cells).

[0043] Certain compounds of the present invention can exist in unsolvated and solvated forms (including hydrated forms). In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0044] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present invention. Examples of acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.).

[0045] Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds and can be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids, as (D)- or (L)-. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers, and individual isomers are encompassed within the scope of the present invention. Compounds of the present invention do not include those known in the art to be too unstable to synthesize and / or isolate. The present invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0046] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and hence the same molecular weight, but that differ with respect to the structural arrangement or configuration of the atoms.

[0047] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0048] It will be apparent to one skilled in the art that certain compounds of this invention can exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

[0049] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0050] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon by a C-enriched carbon are within the scope of this invention.

[0051] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 The compounds may be radiolabeled with radioactive isotopes such as C. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0052] The symbol " " indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0053] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, "substituted with a[n]" means that the specified group can be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl or heteroaryl group is "unsubstituted C-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is also substituted with one or more unsubstituted C-C 20The moiety may include alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl. Furthermore, when a moiety is substituted with R substituents, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

[0054] The description of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of several substituents, such substitutions are selected to comply with the principles of chemical bonding and to bring about a compound that is known to those skilled in the art as not inherently unstable and / or likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0055] The term "treating" or "treatment" refers to any objective or subjective parameter, such as alleviation, remission, or reduction of symptoms, or any indication of success in treating or ameliorating an injury, disease, condition, or condition, including making the injury, condition, or condition more tolerable to the patient, slowing the rate of degeneration or decline; making the end point of degeneration less debilitating, or improving the patient's physical or mental health. The treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, certain methods herein treat diseases associated with PCNA activity. Certain methods described herein can treat diseases associated with PCNA activity (e.g., cancer or neuroblastoma) by inhibiting PCNA activity. For example, certain methods herein treat cancer. For example, certain methods herein treat cancer by reducing the symptoms of cancer. Symptoms of cancer will be known to or can be determined by those skilled in the art. The term "treating" and its conjugations include prevention of an injury, condition, state, or disease.

[0056] An "effective amount" is an amount sufficient to achieve a stated purpose (e.g., achieve the purpose for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce protein function, or reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, which can also be referred to as a "therapeutically effective amount." A "reduction" of one or more symptoms (and grammatical equivalents of this expression) means a decrease in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug or prodrug is an amount of a drug or prodrug that, when administered to a subject, has the intended preventive effect, for example, preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete preventive effect does not necessarily occur by administering a single dose, but may occur only after administering a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. The precise amount will depend on the purpose of the treatment, and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0057] The term "associated with" or "associated with," in the context of a substance or the activity or function of a substance associated with a disease (e.g., cancer), means that the disease is caused (in whole or in part) by the substance or the activity or function of the substance, or that the symptoms of the disease are caused (in whole or in part) by the substance or the activity or function of the substance. As used herein, what is described as associated with a disease may be a target for treating the disease if it is a causative factor. For example, a disease associated with PCNA activity can be treated with an agent (e.g., a compound described herein) that is effective in reducing the level of PCNA activity.

[0058] "Control" or "control experiment" or "standard control" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subjects or reagents are treated identically to a parallel experiment, except for the omission of the experimental procedure, reagent, or variable. In some cases, a control is used as a standard of comparison when evaluating the effectiveness of an experiment. In embodiments, a control is the same experiment or treatment regimen in the absence of a compound (e.g., as described herein) used in the non-controlled experiment or treatment regimen to which the control is compared.

[0059] "Contacting" is used according to its plain and ordinary meaning to refer to the process of allowing at least two different species (e.g., chemical compounds, including biomolecules or cells) to come into sufficient proximity to react, interact, or come into physical contact. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate from one or more of the added reagents that may be produced in the reaction mixture. The term "contacting" can include allowing two species to react, interact, or come into physical contact (where the two species can be a compound described herein and a protein or enzyme). In some embodiments, contacting includes allowing a compound described herein to interact with a protein (e.g., PCNA) or enzyme. In embodiments, contacting includes allowing a compound described herein to interact with SEQ ID NO:2. In embodiments, contacting includes allowing a compound described herein to interact with SEQ ID NO:3. In embodiments, contacting includes allowing a compound described herein to interact with SEQ ID NO:4.

[0060] As defined herein, "inhibition," "inhibit," "inhibiting," and the like, in reference to protein-inhibitor (e.g., antagonist) interaction, mean to negatively affect (e.g., reduce) the level of protein activity or function compared to the level of protein activity or function in the absence of the inhibitor. In some embodiments, inhibition refers to the reduction of a disease or disease symptom. Thus, inhibition can include at least partially, partially, or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity or protein amount.

[0061] As defined herein, the terms "activation," "activate," "activating," and the like, in reference to protein-activator (e.g., agonist) interaction, mean to positively affect (e.g., increase) the activity or function of a protein compared to the activity or function of the protein in the absence of the activator (e.g., a compound described herein). Thus, activation can include at least partially, partially, or fully increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signaling or enzymatic activity or protein levels that are reduced in disease. Activation can include at least partially, partially, or fully increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signaling or enzymatic activity or protein levels.

[0062] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule. In embodiments, the modulator is an anti-cancer agent. In embodiments, the modulator is a PCNA antagonist. In embodiments, the modulator is a PCNA inhibitor.

[0063] "Anticancer agent" or "anticancer drug" is used according to its plain and ordinary meaning and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has anti-neoplastic properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anticancer agent is a chemotherapeutic agent. In some embodiments, the anticancer agent is a drug approved by the FDA or similar regulatory agency in a country other than the USA for treating cancer. Examples of anticancer agents include, but are not limited to, antiandrogens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD833 0, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meifalan), ethyleneimine methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), pyrimidines analogs (e.g., fluorouracil, floxouridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate,teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaloplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase) , inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., Rituxan), 5-aza-2'-deoxycytidine, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.®), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), bortezomib, trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogens,Antiestrogens; Antisense oligonucleotides; Apoptosis gene modulators; Apoptosis regulators; Arginine deaminase; BCR / ABL antagonists; Beta-lactam derivatives; bFGF inhibitors; Bicalutamide; Camptothecin derivatives; Casein kinase inhibitors (ICOS); Clomiphene analogs; Cytarabinecliximab; Dexamethasone; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Finasteride; Fludarabine; Fluorodafone Unolnisine hydrochloride; gadolinium texaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfame; immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; letrozole; leukemia inhibitory factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors; MIF inhibitors; mifepristone; mismatched double-stranded R NA; Monoclonal antibodies; Mycobacterial cell wall extracts; Nitric oxide modulators; Oxaliplatin; Panomiphen; Pentrazole; Phosphatase inhibitors; Plasminogen activator inhibitors; Platinum complexes; Platinum compounds; Prednisone; Proteasome inhibitors; Protein A-based immunomodulators; Protein kinase C inhibitors; Protein tyrosine phosphatase inhibitors; Purine nucleoside phosphorylase inhibitors; Ras farnesyl protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Ribozymes; Synthetic signal transduction inhibitors; signal transduction modulators; single-chain antigen binding proteins; stem cell inhibitors; stem cell division inhibitors; stromelysin inhibitors; synthetic glycosaminoglycans; tamoxifen methiodide; telomerase inhibitors; thyroid-stimulating hormone; translation inhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists; steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH), e.g., goserelin or leuprolide, corticosteroids (e.g., prednisone),Progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 111 In, 90 Y, or 131anti-CD20 monoclonal antibodies conjugated to IFN-γ, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or therapeutic agents (e.g., gefitinib (Iressa™), erlotinib, ... Lotinib (Tarceva™), Cetuximab (Erbitux™), Lapatinib (Tykerb™), Panitumumab (Vectibix™), Vandetanib (Caprelsa™), Afatinib / BIBW2992, CI-1033 / Canertinib, Neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, Dacomitinib / PF299804, OSI-420 / Desmethylerlotinib, AZD8931, AEE788, Pembrolizumab / Pembrolizumab ... Litinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, pyrrolobenzodiazepines (e.g., tomaymycin), carboplatin, CC-1065 and CC-1065 analogs including amino-CBI, nitrogen mustards (e.g., chlorambucil and melphalan), dolastatins and dolastatin analogs (including auristatins: e.g., monomethyl auristatin E), antagonizing agents (e.g., antagonizing agents), anti-cancer drugs (e.g., anti-cancer drugs ... These include lacycline antibiotics (e.g., doxorubicin, daunorubicin, etc.), duocarmycins and duocarmycin analogs, enediynes (e.g., neocarzinostatin and calicheamicin), leptomycin derivatives, maytansinoids and maytansinoid analogs (e.g., mertansine), methotrexate, mitomycin C, taxoids, vinca alkaloids (e.g., vinblastine and vincristine), epothilones (e.g., epothilone B), camptothecin and its clinical analogs topotecan and irinotecan.

[0064] "Chemotherapeutic agent" or "chemotherapeutic agent" is used according to its plain and ordinary meaning to refer to a chemical composition or compound having antineoplastic properties or the ability to inhibit cell growth or proliferation.

[0065] "Patient" or "subject in need thereof" or "subject" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a compound or pharmaceutical composition or by a method provided herein. Non-limiting examples include humans, other mammals, bovine animals, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the subject is a human. In some embodiments, the subject is a human child (e.g., under 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year old).

[0066] "Disease" or "condition" refers to a state of life or health of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the disease is a disease symptomated by cellular hyperproliferation. In some embodiments, the disease is a disease symptomated by abnormal levels of PCNA activity. In some embodiments, the disease is cancer. In some further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testes, glioma, esophageal, and liver cancer (including hepatocarcinoma), lymphomas such as B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma. In an embodiment, the disease is brain cancer. In embodiments, the disease is neuroblastoma. In embodiments, the disease is glioblastoma. In embodiments, the disease is central nervous system (CNS) cancer. In embodiments, the disease is sympathetic nervous system (SNS) cancer. In embodiments, the disease is adrenal cancer. In embodiments, the disease is cancer of nerve cells in the neck, chest, abdomen, or pelvis. In embodiments, the disease is nasal neuroblastoma. In embodiments, the disease is stage 1 neuroblastoma (e.g., a localized tumor confined to an area near its origin). In embodiments, the disease is stage 2A neuroblastoma (e.g., a unilateral tumor with an incomplete total resection and / or identifiable ipsilateral and contralateral lymph nodes negative for tumor). In embodiments, the disease is stage 2B neuroblastoma (e.g., a unilateral tumor with a complete or incomplete total resection; ipsilateral lymph nodes positive for tumor; identifiable contralateral lymph nodes negative for tumor). In embodiments, the disease is stage 3 neuroblastoma (e.g., a tumor that has spread across the midline with or without regional lymph node metastasis; or a unilateral tumor with contralateral lymph node metastasis; or a midline tumor with bilateral lymph node metastasis).In embodiments, the disease is stage 4 neuroblastoma (e.g., metastasis of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs, except as defined by stage 4S). In embodiments, the disease is stage 4S neuroblastoma (e.g., age less than 1 year with localized primary tumor as described in stage 1 or stage 2, with metastasis limited to the liver, skin, or bone marrow (fewer than 10 percent of nucleated bone marrow cells are tumor)). In embodiments, the disease is stage L1 neuroblastoma (e.g., localized disease without imaging risk factors) according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the disease is stage L2 neuroblastoma (e.g., localized disease with imaging risk factors) according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the disease is stage M neuroblastoma (e.g., metastatic disease) according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the disease is neuroblastoma at stage MS according to the International Neuroblastoma Risk Group (INRG) staging system (e.g., "atypical" metastatic disease where MS is equivalent to stage 4S as described above). In embodiments, the disease is in the pre-treated group of the very low-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the disease is in the pre-treated group of the low-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the disease is in the pre-treated group of the intermediate-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system. In embodiments, the disease is in the pre-treated group of the high-risk neuroblastoma risk stratification according to the International Neuroblastoma Risk Group (INRG) staging system.

[0067] As used herein, the term "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemias, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include cancer of the prostate, thyroid, endocrine system, brain, breast, cervical, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterine, medulloblastoma, colorectal, and pancreatic cancers. Further examples may include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, premalignant skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreatic glands, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0068] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease, i.e., acute or chronic, (2) the type of cells involved: myeloid (myeloid), lymphoid (lymphatic), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood, i.e., leukemic or non-leukemic (subleukemic). Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, and leukemia of the genotype. leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0069] The term "sarcoma" generally refers to a tumor composed of a substance like embryonic connective tissue and generally consisting of closely packed cells embedded in fibrillar or homogeneous substance. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloromatous sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, and idiopathic multiple pigmented hemorrhagic sarcoma. sarcoma), B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0070] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentiginous malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0071] The term "carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatous, carcinoma of the adrenal cortex, alveolar adenocarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedone carcinoma, uterine carcinoma, and uterine carcinoma. carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, encephalomyocarcinoma, epidermoid carcinoma, epithelial adenoid carcinoma (carcinoma epitheliale adenoids), exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatinous carcinoma (gelatiniforni carcinoma), gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma (carcinoma gigantocellulare), adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, embryonal carcinoma of infancy, carcinoma in situ, carcinoma in epidermis, carcinoma in situ, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, mucinous secretory carcinoma, mucinous cell carcinomamucocellulare, mucoepidermoid carcinoma, mucinous carcinoma, mucous carcinoma, mucoid carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, sarcomatous carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma carcinoma, verrucous carcinoma or choriocarcinoma (carcinoma villosum).

[0072] As used herein, the term "signaling pathway" refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that communicate a change in one component to one or more other components, which can then communicate changes to additional components, which are optionally propagated to other signaling pathway components.

[0073] As used herein, the term "abnormal" refers to something that is different from normal. When used to describe enzyme activity, abnormal refers to activity that is higher or lower than the average of a normal control or a normal, non-diseased control sample. Abnormal activity can refer to the amount of activity that results in disease, where restoring the abnormal activity to a normal amount or a non-disease-related amount (e.g., by administering a compound or using a method as described herein) results in a reduction of the disease or one or more disease symptoms.

[0074] As used herein, "nucleic acid" or "oligonucleotide" or "polynucleotide" or grammatical equivalents refer to at least two nucleotides covalently linked to each other. The term "nucleic acid" includes single-, double-, or multi-stranded DNA, RNA, and analogs (derivatives) thereof. Oligonucleotides are typically about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50, or more nucleotides in length, up to about 100 nucleotides in length. Nucleic acids and polynucleotides are polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. Nucleic acids containing one or more carbocyclic sugars are also included within the definition of nucleic acid.

[0075] A particular nucleic acid sequence also encompasses "splice variants." Similarly, a particular protein encoded by a nucleic acid encompasses any protein encoded by a splice variant of that nucleic acid. As the name suggests, a "splice variant" is a product of alternative splicing of a gene. After transcription, an initial nucleic acid transcript can be spliced ​​such that different (alternate) nucleic acid splice products encode different polypeptides. The mechanism for producing splice variants varies but includes alternative splicing of exons. Alternative polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of splice products, are included in this definition.

[0076] A nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous with each other and, in the case of a secretory leader, contiguous and in reading phase. Enhancers, however, need not be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adapters or linkers are used in accordance with conventional practice.

[0077] The term "identity" or percent "identity" with respect to two or more nucleic acid or polypeptide sequences refers to sequences that are the same or have a specified percentage of the same amino acid residues or nucleotides (i.e., for maximum correspondence over a comparison window or designated region), as measured using the BLAST or BLAST 2.0 sequence comparison algorithm with the default parameters described below, or through manual alignment and even visual inspection (see, e.g., the NCBI website, etc.). "Substantially identical" refers to two or more sequences or subsequences that, when compared and aligned, share about 60% identity over a specified region, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more. Such sequences are then said to be "substantially identical." This definition also refers to, or can apply to, the complement of a test sequence. This definition also includes sequences that contain deletions and / or additions, as well as those that contain substitutions. As described herein, preferred algorithms may account for gaps and the like. Preferably, identity exists over a region at least about 10 amino acids or 20 nucleotides in length, or more preferably over a region 10-50 amino acids or 20-50 nucleotides in length. As used herein, percent amino acid sequence identity is defined as the percentage of amino acids in a candidate sequence that are identical to those in a reference sequence after alignment of the sequences and, if necessary, introduction of gaps to achieve the maximum percent sequence identity. Alignment to determine percent sequence identity can be accomplished in a variety of ways within the capabilities of one of ordinary skill in the art, for example, using publicly available computer programs such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software.Appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared, can be determined by known methods.

[0078] For sequence comparison, typically, one sequence serves as a reference sequence, and test sequences are compared to it.When using sequence comparison algorithm, test and reference sequences are input into computer, subsequence coordinates are designated, and if necessary, sequence algorithm program parameters are designated.Preferably, default program parameters can be used, or alternative parameters can be designated.The sequence comparison algorithm then calculates the percent sequence identity of test sequences to reference sequences based on program parameters.

[0079] As used herein, a "comparison window" includes reference to any one segment of consecutive position numbers selected from the group consisting of 10 to 600, usually about 50 to about 200, and more usually about 100 to about 150, within which a sequence can be compared to a reference sequence of the same consecutive position number after the two sequences are optimally aligned. Methods for aligning sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be performed, for example, by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Current Protocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

[0080] The phrase "selectively (or specifically) hybridizes to" refers to a molecule that binds, duplexes, or hybridizes with greater affinity only to a particular nucleotide sequence under more stringent conditions than to other nucleotide sequences (e.g., total cellular DNA or RNA, or library DNA or RNA).

[0081] The phrase "stringent hybridization conditions" refers to conditions under which a probe will hybridize to a subsequence of its target, typically in a complex mixture of nucleic acids, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. Extensive guidance on nucleic acid hybridization is found in Tijssen, Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Probes, "Overview of principles of hybridization and the strategy of nucleic acid assays" (1993). Generally, stringent conditions are those that meet the thermal melting point (T) for a specific sequence at a defined ionic strength pH. m ) is selected to be approximately 5 to 10°C lower than T m is the temperature (under defined ionic strength, pH, and nucleic acid concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (because the target sequence is present in excess, T m (At equilibrium, 50% of the probes are occupied). Stringent conditions can also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least two times background, preferably 10 times background hybridization. Exemplary stringent hybridization conditions can be as follows: 50% formamide, 5xSSC, and 1% SDS, incubated at 42°C, or 5xSSC, 1% SDS, incubated at 65°C, washed in 0.2xSSC and 0.1% SDS at 65°C.

[0082] Nucleic acids that do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides they encode are substantially identical. This occurs, for example, when copies of a nucleic acid are created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions. Exemplary "moderately stringent hybridization conditions" include hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37°C, and washing in 1×SSC at 45°C. Positive hybridization is at least twice background. Those skilled in the art will readily recognize that alternative hybridization and washing conditions can be utilized to provide similarly stringent conditions. Further guidance for determining hybridization parameters is provided, for example, in numerous references and Current Protocols in Molecular Biology, ed. Ausubel, et al.

[0083] Twenty amino acids are commonly found in proteins. These amino acids can be divided into nine classes or groups based on the chemical properties of their side chains. The substitution of one amino acid residue for another within the same class or group is referred to herein as a "conservative" substitution. Conservative amino acid substitutions can often be made in proteins without significantly changing the conformation or function of the protein. The substitution of one amino acid residue for another from a different class or group is referred to herein as a "non-conservative" substitution. In contrast, non-conservative amino acid substitutions tend to alter the conformation and function of proteins. Examples of amino acid classification Small / aliphatic residues: Gly, Ala, Val, Leu, Ile Cyclic imino acid: Pro Hydroxyl-containing residues: Ser, Thr Acidic residues: Asp, Glu Amide residues: Asn, Gln Basic residues: Lys, Arg Imidazole residue: His Aromatic residues: Phe, Tyr, Trp Sulfur-containing residues: Met, Cys

[0084] In some embodiments, conservative amino acid substitutions include substituting any of these aliphatic amino acids with glycine (G), alanine (A), isoleucine (I), valine (V), and leucine (L); substituting threonine (T) with serine (S), and vice versa; substituting glutamic acid (E) with aspartic acid (D), and vice versa; substituting asparagine (N) with glutamine (Q), and vice versa; substituting arginine (R) with lysine (K), and vice versa; substituting any of these aromatic amino acids with phenylalanine (F), tyrosine (Y), and tryptophan (W); and substituting cysteine ​​(C) with methionine (M), and vice versa. Other substitutions can also be considered conservative, depending on the environment of the particular amino acid and its role in the three-dimensional structure of the protein. For example, glycine (G) and alanine (A) are often interchangeable, as are alanine (A) and valine (V). Methionine (M), which is relatively hydrophobic, can often be interchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are often interchangeable in positions where the important feature of the amino acid residue is its charge and the different pKs of these two amino acid residues are not important. Still other changes can be considered "conservative" in certain circumstances (see, e.g., BIOCHEMISTRY at pp. 13-15, 2nd ed. Lubert Stryer ed. (Stanford University); Henikoff et al., Proc. Nat'l Acad. Sci. USA (1992) 89:10915-10919; Lei et al., J. Biol. Chem. (1995) 270(20):11882-11886).

[0085] "Polypeptide," "peptide," and "protein" are used interchangeably herein to refer to any peptide-linked chain of amino acids, regardless of length or post-translational modification. As discussed below, a polypeptide described herein can be, for example, a wild-type protein, a biologically active fragment of a wild-type protein, or a variant of the wild-type protein or fragment. Variants according to the present disclosure can include amino acid substitutions, deletions, or insertions. Substitutions can be conservative or non-conservative.

[0086] Following expression, the protein can be isolated. The terms "purified" or "isolated," as applied to any of the proteins described herein, refer to a polypeptide that has been separated or purified from components (e.g., proteins or other naturally occurring biomolecules or organic molecules) that naturally accompany the polypeptide (e.g., other proteins, lipids, and nucleic acids in cells expressing the protein). Typically, a polypeptide is purified if it constitutes at least 60% (e.g., at least 65, 70, 75, 80, 85, 90, 92, 95, 97, or 99%) by weight of the total protein in a sample.

[0087] An amino acid residue of a protein "corresponds" to a given residue if it occupies the same essential structural position within the protein as the given residue. For example, a selected residue of a selected protein corresponds to L126-Y133 of human PCNA if the selected residue is in the same essential spatial or other structural relationship as L126-Y133 in human PCNA. In some embodiments, when a selected protein is aligned for maximum homology with the human PCNA protein, the position in the aligned selected protein that aligns with L126-Y133 is said to correspond to L126-Y133. For example, when the structure of a selected protein is aligned for maximum identity with the human PCNA protein and the overall structures are compared, a three-dimensional structural alignment can also be used instead of a primary sequence alignment. In this case, the amino acid occupying the same essential position in the structural model as L126-Y133 is said to correspond to the L126-Y133 residue.

[0088] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration and absorption of active agents by a subject and can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (e.g., Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if necessary, can be mixed with auxiliary substances that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0089] The term "preparation" is intended to include formulations of an active compound with an encapsulating material as a carrier, resulting in a capsule in which the active ingredient is surrounded by the carrier, with or without other carriers, and thus together with the carrier. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0090] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact administration, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration to a subject, or implantation of a sustained-release device, e.g., a mini-osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "co-administered" is meant that the compositions described herein are administered simultaneously with, immediately prior to, or immediately following the administration of one or more additional therapeutic agents (e.g., anti-cancer agents). The compounds of the present invention may be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds, individually or in combination (more than one compound or agent). Thus, preparations may also be combined with other active agents, if desired (e.g., to reduce metabolic degradation, to increase prodrug degradation and drug, detectable agent release). The compositions of the present invention may be delivered transdermally, topically, and may be formulated as an applicator stick, solution, suspension, emulsion, gel, cream, ointment, peel, or other suitable formulation. The compositions can be formulated as toasts, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for oral ingestion by patients. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, e.g., water or water / propylene glycol solutions. The compositions of the present invention can further contain ingredients that provide sustained release and / or comfort. Such ingredients include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and micronized drug carrier substrates.These components are discussed in more detail in U.S. Pat. Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be delivered by intradermal injection of drug-containing microspheres that release slowly under the skin (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gels (see, e.g., Gao, Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the present invention can be delivered by the use of liposomes that fuse with or are endocytosed by cell membranes, i.e., by using receptor ligands attached to liposomes that bind to cell surface membrane protein receptors that cause endocytosis. Using liposomes This can focus the delivery of the compositions of the present invention to target cells in vivo, particularly if the liposome surface carries target cell-specific receptor ligands or is otherwise preferentially directed to a particular organ (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions of the present invention can also be delivered as nanoparticles.

[0091] Pharmaceutical compositions provided by the present invention include compositions containing the active ingredient (e.g., a compound described herein, including embodiments or examples) in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in a method for treating a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., reducing, eliminating, or slowing the progression of disease symptoms (e.g., symptoms of cancer or abnormal PCNA activity). Determining a therapeutically effective amount of a compound of the present invention is well within the capabilities of one skilled in the art, especially in light of the detailed disclosure herein.

[0092] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending on a variety of factors, such as whether the mammal is suffering from another disease and the route of administration; the recipient's size, age, sex, health, weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated (e.g., cancer symptoms), the type of concomitant therapy, complications from the disease being treated, or other health-related problems. Other treatment regimens or agents can be used in conjunction with the methods and compounds of Applicants' invention. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the skill of the art.

[0093] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration is the concentration of active compound(s) that can achieve the methods described herein, as measured using methods described herein or known in the art.

[0094] As is well known in the art, the therapeutically effective amount for use in humans can also be determined from animal models.For example, the dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward, as described above.Based on the above and other methods, it is well within the ability of a person skilled in the art to adjust the dosage to achieve maximum efficacy in humans.

[0095] Dosage may vary depending on the patient's needs and the compound used. In the present invention, the dosage administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of a physician. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.

[0096] Dosage amount and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, providing a treatment regimen appropriate to the severity of the individual's condition.

[0097] The teachings provided herein can be used to design effective prophylactic or therapeutic treatment regimens that do not cause substantial toxicity yet are effective in treating the clinical symptoms exhibited in a particular patient. This design should involve careful selection of an active compound by considering factors such as the potency of the compound, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred mode of administration and toxicity profile of the selected agent, etc.

[0098] The compounds described herein can be used in combination with each other, with other active agents known to be useful in treating cancer, or with adjunctive agents that may not be effective alone but can contribute to the efficacy of the active agent.

[0099] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Simultaneous administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or ancillary agents can be linked or conjugated to each other. In some embodiments, the compounds described herein can be combined with cancer treatments such as radiation or surgery.

[0100] As used herein, the term "about" refers to a range of values ​​including the specified value that one of ordinary skill in the art would reasonably consider similar to the specified value. In embodiments, about refers to within one standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range extending to + / - 10% of the specified value. In embodiments, about refers to the specified value.

[0101] The term "proliferating cell nuclear antigen" or "PCNA" refers to an approximately 29 kDa protein that self-associates into a protein complex consisting of three individual PCNA protein subunits. Together, these bound PCNA molecules form a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. The term "PCNA" can refer to the nucleotide sequence or protein sequence of human PCNA (e.g., Entrez 5111, Uniprot P12004, RefSeq NM_002592 (SEQ ID NO: 1), or RefSeq NP_002583 (SEQ ID NO: 2)). The term "PCNA" includes both the wild-type form of the nucleotide sequence or protein, as well as any mutants thereof. In some embodiments, "PCNA" is wild-type PCNA. In some embodiments, "PCNA" is one or more mutant forms. The term "PCNA" XYZ refers to a mutant PCNA nucleotide sequence or protein, where the Y-numbered amino acid of PCNA that normally has the X amino acid in the wild-type has instead the Z amino acid in the mutant. In embodiments, PCNA is human PCNA. In embodiments, PCNA has a nucleotide sequence corresponding to reference number GI:33239449 (SEQ ID NO: 1). In embodiments, PCNA has a nucleotide sequence corresponding to RefSeq NM_002592.2 (SEQ ID NO: 1). In embodiments, PCNA has a protein sequence corresponding to reference number GI:4505641 (SEQ ID NO: 2). In embodiments, PCNA has a nucleotide sequence corresponding to RefSeq NP_002583.1 (SEQ ID NO: 2). In embodiments, PCNA has the following amino acid sequence: MFEARLVQGSILKKVLEALKDLINEACWDISSSGVNLQSMDSSHVSLVQLTLRSEGFDTYRCDRNLAMGVNLTSMSKILKCAGNEDIITLRAEDNADTLALVFEAPNQEKVSDYEMKLMDLDVEQLGIPEQEYSCVVKMPSGEFARICRDLSHIGDAVVISCAKDGVKFSASGELGNGNIKLSQTSNVDKEEEAVTIEMNEPVQLTFALRYLNFFTKATPLSSTVTLSMSADVPLVVEYKIADMGHLKYYLAPKIEDEEGS (SEQ ID NO: 2).

[0102] In embodiments, the PCNA is a mutant PCNA. In embodiments, the mutant PCNA is associated with a disease not associated with wild-type PCNA. In embodiments, the PCNA comprises at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared to the above sequence. PCNA may be post-translationally modified. Modifications may include phosphorylation, methylation, methyl esters of acidic amino acids, ribosylation, acetylation, glycosylation with various sugars, lipidation with various different lipids, poly(ADP)-ribosylation, or other post-translational modifications known in the art. Differences in the degree and type of modification affect the levels (e.g., protein levels) of ca- and nm-PCNA isoforms. In embodiments, the post-translational modification or modifications modify the inhibition of PCNA by the compounds described herein (e.g., AOH1160, PCNA7), i.e., the binding of the compounds described herein (e.g., AOH1160, PCNA7) to PCNA relative to PCNA that does not have the post-translational modification(s).

[0103] As used herein, the term "cancer-associated proliferating cell nuclear antigen" or "caPCNA" refers to an isoform of PCNA with an acidic isoelectric point (e.g., a peptide containing a protonated amine and / or carboxyl group, an acidic isoelectric point relative to non-cancer-associated PCNA, PCNA in non-cancerous cells, non-malignant PCNA, a PCNA isoform prevalent in non-cancerous cells, or a less acidic PCNA isoform in non-cancerous cells). In embodiments, the caPCNA protein refers to a methylated amino acid (e.g., glutamic acid, aspartic acid). In embodiments, the caPCNA protein is post-translationally modified with methyl esters of acidic amino acids. In embodiments, methyl esterification of acidic amino acid residues on PCNA occurs at a T of approximately 20 minutes at pH 8.5. 1 / 2 In embodiments, caPCNA is post-translationally modified as described in F. Shen, et al. J Cell Biochem. 2011 Mar;112(3):756-760, which is incorporated by reference in its entirety for all purposes.

[0104] As used herein, the term "non-malignant proliferating cell nuclear antigen" or "nmPCNA" refers to an isoform of PCNA with a basic isoelectric point (e.g., a peptide containing a deprotonated amine and / or carboxyl group, a basic isoelectric point compared to caPCNA, caPCNA in cancerous cells). In embodiments, nmPCNA is the PCNA isoform that is prevalent in non-cancerous cells.

[0105] B. Compound Provided herein, inter alia, are compositions of compounds having the following formula, or pharmaceutically acceptable salts thereof: [ka] .

[0106] Ring A is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- to 6-membered heteroaryl, and ring B is a substituted or unsubstituted naphthyl, a substituted or unsubstituted quinolinyl, or a substituted or unsubstituted isoquinolinyl.

[0107] R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -CN, -SOCl, -SO n1 R 10 , -SO v1 NR 7 R 8 , -NHNR 7 R 8 , -ONR 7 R 8 , -NHC=(O)NHNR 7 R 8 , -NHC=(O)NR 7 R 8 , -N(O) m1 , -NR 7 R 8 , -C(O)R 9 , -C(O)-OR 9 , -C(O)NR 7 R 8 , -OR 10 , -NR 7 SO2R 10 , -NR 7 C=(O)R 9 , -NR 7 C(O)-OR 9 , -NR 7 OR 9 , -OCX 1 3. -OCHX 1 2, -OCH2X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 1The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -CN, -SO n1 R 10 , -SO v1 NR 7 R 8 , -NHNH2, -ONR 7 R 8 , -NHC=(O)NHNH2, -NHC=(O)NR 7 R 8 , -N(O) m1 , -NR 7 R 8 , -C(O)R 9 , -C(O)-OR 9 , -C(O)NR 7 R 8 , -OR 10 , -NR 7 SO2R 10 , -NR 7 C=(O)R 9 , -NR 7 C(O)-OR 9 , -NR 7 OR 9 , -OCX 1 3. -OCHX 1 2, -OCH2X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 1 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. When z1 is 0, R 1 is understood to be hydrogen.

[0108] R 2 are independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 2 3. -OCHX 2 2, -OCH2X 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0109] R 3 are independently hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 3 3. -OCHX 3 2, -OCH2X 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0110] R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, -CX A 3. -CHX A 2. -CH2X A, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX A 3. -OCHX A 2, -OCH2X A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 7 and R 8 The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0111] Symbol z1 is an integer of 0 to 4. Symbols m1 and v1 are independently an integer of 1 or 2. Symbol n1 is an integer of 0 to 4. Symbol X 1 , X 2 , X 3 , and X A are independently -Cl, -Br, -I, or -F.

[0112] In embodiments, the compound has the formula: [ka] . R 1 , R 2 , R 3 , ring A, ring B, and z1 are as described herein, including in the compounds and embodiments of formula (I). In an embodiment, ring A is phenyl (R 4 substituted or unsubstituted) or 5-6 membered heteroaryl (R 4 and ring B is naphthyl (R 5 substituted or unsubstituted), quinolinyl (R 5 substituted or unsubstituted), or isoquinolinyl (R5 (substituted or unsubstituted).

[0113] R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -CN, -SOCl, -SO n4 R 14 , -SO v4 NR 11 R 12 , -NHNR 11 R 12 , -ONR 11 R 12 , -NHC=(O)NHNR 11 R 12 , -NHC=(O)NR 11 R 12 , -N(O) m4 , -NR 11 R 12 , -C(O)R 13 , -C(O)-OR 13 , -C(O)NR 11 R 12 , -OR 14 , -NR 11 SO2R 14 , -NR 11 C=(O)R 13 , -NR 11 C(O)-OR 13 , -NR 11 OR 13 , -OCX 4 3. -OCHX 4 2, -OCH2X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 4 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 4 are independently halogen, -CX 4 3. -CHX4 2. -CH2X 4 , -CN, -SO n4 R 14 , -SO v4 NR 11 R 12 , -NHNR 11 R 12 , -ONR 11 R 12 , -NHC=(O)NHNR 11 R 12 , -NHC=(O)NR 11 R 12 , -N(O) m4 , -NR 11 R 12 , -C(O)R 13 , -C(O)-OR 13 , -C(O)NR 11 R 12 , -OR 14 , -NR 11 SO2R 14 , -NR 11 C=(O)R 13 , -NR 11 C(O)-OR 13 , -NR 11 OR 13 , -OCX 4 3. -OCHX 4 2, -OCH2X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 4 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. When z2 is 0, R 4 is understood to be hydrogen.

[0114] R 5 are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -CN, -SOCl, -SOn5 R 18 , -SO v5 NR 15 R 16 , -NHNR 15 R 16 , -ONR 15 R 16 , -NHC=(O)NHNR 15 R 16 , -NHC=(O)NR 15 R 16 , -N(O) m5 , -NR 15 R 16 , -C(O)R 17 , -C(O)-OR 17 , -C(O)NR 15 R 16 , -OR 18 , -NR 15 SO2R 18 , -NR 15 C=(O)R 17 , -NR 15 C(O)-OR 17 , -NR 15 OR 17 , -OCX 5 3. -OCHX 5 2, -OCH2X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 5 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 5 are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -CN, -SO n5 R 18 , -SO v5 NR 15 R 16 , -NHNR 15 R 16 , -ONR15 R 16 , -NHC=(O)NHNR 15 R 16 , -NHC=(O)NR 15 R 16 , -N(O) m5 , -NR 15 R 16 , -C(O)R 17 , -C(O)-OR 17 , -C(O)NR 15 R 16 , -OR 18 , -NR 15 SO2R 18 , -NR 15 C=(O)R 17 , -NR 15 C(O)-OR 17 , -NR 15 OR 17 , -OCX 5 3. -OCHX 5 2, -OCH2X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R 5 The substituents may optionally be combined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. When z3 is 0, R 5 is understood to be hydrogen.

[0115] R 11 , R 12 , R 13 , and R 14 are independently hydrogen, halogen, -CX B 3. -CHX B 2. -CH2X B, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX B 3. -OCHX B 2, -OCH2X B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 11 and R 12 The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0116] R 15 , R 16 , R 17 , and R 18 are independently hydrogen, halogen, -CX C 3. -CHX C 2. -CH2X C , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX C 3. -OCHX C 2, -OCH2X C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 15 and R 16 The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0117] The symbol z2 is an integer of 0 to 5. The symbol z3 is an integer of 0 to 7. The symbols m4, m5, v4 and v5 are independently an integer of 1 or 2. The symbols n4 and n5 are independently an integer of 0 to 4. The symbol X 4 , X 5 , X B , and X C are independently -Cl, -Br, -I, or -F.

[0118] In embodiments, ring A is substituted phenyl. In embodiments, ring A is unsubstituted phenyl. In embodiments, ring A is phenyl. In embodiments, ring A is substituted 5-6 membered heteroaryl. In embodiments, ring A is unsubstituted 5-6 membered heteroaryl. In embodiments, ring A is 5-6 membered heteroaryl. In embodiments, ring A is substituted thienyl. In embodiments, ring A is unsubstituted thienyl. In embodiments, ring A is thienyl. In embodiments, ring A is 2-thienyl. In embodiments, ring A is 3-thienyl. In embodiments, ring A is substituted pyridyl. In embodiments, ring A is unsubstituted pyridyl. In embodiments, ring A is pyridyl. In embodiments, ring A is 2-pyridyl. In embodiments, ring A is 3-pyridyl. In embodiments, ring A is 4-pyridyl. In embodiments, ring A is unsubstituted pyrrolyl. In embodiments, Ring A is substituted pyrrolyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring A is unsubstituted furanyl. In embodiments, Ring A is substituted furanyl. In embodiments, Ring A is furanyl. In embodiments, Ring A is unsubstituted pyrazolyl. In embodiments, Ring A is substituted pyrazolyl. In embodiments, Ring A is pyrazolyl. In embodiments, Ring A is unsubstituted imidazolyl. In embodiments, Ring A is substituted imidazolyl. In embodiments, Ring A is imidazolyl. In embodiments, Ring A is unsubstituted oxazolyl. In embodiments, Ring A is substituted oxazolyl. In embodiments, Ring A is oxazolyl. In embodiments, Ring A is unsubstituted isoxazolyl. In embodiments, Ring A is substituted isoxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is unsubstituted thiazolyl. In embodiments, Ring A is substituted thiazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is unsubstituted triazolyl. In embodiments, Ring A is substituted triazolyl. In embodiments, Ring A is triazolyl. In embodiments, Ring B is substituted naphthyl. In embodiments, Ring B is unsubstituted naphthyl. In embodiments, Ring B is naphthyl. In embodiments, Ring B is 1-naphthyl.In embodiments, Ring B is 2-naphthyl. In embodiments, Ring B is quinolinyl. In embodiments, Ring B is substituted quinolinyl. In embodiments, Ring B is unsubstituted quinolinyl. In embodiments, Ring B is isoquinolinyl. In embodiments, Ring B is substituted isoquinolinyl. In embodiments, Ring B is unsubstituted isoquinolinyl. In embodiments, Ring B is 1-isoquinolinyl. In embodiments, Ring B is 3-isoquinolinyl. In embodiments, Ring B is 4-isoquinolinyl.

[0119] In embodiments, R 1 are independently halogen, -CF3, -CHF2, -OCF3, -OCHF2, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2- to 8-membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl. 1 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 1 are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 1 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 1 are independently halogen. In embodiments, R 1 is independently —CF. In an embodiment, R 1 is independently -CHF. In an embodiment, R 1 is independently -CHF. In an embodiment, R 1 is independently -OCF. In an embodiment, R 1is independently -OCHF. In an embodiment, R 1 is independently -OCHF. In an embodiment, R 1 is independently a substituted or unsubstituted C1-C8 alkyl. In embodiments, R 1 are independently substituted or unsubstituted 2-8 membered heteroalkyl. In embodiments, R 1 is independently a substituted or unsubstituted C-C cycloalkyl. 1 are independently substituted or unsubstituted 3- to 8-membered heterocycloalkyl. In embodiments, R 1 are independently substituted or unsubstituted C6-C 10 In embodiments, R 1 is independently a substituted or unsubstituted 5-10 membered heteroaryl. 1 is independently —OH. In embodiments, R 1 is independently —NH. In an embodiment, R 1 is independently -SH. In an embodiment, R 1 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1 are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 1 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1 is independently substituted or unsubstituted phenyl. In embodiments, R 1 is independently a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0120] In embodiments, R 1 is independently a substituted C1-C8 alkyl. In embodiments, R 1 is independently a substituted 2-8 membered heteroalkyl. In embodiments, R 1 is independently a substituted C-C cycloalkyl. In embodiments, R 1 is independently a substituted 3-8 membered heterocycloalkyl. In embodiments, R1 are independently substituted C6-C 10 In embodiments, R 1 is independently a substituted 5-10 membered heteroaryl. In embodiments, R 1 is independently a substituted C1-C4 alkyl. In embodiments, R 1 is independently a substituted 4-membered heteroalkyl. In embodiments, R 1 is independently a substituted C-C cycloalkyl. In embodiments, R 1 is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1 is independently substituted phenyl. In embodiments, R 1 is independently a substituted 5-6 membered heteroaryl. 1 is independently unsubstituted C1-C8 alkyl. In embodiments, R 1 is independently an unsubstituted 2-8 membered heteroalkyl. In an embodiment, R 1 is independently unsubstituted C-C cycloalkyl. In embodiments, R 1 is independently an unsubstituted 3-8 membered heterocycloalkyl. In an embodiment, R 1 are independently unsubstituted C6-C 10 In embodiments, R 1 is independently an unsubstituted 5-10 membered heteroaryl. 1 is independently unsubstituted C1-C4 alkyl. In embodiments, R 1 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted C-C cycloalkyl. In embodiments, R 1 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1 is independently unsubstituted phenyl. In embodiments, R 1 is independently an unsubstituted 5-6 membered heteroaryl. 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently unsubstituted methoxy. In embodiments, R 1 is independently unsubstituted ethoxy. In embodiments, R 1 is independently -F. In an embodiment, R 1 is independently -Cl. In an embodiment, R 1 is independently -Br. In an embodiment, R 1 is independently -I. In an embodiment, R 1 are independently hydrogen. In embodiments, R 1 are independently halogen, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, —OH, —NH2, —SH, unsubstituted C1-C4 alkyl, or unsubstituted 2-4 membered heteroalkyl.

[0121] In an embodiment, z1 is 1. In an embodiment, z1 is 0. In an embodiment, z1 is 2. In an embodiment, z1 is 3. In an embodiment, z1 is 4.

[0122] In embodiments, R 2 are independently hydrogen, -CX 2 3. -CHX 2 2. -CH2X 2 , —CN, —C(O)H, —C(O)OH, —C(O)NH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 2 is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. 2 are independently hydrogen. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted tert-butyl.

[0123] In embodiments, R 2 are independently hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0124] In embodiments, R 3 are independently hydrogen, -CX 2 3. -CHX 2 2. -CH2X 2 , —CN, —C(O)H, —C(O)OH, —C(O)NH, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 3 is independently hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. 3 are independently hydrogen. In embodiments, R 3 is independently unsubstituted methyl. In embodiments, R 3 is independently unsubstituted ethyl. In embodiments, R 3 is independently unsubstituted isopropyl. In embodiments, R 3 is independently unsubstituted tert-butyl. In embodiments, R 3 are independently hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3, -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0125] In embodiments, R 4 are independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2- to 8-membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl. 4 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4 are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 4 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 4 are independently halogen. In embodiments, R 4 is independently —OH. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted methoxy. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently -F. In an embodiment, R 4 is independently -Cl. In an embodiment, R4 is independently -Br. In an embodiment, R 4 is independently -I. In an embodiment, R 4 is independently —CF. In an embodiment, R 4 is independently —NH. In an embodiment, R 4 is independently -SH. In an embodiment, R 4 is independently unsubstituted isopropyl. In embodiments, R 4 is independently unsubstituted tert-butyl. In embodiments, R 4 is independently unsubstituted ethoxy. In embodiments, R 4 is independently unsubstituted propoxy.

[0126] In embodiments, R 4 are independently halogen. In embodiments, R 4 is independent, -CX 4 3. In an embodiment, R 4 are independently -CHX 4 2. In an embodiment, R 4 are independently, -CH2X 4 In an embodiment, R 4 is independently —CN. In embodiments, R 4 are independent, -SO n4 R 14 In an embodiment, R 4 are independent, -SR 14 In an embodiment, R 4 are independent, -SO v4 NR 11 R 12 In an embodiment, R 4 are independently -NHNR 11 R 12 In an embodiment, R 4 independently, -ONR 11 R 12 In an embodiment, R 4 are independently -NHC=(O)NHNR 11 R 12 In an embodiment, R 4 are independently -NHC=(O)NR 11R 12 In an embodiment, R 4 are independently -N(O) m4 In an embodiment, R 4 are independently, -NR 11 R 12 In an embodiment, R 4 are independently -C(O)R 13 In an embodiment, R 4 are independently -C(O)-OR 13 In an embodiment, R 4 are independently -C(O)NR 11 R 12 In an embodiment, R 4 are independently -OR 14 In an embodiment, R 4 are independently, -NR 11 SO2R 14 In an embodiment, R 4 are independently, -NR 11 C=(O)R 13 In an embodiment, R 4 are independently, -NR 11 C(O)-OR 13 In an embodiment, R 4 are independently, -NR 11 OR 13 In an embodiment, R 4 independently, -OCX 4 3. In an embodiment, R 4 independently, -OCHX 4 2. In an embodiment, R 4 are independently, -OCH2X 4 In an embodiment, R 4 is independently —CF. In an embodiment, R 4 is independently -CHF. In an embodiment, R 4 is independently -CHF. In an embodiment, R 4 is independently —SO2CH3. In an embodiment, R 4 is independently —SO2NH2. In embodiments, R 4 is independently -SH. In an embodiment, R 4is independently —N(O). In embodiments, R 4 is independently —NH. In an embodiment, R 4 is independently —C(O)CH. In embodiments, R 4 is independently —C(O)OH. In embodiments, R 4 is independently —C(O)NH. In embodiments, R 4 is independently —OH. In embodiments, R 4 is independently -OCF. In an embodiment, R 4 is independently -OCHF. In an embodiment, R 4 are independently -OCH2F.

[0127] In embodiments, R 4 are independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2- to 8-membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl. 4 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4 are independently halogen, —CF3, —CHF2, —CH2F, —OCF3, —OCHF2, —OCH2F, —OH, —NH2, —SH, unsubstituted C1-C4 alkyl, or unsubstituted 2-4 membered heteroalkyl.

[0128] In embodiments, R 4 is independently substituted or unsubstituted alkyl. In embodiments, R4 is independently a substituted or unsubstituted heteroalkyl. In embodiments, R 4 is independently a substituted or unsubstituted cycloalkyl. In embodiments, R 4 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 4 is independently substituted or unsubstituted aryl. In embodiments, R 4 are independently substituted or unsubstituted heteroaryl. In embodiments, two adjacent R 4 The substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R 4 The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R 4 The substituents may optionally be joined to form a substituted or unsubstituted aryl. In embodiments, two adjacent R 4 The substituents may optionally be combined to form a substituted or unsubstituted heteroaryl.

[0129] In embodiments, R 4 are independently substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 4are independently substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted aryl (e.g., C6-C 10 In embodiments, R4 is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0130] In embodiments, R 14 are independently hydrogen, -CX B 3. -CHX B 2. -CH2X B , -CN, -COOH, -CONH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 14are independently hydrogen. In embodiments, R 14 is independent, -CX B 3. In an embodiment, R 14 are independently -CHX B 2. In an embodiment, R 14 are independently, -CH2X B In an embodiment, R 14 is independently —CN. In embodiments, R 14 is independently —COOH. In embodiments, R 14 is independently -CONH. In an embodiment, R 14 is independently substituted or unsubstituted alkyl. In embodiments, R 14 is independently a substituted or unsubstituted heteroalkyl. In embodiments, R 14 is independently a substituted or unsubstituted cycloalkyl. In embodiments, R 14 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 14 is independently substituted or unsubstituted aryl. In embodiments, R 14 is independently a substituted or unsubstituted heteroaryl. In embodiments, R 14 is independently substituted alkyl. In embodiments, R 14 is independently substituted heteroalkyl. In embodiments, R 14 is independently substituted cycloalkyl. In embodiments, R 14 is independently substituted heterocycloalkyl. In embodiments, R 14 is independently substituted aryl. In embodiments, R 14 is independently substituted heteroaryl. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 is independently unsubstituted heteroalkyl. In embodiments, R 14 is independently unsubstituted cycloalkyl. In embodiments, R 14 is independently unsubstituted heterocycloalkyl. In embodiments, R 14 is independently unsubstituted aryl. In embodiments, R14 is independently unsubstituted heteroaryl. In embodiments, R 14 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 14 are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 14 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 14 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 14 is independently substituted or unsubstituted phenyl. In embodiments, R 14 are independently substituted or unsubstituted 5-6 membered heteroaryl. 14 is independently a substituted C1-C4 alkyl. In embodiments, R 14 is independently a substituted 2-4 membered heteroalkyl. In embodiments, R 14 is independently a substituted C-C cycloalkyl. In embodiments, R 14 is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 14 is independently substituted phenyl. In embodiments, R 14 is independently a substituted 5-6 membered heteroaryl. 14 is independently unsubstituted C1-C4 alkyl. In embodiments, R 14 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 14 is independently unsubstituted C-C cycloalkyl. In embodiments, R 14 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 14 is independently unsubstituted phenyl. In embodiments, R 14 is independently an unsubstituted 5-6 membered heteroaryl. 14 is hydrogen or unsubstituted methyl.

[0131] In embodiments, R 14 is a substituted or unsubstituted pyrazolyl. In embodiments, R 14is substituted or unsubstituted pyridyl. In embodiments, R 14 is a substituted or unsubstituted imidazolyl. In embodiments, R 14 is a substituted or unsubstituted oxazolyl. In embodiments, R 14 is a substituted or unsubstituted isoxazolyl. In embodiments, R 14 is a substituted or unsubstituted thiazolyl. In embodiments, R 14 is a substituted or unsubstituted furanyl. In embodiments, R 14 is substituted or unsubstituted pyrrolyl. In embodiments, R 14 is a substituted or unsubstituted thienyl. In embodiments, R 14 is a substituted pyrazolyl. In embodiments, R 14 is a substituted pyridyl. In embodiments, R 14 is a substituted imidazolyl. In embodiments, R 14 is a substituted oxazolyl. In embodiments, R 14 is a substituted isoxazolyl. In embodiments, R 14 is a substituted thiazolyl. In embodiments, R 14 is a substituted furanyl. In embodiments, R 14 is a substituted pyrrolyl. In embodiments, R 14 is substituted thienyl. In embodiments, R 14 is unsubstituted pyrazolyl. In embodiments, R 14 is unsubstituted pyridyl. In embodiments, R 14 is unsubstituted imidazolyl. In embodiments, R 14 is unsubstituted oxazolyl. In embodiments, R 14 is unsubstituted isoxazolyl. In embodiments, R 14 is unsubstituted thiazolyl. In embodiments, R 14 is unsubstituted furanyl. In embodiments, R 14 is unsubstituted pyrrolyl. In embodiments, R 14 is unsubstituted thienyl.

[0132] In embodiments, R 14are independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 14 are independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 is independently unsubstituted C1-C6 alkyl. In embodiments, R 14 is independently unsubstituted C1-C5 alkyl. In embodiments, R 14 is independently unsubstituted C1-C4 alkyl. In embodiments, R 14 is independently unsubstituted C1-C3 alkyl. In embodiments, R 14 is independently unsubstituted C1-C2 alkyl. In embodiments, R 14 is independently unsubstituted C2-C6 alkyl. In embodiments, R 14 is independently unsubstituted C2-C5 alkyl. In embodiments, R 14is independently unsubstituted C2-C4 alkyl. In embodiments, R 14 is independently unsubstituted C2-C3 alkyl. In embodiments, R 14 is independently unsubstituted C-C alkyl. In embodiments, R 14 is independently unsubstituted C4-C6 alkyl. In embodiments, R 14 is independently unsubstituted C5-C6 alkyl. In embodiments, R 14 is independently —CF. In an embodiment, R 14 is independently -CHF. In an embodiment, R 14 is independently -CHF. In an embodiment, R 14 is independently —CCl. In embodiments, R 14 is independently —CHCl. ​​In embodiments, R 14 is independently —CH2Cl. In embodiments, R 14 is independently —CBr. In embodiments, R 14 is independently —CHBr. In embodiments, R 14 is independently —CHBr. In embodiments, R 14 is independently -CI. In an embodiment, R 14 is independently -CHI. In embodiments, R 14 is independently -CH2I. In embodiments, R 14 is independently an unsubstituted C1-C4 haloalkyl. In embodiments, R 14 is independently an unsubstituted C1-C3 haloalkyl. In embodiments, R 14 is independently an unsubstituted C1-C2 haloalkyl. In embodiments, R 14 is independently an unsubstituted C-C haloalkyl. In embodiments, R 14 is independently an unsubstituted C2-C5 haloalkyl. In embodiments, R 14 is independently an unsubstituted C-C haloalkyl. In embodiments, R 14 is independently an unsubstituted C2-C3 haloalkyl. In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R 14 is independently unsubstituted butyl. In embodiments, R 14 is independently unsubstituted isobutyl. In embodiments, R 14 is independently unsubstituted tert-butyl.

[0133] In embodiments, z2 is 1. In embodiments, z2 is 0. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5.

[0134] In embodiments, R 5 are independently halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2- to 8-membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl. 5 are independently halogen, —CF3, —CHF2, —CH2F, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —OCF3, —OCHF2, —OCH2F, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2- to 8-membered heteroalkyl.

[0135] In embodiments, R 5are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 5 are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 5 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 5 are independently halogen. In embodiments, R 5 is independently —OH. In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted methoxy. In embodiments, R 5 is independently unsubstituted ethyl. In embodiments, R 5 is independently -F. In an embodiment, R 5 is independently -Cl. In an embodiment, R 5 is independently -Br. In an embodiment, R 5 is independently -I. In an embodiment, R 5 is independently —CF. In an embodiment, R 5 is independently —NH. In an embodiment, R 5 is independently -SH. In an embodiment, R 5 is independently unsubstituted isopropyl. In embodiments, R 5 is independently unsubstituted tert-butyl. In embodiments, R 5 is independently unsubstituted ethoxy. In embodiments, R 5 is independently unsubstituted propoxy.

[0136] In embodiments, R 5are independently substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 5 are independently substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted aryl (e.g., C6-C 10 aryl or C aryl), or substituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). 5are independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 5 are independently halogen, —CF, —CHF, —CHF, —OCF, —OCHF, —OCHF, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 5 is unsubstituted C1-C4 alkyl, or unsubstituted 2-4 membered heteroalkyl. 5 is unsubstituted C1-C4 alkyl. In embodiments, R 5 is an unsubstituted 2-4 membered heteroalkyl.

[0137] In embodiments, R 5 is independently unsubstituted alkyl. In embodiments, R 5 is independently unsubstituted C1-C6 alkyl. In embodiments, R 5 is independently unsubstituted C1-C5 alkyl. In embodiments, R 5 is independently unsubstituted C1-C4 alkyl. In embodiments, R 5 is independently unsubstituted C1-C3 alkyl. In embodiments, R 5 is independently unsubstituted C1-C2 alkyl. In embodiments, R 5 is independently unsubstituted C2-C6 alkyl. In embodiments, R 5is independently unsubstituted C2-C5 alkyl. In embodiments, R 5 is independently unsubstituted C2-C4 alkyl. In embodiments, R 5 is independently unsubstituted C2-C3 alkyl. In embodiments, R 5 is independently unsubstituted C-C alkyl. In embodiments, R 5 is independently unsubstituted C4-C6 alkyl. In embodiments, R 5 is independently unsubstituted C5-C6 alkyl.

[0138] In embodiments, z3 is 1. In embodiments, z3 is 0. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7.

[0139] In embodiments, R 11 , R 12 , R 13 , or R 14 are independently hydrogen, -CX B 3. -CHX B 2. -CH2X B , -CN, -COOH, -CONH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 11 , R 12 , R 13 , or R 14 are independently hydrogen. In embodiments, R 11 , R 12 , R 13 , or R 14 is independent, -CX B 3. In an embodiment, R 11 , R 12 , R 13 , or R 14 are independently -CHX B 2. In an embodiment, R 11, R 12 , R 13 , or R 14 are independently, -CH2X B In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently —CN. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently —COOH. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently -CONH. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted aryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted heteroaryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted alkyl. In embodiments, R 11, R 12 , R 13 , or R 14 is independently substituted heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted heterocycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted aryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted heteroaryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted heterocycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted aryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted heteroaryl. In embodiments, R 11 , R 12 , R 13, or R 14 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted phenyl. In embodiments, R 11 , R 12 , R 13 , or R 14 are independently substituted or unsubstituted 5-6 membered heteroaryl. 11 , R 12 , R 13 , or R 14 is independently a substituted C1-C4 alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted 2-4 membered heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted C-C cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted phenyl. In embodiments, R11 , R 12 , R 13 , or R 14 is independently a substituted 5-6 membered heteroaryl. 11 , R 12 , R 13 , or R 14 is independently unsubstituted C1-C4 alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted C-C cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted phenyl. In embodiments, R 11 , R 12 , R 13 , or R 14 are independently unsubstituted 5- to 6-membered heteroaryl.

[0140] In embodiments, R 11 and R 12 The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form a substituted or unsubstituted heteroaryl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form a substituted heterocycloalkyl. In embodiments, R 11 and R 12The substituents may optionally be joined to form a substituted heteroaryl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form an unsubstituted heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form an unsubstituted heteroaryl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form a substituted or unsubstituted 5- to 6-membered heteroaryl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form a substituted 5-6 membered heteroaryl. In embodiments, R 11 and R 12 The substituents may optionally be joined to form an unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may be optionally combined to form an unsubstituted 5- to 6-membered heteroaryl.

[0141] In embodiments, R 15 , R 16 , R 17 , or R 18 are independently hydrogen, -CX C 3. -CHX C 2. -CH2X C, -CN, -COOH, -CONH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 15 , R 16 , R 17 , or R 18 are independently hydrogen. In embodiments, R 15 , R 16 , R 17 , or R 18 is independent, -CX C 3. In an embodiment, R 15 , R 16 , R 17 , or R 18 are independently -CHX C 2. In an embodiment, R 15 , R 16 , R 17 , or R 18 are independently, -CH2X C In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently —CN. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently —COOH. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently -CONH. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R18 is independently a substituted or unsubstituted cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted aryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted heteroaryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted aryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted heteroaryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18is independently unsubstituted heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted aryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted heteroaryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted phenyl. In embodiments, R 15 , R 16 , R 17 , or R 18 are independently substituted or unsubstituted 5-6 membered heteroaryl. 15 , R 16, R 17 , or R 18 is independently a substituted C1-C4 alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted 2-4 membered heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted C-C cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted phenyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted 5-6 membered heteroaryl. 15 , R 16 , R 17 , or R 18 is independently unsubstituted C1-C4 alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted C-C cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted phenyl. In embodiments, R 15 , R16 , R 17 , or R 18 are independently unsubstituted 5- to 6-membered heteroaryl.

[0142] In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted or unsubstituted heteroaryl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted heteroaryl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form an unsubstituted heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form an unsubstituted heteroaryl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted or unsubstituted 5- to 6-membered heteroaryl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may optionally be joined to form a substituted 5-6 membered heteroaryl. In embodiments, R 15 and R16 The substituents may optionally be joined to form an unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may be optionally combined to form an unsubstituted 5- to 6-membered heteroaryl.

[0143] In an embodiment, m1 is 1. In an embodiment, m1 is 2. In an embodiment, v1 is 1. In an embodiment, v1 is 2. In an embodiment, m4 is 1. In an embodiment, m4 is 2. In an embodiment, m5 is 1. In an embodiment, m5 is 2. In an embodiment, v4 is 1. In an embodiment, v4 is 2. In an embodiment, v5 is 1. In an embodiment, v5 is 2. In an embodiment, n1 is 0. In an embodiment, n1 is 1. In an embodiment, n1 is 2. In an embodiment, n1 is 3. In an embodiment, n1 is 4. In an embodiment, n4 is 0. In an embodiment, n4 is 1. In an embodiment, n4 is 2. In an embodiment, n4 is 3. In an embodiment, n4 is 4. In an embodiment, n5 is 0. In an embodiment, n5 is 1. In an embodiment, n5 is 2. In an embodiment, n5 is 3. In an embodiment, n5 is 4.

[0144] In embodiments, X 1 is independently -Cl. In an embodiment, X 1 is independently -Br. In an embodiment, X 1 is independently -I. In an embodiment, X 1 is independently -F. In an embodiment, X 2 is independently -Cl. In an embodiment, X 2 is independently -Br. In an embodiment, X 2 is independently -I. In an embodiment, X 2 is independently -F. In an embodiment, X 3 is independently -Cl. In an embodiment, X 3 is independently -Br. In an embodiment, X 3is independently -I. In an embodiment, X 3 is independently -F. In an embodiment, X 4 is independently -Cl. In an embodiment, X 4 is independently -Br. In an embodiment, X 4 is independently -I. In an embodiment, X 4 is independently -F. In an embodiment, X 5 is independently -Cl. In an embodiment, X 5 is independently -Br. In an embodiment, X 5 is independently -I. In an embodiment, X 5 is independently -F. In an embodiment, X A is independently -Cl. In an embodiment, X A is independently -Br. In an embodiment, X A is independently -I. In an embodiment, X A is independently -F. In an embodiment, X B is independently -Cl. In an embodiment, X B is independently -Br. In an embodiment, X B is independently -I. In an embodiment, X B is independently -F. In an embodiment, X C is independently -Cl. In an embodiment, X C is independently -Br. In an embodiment, X C is independently -I. In an embodiment, X C are independently -F.

[0145] In embodiments, the compound has the formula: [ka] . R 1 , R 2 , R3, R 4 , R 5, Ring A, Ring B, z1, z2, and z3 are as described herein, including in compounds of Formula (I) and (II). In embodiments, z1 is 0. In embodiments, z2 is 0. In embodiments, z3 is 0. In embodiments, R 2 is hydrogen. In embodiments, R 3 is hydrogen.

[0146] In embodiments, the compound has the formula: [ka] . R 1 , R 2 , R3, R 4 , R 5 , Ring A, Ring B, z1, z2, and z3 are as described herein, including in compounds of formula (I) and (II).

[0147] In embodiments, the compound has the formula: [ka] . R 1 , R 2 , R3, R 4 , R 5 , Ring A, Ring B, z1, z2, and z3 are as described herein, including in compounds of formula (I) and (II).

[0148] In embodiments, the compound has the formula: [ka] . R 1 , R 2 , R3, R 4 , R 5 , z1, z2, and z3 are as described herein, including in compounds of Formulae (I)-(V).

[0149] In embodiments, the compound has the formula: [ka] . R 1 , R 2 , R 3 , R 4 , R 5 and z2 are as described herein, including in compounds of formulae (I)-(V).

[0150] In embodiments, the compound has the formula: [ka] .R 2 , R 3 , R 4 , R 7 , R 8 , R 15 , R 16 and z2 are as described herein, including in compounds of formulae (I)-(V).

[0151] In embodiments, the compound has the formula: [ka] . R 1 , R 2 , R 3 , R 4 , z1, and z2 are as described herein, including in compounds of Formulae (I)-(V).

[0152] In embodiments, the compound has the formula: [ka] . R 2 , R 3 , R 4 and z2 are as described herein, including in compounds of formulae (I)-(V).

[0153] In embodiments, the compound has the formula: [ka] . R 2 , R 3 , and R 4 is as described herein, including in compounds of formulas (I)-(V).

[0154] In embodiments, the compound has the formula: [ka] . R 4 is as described herein, including in compounds of formulas (I)-(V). In embodiments, R 4 are independently -OR 14 In an embodiment, R 4 are independent, -SR 14 In an embodiment, R 14 are independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 14 are independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 is independently unsubstituted C1-C6 alkyl. In embodiments, R 14 is independently unsubstituted C1-C5 alkyl. In embodiments, R 14 is independently unsubstituted C1-C4 alkyl. In embodiments, R 14 is independently unsubstituted C1-C3 alkyl. In embodiments, R 14 is independently unsubstituted C1-C2 alkyl. In embodiments, R 14 is independently unsubstituted C2-C6 alkyl. In embodiments, R 14 is independently unsubstituted C2-C5 alkyl. In embodiments, R 14 is independently unsubstituted C2-C4 alkyl. In embodiments, R 14 is independently unsubstituted C2-C3 alkyl. In embodiments, R 14 is independently unsubstituted C-C alkyl. In embodiments, R 14 is independently unsubstituted C4-C6 alkyl. In embodiments, R 14 is independently unsubstituted C5-C6 alkyl. In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14 is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R 14 is independently unsubstituted tert-butyl.

[0155] In embodiments, the compound has the formula: [ka] . R 4 is as described herein, including in compounds of formulas (I)-(V). In embodiments, R 4 are independently -OR 14 In an embodiment, R 4 are independent, -SR 14 In an embodiment, R 14 are independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 14 are independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 is independently unsubstituted C1-C6 alkyl. In embodiments, R 14 is independently unsubstituted C1-C5 alkyl. In embodiments, R 14is independently unsubstituted C1-C4 alkyl. In embodiments, R 14 is independently unsubstituted C1-C3 alkyl. In embodiments, R 14 is independently unsubstituted C1-C2 alkyl. In embodiments, R 14 is independently unsubstituted C2-C6 alkyl. In embodiments, R 14 is independently unsubstituted C2-C5 alkyl. In embodiments, R 14 is independently unsubstituted C2-C4 alkyl. In embodiments, R 14 is independently unsubstituted C2-C3 alkyl. In embodiments, R 14 is independently unsubstituted C-C alkyl. In embodiments, R 14 is independently unsubstituted C4-C6 alkyl. In embodiments, R 14 is independently unsubstituted C5-C6 alkyl. In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14 is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R 14 is independently unsubstituted tert-butyl.

[0156] In embodiments, the compound has the formula: [ka] . R 4 is as described herein, including in compounds of formulas (I)-(V). In embodiments, R 4 are independently -OR 14 In an embodiment, R 4 are independent, -SR 14 In an embodiment, R 14 are independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R14 are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 14 are independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 is independently unsubstituted C1-C6 alkyl. In embodiments, R 14 is independently unsubstituted C1-C5 alkyl. In embodiments, R 14 is independently unsubstituted C1-C4 alkyl. In embodiments, R 14 is independently unsubstituted C1-C3 alkyl. In embodiments, R 14 is independently unsubstituted C1-C2 alkyl. In embodiments, R 14 is independently unsubstituted C2-C6 alkyl. In embodiments, R 14 is independently unsubstituted C2-C5 alkyl. In embodiments, R 14 is independently unsubstituted C2-C4 alkyl. In embodiments, R 14 is independently unsubstituted C2-C3 alkyl. In embodiments, R 14is independently unsubstituted C-C alkyl. In embodiments, R 14 is independently unsubstituted C4-C6 alkyl. In embodiments, R 14 is independently unsubstituted C5-C6 alkyl. In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14 is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R 14 is independently unsubstituted tert-butyl.

[0157] In embodiments, the compound has the formula: [ka] .

[0158] In embodiments, the compound has the formula: [ka] .

[0159] In embodiments, the compound has the formula: [ka] .

[0160] In embodiments, the compound has the formula: [ka] .

[0161] In embodiments, the compound has the formula: [ka] .

[0162] In embodiments, the compound has the formula: [ka] .

[0163] In embodiments, the compound has the formula: [ka] .

[0164] In embodiments, R 1 are independently hydrogen, oxo, halogen, -CX 1 3. -CHX 1 2, -OCH2X 1 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 1 3. -OCHX 1 2, -OCH2X 1 , R 30 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 30 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 30 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 30 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 30 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 30X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 1 is a halogen. In an embodiment, X 1 is F. In an embodiment, R 1 are independently halogen, -CX 1 3. -CHX 1 2, -OCH2X 1 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 1 3. -OCHX 1 2, -OCH2X 1 , R 30 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 30 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 30 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 30 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 30 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 30 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0165] R 30 are independently oxo, halogen, -CX 30 3. -CHX 30 2. -CH2X 30, -OCH2X 30 , -OCHX 30 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 30 3. R 31 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 31 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 31 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 31 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 31 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 31 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 30 is a halogen. In an embodiment, X 30 is F.

[0166] R 31 are independently oxo, halogen, -CX 31 3. -CHX 31 2. -CH2X 31 , -OCH2X 31 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX31 3. -OCHX 31 2. R 32 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 32 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 32 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 32 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 32 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 32 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 31 is a halogen. In an embodiment, X 31 is F.

[0167] In embodiments, R 2 are independently hydrogen, oxo, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCH2X 2 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 2 3. -OCHX 2 2. R 33 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 33substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 33 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 33 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 33 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 33 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 2 is a halogen. In an embodiment, X 2 is F.

[0168] In embodiments, R 2 are independently halogen, -CX 2 3. -CHX 2 2, -OCH2X 2 , -CH2X 2 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 2 3. -OCHX 2 2. R 33 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 33 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 33substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 33 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 33 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 33 and substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 2 is hydrogen.

[0169] R 33 are independently oxo, halogen, -CX 33 3. -CHX 33 2. -CHX 33 2, -OCH2X 33 , -OCHX 33 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 33 3. -OCHX 33 2. R 34 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 34 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 34 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 34 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R34 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 34 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 33 is a halogen. In an embodiment, X 33 is F.

[0170] R 34 are independently oxo, halogen, -CX 34 3. -CHX 34 2. -CH2X 34 2, -OCH2X 34 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 34 3. -OCHX 34 2. R 35 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 35 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 35 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 35 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 35 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 35 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).34 is a halogen. In an embodiment, X 34 is F.

[0171] In embodiments, R 3 are independently hydrogen, oxo, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCH2X 3 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 3 3. -OCHX 3 2. R 36 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 36 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 36 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 36 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 36 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 36 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 3 is a halogen. In an embodiment, X 3 is F. In an embodiment, R 3 are independently halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCH2X3 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 3 3. -OCHX 3 2. R 36 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 36 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 36 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 36 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 36 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 36 and substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 3 is hydrogen.

[0172] R 36 are independently oxo, halogen, -CX 36 3. -CHX 36 2. -CH2X 36 , -OCH2X 36 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 36 3. -OCHX 362. R 37 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 37 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 37 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 37 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 37 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 37 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 36 is a halogen. In an embodiment, X 36 is F.

[0173] R 37 are independently oxo, halogen, -CX 37 3. -CHX 37 2. -CH2X 37 , -OCH2X 37 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 37 3. -OCHX 37 2. R 38 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 38substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 38 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 38 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 38 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 38 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 37 is a halogen. In an embodiment, X 37 is F.

[0174] In embodiments, R 4 are independently hydrogen, oxo, halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCH2X 4 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 4 3. -OCHX 4 2. R 39 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 39 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 39substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 39 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 39 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 39 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4 is a halogen. In an embodiment, X 4 is F. In an embodiment, R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCH2X 4 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 4 3. -OCHX 4 2. R 39 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 39 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 39 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 39 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 39 Substituted or unsubstituted aryl (e.g., C6-C10 aryl or C6 aryl), or R 39 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0175] R 39 are independently oxo, halogen, -CX 39 3. -CHX 39 2. -CH2X 39 , -OCH2X 39 , -OCHX 39 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 39 3. -OCHX 39 2. R 40 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 40 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 40 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 40 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 40 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 40 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 39 is a halogen. In an embodiment, X 39 is F.

[0176] R 40 are independently oxo, halogen, -CX 40 3. -CHX 40 2. -CH2X 40 , -OCH2X 40 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 40 3. -OCHX 40 2. R 41 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 41 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 41 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 41 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 41 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 41 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 40 is a halogen. In an embodiment, X 40 is F.

[0177] In embodiments, R 5 are independently hydrogen, oxo, halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -OCH2X 5, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 5 3. -OCHX 5 2. R 42 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 42 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 42 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 42 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 42 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 42 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 5 is a halogen. In an embodiment, X 5 is F. In an embodiment, R 5 are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -OCH2X 5 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 5 3. -OCHX 5 2. R 42substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 42 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 42 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 42 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 42 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 42 It is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0178] R 42 are independently oxo, halogen, -CX 42 3. -CHX 42 2. -CH2X 42 , -OCH2X 42 , -OCHX 42 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 42 3. -OCHX 42 2. R 43 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 43 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 43substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 43 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 43 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 43 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 42 is a halogen. In an embodiment, X 42 is F.

[0179] R 43 are independently oxo, halogen, -CX 43 3. -CHX 43 2. -CH2X 43 , -OCH2X 43 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 43 3. -OCHX 43 2. R 44 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 44 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 44 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 44 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R44 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 44 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 43 is a halogen. In an embodiment, X 43 is F.

[0180] In embodiments, R 7 are independently hydrogen, oxo, halogen, -CX 7 3. -CHX 7 2. -CH2X 7 , -OCH2X 7 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 7 3. -OCHX 7 2. R 48 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 48 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 48 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 48 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 48 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 48X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 7 is a halogen. In an embodiment, X 7 is F. In an embodiment, R 7 and R 8 The substituents may optionally be joined together to form R 48 a substituted or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 4- to 8-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), or R 48 A substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl) may be formed.

[0181] In embodiments, R 7 are independently hydrogen or unsubstituted alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 7are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 7 are independently hydrogen. In embodiments, R 7 is independently unsubstituted alkyl. In embodiments, R 7 is independently unsubstituted C1-C6 alkyl. In embodiments, R 7 is independently unsubstituted C1-C5 alkyl. In embodiments, R 7 is independently unsubstituted C1-C4 alkyl. In embodiments, R 7 is independently unsubstituted C1-C3 alkyl. In embodiments, R 7 is independently unsubstituted C1-C2 alkyl. In embodiments, R 7 is independently unsubstituted C2-C6 alkyl. In embodiments, R 7 is independently unsubstituted C2-C5 alkyl. In embodiments, R 7 is independently unsubstituted C2-C4 alkyl. In embodiments, R 7 is independently unsubstituted C2-C3 alkyl. In embodiments, R 7 is independently unsubstituted C-C alkyl. In embodiments, R 7 is independently unsubstituted C4-C6 alkyl. In embodiments, R 7 is independently unsubstituted C5-C6 alkyl. In embodiments, R 7 is hydrogen. In embodiments, R 7 are independently hydrogen, halogen, -CX 7 3. -CHX 7 2. -CH2X 7 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R attached to the same nitrogen atom 7 and R 8 The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0182] R 48 are independently oxo, halogen, -CX 48 3. -CHX 48 2. -CH2X 48 , -OCH2X 48 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 48 3. -OCHX 48 2. R 49 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 49 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 49 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 49 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 49 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 49 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 48 is a halogen. In an embodiment, X 48 is F.

[0183] R 49 are independently oxo, halogen, -CX 49 3. -CHX 49 2. -CH2X 49 , -OCH2X 49, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 49 3. -OCHX 49 2. R 50 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 50 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 50 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 50 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 50 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 50 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 49 is a halogen. In an embodiment, X 49 is F.

[0184] In embodiments, R 8 are independently hydrogen, oxo, halogen, -CX 8 3. -CHX 8 2. -CH2X 8 , -OCH2X 8 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX8 3. -OCHX 8 2. R 51 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 51 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 51 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 51 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 51 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 51 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 8 is a halogen. In an embodiment, X 8 is F. In an embodiment, X 7 is F. In an embodiment, R 7 and R 8 The substituents may optionally be joined together to form R 51 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 51 A substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl) may be formed.

[0185] In embodiments, R 8 are independently hydrogen or unsubstituted alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 8are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 8 are independently hydrogen. In embodiments, R 8 is independently unsubstituted alkyl. In embodiments, R 8 is independently unsubstituted C1-C6 alkyl. In embodiments, R 8 is independently unsubstituted C1-C5 alkyl. In embodiments, R 8 is independently unsubstituted C1-C4 alkyl. In embodiments, R 8 is independently unsubstituted C1-C3 alkyl. In embodiments, R 8 is independently unsubstituted C1-C2 alkyl. In embodiments, R 8 is independently unsubstituted C2-C6 alkyl. In embodiments, R 8 is independently unsubstituted C2-C5 alkyl. In embodiments, R 8 is independently unsubstituted C2-C4 alkyl. In embodiments, R 8 is independently unsubstituted C2-C3 alkyl. In embodiments, R 8is independently unsubstituted C-C alkyl. In embodiments, R 8 is independently unsubstituted C4-C6 alkyl. In embodiments, R 8 is independently unsubstituted C5-C6 alkyl. In embodiments, R 8 is hydrogen. In embodiments, R 8 are independently hydrogen, halogen, -CX 8 3. -CHX 8 2. -CH2X 8 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0186] R 51 are independently oxo, halogen, -CX 51 3. -CHX 51 2. -CH2X 51 , -OCH2X 51 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 51 3. -OCHX 51 2. R 52 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 52 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 52 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 52substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 52 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 52 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 51 is a halogen. In an embodiment, X 51 is F.

[0187] R 52 are independently oxo, halogen, -CX 52 3. -CHX 52 2. -CH2X 52 , -OCH2X 52 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 52 3. -OCHX 52 2. R 53 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 53 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 53 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 53 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 53 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 53X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 52 is a halogen. In an embodiment, X 52 is F.

[0188] In embodiments, R 9 are independently hydrogen, oxo, halogen, -CX 9 3. -CHX 9 2. -CH2X 9 , -OCH2X 9 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 9 3. -OCHX 9 2. R 54 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 54 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 54 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 54 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 54 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 54 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 9 is a halogen. In an embodiment, X 9 is F. In an embodiment, R 9is hydrogen. In embodiments, R 9 are independently hydrogen, halogen, -CX 9 3. -CHX 9 2. -CH2X 9 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0189] R 54 are independently oxo, halogen, -CX 54 3. -CHX 54 2. -CH2X 54 , -OCH2X 54 , -OCHX 54 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 54 3. -OCHX 54 2. R 55 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 55 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 55 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 55 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 55 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 55X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 54 is a halogen. In an embodiment, X 54 is F.

[0190] R 55 are independently oxo, halogen, -CX 55 3. -CHX 55 2. -CH2X 55 , -OCH2X 55 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 55 3. -OCHX 55 2. R 56 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 56 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 56 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 56 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 56 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 56 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 55 is a halogen. In an embodiment, X 55 is F.

[0191] In embodiments, R 10 are independently hydrogen, oxo, halogen, -CX 10 3. -CHX 10 2. -CH2X 10 , -OCH2X 10 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 10 3. -OCHX 10 2. R 57 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 57 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 57 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 57 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 57 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 57 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 10 is a halogen. In an embodiment, X 10 is F. In an embodiment, R 10 is hydrogen. In embodiments, R 10 are independently hydrogen, halogen, -CX 10 3. -CHX 10 2. -CH2X 10, -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0192] R 57 are independently oxo, halogen, -CX 57 3. -CHX 57 2. -CH2X 57 , -OCH2X 57 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 57 3. -OCHX 57 2. R 58 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 58 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 58 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 58 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 58 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 58 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 57 is a halogen. In an embodiment, X 57 is F.

[0193] R 58 are independently oxo, halogen, -CX 58 3. -CHX 58 2. -CH2X 58 , -OCH2X 58 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 58 3. -OCHX 58 2. R 59 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 59 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 59 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 59 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 59 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 59 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 58 is a halogen. In an embodiment, X 58 is F.

[0194] In embodiments, R 11 are independently hydrogen, oxo, halogen, -CX 11 3. -CHX 11 2. -CH2X 11 , -OCH2X 11, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 11 3. -OCHX 11 2. R 60 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 60 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 60 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 60 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 60 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 60 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 11 is a halogen. In an embodiment, X 11 is F. In an embodiment, R 11 and R 12 The substituents may optionally be joined together to form R 60 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 60 It may form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 11 is hydrogen. In embodiments, R 11are independently hydrogen, halogen, -CX 11 3. -CHX 11 2. -CH2X 11 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0195] R 60 are independently oxo, halogen, -CX 60 3. -CHX 60 2. -CH2X 60 , -OCH2X 60 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 60 3. -OCHX 60 2. R 61 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 61 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 61 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 61 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 61 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 61 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).60 is a halogen. In an embodiment, X 60 is F.

[0196] R 61 are independently oxo, halogen, -CX 61 3. -CHX 61 2. -CH2X 61 , -OCH2X 61 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 61 3. -OCHX 61 2. R 62 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 62 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 62 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 62 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 62 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 62 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 61 is a halogen. In an embodiment, X 61 is F.

[0197] In embodiments, R 12 are independently hydrogen, oxo, halogen, -CX 12 3. -CHX12 2. -CH2X 12 , -OCH2X 12 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 12 3. -OCHX 12 2. R 63 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 63 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 63 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 63 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 63 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 63 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 12 is a halogen. In an embodiment, X 12 is F. In an embodiment, R 11 and R 12 The substituents may optionally be joined together to form R 63 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 63 It may form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).12 is hydrogen. In embodiments, R 12 are independently hydrogen, halogen, -CX 12 3. -CHX 12 2. -CH2X 12 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0198] R 63 are independently oxo, halogen, -CX 63 3. -CHX 63 2. -CH2X 63 , -OCH2X 63 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 63 3. -OCHX 63 2. R 64 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 64 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 64 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 64 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 64 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 64X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 63 is a halogen. In an embodiment, X 63 is F.

[0199] R 64 are independently oxo, halogen, -CX 64 3. -CHX 64 2. -CH2X 64 , -OCH2X 64 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 64 3. -OCHX 64 2. R 65 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 65 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 65 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 65 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 65 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 65 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 64 is a halogen. In an embodiment, X 64 is F.

[0200] In embodiments, R 13 are independently hydrogen, oxo, halogen, -CX 13 3. -CHX 13 2. -CH2X 13 , -OCH2X 13 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 13 3. -OCHX 13 2. R 66 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 66 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 66 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 66 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 66 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 66 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 13 is a halogen. In an embodiment, X 13 is F. In an embodiment, R 13 is hydrogen. In embodiments, R 13 are independently hydrogen, halogen, -CX 13 3. -CHX 13 2. -CH2X 13, -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0201] R 66 are independently oxo, halogen, -CX 66 3. -CHX 66 2. -CH2X 66 , -OCH2X 66 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 66 3. -OCHX 66 2. R 67 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 67 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 67 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 67 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 67 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 67 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 66 is a halogen. In an embodiment, X 66 is F.

[0202] R 67 are independently oxo, halogen, -CX 67 3. -CHX 67 2. -CH2X 67 , -OCH2X 67 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 67 3. -OCHX 67 2. R 68 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 68 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 68 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 68 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 68 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 68 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 67 is a halogen. In an embodiment, X 67 is F.

[0203] In embodiments, R 14 are independently hydrogen, oxo, halogen, -CX 14 3. -CHX 14 2. -CH2X 14 , -OCH2X 14, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 14 3. -OCHX 14 2. R 69 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 69 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 69 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 69 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 69 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 69 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 14 is a halogen. In an embodiment, X 14 is F. In an embodiment, R 14 is hydrogen. In embodiments, R 14 are independently hydrogen, halogen, -CX 14 3. -CHX 14 2. -CH2X 14 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0204] R69 are independently oxo, halogen, -CX 69 3. -CHX 69 2. -CH2X 69 , -OCH2X 69 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 69 3. -OCHX 69 2. R 70 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 70 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 70 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 70 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 70 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 70 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 69 is a halogen. In an embodiment, X 69 is F.

[0205] R 70 are independently oxo, halogen, -CX 70 3. -CHX 70 2. -CH2X 70 , -OCH2X 70, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 70 3. -OCHX 70 2. R 71 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 71 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 71 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 71 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 71 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 71 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 70 is a halogen. In an embodiment, X 70 is F.

[0206] In embodiments, R 15 are independently hydrogen, oxo, halogen, -CX 15 3. -CHX 15 2. -CH2X 15 , -OCH2X 15 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX15 3. -OCHX 15 2. R 72 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 72 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 72 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 72 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 72 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 72 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 15 is a halogen. In an embodiment, X 15 is F. In an embodiment, R 15 and R 16 The substituents may optionally be joined together to form R 72 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 72 It may form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 15 is hydrogen. In embodiments, R 15 are independently hydrogen, halogen, -CX 15 3. -CHX 15 2. -CH2X 15, -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0207] In embodiments, R 15 are independently hydrogen or unsubstituted alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 15 are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 15 are independently hydrogen. In embodiments, R 15 is independently unsubstituted alkyl. In embodiments, R 15 is independently unsubstituted C1-C6 alkyl. In embodiments, R 15 is independently unsubstituted C1-C5 alkyl. In embodiments, R 15 is independently unsubstituted C1-C4 alkyl. In embodiments, R15 is independently unsubstituted C1-C3 alkyl. In embodiments, R 15 is independently unsubstituted C1-C2 alkyl. In embodiments, R 15 is independently unsubstituted C2-C6 alkyl. In embodiments, R 15 is independently unsubstituted C2-C5 alkyl. In embodiments, R 15 is independently unsubstituted C2-C4 alkyl. In embodiments, R 15 is independently unsubstituted C2-C3 alkyl. In embodiments, R 15 is independently unsubstituted C-C alkyl. In embodiments, R 15 is independently unsubstituted C4-C6 alkyl. In embodiments, R 15 is independently unsubstituted C5-C6 alkyl.

[0208] R 72 are independently oxo, halogen, -CX 72 3. -CHX 72 2. -CH2X 72 , -OCH2X 72 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 72 3. -OCHX 72 2. R 73 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 73 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 73 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 73substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 73 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 73 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 72 is a halogen. In an embodiment, X 72 is F.

[0209] R 73 are independently oxo, halogen, -CX 73 3. -CHX 73 2. -CH2X 73 , -OCH2X 73 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 73 3. -OCHX 73 2. R 74 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 74 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 74 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 74 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 74 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 74X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 73 is a halogen. In an embodiment, X 73 is F.

[0210] In embodiments, R 16 are independently hydrogen, oxo, halogen, -CX 16 3. -CHX 16 2. -CH2X 16 , -OCH2X 16 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 16 3. -OCHX 16 2. R 75 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 75 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 75 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 75 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 75 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 75 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 16 is a halogen. In an embodiment, X 16 is F. In an embodiment, R15 and R 16 The substituents may optionally be joined together to form R 75 Substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 75 It may form a substituted or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 16 is hydrogen. In embodiments, R 16 are independently hydrogen, halogen, -CX 16 3. -CHX 16 2. -CH2X 16 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0211] In embodiments, R 16 are independently hydrogen or unsubstituted alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C1-C6 alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C1-C5 alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C1-C3 alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C1-C2 alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C2-C5 alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 16are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C-C alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C5-C6 alkyl. In embodiments, R 16 are independently hydrogen. In embodiments, R 16 is independently unsubstituted alkyl. In embodiments, R 16 is independently unsubstituted C1-C6 alkyl. In embodiments, R 16 is independently unsubstituted C1-C5 alkyl. In embodiments, R 16 is independently unsubstituted C1-C4 alkyl. In embodiments, R 16 is independently unsubstituted C1-C3 alkyl. In embodiments, R 16 is independently unsubstituted C1-C2 alkyl. In embodiments, R 16 is independently unsubstituted C2-C6 alkyl. In embodiments, R 16 is independently unsubstituted C2-C5 alkyl. In embodiments, R 16 is independently unsubstituted C2-C4 alkyl. In embodiments, R 16 is independently unsubstituted C2-C3 alkyl. In embodiments, R 16 is independently unsubstituted C-C alkyl. In embodiments, R 16 is independently unsubstituted C4-C6 alkyl. In embodiments, R 16 is independently unsubstituted C5-C6 alkyl.

[0212] R 75 are independently oxo, halogen, -CX 75 3. -CHX 75 2. -CH2X 75 , -OCH2X 75 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 753. -OCHX 75 2. R 76 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 76 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 76 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 76 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 76 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 76 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 75 is a halogen. In an embodiment, X 75 is F.

[0213] R 76 are independently oxo, halogen, -CX 76 3. -CHX 76 2. -CH2X 76 , -OCH2X 76 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 76 3. -OCHX 76 2. R 77 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 77substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 77 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 77 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 77 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 77 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 76 is a halogen. In an embodiment, X 76 is F.

[0214] In embodiments, R 17 are independently hydrogen, oxo, halogen, -CX 17 3. -CHX 17 2. -CH2X 17 , -OCH2X 17 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 17 3. -OCHX 17 2. R 78 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 78 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 78substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 78 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 78 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 78 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 17 is a halogen. In an embodiment, X 17 is F. In an embodiment, R 17 is hydrogen. In embodiments, R 17 are independently hydrogen, halogen, -CX 17 3. -CHX 17 2. -CH2X 17 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0215] R 78 are independently oxo, halogen, -CX 78 3. -CHX 78 2. -CH2X 78 , -OCH2X 78 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 78 3. -OCHX 78 2. R 79 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 79substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 79 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 79 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 79 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 79 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 78 is a halogen. In an embodiment, X 78 is F.

[0216] R 79 are independently oxo, halogen, -CX 79 3. -CHX 79 2. -CH2X 79 , -OCH2X 79 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 79 3. -OCHX 79 2. R 80 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 80 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 80substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 80 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 80 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 80 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 79 is a halogen. In an embodiment, X 79 is F.

[0217] In embodiments, R 18 are independently hydrogen, oxo, halogen, -CX 18 3. -CHX 18 2. -CH2X 18 , -OCH2X 18 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 18 3. -OCHX 18 2. R 81 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 81 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 81 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 81substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 81 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 81 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 18 is a halogen. In an embodiment, X 18 is F. In an embodiment, R 18 is hydrogen. In embodiments, R 18 are independently hydrogen, halogen, -CX 18 3. -CHX 18 2. -CH2X 18 , -CN, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0218] R 81 are independently oxo, halogen, -CX 81 3. -CHX 81 2. -CH2X 81 , -OCH2X 81 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 81 3. -OCHX 81 2. R 82 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 82substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 82 substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 82 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 82 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 82 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 81 is a halogen. In an embodiment, X 81 is F.

[0219] R 82 are independently oxo, halogen, -CX 82 3. -CHX 82 2. -CH2X 82 , -OCH2X 82 , -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 82 3. -OCHX 82 2. R 83 substituted or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 83 substituted or unsubstituted heteroalkyl (e.g., 2- to 10-membered heteroalkyl, 2- to 8-membered heteroalkyl, 4- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), R 83substituted or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), R 83 substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 83 Substituted or unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or R 83 X is a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 82 is a halogen. In an embodiment, X 82 is F.

[0220] R 32 , R 35 , R 38 , R 41 , R 44 , R 50 , R 53 , R 56 , R 59 , R 62 , R 65 , R 68 , R 71 , R 74 , R 77 , R 80 , and R 83are independently hydrogen, oxo, halogen, -CF3, -CHF2, -CH2F, -OCH2F, -OCF3, -OCHF2, -CCl3, -CHCl2, -CH2Cl, -OCH2Cl, -OCCl3, -OCHCl2, -CBr3, -CHBr2, -CH2Br, -OCH2Br, -OCBr3, -OCHBr2, -CI3, -CHI2, -CH2I, -OCH2I, -OCI3, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O )H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 32 , R 35 , R 38 , R 41 , R 44 , R 50 , R 53 , R 56 , R 59 , R 62 , R 65 , R 68 , R 71 , R 74 , R 77 , R 80 , and R 83are independently oxo, halogen, -CF3, -CHF2, -CH2F, -OCH2F, -OCF3, -OCHF2, -CCl3, -CHCl2, -CH2Cl, -OCH2Cl, -OCCl3, -OCHCl2, -CBr3, -CHBr2, -CH2Br, -OCH2Br, -OCBr3, -OCHBr2, -CI3, -CHI2, -CH2I, -OCH2I, -OCI3, -OCHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O) H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C4-C8 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 aryl or C6 aryl), or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0221] In some embodiments, the compound is any one of the compounds described herein (eg, in the aspects, embodiments, claims, figures, tables, or examples).

[0222] In some embodiments, the compounds described herein include R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R15 , R 16 , R 17 , R 18 , R 19 In such embodiments, each variable may optionally be different and may be appropriately labeled to more clearly distinguish each group. For example, each R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and / or R 19 are different, they are respectively, e.g., R 1.1 , R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 , R 5.6 , R 5.7 , R 7.1 , R 7.2 , R 7.3 , R 7.4 , R 7.5 , R 7.6 , R 7.7 , R 7.8 , R 7.9 , R 7.10 , R 7.11 , R 7.12 , R 7.13 , R 7.14 , R 7.15 , R 7.16 , R 7.17 , R 7.18 , R 7.19 , R 7.20 , R 7.21 , R7.22 、R 7.23 、R 7.24 、R 7.25 、R 7.26 、R 7.27 、R 7.28 、R 7.29 、R 7.30 、R 7.31 、R 7.32 、R 7.33 、R 7.34 、R 7.35 、R 7.36 、R 7.37 、R 7.38 、R 7.39 、R 7.40 、R 7.41 、R 7.42 、R 8.1 、R 8.2 、R 8.3 、R 8.4 、R 8.5 、R 8.6 、R 8.7 、R 8.8 、R 8.9 、R 8.10 、R 8.11 、R 8.12 、R 8.13 、R 8.14 、R 8.15 、R 8.16 、R 8.17 、R 8.18 、R 8.19 、R 8.20 、R 8.21 、R 8.22 、R 8.23 、R 8.24 、R 8.25 、R 8.26 、R 8.27 、R 8.28 、R 8.29 、R 8.30 、R 8.31 、R 8.32 、R 8.33 、R 8.34 、R 8.35 、R 8.36 、R 8.37 、R 8.38 、R 8.39 、R 8.40 、R 8.41 、R 8.42 、R 9.1 、R 9.2 、R 9.3 、R 9.4、R 9.5 、R 9.6 、R 9.7 、R 9.8 、R 9.9 、R 9.10 、R 9.11 、R 9.12 、R 9.13 、R 9.14 、R 9.15 、R 9.16 、R 9.17 、R 9.18 、R 9.19 、R 9.20 、R 9.21 、R 9.22 、R 9.23 、R 9.24 、R 9.25 、R 9.26 、R 9.27 、R 9.28 、R 9.29 、R 9.30 、R 9.31 、R 9.32 、R 9.33 、R 9.34 、R 9.35 、R 9.36 、R 9.37 、R 9.38 、R 9.39 、R 9.40 、R 9.41 、R 9.42 、R 10.1 、R 10.2 、R 10.3 、R 10.4 、R 10.5 、R 10.6 、R 10.7 、R 10.8 、R 10.9 、R 10.10 、R 10.11 、R 10.12 、R 10.13 、R 10.14 、R 10.15 、R 10.16 、R 10.17 、R 10.18 、R 10.19 、R 10.20 、R 10.21 、R 10.22 、R 10.23 、R 10.24 、R 10.25 、R 10.26 、R 10.27 、R 10.28 、R10.29 、R 10.30 、R 10.31 、R 10.32 、R 10.33 、R 10.34 、R 10.35 、R 10.36 、R 10.37 、R 10.38 、R 10.39 、R 10.40 、R 10.41 、R 10.42 、R 11.1 、R 11.2 、R 11.3 、R 11.4 、R 11.5 、R 11.6 、R 11.7 、R 11.8 、R 11.9 、R 11.10 、R 11.11 、R 11.12 、R 11.13 、R 11.14 、R 11.15 、R 11.16 、R 11.17 、R 11.18 、R 11.19 、R 11.20 、R 11.21 、R 11.22 、R 11.23 、R 11.24 、R 11.25 、R 11.26 、R 11.27 、R 11.28 、R 11.29 、R 11.30 、R 11.31 、R 11.32 、R 11.33 、R 11.34 、R 11.35 、R 11.36 、R 11.37 、R 11.38 、R 11.39 、R 11.40 、R 11.41 、R 11.42 、R 12.1 、R 12.2 、R 12.3 、R 12.4 、R 12.5 、R 12.6 、R 12.7 、R 12.8 、R 12.9 、R 12.10 、R 12.11、R 12.12 、R 12.13 、R 12.14 、R 12.15 、R 12.16 、R 12.17 、R 12.18 、R 12.19 、R 12.20 、R 12.21 、R 12.22 、R 12.23 、R 12.24 、R 12.25 、R 12.26 、R 12.27 、R 12.28 、R 12.29 、R 12.30 、R 12.31 、R 12.32 、R 12.33 、R 12.34 、R 12.35 、R 12.36 、R 12.37 、R 12.38 、R 12.39 、R 12.40 、R 12.41 、R 12.42 、R 13.1 、R 13.2 、R 13.3 、R 13.4 、R 13.5 、R 13.6 、R 13.7 、R 13.8 、R 13.9 、R 13.10 、R 13.11 、R 13.12 、R 13.13 、R 13.14 、R 13.15 、R 13.16 、R 13.17 、R 13.18 、R 13.19 、R 13.20 、R 13.21 、R 13.22 、R 13.23 、R 13.24 、R 13.25 、R 13.26 、R 13.27 、R 13.28 、R 13.29 、R 13.30 、R 13.31 、R 13.32 、R 13.33 、R 13.34 、R 13.35 、R13.36 、R 13.37 、R 13.38 、R 13.39 、R 13.40 、R 13.41 、R 13.42 、R 14.1 、R 14.2 、R 14.3 、R 14.4 、R 14.5 、R 14.6 、R 14.7 、R 14.8 、R 14.9 、R 14.10 、R 14.11 、R 14.12 、R 14.13 、R 14.14 、R 14.15 、R 14.16 、R 14.17 、R 14.18 、R 14.19 、R 14.20 、R 14.21 、R 14.22 、R 14.23 、R 14.24 、R 14.25 、R 14.26 、R 14.27 、R 14.28 、R 14.29 、R 14.30 、R 14.31 、R 14.32 、R 14.33 、R 14.34 、R 14.35 、R 14.36 、R 14.37 、R 14.38 、R 14.39 、R 14.40 、R 14.41 、R 14.42 、R 15.1 、R 15.2 、R 15.3 、R 15.4 、R 15.5 、R 15.6 、R 15.7 、R 15.8 、R 15.9 、R 15.10 、R 15.11 、R 15.12 、R 15.13 、R 15.14 、R 15.15 、R 15.16 、R 15.17 、R 15.18、R 15.19 、R 15.20 、R 15.21 、R 15.22 、R 15.23 、R 15.24 、R 15.25 、R 15.26 、R 15.27 、R 15.28 、R 15.29 、R 15.30 、R 15.31 、R 15.32 、R 15.33 、R 15.34 、R 15.35 、R 15.36 、R 15.37 、R 15.38 、R 15.39 、R 15.40 、R 15.41 、R 15.42 、R 16.1 、R 16.2 、R 16.3 、R 16.4 、R 16.5 、R 16.6 、R 16.7 、R 16.8 、R 16.9 、R 16.10 、R 16.11 、R 16.12 、R 16.13 、R 16.14 、R 16.15 、R 16.16 、R 16.17 、R 16.18 、R 16.19 、R 16.20 、R 16.21 、R 16.22 、R 16.23 、R 16.24 、R 16.25 、R 16.26 、R 16.27 、R 16.28 、R 16.29 、R 16.30 、R 16.31 、R 16.32 、R 16.33 、R 16.34 、R 16.35 、R 16.36 、R 16.37 、R 16.38 、R 16.39 、R 16.40 、R 16.41 、R 16.42、R 17.1 、R 17.2 、R 17.3 、R 17.4 、R 17.5 、R 17.6 、R 17.7 、R 17.8 、R 17.9 、R 17.10 、R 17.11 、R 17.12 、R 17.13 、R 17.14 、R 17.15 、R 17.16 、R 17.17 、R 17.18 、R 17.19 、R 17.20 、R 17.21 、R 17.22 、R 17.23 、R 17.24 、R 17.25 、R 17.26 、R 17.27 、R 17.28 、R 17.29 、R 17.30 、R 17.31 、R 17.32 、R 17.33 、R 17.34 、R 17.35 、R 17.36 、R 17.37 、R 17.38 、R 17.39 、R 17.40 、R 17.41 、R 17.42 、R 18.1 、R 18.2 、R 18.3 、R 18.4 、R 18.5 、R 18.6 、R 18.7 、R 18.8 、R 18.9 、R 18.10 、R 18.11 、R 18.12 、R 18.13 、R 18.14 、R 18.15 、R 18.16 、R 18.17 、R 18.18 、R 18.19 、R 18.20 、R 18.21 、R 18.22 、R 18.23 、R 18.24 、R18.25 , R 18.26 , R 18.27 , R 18.28 , R 18.29 , R 18.30 , R 18.31 , R 18.32 , R 18.33 , R 18.34 , R 18.35 , R 18.36 , R 18.37 , R 18.38 , R 18.39 , R 18.40 , R 18.41 , R 18.42 It can also be called R 1 The definition of R 1.1 , R 1.2 , R 1.3 , R 1.4 , R 1.5 It is assumed that R 4 is R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 It is assumed that R 5 is R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 , R 5.6 , R 5.7 It is assumed that R 7 is R 7.1 , R 7.2 , R 7.3 , R 7.4 , R 7.5 , R 7.6 , R 7.7 , R 7.8 , R 7.9 , R 7.10 , R 7.11 , R 7.12 , R 7.13 , R 7.14 , R 7.15 , R 7.16 , R 7.17 , R 7.18 , R 7.19 , R 7.20 , R 7.21 , R 7.22 , R 7.23 , R 7.24 , R 7.25 , R 7.26, R 7.27 , R 7.28 , R 7.29 , R 7.30 , R 7.31 , R 7.32 , R 7.33 , R 7.34 , R 7.35 , R 7.36 , R 7.37 , R 7.38 , R 7.39 , R 7.40 [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​, R 9.7 , R 9.8 , R 9.9 , R 9.10 , R 9.11 , R 9.12 , R 9.13 , R 9.14 , R 9.15 , R 9.16 , R 9.17 , R 9.18 , R 9.19 , R 9.20 , R 9.21 , R 9.22 , R 9.23 , R 9.24 , R 9.25 , R 9.26 , R 9.27 , R 9.28 , R 9.29 , R 9.30 , R 9.31 , R 9.32 , R 9.33 , R 9.34 , R 9.35 , R 9.36 , R 9.37 , R 9.38 , R 9.39 , R 9.40 , R 9.41 , R 9.42 is assumed; R 10 is R 10.1 , R 10.2 , R 10.3 , R 10.4 , R 10.5 , R 10.6 , R 10.7 , R 10.8 , R 10.9 , R 10.10 , R 10.11 , R 10.12 , R 10.13 , R 10.14 , R 10.15 , R 10.16 , R 10.17 , R 10.18 , R 10.19 , R 10.20 , R 10.21 , R 10.22 , R 10.23 , R 10.24 , R 10.25 , R 10.26 , R 10.27 , R 10.28 , R 10.29 , R10.30 , R 10.31 , R 10.32 , R 10.33 , R 10.34 , R 10.35 , R 10.36 , R 10.37 , R 10.38 , R 10.39 , R 10.40 , R 10.41 , R 10.42 is assumed; R 11 is R 11.1 , R 11.2 , R 11.3 , R 11.4 , R 11.5 , R 11.6 , R 11.7 , R 11.8 , R 11.9 , R 11.10 , R 11.11 , R 11.12 , R 11.13 , R 11.14 , R 11.15 , R 11.16 , R 11.17 , R 11.18 , R 11.19 , R 11.20 , R 11.21 , R 11.22 , R 11.23 , R 11.24 , R 11.25 , R 11.26 , R 11.27 , R 11.28 , R 11.29 , R 11.30 , R 11.31 , R 11.32 , R 11.33 , R 11.34 , R 11.35 , R[[ID=9​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​12.10 , R 12.11 , R 12.12 , R 12.13 , R 12.14 , R 12.15 , R 12.16 , R 12.17 , R 12.18 , R 12.19 , R 12.20 , R 12.21 , R 12.22 , R 12.23 , R 12.24 , R 12.25 , R 12.26 , R 12.27 , R 12.28 , R 12.29 , R 12.30 , R 12.31 , R 12.32 , R 12.33 , R 12.34 , R 12.35 , R 12.36 , R 12.37 , R 12.38 , R 12.39 , R 12.40 , R 12.41 , R 12.42 is assumed; R 13 is R 13.1 , R 13.2 , R 13.3 , R 13.4 , R 13.5 , R 13.6 , R 13.7 , R 13.8 , R 13.9 , R 13.10 , R 13.11 , R 13.12 , R 13.13 , R 13.14 , R 13.15 , R 13.16 , R 13.17 , R 13.18 , R 13.19 , R 13.20 , R 13.21 , R 13.2 2 , R 13.23 , R 13.24 , R 13.25 , R 13.26 , R 13.27 , R 13.28 , R<00033​​​​, R 13.32 , R 13.33 , R 13.34 , R 13.35 , R 13.36 , R 13.37 , R 13.38 , R 13.39 , R 13.40 , R 13.41 , R 13.42 is assumed; R 14 is R 14.1 , R 14.2 , R 14.3 , R 14.4 , R 14.5 , R 14.6 , R 14.7 , R 14.8 , R 14.9 , R 14.10 , R 14.11 , R 14.12 , R 14.13 , R 14.14 , R 14.15 , R 14.16 , R 14.17 , R 14.18 , R 14.19 , R 14.20 , R 14.21 , R 14.22 , R 14.23 , R 14.24 , R 14.25 , R 14.26 , R 14.27 , R 14.28 , R 14.29 , R 14.30 , R 14.31 , R 14.32 , R 14.33 , R 14.34 , R 14.35 , R 14.36 , R 14.37 , R 14.38 , R 14.39 , R 14.40 , R 14.41 , R 14.42 is assumed; R 15 is R 15.1 , R 15.2 , R 15.3 , R 15.4 , R 15.5 , R 15.6 , R 15.7 , R 15.8 , R 15.9 , R 15.10 , R 15.11, R 15.12 , R 15.13 , R 15.14 , R 15.15 , R 15.16 , R 15.17 , R 15.18 , R 15.19 , R 15.20 , R 15.21 , R 15.22 , R 15.23 , R 15.24 , R 15.25 , R 15.26 , R 15.27 , R 15.28 , R 15.29 , R 15.30 , R 15.31 , R 15.32 , R 15.33 , R 15.34 , R 15.35 , R 15.36 , R 15.37 , R 15.38 , R 15.39 , R 15.40 , R 15.41 , R 15.42 is assumed; R 16 is R 16.1 , R 16.2 , R 16.3 , R 16.4 , R 16.5 , R 16.6 , R 16.7 , R 16.8 , R 16.9 , R 16.10 , R 16.11 , R 16.12 , R 16.13 , R 16.14 , R 16.15 , R 16.16 , R 16.17 , R 16.18 , R 16.19 , R 16.20 , R 16.21 , R 16.22 , R 16.23 , R 16.24 , R 16.25 , R 16.26 , R 16.27 , R 16.28 , R 16.29 , R 16.30 , R 16.31 , R 16.32 , R 16.33 , R 16.34 , R16.35 , R 16.36 , R 16.37 , R 16.38 , R 16.39 , R 16.40 , R 16.41 , R 16.42 It is assumed that R 17 is R 17.1 , R 17.2 , R 17.3 , R 17.4 , R 17.5 , R 17.6 , R 17.7 , R 17.8 , R 17.9 , R 17.10 , R 17.11 , R 17.12 , R 17.13 , R 17.14 , R 17.15 , R 17.16 , R 17.17 , R 17.18 , R 17.19 , R 17.20 , R 17.21 , R 17.22 , R 17.23 , R 17.24 , R 17.25 , R 17.26 , R 17.27 , R 17.28 , R 17.29 , R 17.30 , R 17.31 , R 17.32 , R 17.33 , R 17.34 , R 17.35 , R 17.36 , R 17.37 , R 17.38 , R 17.39 , R 17.40 , R 17.41 , R 17.42 and / or R 18 is R 18.1 , R 18.2 , R 18.3 , R 18.4 , R 18.5 , R 18.6 , R 18.7 , R 18.8 , R 18.9 , R 18.10 , R 18.11 , R 18.12 , R 18.13 , R18.14 , R 18.15 , R 18.16 , R 18.17 , R 18.18 , R 18.19 , R 18.20 , R 18.21 , R 18.22 , R 18.23 , R 18.24 , R 18.25 , R 18.26 , R 18.27 , R 18.28 , R 18.29 , R 18.30 , R 18.31 , R 18.32 , R 18.33 , R 18.34 , R 18.35 , R 18.36 , R 18.37 , R 18.38 , R 18.39 , R 18.40 , R 18.41 , R 18.42 It is assumed that R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Variables used within the definitions of and / or other variables that appear in multiple instances and are different may similarly be appropriately labeled to more clearly distinguish each group. In some embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, claim, table, scheme, diagram, or figure).

[0223] In embodiments, the compound has the formula: [ka] . R 2 , R 3 , R 5and z3 are as described herein, including in compounds of formulae (I)-(V). 1.1 , R 1.2 , and R 1.3 are each independently selected from R as described herein, including in embodiments. 1 This is the part of R 4.1 , R 4.2 , and R 4.3 are each independently selected from R as described herein, including in embodiments. 4 In an embodiment, z3 is 0. In an embodiment, one or more R 1.1 , R 1.2 , R 1.3 , R 4.1 , R 4.2 , R 4.3 , R 2 , and / or R 3 is hydrogen. In embodiments, R 1.1 , R 1.2 , and / or R 1.3 is hydrogen. In embodiments, R 4.1 , R 4.2 , and / or R 4.3 is hydrogen. In embodiments, R 2 is hydrogen. In embodiments, R 3 is hydrogen. In embodiments, R 4.1 is hydrogen and R 4.2 is -OH and R 4.3 is hydrogen. In embodiments, R 4.1 is hydrogen and R 4.2 is hydrogen and R 4.3 is —OH. In embodiments, R 4.1 is hydrogen and R 4.2 is unsubstituted methoxy, and R 4.3 is hydrogen. In embodiments, R 4.1 is hydrogen and R 4.2 is hydrogen and R 4.3 is unsubstituted methoxy. 5 It will be understood that is a floating substituent and may be located on either or both of the rings.

[0224] In embodiments, the compound has the formula: [ka] . R 2 , R 3 , R 5 and z3 are as described herein, including in compounds of formulae (I)-(V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 , R 1.2 , and R 1.3 are each independently selected from R as described herein, including in embodiments. 1 This is the part of R 4.1 and R 4.3 are each independently selected from R as described herein, including in embodiments. 4 This is the part.

[0225] W 1 is N or C(R 4.2 ) is. W 2 is N or C(R 5.1 ) is. W 3 is N or C(R 5.2 ) R 5.1 and R 5.2 are each independently selected from R as described herein, including in embodiments. 5 This is the part of R 4.2 are independently selected from R as described herein, including in embodiments. 4 In an embodiment, W 1 is N. In an embodiment, W 2 is N. In an embodiment, W 3 is N. In an embodiment, W 1 is C(R 4.2 In an embodiment, W 2 is C(R 5.1 In an embodiment, W 3 is C(R 5.2 In an embodiment, W 1 is CH. In an embodiment, W2 is CH. In an embodiment, W 3 is CH.

[0226] In embodiments, the compound has the formula: [ka] . R 2 , R 3 , R 5 and z3 are as described herein, including in compounds of formulae (I)-(V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 and R 1.3 are each independently selected from R as described herein, including in embodiments. 1 This is the part of R 4.1 and R 4.3 are each independently selected from R as described herein, including in embodiments. 4 This is the part.

[0227] In embodiments, the compound has the formula: [ka] . R 2 , R 3 , R 5 and z3 are as described herein, including in compounds of formulae (I)-(V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 and R 1.3 are each independently selected from R as described herein, including in embodiments. 1 This is the part of R 4.1 , R 4.2 , and R 4.3 are each independently selected from R as described herein, including in embodiments. 4 This is the part.

[0228] In embodiments, the compound has the formula: [ka] . R 2 , R 3 , R 5 and z3 are as described herein, including in compounds of formulae (I)-(V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 and R 1.3 are each independently selected from R as described herein, including in embodiments. 1 This is the part of R 4.1 and R 4.3 are each independently selected from R as described herein, including in embodiments. 4 This is the part.

[0229] W 1 is N or C(R 4.2 ) is. W 2 is N or C(R 5.1 ) is. W 3 is N or C(R 5.2 ) R 5.1 and R 5.2 are each independently selected from R as described herein, including in embodiments. 5 This is the part of R 4.2 are independently selected from R as described herein, including in embodiments. 4 In an embodiment, W 1 is N. In an embodiment, W 2 is N. In an embodiment, W 3 is N. In an embodiment, W 1 is C(R 4.2 In an embodiment, W 2 is C(R 5.1 In an embodiment, W 3 is C(R 5.2 In an embodiment, W 1 is CH. In an embodiment, W 2is CH. In an embodiment, W 3 is CH.

[0230] In embodiments of compounds of Formulae (VI)-(X), R 2 is hydrogen. In embodiments of compounds of Formulas (VI)-(X), R 3 is hydrogen. In embodiments of compounds of Formulas (VI)-(X), R 2 and R 3 is hydrogen.

[0231] In embodiments, R 1.1 are independently halogen. In embodiments, R 1.1 is independently —CF. In an embodiment, R 1.1 is independently -CHF. In an embodiment, R 1.1 is independently -CHF. In an embodiment, R 1.1 is independently -OCF. In an embodiment, R 1.1 is independently -OCHF. In an embodiment, R 1.1 is independently -OCHF. In an embodiment, R 1.1 is independently —OH. In embodiments, R 1.1 is independently —NH. In an embodiment, R 1.1 is independently -SH. In an embodiment, R 1.1 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1.1 are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.1 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 1.1 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.1 is independently substituted or unsubstituted phenyl. In embodiments, R 1.1 are independently substituted or unsubstituted 5-6 membered heteroaryl. 1.1 is independently a substituted C1-C4 alkyl. In embodiments, R 1.1is independently a substituted 4-membered heteroalkyl. In embodiments, R 1.1 is independently a substituted C-C cycloalkyl. In embodiments, R 1.1 is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.1 is independently substituted phenyl. In embodiments, R 1.1 is independently a substituted 5-6 membered heteroaryl. 1.1 is independently unsubstituted C1-C4 alkyl. In embodiments, R 1.1 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.1 is independently unsubstituted C-C cycloalkyl. In embodiments, R 1.1 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.1 is independently unsubstituted phenyl. In embodiments, R 1.1 is independently an unsubstituted 5-6 membered heteroaryl. 1.1 is independently unsubstituted methyl. In embodiments, R 1.1 is independently unsubstituted ethyl. In embodiments, R 1.1 is independently unsubstituted isopropyl. In embodiments, R 1.1 is independently unsubstituted tert-butyl. In embodiments, R 1.1 is independently unsubstituted methoxy. In embodiments, R 1.1 is independently unsubstituted ethoxy. In embodiments, R 1.1 is independently -F. In an embodiment, R 1.1 is independently -Cl. In an embodiment, R 1.1 is independently -Br. In an embodiment, R 1.1 is independently -I. In an embodiment, R 1.1 are independently hydrogen.

[0232] In embodiments, R 1.2 are independently halogen. In embodiments, R 1.2 is independently —CF. In an embodiment, R 1.2is independently -CHF. In an embodiment, R 1.2 is independently -CHF. In an embodiment, R 1.2 is independently -OCF. In an embodiment, R 1.2 is independently -OCHF. In an embodiment, R 1.2 is independently -OCHF. In an embodiment, R 1.2 is independently —OH. In embodiments, R 1.2 is independently —NH. In an embodiment, R 1.2 is independently -SH. In an embodiment, R 1.2 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1.2 are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.2 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 1.2 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.2 is independently substituted or unsubstituted phenyl. In embodiments, R 1.2 are independently substituted or unsubstituted 5-6 membered heteroaryl. 1.2 is independently a substituted C1-C4 alkyl. In embodiments, R 1.2 is independently a substituted 4-membered heteroalkyl. In embodiments, R 1.2 is independently a substituted C-C cycloalkyl. In embodiments, R 1.2 is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.2 is independently substituted phenyl. In embodiments, R 1.2 is independently a substituted 5-6 membered heteroaryl. 1.2 is independently unsubstituted C1-C4 alkyl. In embodiments, R 1.2 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.2 is independently unsubstituted C-C cycloalkyl. In embodiments, R 1.2is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.2 is independently unsubstituted phenyl. In embodiments, R 1.2 is independently an unsubstituted 5-6 membered heteroaryl. 1.2 is independently unsubstituted methyl. In embodiments, R 1.2 is independently unsubstituted ethyl. In embodiments, R 1.2 is independently unsubstituted isopropyl. In embodiments, R 1.2 is independently unsubstituted tert-butyl. In embodiments, R 1.2 is independently unsubstituted methoxy. In embodiments, R 1.2 is independently unsubstituted ethoxy. In embodiments, R 1.2 is independently -F. In an embodiment, R 1.2 is independently -Cl. In an embodiment, R 1.2 is independently -Br. In an embodiment, R 1.2 is independently -I. In an embodiment, R 1.2 are independently hydrogen.

[0233] In embodiments, R 1.3 are independently halogen. In embodiments, R 1.3 is independently —CF. In an embodiment, R 1.3 is independently -CHF. In an embodiment, R 1.3 is independently -CHF. In an embodiment, R 1.3 is independently -OCF. In an embodiment, R 1.3 is independently -OCHF. In an embodiment, R 1.3 is independently -OCHF. In an embodiment, R 1.3 is independently —OH. In embodiments, R 1.3 is independently —NH. In an embodiment, R 1.3 is independently -SH. In an embodiment, R 1.3 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1.3are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.3 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 1.3 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.3 is independently substituted or unsubstituted phenyl. In embodiments, R 1.3 are independently substituted or unsubstituted 5-6 membered heteroaryl. 1.3 is independently a substituted C1-C4 alkyl. In embodiments, R 1.3 is independently a substituted 4-membered heteroalkyl. In embodiments, R 1.3 is independently a substituted C-C cycloalkyl. In embodiments, R 1.3 is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.3 is independently substituted phenyl. In embodiments, R 1.3 is independently a substituted 5-6 membered heteroaryl. 1.3 is independently unsubstituted C1-C4 alkyl. In embodiments, R 1.3 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.3 is independently unsubstituted C-C cycloalkyl. In embodiments, R 1.3 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.3 is independently unsubstituted phenyl. In embodiments, R 1.3 is independently an unsubstituted 5-6 membered heteroaryl. 1.3 is independently unsubstituted methyl. In embodiments, R 1.3 is independently unsubstituted ethyl. In embodiments, R 1.3 is independently unsubstituted isopropyl. In embodiments, R 1.3 is independently unsubstituted tert-butyl. In embodiments, R 1.3 is independently unsubstituted methoxy. In embodiments, R 1.3 is independently unsubstituted ethoxy. In embodiments, R1.3 is independently -F. In an embodiment, R 1.3 is independently -Cl. In an embodiment, R 1.3 is independently -Br. In an embodiment, R 1.3 is independently -I. In an embodiment, R 1.3 are independently hydrogen.

[0234] In embodiments, R 1.4 are independently halogen. In embodiments, R 1.4 is independently —CF. In an embodiment, R 1.4 is independently -CHF. In an embodiment, R 1.4 is independently -CHF. In an embodiment, R 1.4 is independently -OCF. In an embodiment, R 1.4 is independently -OCHF. In an embodiment, R 1.4 is independently -OCHF. In an embodiment, R 1.4 is independently —OH. In embodiments, R 1.4 is independently —NH. In an embodiment, R 1.4 is independently -SH. In an embodiment, R 1.4 is independently a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 1.4 are independently substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.4 is independently a substituted or unsubstituted C-C cycloalkyl. In embodiments, R 1.4 are independently substituted or unsubstituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.4 is independently substituted or unsubstituted phenyl. In embodiments, R 1.4 are independently substituted or unsubstituted 5-6 membered heteroaryl. 1.4 is independently a substituted C1-C4 alkyl. In embodiments, R 1.4 is independently a substituted 4-membered heteroalkyl. In embodiments, R 1.4 is independently a substituted C-C cycloalkyl. In embodiments, R 1.4is independently a substituted 3- to 6-membered heterocycloalkyl. In embodiments, R 1.4 is independently substituted phenyl. In embodiments, R 1.4 is independently a substituted 5-6 membered heteroaryl. 1.4 is independently unsubstituted C1-C4 alkyl. In embodiments, R 1.4 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.4 is independently unsubstituted C-C cycloalkyl. In embodiments, R 1.4 is independently an unsubstituted 3- to 6-membered heterocycloalkyl. In an embodiment, R 1.4 is independently unsubstituted phenyl. In embodiments, R 1.4 is independently an unsubstituted 5-6 membered heteroaryl. 1.4 is independently unsubstituted methyl. In embodiments, R 1.4 is independently unsubstituted ethyl. In embodiments, R 1.4 is independently unsubstituted isopropyl. In embodiments, R 1.4 is independently unsubstituted tert-butyl. In embodiments, R 1.4 is independently unsubstituted methoxy. In embodiments, R 1.4 is independently unsubstituted ethoxy. In embodiments, R 1.4 is independently -F. In an embodiment, R 1.4 is independently -Cl. In an embodiment, R 1.4 is independently -Br. In an embodiment, R 1.4 is independently -I. In an embodiment, R 1.4 are independently hydrogen.

[0235] In embodiments, R 4.1 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.4.1 are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 4.1 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 4.1 are independently halogen. In embodiments, R 4.1 is independently —OH. In embodiments, R 4.1 is independently unsubstituted methyl. In embodiments, R 4.1 is independently unsubstituted methoxy. In embodiments, R 4.1 is independently unsubstituted ethyl. In embodiments, R 4.1 is independently -F. In an embodiment, R 4.1 is independently -Cl. In an embodiment, R 4.1 is independently -Br. In an embodiment, R 4.1 is independently -I. In an embodiment, R 4.1 is independently —CF. In an embodiment, R 4.1 is independently —NH. In an embodiment, R 4.1 is independently -SH. In an embodiment, R 4.1 are independently hydrogen. In embodiments, R 4.1 is independently unsubstituted isopropyl. In embodiments, R 4.1 is independently unsubstituted ethoxy. In embodiments, R 4.1 is independently unsubstituted tert-butyl. In embodiments, R 4.1 is independently unsubstituted propoxy.

[0236] In embodiments, R 4.2 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.2are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 4.2 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 4.2 are independently halogen. In embodiments, R 4.2 is independently —OH. In embodiments, R 4.2 is independently unsubstituted methyl. In embodiments, R 4.2 is independently unsubstituted methoxy. In embodiments, R 4.2 is independently unsubstituted ethoxy. In embodiments, R 4.2 is independently unsubstituted ethyl. In embodiments, R 4.2 is independently -F. In an embodiment, R 4.2 is independently -Cl. In an embodiment, R 4.2 is independently -Br. In an embodiment, R 4.2 is independently -I. In an embodiment, R 4.2 is independently —CF. In an embodiment, R 4.2 is independently —NH. In an embodiment, R 4.2 is independently -SH. In an embodiment, R 4.2 are independently hydrogen. In embodiments, R 4.2 is independently unsubstituted isopropyl. In embodiments, R 4.2 is independently unsubstituted ethoxy. In embodiments, R 4.2 is independently unsubstituted tert-butyl. In embodiments, R 4.2 is independently unsubstituted propoxy.

[0237] In embodiments, R 4.3 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.4.3 are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 4.3 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 4.3 are independently halogen. In embodiments, R 4.3 is independently —OH. In embodiments, R 4.3 is independently unsubstituted methyl. In embodiments, R 4.3 is independently unsubstituted methoxy. In embodiments, R 4.3 is independently unsubstituted ethyl. In embodiments, R 4.3 is independently -F. In an embodiment, R 4.3 is independently -Cl. In an embodiment, R 4.3 is independently -Br. In an embodiment, R 4.3 is independently -I. In an embodiment, R 4.3 is independently —CF. In an embodiment, R 4.3 is independently —NH. In an embodiment, R 4.3 is independently -SH. In an embodiment, R 4.3 are independently hydrogen. In embodiments, R 4.3 is independently unsubstituted isopropyl. In embodiments, R 4.3 is independently unsubstituted ethoxy. In embodiments, R 4.3 is independently unsubstituted tert-butyl. In embodiments, R 4.3 is independently unsubstituted propoxy.

[0238] In embodiments, R 4.4 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.4are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 4.4 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 4.4 are independently halogen. In embodiments, R 4.4 is independently —OH. In embodiments, R 4.4 is independently unsubstituted methyl. In embodiments, R 4.4 is independently unsubstituted methoxy. In embodiments, R 4.4 is independently unsubstituted ethyl. In embodiments, R 4.4 is independently -F. In an embodiment, R 4.4 is independently -Cl. In an embodiment, R 4.4 is independently -Br. In an embodiment, R 4.4 is independently -I. In an embodiment, R 4.4 is independently —CF. In an embodiment, R 4.4 is independently —NH. In an embodiment, R 4.4 is independently -SH. In an embodiment, R 4.4 are independently hydrogen. In embodiments, R 4.4 is independently unsubstituted isopropyl. In embodiments, R 4.4 is independently unsubstituted ethoxy. In embodiments, R 4.4 is independently unsubstituted tert-butyl. In embodiments, R 4.4 is independently unsubstituted propoxy.

[0239] In embodiments, R 4.5 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.5are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 4.5 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 4.5 are independently halogen. In embodiments, R 4.5 is independently —OH. In embodiments, R 4.5 is independently unsubstituted methyl. In embodiments, R 4.5 is independently unsubstituted methoxy. In embodiments, R 4.5 is independently unsubstituted ethyl. In embodiments, R 4.5 is independently -F. In an embodiment, R 4.5 is independently -Cl. In an embodiment, R 4.5 is independently -Br. In an embodiment, R 4.5 is independently -I. In an embodiment, R 4.5 is independently —CF. In an embodiment, R 4.5 is independently —NH. In an embodiment, R 4.5 is independently -SH. In an embodiment, R 4.5 are independently hydrogen. In embodiments, R 4.5 is independently unsubstituted isopropyl. In embodiments, R 4.5 is independently unsubstituted ethoxy. In embodiments, R 4.5 is independently unsubstituted tert-butyl. In embodiments, R 4.5 is independently unsubstituted propoxy.

[0240] In embodiments, R 5.1 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 5.1are independently halogen, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 5.1 is independently halogen, —OH, unsubstituted methyl, or unsubstituted methoxy. 5.1 are independently halogen. In embodiments, R 5.1 is independently —OH. In embodiments, R 5.1 is independently unsubstituted methyl. In embodiments, R 5.1 is independently unsubstituted methoxy. In embodiments, R 5.1 is independently unsubstituted ethyl. In embodiments, R 5.1 is independently -F. In an embodiment, R 5.1 is independently -Cl. In an embodiment, R 5.1 is independently -Br. In an embodiment, R 5.1 is independently -I. In an embodiment, R 5.1 is independently —CF. In an embodiment, R 5.1 is independently —NH. In an embodiment, R 5.1 is independently -SH. In an embodiment, R 5.1 are independently hydrogen. In embodiments, R 5.1 is independently unsubstituted isopropyl. In embodiments, R 5.1 is independently unsubstituted ethoxy. In embodiments, R 5.1 is independently unsubstituted tert-butyl. In embodiments, R 5.1 is independently unsubstituted propoxy.

[0241] In embodiments, R 5.2 are independently halogen, —CF3, —OH, —NH2, —SH, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3...

Claims

1. A compound having the formula: 【Chemical 1】 During the ceremony, Ring A is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- to 6-membered heteroaryl; Ring B is a substituted or unsubstituted naphthyl, a substituted or unsubstituted quinolinyl, or a substituted or unsubstituted isoquinolinyl; R １ are independently a halogen, -CX １ ３ , -CHX １ ２ , -CH ２ X １ , -CN, -SO ｎ１ R １０ , -SO ｖ１ NR ７ R ８ , -NHNH ２ , -ONR ７ R ８ , -NHC=(O)NHNH ２ , -NHC=(O)NR ７ R ８ , -N(O) ｍ１ , -NR ７ R ８ , -C(O)R ９ , —C(O)—OR ９ , —C(O)NR ７ R ８ , -OR １０ , -NR ７ SO ２ R １０ , -NR ７ C=(O)R ９ , -NR ７ C(O)-OR ９ , -NR ７ OR ９ , -OCX １ ３ , -OCHX １ ２ , -OCH ２ X １ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; １ The substituents may optionally be combined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R ２ are independently hydrogen, halogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ３ are independently hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ７ , R ８ , R ９ , and R １０ are independently hydrogen, halogen, -CX Ａ ３ , -CHX Ａ ２ , -CH ２ X Ａ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; ７ and R ８ The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z1 is independently an integer from 0 to 4; m1 and v1 are independently 1 or 2; n1 is independently an integer from 0 to 4; X １ , X ２ , X ３ , and X Ａ are independently —Cl, —Br, —I, or —F.

2. 10. The compound of claim 1 having the formula: 【Chemistry 2】 During the ceremony, R ４ are independently a halogen, -CX ４ ３ , -CHX ４ ２ , -CH ２ X ４ , -CN, -SO ｎ４ R １４ , -SO ｖ４ NR １１ R １２ , -NHNH ２ , -ONR １１ R １２ , -NHC=(O)NHNH ２ , -NHC=(O)NR １１ R １２ , -N(O) ｍ４ , -NR １１ R １２ , -C(O)R １３ , —C(O)—OR １３ , —C(O)NR １１ R １２ , -OR １４ , -NR １１ SO ２ R １４ , -NR １１ C=(O)R １３ , -NR １１ C(O)-OR １３ , -NR １１ OR １３ , -OCX ４ ３ , -OCHX ４ ２ , -OCH ２ X ４ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; ４ The substituents may optionally be combined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R ５ are independently a halogen, -CX ５ ３ , -CHX ５ ２ , -CH ２ X ５ , -CN, -SO ｎ５ R １８ , -SO ｖ５ NR １５ R １６ , -NHNH ２ , -ONR １５ R １６ , -NHC=(O)NHNH ２ , -NHC=(O)NR １５ R １６ , -N(O) ｍ５ , -NR １５ R １６ , -C(O)R １７ , —C(O)—OR １７ , —C(O)NR １５ R １６ , -OR １８ , -NR １５ SO ２ R １８ , -NR １５ C=(O)R １７ , -NR １５ C(O)-OR １７ , -NR １５ OR １７ , -OCX ５ ３ , -OCHX ５ ２ , -OCH ２ X ５ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; ５ The substituents may optionally be combined to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R １１ , R １２ , R １３ , and R １４ are independently hydrogen, halogen, -CX Ｂ ３ , -CHX Ｂ ２ , -CH ２ X Ｂ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; １１ and R １２ The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R １５ , R １６ , R １７ , and R １８ are independently hydrogen, halogen, -CX Ｃ ３ , -CHX Ｃ ２ , -CH ２ X Ｃ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; １５ and R １６ The substituents may optionally be combined to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z2 is independently an integer from 0 to 5; z3 is independently an integer from 0 to 7; m4, m5, v4 and v5 are independently 1 or 2; n4 and n5 are independently an integer from 0 to 4; X ４ , X ５ , X Ｂ , and X Ｃ are independently —Cl, —Br, —I, or —F.

3. The following formula: 【Chemistry 3】 2. The compound of claim 1 having the formula:

4. The following formula: 【Chemistry 4】 2. The compound of claim 1 having the formula:

5. The following formula: 【Chemistry 5】 2. The compound of claim 1 having the formula:

6. R １ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -OCF ３ , -OCHF ２ , -OCH ２ F, substituted or unsubstituted C １ -C ８ Alkyl, substituted or unsubstituted 2- to 8-membered heteroalkyl, substituted or unsubstituted C ３ -C8 cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C ６ -C １０ The compound according to claim 1, which is an aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl.

7. R １ are independently halogen, —CF ３ , —OH, —NH ２ , —SH, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C ３ -C ６ The compound of claim 1, which is cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

8. R １ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, —OH, —NH ２ , -SH, unsubstituted C １ -C ４ The compound of claim 1, which is alkyl or unsubstituted 2-4 membered heteroalkyl.

9. R １ are independently halogen, —OH, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ 2. The compound of claim 1, wherein the aryl group is F, unsubstituted methyl, or unsubstituted methoxy.

10. The compound of claim 1, wherein z1 is 1.

11. The compound of claim 1, wherein z1 is 0.

12. R ４ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -OCF ３ , -OCHF ２ , -OCH ２ F, substituted or unsubstituted C １ -C ８ Alkyl, substituted or unsubstituted 2- to 8-membered heteroalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C ６ -C １０ The compound according to claim 1, which is an aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl.

13. R ４ are independently halogen, —CF ３ , —OH, —NH ２ , —SH, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C ３ -C ６ The compound of claim 1, which is cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

14. R ４ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, —OH, —NH ２ , -SH, unsubstituted C １ -C ４ The compound of claim 1, which is alkyl or unsubstituted 2-4 membered heteroalkyl.

15. R ４ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ The compound of claim 1 , which is F, —OH, unsubstituted methyl, or unsubstituted methoxy.

16. R ４ are independently -OR １４ 2. The compound of claim 1, wherein:

17. R １４ 17. The compound of claim 16, wherein is hydrogen or substituted or unsubstituted alkyl.

18. R １４ 17. The compound of claim 16, wherein is hydrogen or unsubstituted alkyl.

19. R １４ is hydrogen or unsubstituted C １ -C ５ 17. The compound of claim 16, wherein the compound is alkyl.

20. R １４ is hydrogen or unsubstituted C １ -C ３ 17. The compound of claim 16, wherein the compound is alkyl.

21. R １４ The compound of claim 16 , wherein is hydrogen or unsubstituted methyl.

22. R １４ The compound of claim 16, wherein is unsubstituted methyl.

23. The compound of claim 1, wherein z2 is 1.

24. The compound of claim 1, wherein z2 is 0.

25. R ５ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -OCF ３ , -OCHF ２ , -OCH ２ F, substituted or unsubstituted C １ -C ８ Alkyl, substituted or unsubstituted 2- to 8-membered heteroalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C ６ -C １０ The compound according to claim 1, which is an aryl or a substituted or unsubstituted 5- to 10-membered heteroaryl.

26. R ５ are independently halogen, —CF ３ , —OH, —NH ２ , —SH, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted 2- to 4-membered heteroalkyl, substituted or unsubstituted C ３ -C ６ The compound of claim 1, which is cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

27. R ５ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, —OH, —NH ２ , -SH, unsubstituted C １ -C ４ The compound of claim 1, which is alkyl or unsubstituted 2-4 membered heteroalkyl.

28. R ５ are independently halogen, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ The compound of claim 1 , which is F, —OH, unsubstituted methyl, or unsubstituted methoxy.

29. The compound of claim 1, wherein z3 is 1.

30. The compound of claim 1, wherein z3 is 0.

31. R ２ But hydrogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -CN, -C(O)H, -C(O)OH, -C(O)NH ２ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C ３ -C ６ The compound of claim 1, which is cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

32. R ２ The compound of claim 1 , wherein is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

33. R ２ The compound of claim 1 , wherein is hydrogen.

34. R ３ But hydrogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -CN, -C(O)H, -C(O)OH, -C(O)NH ２ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted 2- to 6-membered heteroalkyl, substituted or unsubstituted C ３ -C ６ The compound of claim 1, which is cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl.

35. R ３ The compound of claim 1 , wherein is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

36. R ３ The compound of claim 1 , wherein is hydrogen.

37. The compound of claim 1 , wherein ring A is a substituted or unsubstituted phenyl.

38. The compound of claim 2 , wherein ring A is phenyl.

39. The compound according to claim 1, wherein ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl.

40. The compound of claim 2, wherein ring A is a 5- to 6-membered heteroaryl.

41. The compound of claim 1 , wherein ring A is a substituted or unsubstituted thienyl.

42. The compound of claim 2, wherein Ring A is thienyl.

43. The compound according to claim 1, wherein ring A is a substituted or unsubstituted 2-thienyl.

44. The compound of claim 2, wherein ring A is 2-thienyl.

45. The compound according to claim 1, wherein ring A is a substituted or unsubstituted 3-thienyl.

46. The compound of claim 2, wherein ring A is 3-thienyl.

47. The compound of claim 1 , wherein ring A is a substituted or unsubstituted pyridyl.

48. The compound of claim 2, wherein Ring A is pyridyl.

49. The compound according to claim 1, wherein ring A is a substituted or unsubstituted 2-pyridyl.

50. The compound of claim 2, wherein ring A is 2-pyridyl.

51. The compound according to claim 1, wherein ring A is a substituted or unsubstituted 3-pyridyl.

52. The compound of claim 2, wherein ring A is 3-pyridyl.

53. The compound according to claim 1, wherein ring A is a substituted or unsubstituted 4-pyridyl.

54. The compound of claim 2, wherein ring A is 4-pyridyl.

55. The compound according to claim 1 , wherein ring B is a substituted or unsubstituted naphthyl.

56. The compound of claim 2, wherein Ring B is naphthyl.

57. The compound according to claim 1, wherein ring B is a substituted or unsubstituted 1-naphthyl.

58. The compound of claim 2, wherein ring B is 1-naphthyl.

59. The compound according to claim 1, wherein ring B is a substituted or unsubstituted 2-naphthyl.

60. The compound of claim 2, wherein ring B is 2-naphthyl.

61. The compound of claim 1 , wherein Ring B is a substituted or unsubstituted quinolinyl.

62. The compound of claim 2 , wherein Ring B is quinolinyl.

63. The compound according to claim 1 , wherein ring B is a substituted or unsubstituted isoquinolinyl.

64. The compound of claim 2 , wherein Ring B is isoquinolinyl.

65. The compound according to claim 1, wherein ring B is a substituted or unsubstituted 1-isoquinolinyl.

66. The compound of claim 2, wherein ring B is 1-isoquinolinyl.

67. The compound according to claim 1, wherein ring B is a substituted or unsubstituted 3-isoquinolinyl.

68. The compound of claim 2, wherein ring B is 3-isoquinolinyl.

69. The compound according to claim 1, wherein ring B is a substituted or unsubstituted 4-isoquinolinyl.

70. The compound according to claim 2, wherein Ring B is 4-isoquinolinyl.

71. The following formula: 【Chemistry 6】 2. The compound of claim 1 having the formula:

72. The following formula: 【Chemistry 7】 2. The compound of claim 1 having the formula:

73. The following formula: 【Chemistry 8】 2. The compound of claim 1 having the formula:

74. The following formula: 【Chemistry 9】 2. The compound of claim 1 having the formula:

75. The following formula: 【Chemistry 10】 2. The compound of claim 1 having the formula:

76. The following formula: 【Chemistry 11】 2. The compound of claim 1 having the formula:

77. The following formula: 【Chemistry 12】 2. The compound of claim 1 having the formula:

78. The following formula: 【Chemistry 13】 2. The compound of claim 1 having the formula:

79. The following formula: 【Chemistry 14】 2. The compound of claim 1 having the formula:

80. The following formula: 【Chemistry 15】 2. The compound of claim 1 having the formula:

81. The following formula: 【Chemistry 16】 2. The compound of claim 1 having the formula:

82. The following formula: 【Chemistry 17】 2. The compound of claim 1 having the formula:

83. The following formula: 【Chemistry 18】 2. The compound of claim 1 having the formula:

84. 84. A pharmaceutical composition comprising a compound according to any one of claims 1 to 83 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

85. 85. The pharmaceutical composition of claim 84, further comprising an anti-cancer agent.

86. 86. The pharmaceutical composition of claim 85, wherein the anticancer agent is a platinum-based compound.

87. 86. The pharmaceutical composition of claim 85, wherein the anticancer agent is cisplatin.

88. 1. A method for treating a disease associated with PCNA activity in a patient in need thereof, comprising: The method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 83, or a pharmaceutically acceptable salt thereof.

89. 1. A method for treating cancer in a patient in need thereof, comprising: The method comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 83, or a pharmaceutically acceptable salt thereof.

90. 90. The method of claim 89, wherein the cancer is leukemia, lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.

91. 90. The method of claim 89, wherein the cancer is non-small cell lung cancer.

92. 90. The method of claim 89, wherein the cancer is triple-negative breast cancer.

93. 90. The method of claim 89, wherein the cancer is a central nervous system cancer.

94. 90. The method of claim 89, wherein the cancer is a brain cancer.

95. 90. The method of claim 89, wherein the cancer is neuroblastoma.

96. 1. A method for inhibiting PCNA activity, comprising: The method comprising contacting PCNA with an effective amount of a compound of any one of claims 1 to 83, or a pharmaceutically acceptable salt thereof.

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