PCNA inhibitors and their uses

Abstract

Among other things, PCNA inhibitors and uses thereof are described herein.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 317,430, filed March 7, 2022, the contents of which are incorporated herein in their entirety for all purposes.

[0002] (Reference to Electronic Sequence Listing) The contents of the electronic sequence listing (048440-826001WO_Sequence_Listing_ST26.xml, size 15,199 bytes, and created on February 13, 2023) are incorporated herein by reference in their entirety.

[0003] STATEMENT OF RIGHTS TO INVENTIONS MADE IN FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under W81XWH-19-1-0326 awarded by the Medical Research and Development Command. The government has certain rights in this invention. [Background technology]

[0004] Proliferating cell nuclear antigen (PCNA) is important for DNA replication and repair processes and is also a proliferation biomarker in various human tumors. A unique cancer-associated isoform of this protein, caPCNA, has previously been identified, which may enable selective therapeutic targeting of cancer cells. Many strategies have been used to develop agents that target caPCNA, including peptide- and small-molecule-based inhibitors, but there has been limited success in developing therapeutically tractable compounds. Disclosed herein are, among other things, solutions to these and other problems in the art. Summary of the Invention

[0005] In one aspect, a compound, or a pharmaceutically acceptable salt thereof, is provided having the formula:

[0006] [ka] or a pharmaceutically acceptable salt thereof.

[0007] L 1 -O-, -NR 7 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR 7 C(O)-, -C(O)NR 7 -, -NR 7 C(O)NR 8 -, -NR 7 S(O)2O-, -OS(O)2NR 7 -, -NR 7 S(O)2-, -S(O)2NR 7 -, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OR 7 )-, -OP(O)(OR 7 )O-, -OP(O)(OR 7 )-, -P(O)(OR 7 )O- or -CR 8 R 9 -It is.

[0008] R 7 , R 8 , and R 9 are independently hydrogen, halogen, —OH, —N 3 , or substituted or unsubstituted alkyl.

[0009] Ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0010] Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.

[0011] R 1 are independently halogen-CX 1 3. -CHX 12. -CH2X 1 , -OCX 1 3. -OCHX 1 2, -OCH2X 1 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -OC(O)NR 1A R 1B , -NR 1A OR 1C , -P(O)R 1A R 1B , -N3, 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, and two adjacent R 1 The substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0012] R 2 is hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -CN, -COOH, -CONH2, -N3, 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.

[0013] R 3 is hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -CN, -COOH, -CONH2, -N3, 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.

[0014] R 6 is hydrogen, halogen, -CX 6 3. -CHX 6 2. -CH2X 6 , -OCX 6 3. -OCHX 6 2, -OCH2X 6 , -CN, -SO n6 R 6D , -SO v6 NR 6A R 6B , -NR 6C NR 6A R 6B , -ONR 6A R 6B , -NHC(O)NR 6C NR 6A R 6B , -NR 6C C(O)NR 6A R 6B , -N(O) m6 , -NR 6A R 6B , -C(O)R 6C , -C(O)OR 6C , -OC(O)R6C , -OC(O)OR 6C , -C(O)NR 6A R 6B , -OR 6D , -SR 6D , -NR 6A SO2R 6D , -NR 6A C(O)R 6C , -NR 6A C(O)OR 6C , -OC(O)NR 6A R 6B , -NR 6A OR 6C , -P(O)R 6A R 6B , -N3, 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.

[0015] R 3 and R 6 may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0016] R 1A , R 1B , R 1C , R 1D , R 6A , R 6B , R 6C , and R 6D are independently hydrogen, halogen, -CX, -CHX, -CHX, -CN, -COOH, -CONH, -N, 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, and R attached to the same nitrogen atom 1A and R 1B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, and R 6A and R 6BThe substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0017] The symbol z1 is an integer of 0 to 4. The symbols m1, m6, v1, and v6 are independently 1 or 2. The symbols n1 and n6 are independently an integer of 0 to 4.

[0018] X, X 1 , X 2 , X 3 , and X 6 is independently -Cl, -Br, -I, or -F.

[0019] The symbol m is an integer from 0 to 5. The symbol n is an integer from 0 to 10.

[0020] In one aspect, a compound, or a pharmaceutically acceptable salt thereof, is provided having the formula:

[0021] [ka] or a pharmaceutically acceptable salt thereof. 1 , ring A, R 1 , z1, R 2 , R 3 , R 6 , and m are as described herein, including embodiments.

[0022] In one aspect, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0023] In one aspect, a method is provided for treating a disease associated with PCNA activity in a subject in need of such treatment, the method comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0024] In one aspect, a method of treating cancer in a subject in need of such treatment is provided, the method comprising administering to the subject in need of such treatment a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0025] In one aspect, a method of inhibiting PCNA activity is provided, the method comprising contacting PCNA with an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0026] In one aspect, a method of making Compound (I) or a pharmaceutically acceptable salt thereof is provided, the method comprising mixing Compound (VII) and Compound (X) together in a reaction vessel. Compound (I) has the formula:

[0027] [ka] Compound (VII) has the formula:

[0028] [ka] Compound (X) has the formula:

[0029] [ka] L 1 , ring A, R 1 , z1, R 2 , R 3 , R 6 , m, and n are as described herein, including embodiments. LG is a leaving group. [Brief explanation of the drawings]

[0030] [Figure 1A]AOH1160 analog interaction with PCNA. Thermal shift assay: Normalized reverse derivative thermal denaturation plots of 9 μM apo-PCNA with DMSO control are shown in black dashed lines, PCNA in the presence of 10 μM AOH1160LE are shown in light gray, and 30 μM AOH1160LE are shown in dark gray. ΔTm values ​​are provided. [Figure 1B] AOH1160 analog interaction with PCNA, shown in light gray in the presence of 10 μM AOH1996 and in dark gray in the presence of 30 μM AOH1996, as described in Figure 1A. [Figure 1C] AOH1160 analog interaction with PCNA. Four monomers of PCNA (chains A–D) are present in the asymmetric unit of the crystal. Chains A, B, and C form a homotrimeric biological unit, with chain D oriented perpendicular to the plane of the ring below the interface of chains B and C, which belongs to the adjacent ring. Inset: Three molecules of AOH1160LE bind within and adjacent to the PIP box cavity of each PCNA ring subunit. Omitted map; gray shaded areas are aligned to 1.5σ. Two PCNA monomer subunits from adjacent rings stack on top of each other, orienting the PIP box and IDCL of each subunit in opposite directions. [Figure 1D] AOH1160 analog interactions with PCNA. Three AOH1160LE molecules are shown as stick diagram representations. Two of the compounds on the left and center bind to the PIP box cavity at the known PCNA-partner / compound interaction site. [Figure 1E] AOH1160 analog interaction with PCNA. Superposition of the PCNA:T2AA and PCNA:AOH1160LE complexes is centered on the PIP box cavity, with the T2AA carbons in dark gray. Electrostatic surface maps are shown with Poisson-Boltzmann electrostatic surface potentials shown in dark gray and light gray, corresponding to -10 to +10 kT / e, respectively. [Figure 2A]Interaction of AOH1996 with PCNA. The PCNA gene was mutated using CRISPR, resulting in a codon substitution of leucine 47 with valine. DNA sequencing results of cell lines heterozygous or homozygous for the mutated gene are shown. Original sequence: ACGTCTCTTTGGTGCAGCTCACC (SEQ ID NO: 1), donor sequence: ACGTCTCTGTCGTGCAGCTCACC (SEQ ID NO: 2), homozygous: ACGTCTCTGTCGTGCAGCTCACCC (SEQ ID NO: 3). [Figure 2B] Interaction of AOH1996 with PCNA. Cell lines heterozygous or homozygous for the mutant PCNA gene were treated with the indicated concentrations of AOH1996 or R9-caPep, respectively, for 72 hours. Parental SK-N-AS cells were used as a control. Relative cell proliferation in triplicates was averaged and graphed ±SD. [Figure 2C] Interaction of AOH1996 with PCNA. Cell lines heterozygous or homozygous for the mutant PCNA gene were treated with the indicated concentrations of AOH1996 or R9-caPep, respectively, for 72 hours. Parental SK-N-AS cells were used as a control. Relative cell proliferation in triplicates was averaged and graphed ±SD. [Figure 2D] Interaction of AOH1996 with PCNA. Expression of γH2A.X was measured by Western blot in cell lines heterozygous (#25H and #37H) or homozygous (#33 and #35) for the mutant PCNA allele after treating cells with 500 nM AOH1996 or 30 μM R9-caPep for the indicated times. [Figure 3A-1] Therapeutic properties of AOH1996. Normal (7SM0032) or cancer (SH-SY5Y and SK-N-BE(2)c) cells were fixed, stained with PI, and treated with 500 nM AOH1996 for the indicated times, followed by analysis by flow cytometry. [Figure 3A-2] Therapeutic properties of AOH1996. Normal (7SM0032) or cancer (SH-SY5Y and SK-N-BE(2)c) cells were fixed, stained with PI, and treated with 500 nM AOH1996 for the indicated times, followed by analysis by flow cytometry. [Figure 3B] Therapeutic properties of AOH1996. SK-N-DZ neuroblastoma cells and non-malignant 7SM0032 stem cells were incubated with 500 nM AOH1996 for 24 hours. Then, after fixation on slides, cell apoptosis was analyzed by TUNEL assay. Left: TMR fluorophore attached to free ends of DNA indicates cells undergoing apoptosis. DAPI-stained nuclei are also shown. Right: The mean abundance ± SD of apoptotic 7SM0032 (black histogram) and SK-N-DZ (gray histogram) cells relative to the total number of cells is shown for five randomly selected fields. [Figure 3C] Therapeutic properties of AOH1996. Human SK-N-DZ neuroblastoma cells were treated with or without the indicated concentrations of cisplatin for 18 hours in the absence or presence of 500 nM AOH1996. Cells were washed twice with growth medium and cultured in fresh medium for 18 days to allow colony formation. The number of colonies in dishes treated with cisplatin but not AOH1996 (black) was normalized to the number of colonies in dishes untreated with either drug. The number of colonies in dishes treated with both cisplatin and AOH1996 (gray) was normalized to the number of colonies in dishes treated with 500 nM AOH1996 alone. The relative number of colonies determined in triplicate for each treatment condition was averaged and graphed ± SD (*, P < 0.01). [Figure 3D] Therapeutic properties of AOH1996. SK-N-AS cells were treated with the indicated concentrations of AOH1996, topotecan, or a combination of both drugs. Cell proliferation was measured as a percentage of cell confluence by imaging every 6 hours for a total of 48 hours. [Figure 4A] Pharmacokinetics and antitumor growth activity of AOH1996 in vivo. After oral administration, plasma concentrations of AOH1996 from three male and three female ES1e / SCID mice at the indicated time points were averaged and graphed ±SD. The inset contains PK parameters determined by standard noncompartmental methods. [Figure 4B]Pharmacokinetics and Antitumor Growth Activity of AOH1996 In Vivo A similar PK study of AOH1996 was conducted in dogs. [Figure 4C] Pharmacokinetics and antitumor growth activity of AOH1996 in vivo. Mice bearing xenograft tumors of neuroblastoma (Fig. 4C: SK-N-BE(2)c), breast cancer (Fig. 4D: MDA-MB-468), and small cell lung cancer (Fig. 4E: H82) were given vehicle alone (black) or 40 mg / kg AOH1996 (gray) twice daily immediately after the first measurement. Tumor size was measured weekly using a dial caliper. Tumor volumes (0.4 × L × W²) were averaged and graphed ± SE. (*, P < 0.01). [Figure 4D] Pharmacokinetics and antitumor growth activity of AOH1996 in vivo. Mice bearing xenograft tumors of neuroblastoma (Fig. 4C: SK-N-BE(2)c), breast cancer (Fig. 4D: MDA-MB-468), and small cell lung cancer (Fig. 4E: H82) were given vehicle alone (black) or 40 mg / kg AOH1996 (gray) twice daily immediately after the first measurement. Tumor size was measured weekly using a dial caliper. Tumor volumes (0.4 × L × W²) were averaged and graphed ± SE. (*, P < 0.01). [Figure 4E] Pharmacokinetics and antitumor growth activity of AOH1996 in vivo. Mice bearing xenograft tumors of neuroblastoma (Fig. 4C: SK-N-BE(2)c), breast cancer (Fig. 4D: MDA-MB-468), and small cell lung cancer (Fig. 4E: H82) were given vehicle alone (black) or 40 mg / kg AOH1996 (gray) twice daily immediately after the first measurement. Tumor size was measured weekly using a dial caliper. Tumor volumes (0.4 × L × W²) were averaged and graphed ± SE. (*, P < 0.01). [Figure 4F] Pharmacokinetics and antitumor growth activity of AOH1996 in vivo. Animal body weight was monitored throughout the study as an indicator of toxicity. Typical results from the SK-N-BE(2)c tumor model study are shown in (Figure 4C). [Figure 4G]Pharmacokinetics and antitumor growth activity of AOH1996 in vivo. Levels of phosphor-Chk1 (pChk1) and γH2A.X in SK-N-BE(2)c-derived tumors were analyzed by IHC. Representative images taken from tumors treated with vehicle alone or 40 mg / kg AOH1996 are shown. [Figure 4H] Pharmacokinetics and antitumor growth activity of AOH1996 in vivo. ES1e / SCID mice bearing SK-N-AS-derived xenograft tumors were treated with 80 mg / kg AOH1996 (black, n = 7) for 8 days starting 8 days after tumor implantation, 15 mg / kg CPT-11 (n = 8) for 3 days starting 12 days after tumor implantation, or both drugs (combination, n = 8) at the same dosage and schedule as when they were administered alone. Mice implanted with the same tumors but left untreated served as controls (n = 8). Survival graphs are shown. The p-values ​​determined by the Log-rank (Mantel-Cox) test between the combination treatment and each control group were p = 0.0003 (combination vs. NoRx), p = 0.005 (combination vs. AOH1996 alone), and p = 0.024 (combination vs. CPT-11 alone). [Figure 5A] Regulation of PCNA interaction with RNA polymerase II. Chromatin-bound (CB) proteins were fractionated from HEK293T cells expressing FLAG-tagged PCNA after treating the cells with or without 500 nM AOH1996. Proteins complexed with FLAG-PCNA were immunoprecipitated and analyzed by mass spectrometry. The number of proteins whose abundance changed by more than two-fold (gray) or remained unchanged (black) upon AOH1996 treatment is shown. [Figure 5B] Regulation of PCNA interaction with RNA polymerase II. SK-N-AS cells exogenously expressing a FLAG-tagged RPB1 gene were fractionated before and after overnight treatment with 500 nM AOH1996. PCNA complexed with chromatin-bound (CB) FLAG-RBP1 was analyzed by Western blotting. [Figure 5C]Regulation of PCNA interaction with RNA polymerase II. Human SK-N-AS cells were treated with UV light in the presence or absence of AOH1996 (AOH) or R9-caPep (caPep). Whole cell extracts were analyzed by Western blotting. [Figure 5D] Regulation of PCNA interaction with RNA polymerase II. Cells exogenously expressing FLAG-tagged wild-type RPB1 or FLAG-tagged APIM mutant RPB1 genes were fractionated. PCNA complexed with chromatin-bound (CB) FLAG-RBP1 was analyzed by Western blotting. [Figure 5E] Regulation of PCNA interaction with RNA polymerase II. HEK293T cells were transiently transfected with FLAG-tagged wild-type RPB1 (APIM WT) or mutant RPB1 (APIM mutant) genes. Intracellular MCM7 and RBP1 (both hypophosphorylated and hyperphosphorylated RNAPIIa and RNAPIIo forms) were analyzed by Western blot after cells were treated with the indicated drugs and / or UV. [Figure 6A] The effect of AOH1996 is mediated through PCNA interaction with RPB1. Cell lines heterozygous or homozygous for the APIM-mutant RPB1 gene were treated with the indicated concentrations of AOH1996 for 72 hours. Parental SK-N-AS cells were used as a control. Relative cell proliferation in triplicates was averaged and graphed ±SD. [Figure 6B]The effect of AOH1996 is mediated through PCNA interaction with RPB1. Whole-cell proteomes from SK-N-AS cells homozygous for the APIM-mutant RPB1 gene were analyzed by mass spectrometry before and after treatment with 500 nM AOH1996 overnight in quadruplicate. Quadruplicate samples were obtained from two independent RPB1 mutant clones to average out any clonal differences unrelated to the RPB1 mutation. Quadruplicate parental SK-N-AS cells were used as controls. Proteins whose expression was altered by AOH1996 by at least twofold and had a p-value less than 0.05 in cells of either genotype were enriched using the MetaCore (Clarivate Analytics, Philadelphia, PA) gene ontology program. The Cricos diagram shows the enriched GO processes associated with these proteins and the average fold change in their expression induced by AOH1996 treatment. [Figure 6C] The effect of AOH1996 is mediated through PCNA interaction with RPB1. The fold change in expression of the proteins identified in Figure 6B was calculated for each AOH1996-treated sample compared to the average expression level in untreated corresponding cells and visualized in a dot plot heat map. The dot plot heat map also shows the statistical significance expressed as -log10 between treated and untreated samples of the same genotype. [Figure 7A] Transcription-dependent effects on DNA replication and damage. Left: Schematic of the cell fractionation procedure. Right: MDA-MB-468 cells were treated with increasing concentrations of AOH1996 (5, 50, or 500 nM) for 24 h. DMSO-treated cells were used as a control. Whole cell extracts (WCE) and protein fractions associated with actively transcribed chromatin (CB:RNA+) or low-transcribed or non-transcribed chromatin (CB:RNA-) were analyzed by Western blot using antibodies against PCNA, CAF-1, and MCM7. [Figure 7B]Transcription-dependent effects on DNA replication and damage. Synchronized cancer cells were serially incubated in the presence of CldU (light gray) and IdU (dark gray) before and after AOH1996 treatment, respectively. Cells serially incubated with the same two nucleotide analogs but without AOH1996 served as controls. Left: Representative images of labeled DNA strands from cells treated with or without AOH1996. Center and right: Lengths of CldU (light gray) and IdU (dark gray) incorporated DNA segments measured for over 30 independent DNA strands from the indicated cancer cell types were averaged and graphed ±SD. [Figure 7C] Transcription-dependent effects on DNA replication and damage. Whole cell lysates were extracted from SK-N-AS cells homozygous for wild-type RPB1 alleles or APIM mutant alleles. Histones H2A.X and γH2A.X were analyzed by Western blot after overnight treatment with or without AOH1996. [Figure 7D] Transcription-dependent effects on DNA replication and damage. Histones H2A.X and γH2A.X in whole cell lysates from SK-N-AS cells were analyzed by Western blot after overnight treatment with 500 nM AOH1996 and / or 50 μM DRB. [Figure 7E] Transcription-dependent effects on DNA replication and damage. Working model for AOH1996 mechanism of action: AOH1996 binding to PCNA stabilizes PCNA interaction with RNA polymerase II, preventing TRC degradation and leading to PCNA dissociation from chromatin in a transcription-dependent manner. By exploiting this cancer vulnerability, AOH1996 selectively inhibits tumor growth without causing discernible side effects. [Figure 8] Schematic diagram of the interactions of three AOH1160LE molecules in the PCNA PIP box / APIM binding pocket. Individual AOH1160LE molecules are listed from left to right based on their position within the PIP box pocket, as shown in Figure 1A-E. Specific protein-ligand interactions are highlighted based on the provided legend. [Figure 9] Structural superposition of the centrally bound AOH1160LE molecule and the PCNA:APIM peptide complex. The central AOH1160LE (dark gray) binds to the same hydrophobic pocket as the ZRANB3 APIM peptide (PDB code: 5MLW), colored light gray. The ZRANB3 Phe1075 side chain is also shown, which interacts in a second region of the PCNA APIM-binding pocket with another molecule of AOH1160LE (left molecule in Figure 8). Inset: Close-up of the two hydrophobic binding regions of PCNA, with the diphenyl ether of the central AOH1160LE positioned where Ile1072 and Val1077 of the APIM peptide bind. [Figure 10] Orientation of AOH1160LE bound to the PIP box cavity of PCNA. Strands A–D are depicted as solid boxes, with the corresponding symmetric pairs shown as dashed lines, each labeled accordingly. The orientation of the central AOH1160LE diphenyl ether bond is depicted and further indicated by the direction of the black arrow. [Figure 11] The C-chain central AOH1160LE molecule interacts with PCNA via the naphthalene group. Specific protein-ligand interactions are highlighted based on the provided legend. [Figure 12A] AOH1996 metabolism and in vivo pharmacokinetics. Diagram of AOH1160 degradation by carboxylesterase-mediated cleavage or hydroxylation. [Figure 12B] AOH1996 metabolism and in vivo pharmacokinetics. Chromatograms of liver microsomal reaction mixtures of AOH1160 and AOH1996. Metabolites shown in Figure 12A are indicated above their corresponding peaks. [Figure 12C] AOH1996 metabolism and in vivo pharmacokinetics. Aliquots of the liver microsomal reaction mixture of AOH1996 were taken after various incubation times in the presence or absence of NADPH as an energy source. AOH1996 concentrations, determined by LC / MS-MS, were graphed as a percentage of the input concentration. [Figure 12D]AOH1996 metabolism and in vivo pharmacokinetics. After oral administration, plasma concentrations of AOH1996 from three male and three female ES1e / SCID mice at the indicated time points were averaged and graphed ±SD. The inset contains PK parameters determined by standard non-compartmental methods. [Figure 12E] AOH1996 Metabolism and In Vivo Pharmacokinetics. A similar PK study of AOH1996 was conducted in dogs. [Figure 13A] Selective inhibition of cancer cells. NCI60 panel cancer cells were incubated in the presence of various concentrations of AOH1996 for 48 hours. After fixing the cells with ice-cold 10% trichloroacetic acid (TCA), cell proliferation was analyzed by sulforhodamine B (SRB) assay. The molar GI50 for each cell line was calculated by NCI (see Example 2 for details). Cell lines: Leukemia: CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226, SR; Non-small cell lung cancer: A549 / ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, NCI-H522; Colon cancer: COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, SW-620; CNS cancer: SF-268, SF-295, SF-539, SNB-19, SNB-75, U251; Melanoma: LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62; Ovarian cancer: IGROV 1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI / ADR-RES, SK-OV-3; Kidney cancer: 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31; Prostate cancer: PC-3, DU-145; Breast cancer: MCF7, MDA-MC-231 / ATCC, HS 578T, BT-549, T-47D, MDA-MB-468. [Figure 13B]Selective inhibition of cancer cells. Graphs show LogGI50. Small cell lung cancer (Figure 13B: H-82, H-524, H-526, LX22, and LX33), neuroblastoma (Figure 13C: SK-N-BE(2)c, SH-SY5Y, and SK-N-AS), and prostate cancer (Figure 13D: LN-caP, LN-caP-R, 22RV1, H660, LASCPC, PC3, and DU145) cell lines were treated with various concentrations of AOH1996 for 72 hours, as indicated. Non-malignant cells (Figure 13B: hSAEC and PBMC; and Figure 13C: 7SM0032) were used as controls. Cell proliferation was measured by CellTiter-Glo® luminescence assay. Relative cell proliferation in triplicates was averaged and graphed ±SD. [Figure 13C] Selective inhibition of cancer cells. Graphs show LogGI50. Small cell lung cancer (Figure 13B: H-82, H-524, H-526, LX22, and LX33), neuroblastoma (Figure 13C: SK-N-BE(2)c, SH-SY5Y, and SK-N-AS), and prostate cancer (Figure 13D: LN-caP, LN-caP-R, 22RV1, H660, LASCPC, PC3, and DU145) cell lines were treated with various concentrations of AOH1996 for 72 hours, as indicated. Non-malignant cells (Figure 13B: hSAEC and PBMC; and Figure 13C: 7SM0032) were used as controls. Cell proliferation was measured by CellTiter-Glo® luminescence assay. Relative cell proliferation in triplicates was averaged and graphed ±SD. [Figure 13D]Selective inhibition of cancer cells. Graphs show LogGI50. Small cell lung cancer (Figure 13B: H-82, H-524, H-526, LX22, and LX33), neuroblastoma (Figure 13C: SK-N-BE(2)c, SH-SY5Y, and SK-N-AS), and prostate cancer (Figure 13D: LN-caP, LN-caP-R, 22RV1, H660, LASCPC, PC3, and DU145) cell lines were treated with various concentrations of AOH1996 for 72 hours, as indicated. Non-malignant cells (Figure 13B: hSAEC and PBMC; and Figure 13C: 7SM0032) were used as controls. Cell proliferation was measured by CellTiter-Glo® luminescence assay. Relative cell proliferation in triplicates was averaged and graphed ±SD. [Figure 13E] Selective inhibition of cancer cells. Histones H2A.X and γH2A.X in whole cell lysates from the indicated cells were analyzed by Western blot after treatment with 500 nM AOH1996 for various times. [Figure 14] Chemical structures of AOH1996 and AOH1160. [Figure 15] Characterization of the binding pocket within the PIP box domain of PCNA. A, B: A predominantly hydrophobic cavity that extends well beneath the IDCL. Some polarity is "deep inside" but difficult to access. The IDCL is shaded. C: A clear depression, but more polar than A or B. D: The "wall" is hydrophobic but polar. E, F, G: Other hydrophobic pockets important for alternative binding configurations. H: A large hydrophobic region, difficult to access for compounds of shorter length. [Figure 16] Display of the lowest energy conformation of AOH1996 (E=-8.7). [Figure 17] Representation of the lowest energy configuration of fluorinated AOH1996. [Figure 18] Representation of the lowest energy configuration of AOH1160 containing isonipecotic acid instead of the glycine linker. [Figure 19]Conformational representation of AOH1996 and D-homophenylalanine docking with the PIP binding domain of caPCNA. [Figure 20] Conformational representation of AOH1996 analogs containing adamantyl amides of D-aspartic acid and D-glutamic acid docking with the PIP domain of caPCNA. [Figure 21A] Binary complex model of AOH1990-2 (Figure 21A), AOH1160NH (Figure 21B), AOH1160RCHF (Figure 21C), and AOH1160CF2 (Figure 21D) within the PCNA active site. [Figure 21B] Binary complex model of AOH1990-2 (Figure 21A), AOH1160NH (Figure 21B), AOH1160RCHF (Figure 21C), and AOH1160CF2 (Figure 21D) within the PCNA active site. [Figure 21C] Binary complex model of AOH1990-2 (Figure 21A), AOH1160NH (Figure 21B), AOH1160RCHF (Figure 21C), and AOH1160CF2 (Figure 21D) within the PCNA active site. [Figure 21D] Binary complex model of AOH1990-2 (Figure 21A), AOH1160NH (Figure 21B), AOH1160RCHF (Figure 21C), and AOH1160CF2 (Figure 21D) within the PCNA active site. [Figure 22A] A binary complex model of AOH1996 (FIG. 22A) and AOH1160 (FIG. 22B) within the PCNA active site. [Figure 22B] A binary complex model of AOH1996 (FIG. 22A) and AOH1160 (FIG. 22B) within the PCNA active site. [Figure 23A] Binary complex model of AOH1160eNaph (FIG. 23A) and AOH1996eeNaph (FIG. 23B) within the PCNA active site. [Figure 23B] Binary complex model of AOH1160eNaph (FIG. 23A) and AOH1996eeNaph (FIG. 23B) within the PCNA active site. [Figure 24-1]TSA data for AOH1160LV. AOH1160LV showed a very similar ΔTm compared to AOH1996. [Figure 24-2] TSA data for AOH1160LV. AOH1160LV showed a very similar ΔTm compared to AOH1996. [Figure 24-3] TSA data for AOH1160LV. AOH1160LV showed a very similar ΔTm compared to AOH1996. [Figure 25] IC50 data for AOH1160LA. IC50 = approximately 3uM. [Figure 26-1] IC50 data for AOH1996LA. The IC50 was 1.5, 1.6, and 1.8 uM for AK-N-AS, H1752, and H358, respectively. [Figure 26-2] IC50 data for AOH1996LA. The IC50 was 1.5, 1.6, and 1.8 uM for AK-N-AS, H1752, and H358, respectively. [Figure 27] IC50 data for AOH1996TMB. IC50 values: Hela: 6.5uM, A673: 5.5uM, A549: 4.7uM. [Figure 28A] IC50 data for AOH analogs in MDA-MB-468 cell line. IC50 values ​​for AOH1996: 740 nM (Figure 28A), AOH1160S: 316 nM (Figure 28B), AOH1160LA: 4900 nM (Figure 28C), AOH1996LA: 2300 nM (Figure 28D). [Figure 28B] IC50 data for AOH analogs in MDA-MB-468 cell line. IC50 values ​​for AOH1996: 740 nM (Figure 28A), AOH1160S: 316 nM (Figure 28B), AOH1160LA: 4900 nM (Figure 28C), AOH1996LA: 2300 nM (Figure 28D). [Figure 28C]IC50 data for AOH analogs in MDA-MB-468 cell line. IC50 values ​​for AOH1996: 740 nM (Figure 28A), AOH1160S: 316 nM (Figure 28B), AOH1160LA: 4900 nM (Figure 28C), AOH1996LA: 2300 nM (Figure 28D). [Figure 28D] IC50 data for AOH analogs in MDA-MB-468 cell line. IC50 values ​​for AOH1996: 740 nM (Figure 28A), AOH1160S: 316 nM (Figure 28B), AOH1160LA: 4900 nM (Figure 28C), AOH1996LA: 2300 nM (Figure 28D). [Figure 29-1] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-2] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-3]IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-4] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-5] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-6] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-7] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-8] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-9] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-10] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-11] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-12] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-13] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-14] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-15] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. [Figure 29-16] IC50 data for selected compounds. The indicated cell lines were seeded at 104 cells per well in 96-well plates. After overnight attachment, cells were treated with various concentrations of the indicated compounds in triplicate for 72 hours. Cell proliferation was measured by SRB assay. Cell abundance under each treatment condition relative to baseline was averaged and graphed ±SD. Baseline was defined as the median cell abundance under treatment with the two lowest compound concentrations. IC50 was calculated using the Prism program. DETAILED DESCRIPTION OF THE INVENTION

[0031] I. Definition The 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 well known in the chemical arts.

[0032] Substituents, when defined by their conventional chemical formula written from left to right, equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0033] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which may include monovalent, divalent, and polyvalent radicals. An alkyl may contain the specified number of carbons (e.g., C-C 10 means 1 to 10 carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. The alkyl is a non-cyclized chain. 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, methyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those having 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. Alkoxy is an alkyl attached to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. An alkenyl contains one or more double bonds. An alkynyl contains one or more triple bonds.

[0034] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified by, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. 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. The term "alkynylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, an alkylene is fully saturated. In embodiments, an alkylene is monounsaturated. In embodiments, an alkylene is polyunsaturated. An alkenylene contains one or more double bonds. An alkynylene contains one or more triple bonds.

[0035] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable linear or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (e.g., N, S, Si, or P) 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. Heteroalkyl groups are non-cyclizing chains. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-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 can contain two, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain three, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain four, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain five, optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain up to eight, optionally different heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one double bond. A heteroalkenyl can optionally contain, in addition to one or more double bonds, two or more double bonds and / or one or more triple bonds.The term "heteroalkynyl," alone or in combination with another term, means, unless otherwise stated, a heteroalkyl containing at least one triple bond. A heteroalkynyl can optionally contain, in addition to one or more triple bonds, two or more triple bonds and / or one or more double bonds. In embodiments, a heteroalkyl is fully saturated. In embodiments, a heteroalkyl is monounsaturated. In embodiments, a heteroalkyl is polyunsaturated.

[0036] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, 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.). Still further, 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, heteroalkyl groups, as used herein, include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -S02R'. When a "heteroalkyl" is recited followed by a defined heteroalkyl group, such as -NR'R'', it is understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the defined heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding a defined heteroalkyl group, such as -NR'R''. The term "heteroalkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term "heteroalkynylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, a heteroalkylene is fully saturated. In embodiments, a heteroalkylene is monounsaturated. In embodiments, heteroalkylene is polyunsaturated. Heteroalkenylene contains one or more double bonds. Heteroalkynylene contains one or more triple bonds.

[0037] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. 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, 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. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and a heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated.

[0038] In embodiments, the term "cycloalkyl" refers to a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to multiple rings fused together, at least one of the fused rings being a cycloalkyl ring, and the multiple rings being connected to the parent molecular moiety through any carbon atom contained within the cycloalkyl ring of the multiple rings.

[0039] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic, or polycyclic cycloalkenyl ring system. A bicyclic or polycyclic cycloalkenyl ring system refers to multiple rings fused together, at least one of the fused rings being a cycloalkenyl ring, and the multiple rings are bonded to the parent molecular moiety through any carbon atom contained within the cycloalkenyl ring of the multiple rings.

[0040] In embodiments, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, or polycyclic heterocycloalkyl ring system. In embodiments, the heterocycloalkyl group is fully saturated. A bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, where at least one of the fused rings is a heterocycloalkyl ring, and the rings are attached to the parent molecular moiety through any atom contained within the heterocycloalkyl ring of the multiple rings.

[0041] 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 meant 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, and 3-bromopropyl.

[0042] 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.

[0043] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings fused together (i.e., fused-ring aryl) or covalently linked (preferably 1 to 3 rings). Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring, and the multiple rings are bonded to the parent molecular moiety through any carbon atom contained within the aryl ring of the multiple rings. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, at least one of which is a heteroaromatic ring, and the multiple rings are bonded to the parent molecular moiety through any atom contained within the heteroaromatic ring of the multiple rings). A 5,6-fused ring heteroarylene refers to two rings fused together, one ring having 5 members and the other ring having 6 members, and at least one ring being 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 being a heteroaryl ring. Also, 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 being a heteroaryl ring. A heteroaryl group can be attached to the rest of the molecule through a carbon atom or a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, and the like. aryl, 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. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. The heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0044] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring can be the same or different. The individual rings within a spirocyclic ring can be substituted or unsubstituted and can have different substituents than the other individual rings within a set of spirocyclic rings. The possible substituents for the individual rings within a spirocyclic ring are the possible substituents for the same ring (e.g., the substituents for a cycloalkyl ring or heterocycloalkyl ring) when not part of a spirocyclic ring. The spirocyclic ring can be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group can be any of the rings in the list immediately above, including all rings of one type (e.g., all rings can be substituted heterocycloalkylene, and each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic, and each ring may be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substituent may optionally be different.

[0045] symbol

[0046] [ka] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0047] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0048] The term "alkylarylene" as an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

[0049] [ka] It has.

[0050] The alkylarylene moiety may be substituted on the alkylene portion or on the arylene linker (e.g., at carbon 2, 3, 4, or 6) with halogen, oxo, -N, -CF, -CCl, -CBr, -CI, -CN, -CHO, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOCH, -SOH, -OSOH, -SONH, -NHNH, -ONH, -NHC(O)NHNH, substituted or unsubstituted C-C alkyl, or substituted or unsubstituted 2-5 membered heteroalkyl. In embodiments, the alkylarylene is unsubstituted.

[0051] 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.

[0052] Substituents for alkyl and heteroalkyl radicals (including groups also referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from 0 to (2m'+1), where m' is the total number of carbon atoms in such radical, and include -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', - It can be one or more of a variety of groups selected from, but not limited to, NR″C(O)R′, —NR′C(O)NR″R′″, —NR″C(O)2R′, —NRC(NR′R″R′″)═NR′″, —NRC(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, —NR′S02R″, —NR′C(O)R″, —NR′C(O)OR″, —NR′OR″. R, R', R'', R''', and R'''' each preferably independently refer to 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 the compounds described herein include more than one R group, for example, each of the R groups is independently selected as 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.).

[0053] Similar to the substituents described for the alkyl radical, substituents for 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', -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'', -NRSO2 R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'S02R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', where 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 the compounds described herein include 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.

[0054] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be designated as substituents on the ring (generally referred to as floating substituents) rather than on a specific atom of the ring. In such cases, the substituent may be attached to any of the ring atoms (according to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent shown as attached to one member of the fused or spirocyclic ring (a floating substituent on a single ring) may also be a substituent on either the fused or spirocyclic ring (a floating substituent on a polycyclic ring). When a substituent is attached to a ring rather than to a specific atom (a floating substituent), and the substituent subscript is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, according to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with another floating substituent (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown to be attached to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen), it will be understood that when the heteroatom is attached to the floating substituent, the substituent replaces the hydrogen, according to the rules of chemical valence.

[0055] Two or more substituents may optionally be linked 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 base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0056] 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 form a ring of the formula -A-(CH2) r Optionally, one of the single bonds of the new ring so formed may be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') d wherein s and d are independently an integer of 0 to 3; and X′ is —O—, —NR 7 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR 7 C(O)-, -C(O)NR 7 -, -NR 7 C(O)NR 8 -, -NR 7 S(O)2O-, -OS(O)2NR 7-, -NR 7 S(O)2-, -S(O)2NR 7 -, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OR 7 )-, -OP(O)(OR 7 )O-, -OP(O)(OR 7 )-, -P(O)(OR 7 )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.

[0057] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0058] As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCH F2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, - NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2 , -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl: (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2 , -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH-N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl) (substituted with at least one substituent selected from the following: oxo, halogen, —CCl3, —CBr3, —CF3, —CI3, —CHCl2, —CHBr2, —CHF2, —CHI2, —CH2Cl, —CH2Br, —CH2F, —CH2I, —OCCl3, —OCF3, —OCBr3, —OCI3, —OCHCl2, —OCHBr2, —OCHI2, —OCHF2, —OCH2Cl, —OCH2Br, —OCH2I, —OCH2F, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —OSO3H, —SO2NH2, —NHNH2, —O NH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0059] As used herein, "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.

[0060] 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, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0061] In some embodiments, each substituent 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 substituent.

[0062] 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-C8 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C-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 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0063] 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 2-8 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 3-7 membered heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C7 10In 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 2-8 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 3-7 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, Figures, or Tables below.

[0064] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., 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, respectively).

[0065] In embodiments, a substituted moiety (e.g., 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) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0066] In embodiments, a substituted moiety (e.g., 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) is substituted with at least one size-limiting substituent, and when a substituted moiety is substituted with multiple substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0067] In embodiments, a substituted moiety (e.g., 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) is substituted with at least one lower substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0068] In embodiments, a substituted moiety (e.g., a 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) is substituted with at least one substituent, size-limiting substituent, or lower substituent; when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent is different.

[0069] In the recited claims or formula descriptions herein, each R substituent or L linker described as "substituted" (also referred to herein as an "open substitution" or "openly substituted" R substituent or L linker for an "open" R substituent or L linker), without reference to the identity of any chemical moieties that make up the "substituted" group, the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituents, as defined below.

[0070] The first substituent can be, for example, R 1 But R 1.1 and R 2 But R 2.1 and R 3 But R 3.1 and R 4 But R 4.1 and R 5 But R 5.1 and may be substituted with one or more first substituents represented by the formula: 100 But R 100.1As a further example, R 1A But R 1A.1 and R 2A But R 2A.1 and R 3A But R 3A.1 and R 4A But R 4A.1 and R 5A But R 5A.1 and may be substituted with one or more first substituents represented by the formula: 100A But R 100A.1 As a further example, L 1 But R L1.1 and L may be substituted with one or more first substituents represented by 2 But R L2.1 and L may be substituted with one or more first substituents represented by 3 But R L3.1 and L may be substituted with one or more first substituents represented by 4 But R L4.1 and L may be substituted with one or more first substituents represented by 5 But R L5.1 and may be substituted with one or more first substituents represented by the formula: 100 But R L100.1 Thus, each numbered R or L group described herein (alternatively, R WW or L WW and "WW" represents the listed superscript number of the subject R or L group) are generally referred to herein as R WW.1 or R LWW.1 Each first substituent (e.g., R 1.1 , R 2.1 , R 3.1 , R4.1 , R 5.1 ...R 100.1 , R 1A.1 , R 2A.1 , R 3A.1 , R 4A.1 , R 5A.1 ...R 100A.1 R L1.1 , R L2.1 , R L3.1 , R L4.1 , R L5.1 ...R L100.1 ) may be substituted with one or more second substituents (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ...R 100.2 , R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ...R 100A.2 R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ...R L100.2 ) may be further substituted. Therefore, as used herein, R WW.1 Each first substituent may alternatively be represented as R WW.2 The alkyl group may be further substituted with one or more second substituents, which may alternatively be represented as:

[0071] Finally, each second substituent (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ...R 100.2 , R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ...R 100A.2 R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ...R L100.2 ) may be one or more third substituents (e.g., R1.3 , R 2.3 , R 3.3 , R 4.3 , R 5.3 ...R 100.3 , R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.3 ...R 100A.3 R L1.3 , R L2.3 , R L3.3 , R L4.3 , R L5.3 ...R L100.3 ) may be further substituted. Therefore, as used herein, R WW.2 Each second substituent may alternatively be represented as R WW.3 Each of the first substituents may be optionally different. Each of the second substituents may be optionally different. Each of the third substituents may be optionally different.

[0072] Thus, as used herein, R WW represents an openly substituted substituent as listed in the claims or in the formula descriptions herein. "WW" represents the superscript number (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the R group in question. Similarly, L WW is an open-substituted linker as described in the claims or formula descriptions herein. Additionally, "WW" represents the superscript number (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the subject L group. As noted above, in embodiments, each R WW may be unsubstituted, and is referred to herein as R WW.1 and each first substituent R WW.1 may be unsubstituted, and is referred to herein as R WW.2 Each of the groups may be independently substituted with one or more second substituents, referred to herein as R WW.3Similarly, each L may be independently substituted with one or more third substituents, referred to as WW The linker may be unsubstituted and is referred to herein as R LWW.1 and each first substituent R LWW.1 may be unsubstituted, and is referred to herein as R LWW.2 Each of the groups may be independently substituted with one or more second substituents, referred to herein as R LWW.3 Each of the first substituents is optionally different. Each of the second substituents is optionally different. Each of the third substituents is optionally different. For example, R WW When is phenyl, the phenyl group may be one or more R WW.1 Optionally substituted by groups, such as R WW.1 R WW.2 In the case of substituted or unsubstituted alkyl, examples of the groups so formed include one or more R WW.2 and R itself optionally substituted with WW.2 is one or more R WW.3 For example, R WW R is a methyl group WW.1 When the methyl group is phenyl substituted by

[0073] [ka] It may form groups including, but not limited to:

[0074] R WW.1 are independently oxo, halogen, -CX WW.1 3. -CHX WW.1 2. -CH2X WW.1 , -OCX WW.1 3. -OCH2X WW.1 , -OCHX WW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3,R WW.2 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R WW.2 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.2 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R WW.2 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.2 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or R WW.2 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW.1 are independently oxo, halogen, -CX WW.1 3. -CHX WW.1 2. CH2X WW.1 , -OCX WW.1 3. -OCH2X WW.1 , -OCHX WW.12, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4 or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). WW.1 is independently -F, -Cl, -Br, or -I.

[0075] R WW.2 are independently oxo, halogen, -CX WW.2 3. -CHX WW.2 2. -CH2X WW.2 , -OCX WW.2 3. -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.3 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R WW.3 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.3 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R WW.3substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.3 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or R WW.3 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW.2 are independently oxo, halogen, -CX WW.2 3. -CHX WW.2 2. -CH2X WW.2 , -OCX WW.2 3. -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C 1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). WW.2 is independently -F, -Cl, -Br, or -I.

[0076] R WW.3 are independently oxo, halogen, -CX WW.3 3. -CHX WW.3 2. -CH2X WW.3 , -OCX WW.3 3. -OCH2X WW.3 , -OCHX WW.32, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4 or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). WW.3 is independently -F, -Cl, -Br, or -I.

[0077] Two different R WW When substituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), in embodiments, the openly substituted ring is referred to herein as R WW.1 and each first substituent R WW.1 may be unsubstituted, and is referred to herein as R WW.2 and each second substituent R WW.2 may be unsubstituted, and is referred to herein as R WW.3 and each third substituent R WW.3 are unsubstituted. Each first substituent is optionally different. Each second substituent is optionally different. Each third substituent is optionally different. Two different R WW In the context where the substituents are joined together to form an open substituted ring, R WW.1 , RWW.2 , and R WW.3 The "WW" symbol in WW Refers to a specified number of one of the substituents. For example, R 100A and R 100B are optionally linked together to form an open substituted ring, R WW.1 is R 100A.1 and R WW.2 is R 100A.2 and R WW.3 is R 100A.3 Alternatively, R 100A and R 100B are optionally linked together to form an open substituted ring, R WW.1 is R 100B.1 and R WW.2 is R 100B.2 and R WW.3 is R 100B.3 R in this paragraph WW.1 , R WW.2 , and R WW.3 is as defined in the previous paragraph.

[0078] R LWW.1 are independently oxo, halogen, -CX LWW.1 3. -CHX LWW.1 2. -CH2X LWW.1 , -OCX LWW.1 3. -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.2 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW.2 ), R LWW.2 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R LWW.2substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R LWW.2 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.2 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or R LWW.2 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). LWW.1 are independently oxo, halogen, -CX LWW.1 3. -CHX LWW.1 2. -CH2X LWW.1 , -OCX LWW.1 3. -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NH C(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g. C1-C8, C1-C6, C1-C4, or C1-C2, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). LWW.1 is independently -F, -Cl, -Br, or -I.

[0079] R LWW.2 are independently oxo, halogen, -CX LWW.2 3. -CHX LWW.2 2. -CH2XLWW.2 , -OCX LWW.2 3. -OCH2X LWW.2 , -OCHX LWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.3 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW.3 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.3 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R LWW.3 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.3 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or R LWW.3 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). LWW.2 are independently oxo, halogen-CX LWW.2 3. -CHX LWW.2 2. -CH2X LWW.2 , -OCX LWW.2 3. -OCH2X LWW.2 , -OCHX LWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C 1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). LWW.2 is independently -F, -Cl, -Br, or -I.

[0080] R LWW.3 are independently oxo, halogen, -CX LWW.3 3. -CHX LWW.3 2. -CH2X LWW.3 , -OCX LWW.3 3. -OCH2X LWW.3 , -OCHX LWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C 1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 12, C6-C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12-membered, 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered). LWW.3 is independently -F, -Cl, -Br, or -I.

[0081] Any R group (R WW If an R group (R WW The groups) are, as used herein, independently selected from oxo, halogen, -CX WW 3. -CHX WW 2. -CH2X WW , -OCX WW 3. -OCH2X WW , -OCHX WW 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.1 substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R WW.1 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.1 substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R WW.1 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.1 Substituted or unsubstituted aryl (e.g., C6-C 12 , C6-C 10 , or phenyl), or R WW.1 X is defined as substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WWare independently -F, -Cl, -Br, -I. Again, "WW" represents the superscript number of the R group in question (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R WW.1 , R WW.2 , and R WW.3 is as defined above.

[0082] Any L linker group (i.e., L WW If the L group (L WW Groups) are herein independently defined as a bond, -O-, -NH-, -, NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O) 2NH-, -NHS(O)2-, -S(O)2NH-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, R LWW.1 substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), R LWW.1 ), R LWW.1 substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R LWW.1 substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), R LWW.1 substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.1 Substituted or unsubstituted arylene (e.g., C-C 12 , C6-C 10 , or phenyl), or R LWW.1 R is defined as a substituted or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). Additionally, "WW" represents the superscript number (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the subject L group.LWW.1 , and R LWW.2 and R LWW.3 is as defined above.

[0083] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0084] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural arrangement or configuration of the atoms.

[0085] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0086] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.

[0087] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0088] 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 a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0089] The compounds of the present disclosure 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 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0090] It should be noted that throughout this application, options, e.g., each amino acid position containing more than one possible amino acid, are described in terms of a Markush group. It is specifically contemplated that each member of a Markush group should be considered separately, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0091] As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the resulting association between atoms or molecules of a bioconjugate reactive group or bioconjugate reactive moiety. The association can be direct or indirect. For example, provided herein, conjugates between a first bioconjugate reactive group (e.g., -NH, -COOH, -N-hydroxysuccinimide, or -maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine side chain-containing amino acid, or carboxylate) can be direct, e.g., through a covalent bond or linker (e.g., a first linker to a second linker), or indirect, e.g., through a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effect), hydrophobic interactions, etc.). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups), including, but not limited to, nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, activated esters), electrophilic substitution (e.g., enamine reaction), and addition across carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed, for example, in March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, DC, 1982.In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., an -N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., an amine). In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (eg, a -sulfo-N-hydroxysuccinimide moiety) is covalently attached to a second bioconjugate reactive group (eg, an amine).

[0092] Useful bioconjugate reactive groups for use in the bioconjugate chemistry herein include: (a) carboxyl groups and their various derivatives, including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl, and aromatic esters; (b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups, where the halide can be subsequently displaced with a nucleophilic group, such as an amine, carboxylate anion, thiol anion, carbanion, or alkoxide ion, resulting in the covalent attachment of a new group at the halogen atom; (d) dienophile groups, such as maleimide or maleimide groups, that can participate in Diels-Alder reactions; and (e) subsequent derivatization via the formation of carbonyl derivatives, such as imines, hydrazones, semicarbazones, or oximes, or via mechanisms such as Grignard addition or alkyllithium addition. (f) sulfonyl halide groups, e.g., for subsequent reaction with amines to form sulfonamides; (g) thiol groups, which can be converted to disulfides, react with acyl halides, conjugated to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., those present in cysteine), which can be acylated, alkylated, or oxidized; (i) alkenes, which can undergo, e.g., cycloaddition, acylation, Michael addition, etc.; (j) alkyl groups, e.g., amines and hydrides, which can be acylated, alkylated, or oxidized; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal-silicon oxide linkages; (m) metal linkages to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphodiester bonds; (n) azides coupled to alkynes using copper-catalyzed cycloaddition click chemistry; and (o) biotin conjugates that can react with avidin or streptavidin to form avidin-biotin or streptavidin-biotin complexes.

[0093] Bioconjugate reactive groups can be selected so that they do not contribute to or interfere with the chemical stability of the conjugates described herein. Alternatively, reactive functional groups can be protected from participating in crosslinking reactions by the presence of protecting groups. In embodiments, bioconjugates include molecular entities resulting from the reaction of an unsaturated bond, such as a maleimide, with a sulfhydryl group.

[0094] "Analog," "analogue," or "derivative" is used according to its plain and ordinary meaning within chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the substitution of one atom with an atom of a different element, or the presence of a particular functional group, or the substitution of one functional group with another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0095] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with a[n]" means that the specified group can be substituted with one or more of any or all of the named substituents. For example, when a group such as an alkyl group or heteroaryl group is "unsubstituted C-C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is substituted with one or more unsubstituted C-C 20 It may contain alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl groups.

[0096] Furthermore, when a moiety is substituted with an R substituent, 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. When a particular R group occurs in a description of a chemical species (such as formula (I)), Roman alphabet symbols may be used to distinguish between each occurrence of that particular R group. For example, multiple R 13When substituents are present, each R 13 The substituents are R 13.A , R 13.B , R 13.C , R 13.D can be distinguished from R 13.A , R 13.B , R 13.C , R 13.D Each of these is R 13 and optionally defined differently within the definition of . When an R moiety, group, or substituent disclosed herein is attached via a single bond representation and the R moiety, group, or substituent is oxo, one of ordinary skill in the art will immediately recognize that the oxo is attached via a double bond in accordance with the normal rules of chemical valence.

[0097] The description of the compounds of the present disclosure 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 not inherently unstable and / or is known to those skilled in the art to be 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 ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0098] The term "leaving group" is used according to its ordinary meaning in chemistry to refer to a moiety (e.g., atom, functional group, molecule) that separates from a molecule following a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction) involving the atom or chemical moiety to which the leaving group is attached, and is also referred to herein as a "leaving group-reactive moiety" and a complementary reactive moiety (i.e., a chemical moiety that reacts with the leaving group-reactive moiety) to form a new bond between the leaving group-reactive moiety and the remainder of the complementary reactive moiety. Thus, the leaving group-reactive moiety and the complementary reactive moiety form a complementary reactive group pair. Non-limiting examples of leaving groups include hydrogen, hydroxide, organotin moieties (e.g., organotin heteroalkyls), halogens (e.g., Br), perfluoroalkylsulfonates (e.g., triflates), tosylate, mesylate, water, alcohols, nitrates, phosphates, thioethers, amines, ammonia, fluorides, carboxylates, phenoxides, boronic acids, boronic esters, and alkoxides. In embodiments, the leaving group is designed to facilitate the reaction.

[0099] The term "protecting group" is used according to its ordinary meaning in organic chemistry to refer to a moiety covalently attached to a heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity of the heteroatom, heterocycloalkyl, or heteroaryl during one or more chemical reactions performed prior to removal of the protecting group. Typically, a protecting group is attached to a heteroatom (e.g., O) during a part of a multi-part synthesis where it is undesirable to react the heteroatom with a reagent (e.g., chemical reduction). After protection, the protecting group can be removed (e.g., by adjusting the pH). In embodiments, the protecting group is an alcohol protecting group. Non-limiting examples of alcohol protecting groups include acetyl, benzoyl, benzyl, methoxymethyl ether (MOM), tetrahydropyranyl (THP), and silyl ethers (e.g., trimethylsilyl (TMS)). In embodiments, the protecting group is an amine protecting group. Non-limiting examples of amine protecting groups include carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), and tosyl (Ts).

[0100] 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 disclosure contains a relatively acidic functional group, 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, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, 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 salts 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, as well as 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, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0101] Therefore, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids, such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0102] 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 may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0103] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present disclosure. Prodrugs of the compounds described herein can be converted in vivo after administration. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0104] Certain compounds of the present disclosure may exist in unsolvated forms and solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in polycrystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0105] A polypeptide or cell is "recombinant" if it is artificial or engineered, or if it is derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-naturally occurring or non-wild-type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in the genome of a recombinant organism, so that it is not associated with nucleotide sequences that normally flank the polynucleotide as found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Similarly, a polynucleotide sequence not found in nature, e.g., a variant of a naturally occurring gene, is recombinant.

[0106] "Co-administered" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents. The compounds of the present invention can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparations can also be combined with other active agents, if desired (e.g., to reduce metabolic degradation).

[0107] As used herein, a "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a particular dye, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian cells, insect cells (e.g., Spodoptera), and human cells. Cells may be useful if they are naturally non-adherent or have been treated to prevent them from adhering to surfaces, for example, by trypsinization.

[0108] The term "treating" or "treatment" refers to any indication of success in treatment or improvement of an injury, disease, condition, or state, including any objective or subjective parameter, such as relief, remission, reduction in symptoms, or making the injury, condition, or state more tolerable to the patient, slowing the rate of degeneration or decline, making the degenerative end point less debilitating, or improving the patient's physical or mental health. Treating or improving symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. For example, certain methods provided herein successfully treat cancer by reducing the incidence of cancer and / or by causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. For example, certain methods herein treat diseases associated with PCNA activity. Certain methods described herein may treat diseases associated with PCNA activity (e.g., cancer or neuroblastoma) by inhibiting PCNA activity. The term "treating" and its conjugations includes prevention of an injury, lesion, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, treating or treatment is not prophylactic treatment.

[0109] An "effective amount" is an amount sufficient for a compound to achieve a predetermined purpose (e.g., achieve the effect of being administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of a symptom or symptoms of a disease, which may also be referred to as a "therapeutically effective amount" when referred to in this context. "Alleviation" of a symptom(s) (and grammatical equivalents of this phrase) means a reduction in the severity or frequency of the symptom, or elimination of the symptom. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have an intended prophylactic effect, for example, an amount of a drug that prevents or delays the onset (or recurrence) of an injury, disease, pathology, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, a "function-interfering amount" refers to the amount of antagonist required to interfere with the function of an enzyme or protein compared to the absence of the antagonist. As used herein, an "activity-increasing amount" refers to the amount of agonist required to increase the activity of an enzyme compared to the absence of the agonist. As used herein, a "function-increasing amount" refers to the amount of agonist required to increase the function of an enzyme or protein compared to the absence of the agonist.The exact 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).

[0110] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subject or reagent is treated the same as in 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 in evaluating experimental efficacy. In some embodiments, a control is a measurement of a protein activity (e.g., a signaling pathway) in the absence of a compound described herein (including in any embodiment, example, figure, or table).

[0111] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two distinct species (e.g., chemical compounds, including biomolecules or cells) to come into sufficient proximity to react, interact, or physically contact each other. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or may be produced from an intermediate from one or more of the added reagents that may be produced in the reaction mixture.

[0112] 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 cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In some embodiments, contacting includes allowing a compound described herein to interact with a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) involved in a signaling pathway.

[0113] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to proteins, refer to the conversion of a protein from an initial, inactive, or inactivated state to a biologically active derivative. These terms refer to the activation of, or the activation, sensitization, or upregulation of, signal transduction or enzymatic activity or the amount of a protein that is decreased in a disease.

[0114] The terms "agonist," "activator," "up-regulator," and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more, greater than expression or activity in the absence of the agonist.

[0115] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to cellular component-inhibitor interactions, mean to adversely affect (e.g., reduce) the activity or function of the cellular component (e.g., reduce a signal transduction pathway stimulated by the cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) compared to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition means adversely affecting (e.g., reducing) the concentration or level of the cellular component compared to the concentration or level of the cellular component in the absence of the inhibitor. In embodiments, inhibition refers to the alleviation of a disease or disease symptom. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction or signal transduction pathway (e.g., a decrease in a pathway involving the cellular component). Thus, inhibiting includes, at least in part, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating a signaling pathway or enzymatic activity or the amount of a cellular component.

[0116] The terms "inhibitor," "suppressor," "antagonist," or "down-regulator" refer interchangeably to a substance capable of detectably reducing the expression or activity of a given gene or protein. An antagonist can reduce expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more lower than the expression or activity in the absence of the antagonist.

[0117] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the molecule's target compared to the absence of the composition (e.g., the target can be a cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)).

[0118] "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, an anticancer agent is a chemotherapeutic agent. In some embodiments, an anticancer agent is a drug approved by the FDA or a similar regulatory agency in a country other than the United States to treat cancer. Examples of anticancer drugs include 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, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan), ethylenimines and 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, capesin), Tabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogues (e.g., methotrexate), pyrimidine analogues (e.g., fluorouracil, floxuridine, cytarabine), purine analogues (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), adrenal cortical suppression agents (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinases (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, 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 regulators; Apoptosis regulators; Arginine deaminase; BCR / ABL antagonists; Beta-lactam derivatives; bFGF inhibitors; Bicalutamide; Camptothecin derivatives; Casein kinase inhibitors (ICOS); Clomiphene analogs; Cytarabine; Dacliximab; Dexamethasone; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Finasteride; Fludarabine; Fluorodornithin hydrochloride; Gadolinium texaphyrin; Gallium nitrate; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hepsulfame; Immunostimulating peptides; Insulin-like growth factor-1 receptor inhibitors; Interferons 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 RNA; monoclonal antibodies; mycobacterial cell wall extracts; nitric oxide regulators; oxaliplatin; panomyphen; pentrazole; phosphatase inhibitors anti-inflammatory drugs; plasminogen activator inhibitors; platinum complexes; platinum compounds; prednisone; proteasome inhibitors; protein A system immunomodulators; protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; ribozymes; signal transduction inhibitors; signal transduction regulators; 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) such as 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 aeruginosa exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody, 111 In, 90 Y, or 131I, 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 (Tarce va™), 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, pelitinib / EKB-5 69, 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-CBIs, nitrogen mustards (such as chlorambucil and melphalan), dolastatins and dolastatin analogs (including auristatins, e.g., monomethyl auristatin E), anthracycline antibiotics (e.g., Examples of anti-cancer drugs include, but are not limited to, doxorubicin, daunorubicin, 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.

[0119] The term "expression" includes any step involved in the production of a polypeptide, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0120] The term "modulate" is used according to its plain and ordinary meaning to refer to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effect of a modulator on a target protein, modulating means changing the property or function of the target molecule or the amount of the target molecule by increasing or decreasing it.

[0121] "Patient," "patient in need thereof," "subject," or "subject in need thereof" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human. In embodiments, the patient in need thereof is a human. In embodiments, the subject is a human. In embodiments, the subject in need thereof is a human.

[0122] "Disease" or "condition" refers to an existence or state of health of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease is a disease associated with (e.g., caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In embodiments, the disease is cancer (e.g., sarcoma, adenocarcinoma, leukemia, or lymphoma).

[0123] As used herein, the term "cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. 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 lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0124] The term "leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by the distorted proliferation and development of white blood cells and their precursor cells in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease—acute or chronic; (2) the type of cells involved—myeloid (myeloid), lymphatic (lymphoid), or monocytic; and (3) the increased or non-increasing number of abnormal cells in the blood—leukemia or non-leukemia (subleukemia). Exemplary leukemias that may 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, and non-leukemia. leukemia), leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoid leukemia, lymphoid leukemia, Examples of leukemia include lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic 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, and anaplastic cell leukemia.

[0125] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It develops in lymphocytes, which are blood cells found primarily in lymph nodes, spleen, thymus, and bone marrow. The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the rate at which the cancer grows and the type of cell involved. NHL includes aggressive (high-grade) and indolent (low-grade) types of NHL. Based on the type of cell involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytic B-cell) lymphoma, splenic lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0126] The term "sarcoma" generally refers to a tumor composed of closely packed cells that are composed of a substance like embryonic connective tissue and that is generally composed of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, and fibroblastic sarcoma. These include alveolar sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0127] The term "melanoma" is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0128] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, acinic cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, carcinoma adenomatous, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid cell carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, and compact carcinoma. durum, embryonal carcinoma, encephalomyocellular carcinoma, epidermoid carcinoma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, carcinoma in epidermis, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, mucus-secreting carcinoma muciparum, mucous cell carcinoma, mucoepidermoid carcinoma, mucous carcinoma (carcinoma mucosum), mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinomacarcinoma, globular cell carcinoma, spindle cell carcinoma, porocytic carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectasia-like carcinoma, transitional cell carcinoma, carcinoma tuberosum, nodular carcinoma, verrucous carcinoma, or choriocarcinoma.

[0129] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or part of the body. "Metastatic cancer" is also referred to as "stage IV cancer." Cancer originates in a site of origin, e.g., the breast, called a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to penetrate and invade surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular system and circulate through the system to other parts and tissues of the body. Clinically detectable secondary tumors formed from cancer cells of the primary tumor are called metastatic or secondary tumors. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor in the breast site will consist of abnormal lung cells, not abnormal breast cells. The secondary tumor in the breast is called metastatic lung cancer. Therefore, the term metastatic cancer refers to a disease in which a subject has or has had a primary tumor, and has one or more secondary tumors.The term non-metastatic cancer or a subject with non-metastatic cancer refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors.For example, metastatic lung cancer refers to a disease in a subject who has or has had a history of a primary lung tumor, and has one or more secondary tumors, for example, in a second location or multiple locations in the breast.

[0130] The terms "skin metastasis" and "cutaneous metastasis" refer to secondary malignant cell growth in the skin, where the malignant cells originate from a primary cancer site (e.g., breast). In skin metastasis, cancerous cells from the primary cancer site migrate to the skin, where they can divide and cause lesions. Skin metastasis can result from the migration of cancer cells from a breast cancer tumor to the skin.

[0131] The term "visceral metastasis" refers to secondary malignant cell growth in an organ (e.g., heart, lung, liver, pancreas, intestine) or body cavity (e.g., pleura, peritoneum) where the malignant cells originate from the primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from the primary cancer site migrate to a viscera where they can divide and cause lesions. Visceral metastasis can result from the migration of cancer cells from a liver cancer tumor or a head and neck tumor to a viscera.

[0132] The term "drug" is used according to its ordinary meaning to refer to a substance that has a physiological effect (e.g., a beneficial effect, useful for treating a subject) when introduced into or to a subject (e.g., into or on the body of a subject or patient). The drug moiety is the radical of the drug.

[0133] A "detectable agent," "detectable compound," "detectable label," or "detectable moiety" is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, useful detectable agents include: 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr,94 Tc 94 Tc 99m Tc 99 For 105 pd 105 Rh、 111 Ag 111 in 123 I 124 I 125 I 131 I 142 Mr. 143 Mr. 149 PM 153 Sm、 154-158 God 161 Tb 166 Dy 166 Ho 169 Err 175 sun 177 sun 186 Re 188 Re 189 Re 194 Ir 198 I 199 I 211 And 211 Pb、 212 Hello 212 Pb、 213 Hello 223 Ra 225 Ac、Cr、V、Mn、Fe、Co、Ni、Cu、La、Ce、Pr、Nd、Pm、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb、Lu、 32P, fluorophores (e.g., fluorescent dyes), modified oligonucleotides (e.g., portions described in PCT / US2015 / 022063, incorporated herein by reference), electron-dense reagents, enzymes (e.g., commonly used in ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SU ... oxide, "SPIO") nanoparticles, SPIO nanoparticle aggregates, single crystal iron oxide nanoparticles, single crystal iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing gadolinium chelate ("Gd-chelate") molecules, gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma-emitting radionuclide, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., microbubble shells comprising albumin, galactose, lipids, and / or polymers), air, These include heavy gases, perfluorocarbons, nitrogen, octafluoropropane, perflexane lipid microspheres, microbubble gas cores including perflutren, etc., iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens, and proteins or other entities that can be made detectable by, for example, incorporating a radioactive label into a peptide or an antibody that specifically reacts with a target peptide.

[0134] Radioactive substances (e.g., radioisotopes) that may be used as imaging and / or labeling agents according to embodiments of the present disclosure include: 18 F, 32 P, 33 P, 45Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, and 225 Paramagnetic ions that can be used as additional imaging agents according to embodiments of the present disclosure include, but are not limited to, ions of transition metals and lanthanide metals (e.g., metals with atomic numbers 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0135] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration and absorption of an active agent by a subject and can be included in the compositions of the present invention without causing significant adverse toxic 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, coating agents, sweeteners, flavoring agents, saline (such as 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 desired, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0136] The term "preparation" is intended to include formulations of an active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and is therefore associated 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.

[0137] As used herein, the term "about" refers to a range of values ​​that includes the specified value and that one of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about refers to within a standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range that covers + / - 10% of the particular value. In embodiments, about includes the specified value.

[0138] As used herein, the term "administering" is used according to its plain and ordinary meaning and refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, to a subject. 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 administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Concomitant administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, e.g., cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered alone or simultaneously to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparations can also be combined with other active agents, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally or topically, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, paints, powders, and aerosols.

[0139] The compounds described herein can be used in combination with each other, in combination with other active agents known to be useful in treating diseases associated with cells expressing disease-associated cellular components, or in combination with adjunct agents that may not be effective alone but may contribute to the effectiveness of the active agent.

[0140] 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 agent and / or adjunct may be linked or conjugated to each other.

[0141] In therapeutic use for the treatment of disease, the compounds utilized in the pharmaceutical compositions of the present invention may be administered at an initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. Daily dosage ranges of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg can be used. However, dosages may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound or drug being used. For example, dosages can be empirically determined taking into account the type and stage of disease (e.g., cancer) diagnosed in a particular patient. In accordance with the present invention, the dosage administered to a patient should be sufficient to effect 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 associated with the administration of the compound in a particular patient. Determination of the appropriate dosage for a particular situation is within the ability of one of ordinary skill in the art. Generally, treatment is started with a smaller dosage that is less than the optimal dose of compound.Then, dosage is gradually increased until the optimal effect is reached under the circumstances.For convenience, if desired, total daily dosage can be divided and administered in portions throughout the day.

[0142] In the context of a substance or the activity or function of a substance related to a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term "related" or "associated with" means that the substance or the activity or function of the substance causes (in whole or in part) the disease (e.g., cancer) or causes (in whole or in part) a symptom of the disease, or that a symptom of the disease can be treated by modulating (e.g., inhibiting or activating) the substance (e.g., a cellular component). As used herein, something that is described as being associated with a disease, if it is a causative agent, can be a target for treating the disease. For example, a disease associated with PCNA activity can be treated with an agent (e.g., a compound described herein) effective to decrease the level of PCNA activity.

[0143] As used herein, the term "aberrant" refers to something that is different from normal. When used to describe enzyme activity, abnormal refers to activity that is greater than or less than the average of a normal control or normal, non-disease control sample. Abnormal activity can also refer to an amount of activity that results in disease, and restoring the abnormal activity to a normal or non-disease-associated amount (e.g., by administering a compound or using the methods described herein) results in a reduction of the disease or one or more symptoms.

[0144] As used herein, the term "electrophilic" refers to a chemical group that can accept electron density. An "electrophilic substituent," "electrophilic chemical moiety," or "electrophilic moiety" refers to an electron-deficient chemical group, substituent, or moiety (a monovalent chemical group) that can accept an electron pair or electron density to react with an electron-donating group, such as a nucleophile, by forming a bond.

[0145] As used herein, "nucleophile" refers to a chemical group that can donate electron density.

[0146] The term "isolated," when applied to a nucleic acid or protein, means that the nucleic acid or protein is essentially free from other cellular components with which it is associated in its natural state. It can be, for example, in a homogeneous state, either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein present as the predominant species in a preparation is substantially purified.

[0147] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to compounds that have a structure that differs from the general chemical structure of an amino acid but function similarly to a naturally occurring amino acid. The terms "non-naturally occurring amino acid" and "unnatural amino acid" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

[0148] The term "amino acid side chain" refers to the side chain of an amino acid. For example, when an amino acid has the formula

[0149] [ka] where -LR is an amino acid side chain. As an example, leucine has the formula

[0150] [ka] and the L-leucine side chain has

[0151] [ka] is.

[0152] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Similarly, nucleotides may be referred to by their commonly accepted single-letter codes.

[0153] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which may, in embodiments, be conjugated to moieties not composed of amino acids. The term applies to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of corresponding naturally occurring amino acids, as well as to naturally occurring and non-naturally occurring amino acid polymers.

[0154] The "position" of an amino acid or nucleotide base is indicated by a number sequentially identifying each amino acid (or nucleotide base) in a reference sequence based on its position relative to the N-terminus (or 5'-terminus). Due to deletions, insertions, truncations, fusions, etc., which must be considered when determining optimal alignment, the number of amino acid residues in a test sequence, determined simply by counting from the N-terminus, is generally not necessarily the same as the number of corresponding positions in the reference sequence. For example, if a variant has a deletion compared to the aligned reference sequence, there will be no amino acid in the variant corresponding to a position in the reference sequence at the site of the deletion. If there is an insertion in the aligned reference sequence, the insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there may be a stretch of amino acids in either the reference sequence or the aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0155] When used in the context of the numbering of a given amino acid or polynucleotide sequence, the term "numbered with reference to" or "corresponding to" refers to the numbering of residues in a particular reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0156] 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 in a selected protein corresponds to His44 of PCNA if the selected residue occupies the same essential spatial or other structural relationship as His44 of PCNA. In some embodiments, when a selected protein is aligned for maximum homology with PCNA, the position in the aligned selected protein that aligns with His44 is said to correspond to His44. Instead of primary sequence alignment, three-dimensional structural alignment can also be used, for example, when the structure of a selected protein is aligned with PCNA for maximum identity and overall structure comparison is performed. In this case, the amino acid occupying the same essential position as His44 in the structural model is said to correspond to the His44 residue.

[0157] The term "proliferating cell nuclear antigen" or "PCNA" refers to an approximately 29 kDa protein that self-assembles into a protein complex consisting of three individual PCNA protein subunits. These linked PCNA molecules together form a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. The term "PCNA" may refer to the nucleotide sequence or protein sequence of human PCNA (e.g., Entrez 5111, Uniprot P12004, RefSeq NM_002592, or RefSeq NP_002583). The term "PCNA" includes both the wild-type form of the nucleotide sequence or protein and 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 the nucleotide sequence or protein of a mutant PCNA in which the Y-numbered amino acid of PCNA, which normally has the X amino acid in the wild-type form, instead has 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. In embodiments, PCNA has a nucleotide sequence corresponding to RefSeq NM_002592.2. In embodiments, PCNA has a protein sequence corresponding to reference number GI:4505641. In embodiments, PCNA has a nucleotide sequence corresponding to RefSeq NP_002583.1. In embodiments, PCNA has the following amino acid sequence: MFEARLVQGSILKKVLEALKDLINEACWDISSSGVNLQSMDSSHVSLVQLTLRSEGFDTYRCDRNLAMGVNLTSMSKILKCAGNEDIITLRAEDNADTLALVFEAPNQEKVSDYEMKLMDLDVEQLGIPEQEYSCVVKMPSGEFARICRDLSHIGDAVVISCAKDGVKFSASGELGNGNIKLSQTSNVDKEEEAVTIEMNEPVQLTFALRYLNFFTKATPLSSTVTLSMSADVPLVVEYKIADMGHLKYYLAPKIEDEEGS (SEQ ID NO: 4).

[0158] In embodiments, the PCNA is a mutant PCNA. In embodiments, the mutant PCNA is associated with a disease 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 post-translational modifications modify the inhibition of PCNA by the compounds described herein, or the binding of the compounds described herein to PCNA, compared to PCNA without the post-translational modifications.

[0159] As used herein, the term "cancer-associated proliferating cell nuclear antigen" or "caPCNA" refers to an isoform of PCNA having an acidic isoelectric point (e.g., a peptide containing a protonated amine and / or carboxyl group, an acidic isoelectric point compared to non-cancer-associated PCNA, PCNA in non-cancerous cells, non-malignant PCNA, the predominant PCNA isoform in non-cancerous cells, or a less acidic PCNA isoform in non-cancerous cells). In embodiments, the caPCNA protein comprises a methylated amino acid (e.g., glutamate, 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 / 2In 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 herein in its entirety for all purposes.

[0160] As used herein, the term "non-malignant proliferating cell nuclear antigen" or "nmPCNA" refers to an isoform of PCNA having a basic isoelectric point (e.g., a peptide containing a deprotonated amine group and / or a carboxyl group, a basic isoelectric point compared to caPCNA, caPCNA in cancerous cells). In embodiments, nmPCNA is the predominant PCNA isoform in non-cancerous cells.

[0161] II. Compounds In one aspect, a compound, or a pharmaceutically acceptable salt thereof, is provided having the formula:

[0162] [ka] or a pharmaceutically acceptable salt thereof.

[0163] L 1 -O-, -NR 7 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR 7 C(O)-, -C(O)NR 7 -, -NR 7 C(O)NR 8 -, -NR 7 S(O)2O-, -OS(O)2NR 7 -, -NR 7 S(O)2-, -S(O)2NR 7 -, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OR 7 )-, -OP(O)(OR 7 )O-, -OP(O)(OR 7 )-, -P(O)(OR 7 )O- or -CR 8 R9 -.

[0164] R 7 , R 8 , and R 9 are independently hydrogen, halogen, —OH, —N, or substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C).

[0165] Ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0166] Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl.

[0167] R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCHX 1 2, -OCH2X 1 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -OC(O)NR 1A R 1B , -NR 1A OR 1C , -P(O)R 1A R 1B , -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two adjacent R 1 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0168] R 2 is hydrogen, halogen -CX 2 3. -CHX 2 2. -CH2X 2, -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0169] R 3 is hydrogen, halogen -CX 3 3. -CHX 3 2. -CH2X 3 , -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0170] R 6 is hydrogen, halogen, -CX 6 3. -CHX 6 2. -CH2X 6 , -OCX 6 3. -OCHX 6 2, -OCH2X 6 , -CN, -SO n6 R 6D , -SO v6 NR 6A R6B , -NR 6C NR 6A R 6B , -ONR 6A R 6B , -NHC(O)NR 6C NR 6A R 6B , -NR 6C C(O)NR 6A R 6B , -N(O) m6 , -NR 6A R 6B , -C(O)R 6C , -C(O)OR 6C , -OC(O)R 6C , -OC(O)OR 6C , -C(O)NR 6A R 6B , -OR 6D , -SR 6D , -NR 6A SO2R 6D , -NR 6A C(O)R 6C , -NR 6A C(O)OR 6C , -OC(O)NR 6A R 6B , -NR 6A OR 6C , -P(O)R 6A R 6B , -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0171] R 3 and R 6can be optionally linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0172] R 1A , R 1B , R 1C , R 1D , R 6A , R 6B , R 6C , and R 6D are independently hydrogen, halogen -CX, -CHX, -CHX, -CN, -COOH, -CONH, -N, substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 1A and R 1B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 6A and R 6B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0173] The symbol z1 is an integer of 0-4.

[0174] The symbols m1, m6, v1, and v6 are independently 1 or 2.

[0175] The symbols n1 and n6 are independently integers of 0 to 4.

[0176] X, X 1 , X 2 , X 3 , and X 6 is independently -Cl, -Br, -I, or -F.

[0177] The symbol m is an integer from 0 to 5.

[0178] The symbol n is an integer from 0 to 10.

[0179] In embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the formula:

[0180] [ka] L 1 -O-, -NR 7 -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR 7 C(O)-, -C(O)NR 7 -, -NR 7 C(O)NR 8 -, -NR 7 S(O)2O-, -OS(O)2NR 7 -, -NR 7 S(O)2-, -S(O)2NR 7 -, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OR 7 )-, -OP(O)(OR 7 )O-, -OP(O)(OR 7 )-, -P(O)(OR 7 )O- or -CR 8 R 9 -;R 7 , R 8 , and R 9are independently hydrogen, halogen, —OH, —N, or substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5- to 6-membered heteroaryl, ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl, and R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCHX 1 2, -OCH2X 1 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -OC(O)NR 1A R 1B , -NR 1A OR 1C , -P(O)R 1A R 1B, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two adjacent R 1 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 2 is hydrogen, halogen, -CX 2 3,-CHX 2 2,-CH2X 2 , -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 3 is hydrogen, halogen -CX 3 3. -CHX 3 2. -CH2X3 , -CN, -COOH, -CONH2, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 6 is hydrogen, halogen, -CX 6 3. -CHX 6 2. -CH2X 6 , -OCX 6 3. -OCHX 6 2, -OCH2X 6 , -CN, -SO n6 R 6D , -SO v6 NR 6A R 6B , -NR 6C NR 6A R 6B , -ONR 6A R 6B , -NHC(O)NR 6C NR 6A R 6B , -NR 6C C(O)NR 6A R 6B , -N(O) m6 , -NR 6A R 6B , -C(O)R 6C , -C(O)OR 6C , -OC(O)R 6C , -OC(O)OR 6C , -C(O)NR 6A R 6B , -OR 6D , -SR 6D , -NR 6A SO2R 6D , -NR 6A C(O)R 6C, -NR 6A C(O)OR 6C , -OC(O)NR 6A R 6B , -NR 6A OR 6C , -P(O)R 6A R 6B , -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 3 and R 6 can be optionally linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 1A , R 1B , R 1C , R 1D , R 6A , R 6B , R 6C , and R 6D are independently hydrogen, halogen -CX, -CHX, -CHX, -CN, -COOH, -CONH, -N, substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C-C 10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 1A and R 1B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 6A and R 6B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered) or a substituted or unsubstituted heteroaryl (e.g., 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered), wherein the symbol z1 is an integer of 0 to 4; the symbols m1, m6, v1, and v6 are independently 1 or 2; the symbols n1 and n6 are independently integers of 0 to 4; X, X 1 , X 2 , X 3 , and X 6 are independently -Cl, -Br, -I, or -F; the symbol m is an integer of 0 to 5; and the symbol n is an integer of 0 to 10.

[0181] In an embodiment, L 1 is -O-, m is 0, n is 0, and ring B is substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl, R 6 is not hydrogen.

[0182] In embodiments, the compound has the formula:

[0183] [ka] L 1 , R 1 , z1, R 2 , R 3 , R 6 , m, and n are as described herein, including embodiments.

[0184] Ring A is phenyl or 5- to 6-membered heteroaryl.

[0185] Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl.

[0186] R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCHX 4 2, -OCH2X 4 , -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B , -NR 4C NR 4A R 4B , -ONR 4A R 4B , -NHC(O)NR 4C NR 4A R 4B , -NR 4C C(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -OC(O)R 4C , -OC(O)OR 4C , -C(O)NR 4A R 4B , -OR 4D , -SR 4D , -NR 4A SO2R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -OC(O)NR 4A R 4B , -NR 4A OR 4C , -P(O)R 4A R 4B, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two adjacent R 4 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0187] R 5 are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -OCX 5 3. -OCHX 5 2, -OCH2X 5 , -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NR 5C NR 5A R 5B , -ONR 5A R 5B , -NHC(O)NR 5C NR 5A R 5B , -NR 5C C(O)NR 5A R 5B , -N(O) m5 , -NR5A R 5B , -C(O)R 5C , -C(O)OR 5C , -OC(O)R 5C , -OC(O)OR 5C , -C(O)NR 5A R 5B , -OR 5D , -SR 5D , -NR 5A SO2R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -OC(O)NR 5A R 5B , -NR 5A OR 5C , -P(O)R 5A R 5B , -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two adjacent R 5 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0188] R 4A , R 4B , R 4C, R 4D , R 5A , R 5B , R 5C , and R 5D are independently hydrogen, halogen -CX, -CHX, -CHX, -CN, -COOH, -CONH, -N, substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C-C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 4A and R 4B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 5A and R 5B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0189] The symbol z4 is an integer of 0 to 5.

[0190] The symbol z5 is an integer from 0 to 7.

[0191] The symbols m4, m5, v4, and v5 are independently 1 or 2.

[0192] The symbols n4 and n5 are independently integers of 0 to 4.

[0193] X, X 4 , and X 5 is independently -Cl, -Br, -I, or -F.

[0194] In embodiments, the compound has the formula:

[0195] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0196] In embodiments, the compound has the formula:

[0197] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0198] In embodiments, the compound has the formula:

[0199] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0200] In embodiments, the compound has the formula:

[0201] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0202] In embodiments, the compound has the formula:

[0203] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0204] In embodiments, the compound has the formula:

[0205] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0206] In embodiments, the compound has the formula:

[0207] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0208] In embodiments, the compound has the formula:

[0209] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0210] In embodiments, the compound has the formula:

[0211] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0212] In embodiments, the compound has the formula:

[0213] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R5 , z5, and R 6 is as described herein, including the embodiments.

[0214] In embodiments, the compound has the formula:

[0215] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0216] In embodiments, the compound has the formula:

[0217] [ka] L 1 , ring A, ring B, R 1 , z1, R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0218] In an embodiment, L 1 -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O)2NH-, -NHS(O)2- , -S(O)2NH-, -S(O)-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR 9 - or -CR 8 R 9 -, R 8 and R 9is as described herein, including embodiments. In embodiments, L 1 -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -S(O)-, -S( O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR 9 - or -CR 8 R 9 - and R 8 and R 9 is independently halogen or unsubstituted methyl.

[0219] In an embodiment, L 1 -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHS(O)2O-, -OS(O)2NH-, -NHS(O )2-, -S(O)2NH-, -S(O)2-, -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR 9 - or -CR 8 R 9 - and R 8 and R 9 is as described herein, including embodiments. In embodiments, L 1 -O-, -NH-, -NCH3-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -S(O)2- , -OS(O)2O-, -S(O)2O-, -OS(O)2-, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR 9 - or -CR 8 R 9 - and R 8 and R 9 is independently halogen or unsubstituted methyl.

[0220] In an embodiment, L 1 is —O—. In embodiments, L 1 is -NR 7 - and R 7 is as described herein, including embodiments. In embodiments, L 1 is —NH—. In embodiments, L 1 is -NCH3-. In embodiments, L 1 is -S-. In embodiments, L 1 is —C(O)—. In embodiments, L 1 is —C(O)O—. In embodiments, L 1 is -OC(O)-. In embodiments, L 1 is -NR 7 C(O)- and R 7 is as described herein, including embodiments. In embodiments, L 1 is —NHC(O)—. In embodiments, L 1 is -C(O)NR 7 and R 7 is as described herein, including embodiments. In embodiments, L 1 is —C(O)NH—. In embodiments, L 1 is -NR 7 C(O)NR 8 In an embodiment, L 1 is —NHC(O)NH—. In embodiments, L 1 is -NR 7 S(O)2O-. In embodiments, L 1 is —NHS(O)2O—. In embodiments, L 1 is -OS(O)2NR 7 In an embodiment, L 1 is —OS(O)NH—. In embodiments, L 1 is -NR 7 In one embodiment, L 1 is -NHS(O)-. In embodiments, L 1 is -S(O)NR 7 In an embodiment, L1 is —S(O)NH—. In embodiments, L 1 is —S(O)—. In embodiments, L 1 is -S(O)-. In embodiments, L 1 is —OS(O)2O—. In embodiments, L 1 is —S(O)2O—. In embodiments, L 1 is —OS(O)—. In embodiments, L 1 is -P(O)(OR 7 )- and R 7 is as described herein, including embodiments. In embodiments, L 1 is —P(O)(OH)—. In embodiments, L 1 is -OP(O)(OR 7 )O- and R 7 is as described herein, including embodiments. In embodiments, L 1 is -OP(O)(OH)O-. In embodiments, L 1 is -OP(O)(OR 7 )- and R 7 is as described herein, including embodiments. In embodiments, L 1 is -OP(O)(OH)-. In embodiments, L 1 is -P(O)(OR 7 )O- and R 7 is as described herein, including embodiments. In embodiments, L 1 is —P(O)(OH)O—. In embodiments, L 1 is -CHR 9 - and R 9 is as described herein, including embodiments. In embodiments, L 1 -CR 8 R 9 - and R 8 and R 9 is as described herein, including embodiments. In embodiments, L 1 is -CHF-. In embodiments, L 1 is -CF2-.

[0221] In embodiments, the substitution R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1 When R is substituted, it is substituted with at least one substituent. 1 When R is substituted, it is substituted with at least one size-limited substituent. 1 When is substituted, it is substituted with at least one lower substituent.

[0222] In embodiments, two R 1 The substituted ring formed when the substituents are linked (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and two R 1 When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. 1 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. 1 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0223] In embodiments, the substitution R 1A(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1A When R is substituted, it is substituted with at least one substituent. 1A When R is substituted, it is substituted with at least one size-limited substituent. 1A When is substituted, it is substituted with at least one lower substituent.

[0224] In embodiments, the substitution R 1B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1B When R is substituted, it is substituted with at least one substituent. 1B When R is substituted, it is substituted with at least one size-limited substituent. 1B When is substituted, it is substituted with at least one lower substituent.

[0225] In embodiments, R 1A and R 1B The substituted ring formed when the substituents are linked (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and R 1A and R1B When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 1A and R 1B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. In embodiments, R 1A and R 1B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. In embodiments, R 1A and R 1B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0226] In embodiments, the substitution R 1C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1C When R is substituted, it is substituted with at least one substituent. 1C When R is substituted, it is substituted with at least one size-limited substituent. 1C When is substituted, it is substituted with at least one lower substituent.

[0227] In embodiments, the substitution R 1D(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 1D When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 1D When R is substituted, it is substituted with at least one substituent. 1D When R is substituted, it is substituted with at least one size-limited substituent. 1D When is substituted, it is substituted with at least one lower substituent.

[0228] In embodiments, R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCHX 1 2, -OCH2X 1 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , -NR 1C NR 1A R 1B , -ONR 1A R 1B , -NHC(O)NR 1C NR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OR1D , -SR 1D , -NR 1A SO2R 1D , -NR 1A C(O)R 1C , -NR 1A C(O)OR 1C , -OC(O)NR 1A R 1B , -NR 1A OR 1C , -P(O)R 1A R 1B , -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two adjacent R 1 The substituents may be optionally linked to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), an unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0229] In embodiments, R 1 are independently selected from 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-C8 10aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 1 are independently halogen, —CF, —OH, —NH, —SH, substituted or unsubstituted C-C alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. 1 are independently halogen, —CF, —CHF, —CHF, —OCF, —OCHF, —OCHF, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 1 are independently halogen -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, unsubstituted methyl, or unsubstituted methoxy.

[0230] In embodiments, R 1 is independently halogen. In an embodiment, 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 is independently —CCl. In embodiments, R 1 is independently —CBr. In an embodiment, R 1 is independently —CF. In an embodiment, R 1 is independently -CI. In an embodiment, R 1 is independently —CH2Cl. In an embodiment, R 1 is independently —CHBr. In an embodiment, R 1 is independently -CHF. In an embodiment, R 1 is independently -CH2I. In embodiments, R 1 is independently —CHCl. ​​In an embodiment, R 1is independently —CHBr. In embodiments, R 1 is independently -CHF. In an embodiment, R 1 is independently -CHI. In embodiments, R 1 is independently —CN. In an embodiment, R 1 is independently —OH. In an embodiment, R 1 is independently —NH. In an embodiment, R 1 is independently —COOH. In an embodiment, R 1 is independently -CONH. In an embodiment, R 1 is independently —NO. In an embodiment, R 1 is independently -SH. In an embodiment, R 1 is independently —SO3H. In an embodiment, R 1 is independently —OSO3H. In embodiments, R 1 is independently —SO 2 NH 2 . In an embodiment, R 1 is independently -NHNH. In embodiments, R 1 is independently -ONH. In embodiments, R 1 is independently —NHC(O)NHNH. In embodiments, R 1 is independently —NHC(O)NH. In embodiments, R 1 is independently —NHSO2H. In an embodiment, R 1 is independently —NHC(O)H. In an embodiment, R 1 is independently —NHC(O)OH. In embodiments, R 1 is independently —NHOH. In an embodiment, R 1 is independently —OCCl. In an embodiment, R 1 is independently —OCBr. In an embodiment, R 1 is independently -OCF. In an embodiment, R 1 is independently -OCI. In an embodiment, R 1 is independently —OCH2Cl. In an embodiment, R 1is independently —OCHBr. In an embodiment, R 1 is independently —OCHF. In an embodiment, R 1 is independently -OCH2I. In embodiments, R 1 is independently —OCHCl. ​​In an embodiment, R 1 is independently —OCHBr. In embodiments, R 1 is independently -OCHF. In an embodiment, R 1 is independently -OCHI. In embodiments, R 1 is independently unsubstituted C1-C4 alkyl. In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted n-propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted butyl. In embodiments, R 1 is independently unsubstituted n-butyl. In embodiments, R 1 is independently unsubstituted isobutyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted methoxy. In embodiments, R 1 is independently unsubstituted ethoxy. In embodiments, R 1 is independently unsubstituted propoxy. In embodiments, R 1 is independently unsubstituted n-propoxy. In embodiments, R 1 is independently unsubstituted isopropoxy. In embodiments, R 1 is independently unsubstituted butoxy. In embodiments, R 1 is independently unsubstituted n-butoxy. In embodiments, R 1is independently unsubstituted isobutoxy. In embodiments, R 1 is independently unsubstituted tert-butoxy.

[0231] In an embodiment, z1 is 0. In an embodiment, z1 is 1. In an embodiment, z1 is 2. In an embodiment, z1 is 3. In an embodiment, z1 is 4.

[0232] In embodiments, the substitution R 2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 2 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 2 When R is substituted, it is substituted with at least one substituent. 2 When R is substituted, it is substituted with at least one size-limited substituent. 2 When is substituted, it is substituted with at least one lower substituent.

[0233] In embodiments, R 2 is hydrogen, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -CN, -COOH, -CONH2, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0234] In embodiments, R 2 is 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 hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. 2 is hydrogen.

[0235] In embodiments, R 2 is hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 2 is hydrogen. In embodiments, R 2 is unsubstituted C1-C4 alkyl. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is unsubstituted ethyl. In embodiments, R 2 is unsubstituted propyl. In embodiments, R 2 is unsubstituted n-propyl. In embodiments, R 2 is unsubstituted isopropyl. In embodiments, R 2 is unsubstituted butyl. In embodiments, R 2 is unsubstituted n-butyl. In embodiments, R 2 is unsubstituted isobutyl. In embodiments, R 2 is unsubstituted tert-butyl.

[0236] In embodiments, the substitution R 3(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3 When R is substituted, it is substituted with at least one substituent. 3 When R is substituted, it is substituted with at least one size-limited substituent. 3 When is substituted, it is substituted with at least one lower substituent.

[0237] In embodiments, R 3 is hydrogen, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -CN, -COOH, -CONH2, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0238] In embodiments, R 3 is hydrogen, -CX 3 3. -CHX 3 2. -CH2X 3, —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 hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. 3 is hydrogen.

[0239] In embodiments, R 3 is hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 3 is hydrogen. In embodiments, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl. In embodiments, R 3 is unsubstituted propyl. In embodiments, R 3 is unsubstituted n-propyl. In embodiments, R 3 is unsubstituted isopropyl. In embodiments, R 3 is unsubstituted butyl. In embodiments, R 3 is unsubstituted n-butyl. In embodiments, R 3 is unsubstituted isobutyl. In embodiments, R 3 is unsubstituted tert-butyl.

[0240] In embodiments, the substitution R 4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4When R is substituted, it is substituted with at least one substituent. 4 When R is substituted, it is substituted with at least one size-limited substituent. 4 When is substituted, it is substituted with at least one lower substituent.

[0241] In embodiments, two R 4 The substituted ring formed when the substituents are linked (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and two R 4 When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. 4 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. 4 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0242] In embodiments, the substitution R 4A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4A When R is substituted, it is substituted with at least one substituent. 4AWhen R is substituted, it is substituted with at least one size-limited substituent. 4A When is substituted, it is substituted with at least one lower substituent.

[0243] In embodiments, the substitution R 4B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4B When R is substituted, it is substituted with at least one substituent. 4B When R is substituted, it is substituted with at least one size-limited substituent. 4B When is substituted, it is substituted with at least one lower substituent.

[0244] In embodiments, R 4A and R 4B The substituted ring formed when the substituents are linked (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and R 4A and R 4B When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 4A and R 4B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. In embodiments, R 4A and R 4BIf the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. In embodiments, R 4A and R 4B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0245] In embodiments, the substitution R 4C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4C When R is substituted, it is substituted with at least one substituent. 4C When R is substituted, it is substituted with at least one size-limited substituent. 4C When is substituted, it is substituted with at least one lower substituent.

[0246] In embodiments, the substitution R 4D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 4D When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 4D When R is substituted, it is substituted with at least one substituent. 4D When R is substituted, it is substituted with at least one size-limited substituent. 4DWhen is substituted, it is substituted with at least one lower substituent.

[0247] In embodiments, R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCHX 4 2, -OCH2X 4 , -CN, -SO n4 R 4D , -SO v4 NR 4A R 4B , -NR 4C NR 4A R 4B , -ONR 4A R 4B , -NHC(O)NR 4C NR 4A R 4B , -NR 4C C(O)NR 4A R 4B , -N(O) m4 , -NR 4A R 4B , -C(O)R 4C , -C(O)OR 4C , -OC(O)R 4C , -OC(O)OR 4C , -C(O)NR 4A R 4B , -OR 4D , -SR 4D , -NR 4A SO2R 4D , -NR 4A C(O)R 4C , -NR 4A C(O)OR 4C , -OC(O)NR 4A R 4B , -NR 4A OR 4C , -P(O)R 4A R 4B, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two adjacent R 4 The substituents may be optionally linked to form an unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), an unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0248] In embodiments, R 4 are independently selected from 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-C8 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 4 are independently halogen, —CF, —OH, —NH, —SH, substituted or unsubstituted C-C alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. 4are independently halogen, —CF, —CHF, —CHF, —OCF, —OCHF, —OCHF, —OH, —NH, —SH, unsubstituted C-C alkyl, or unsubstituted 2-4 membered heteroalkyl. 4 are independently halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —OH, unsubstituted methyl, or unsubstituted methoxy.

[0249] In embodiments, R 4 is independently halogen. In an embodiment, R 4 is independently -F. In an embodiment, R 4 is independently -Cl. In an embodiment, R 4 is independently -Br. In an embodiment, R 4 is independently -I. In an embodiment, R 4 is independently —CCl. In embodiments, R 4 is independently —CBr. In an embodiment, R 4 is independently —CF. In an embodiment, R 4 is independently -CI. In an embodiment, R 4 is independently —CH2Cl. In an embodiment, R 4 is independently —CHBr. In an embodiment, R 4 is independently -CHF. In an embodiment, R 4 is independently -CH2I. In embodiments, R 4 is independently —CHCl. ​​In an embodiment, R 4 is independently —CHBr. In embodiments, R 4 is independently -CHF. In an embodiment, R 4 is independently -CHI. In embodiments, R 4 is independently —CN. In an embodiment, R 4 is independently —OH. In an embodiment, R 4 is independently —NH. In an embodiment, R 4 is independently —COOH. In an embodiment, R4 is independently -CONH. In an embodiment, R 4 is independently —NO. In an embodiment, R 4 is independently -SH. In an embodiment, R 4 is independently —SO3H. In an embodiment, R 4 is independently —OSO3H. In embodiments, R 4 is independently —SO 2 NH 2 . In an embodiment, R 4 is independently -NHNH. In embodiments, R 4 is independently -ONH. In embodiments, R 4 is independently —NHC(O)NHNH. In embodiments, R 4 is independently —NHC(O)NH. In embodiments, R 4 is independently —NHSO2H. In an embodiment, R 4 is independently —NHC(O)H. In an embodiment, R 4 is independently —NHC(O)OH. In embodiments, R 4 is independently —NHOH. In an embodiment, R 4 is independently —OCCl. In an embodiment, R 4 is independently —OCBr. In an embodiment, R 4 is independently -OCF. In an embodiment, R 4 is independently -OCI. In an embodiment, R 4 is independently —OCH2Cl. In an embodiment, R 4 is independently —OCHBr. In an embodiment, R 4 is independently —OCHF. In an embodiment, R 4 is independently -OCH2I. In embodiments, R 4 is independently —OCHCl. ​​In an embodiment, R 4 is independently —OCHBr. In embodiments, R 4 is independently -OCHF. In an embodiment, R 4 is independently -OCHI. In embodiments, R4 is independently unsubstituted C1-C4 alkyl. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently unsubstituted propyl. In embodiments, R 4 is independently unsubstituted n-propyl. In embodiments, R 4 is independently unsubstituted isopropyl. In embodiments, R 4 is independently unsubstituted butyl. In embodiments, R 4 is independently unsubstituted n-butyl. In embodiments, R 4 is independently unsubstituted isobutyl. In embodiments, R 4 is independently unsubstituted tert-butyl. In embodiments, R 4 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 4 is independently unsubstituted methoxy. In embodiments, R 4 is independently unsubstituted ethoxy. In embodiments, R 4 is independently unsubstituted propoxy. In embodiments, R 4 is independently unsubstituted n-propoxy. In embodiments, R 4 is independently unsubstituted isopropoxy. In embodiments, R 4 is independently unsubstituted butoxy. In embodiments, R 4 is independently unsubstituted n-butoxy. In embodiments, R 4 is independently unsubstituted isobutoxy. In embodiments, R 4 is independently unsubstituted tert-butoxy.

[0250] In embodiments, R 4 are independently -OR 4D and R 4D is as described herein, including embodiments. In embodiments, R 4D is hydrogen, or substituted or unsubstituted alkyl. In embodiments, R 4Dare independently hydrogen or unsubstituted alkyl. In embodiments, R 4D is independently hydrogen or unsubstituted C1-C5 alkyl. In an embodiment, R 4D is independently hydrogen or unsubstituted methyl. In embodiments, R 4D are independently hydrogen. In embodiments, R 4D is independently an unsubstituted C1-C5 alkyl. In embodiments, R 4D is independently unsubstituted methyl. In embodiments, R 4D is independently unsubstituted ethyl. In embodiments, R 4D is independently unsubstituted propyl. In embodiments, R 4D is independently unsubstituted n-propyl. In embodiments, R 4D is independently unsubstituted isopropyl. In embodiments, R 4D is independently unsubstituted butyl. In embodiments, R 4D is independently unsubstituted n-butyl. In embodiments, R 4D is independently unsubstituted isobutyl. In embodiments, R 4D is independently unsubstituted tert-butyl.

[0251] In an embodiment, z4 is 0. In an embodiment, z4 is 1. In an embodiment, z4 is 2. In an embodiment, z4 is 3. In an embodiment, z4 is 4.

[0252] In embodiments, the substitution R 5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5 When R is substituted, it is substituted with at least one substituent.5 When R is substituted, it is substituted with at least one size-limited substituent. 5 When is substituted, it is substituted with at least one lower substituent.

[0253] In embodiments, two R 5 The substituted ring formed when the substituents are linked (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and two R 5 When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. 5 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. 5 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0254] In embodiments, the substitution R 5A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5A When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5A When R is substituted, it is substituted with at least one substituent. 5AWhen R is substituted, it is substituted with at least one size-limited substituent. 5A When is substituted, it is substituted with at least one lower substituent.

[0255] In embodiments, the substitution R 5B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5B When R is substituted, it is substituted with at least one substituent. 5B When R is substituted, it is substituted with at least one size-limited substituent. 5B When is substituted, it is substituted with at least one lower substituent.

[0256] In embodiments, R 5A and R 5B The substituted ring formed when the substituents are linked (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent and has at least one R bonded to the same nitrogen atom. 5A and R 5B When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 5A and R 5B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. In embodiments, R 5A and R 5BIf the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. In embodiments, R 5A and R 5B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0257] In embodiments, the substitution R 5C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5C When R is substituted, it is substituted with at least one substituent. 5C When R is substituted, it is substituted with at least one size-limited substituent. 5C When is substituted, it is substituted with at least one lower substituent.

[0258] In embodiments, the substitution R 5D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5D When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5D When R is substituted, it is substituted with at least one substituent. 5D When R is substituted, it is substituted with at least one size-limited substituent. 5DWhen is substituted, it is substituted with at least one lower substituent.

[0259] In embodiments, R 5 are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -OCX 5 3. -OCHX 5 2, -OCH2X 5 , -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , -NR 5C NR 5A R 5B , -ONR 5A R 5B , -NHC(O)NR 5C NR 5A R 5B , -NR 5C C(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C(O)R 5C , -C(O)OR 5C , -OC(O)R 5C , -OC(O)OR 5C , -C(O)NR 5A R 5B , -OR 5D , -SR 5D , -NR 5A SO2R 5D , -NR 5A C(O)R 5C , -NR 5A C(O)OR 5C , -OC(O)NR 5A R 5B , -NR 5A OR 5C , -P(O)R 5A R 5B, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two adjacent R 5 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), a substituted or unsubstituted aryl (e.g., C6-C 10 or phenyl), or substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0260] In embodiments, R 5 are independently selected from 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-C8 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 5 are independently halogen, —CF, —OH, —NH, —SH, substituted or unsubstituted C-C alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C-C cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl. 5are independently halogen -CF, -CHF, -CHF, -OCF, -OCHF, -OCHF, -OH, -NH, -SH, unsubstituted C-C alkyl, unsubstituted 2-4 membered heteroalkyl, or unsubstituted phenyl. 5 are independently halogen -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.

[0261] In embodiments, R 5 is independently halogen. In an embodiment, 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 —CCl. In embodiments, R 5 is independently —CBr. In an embodiment, R 5 is independently —CF. In an embodiment, R 5 is independently -CI. In an embodiment, R 5 is independently —CH2Cl. In an embodiment, R 5 is independently —CHBr. In an embodiment, R 5 is independently -CHF. In an embodiment, R 5 is independently -CH2I. In embodiments, R 5 is independently —CHCl. ​​In an embodiment, R 5 is independently —CHBr. In embodiments, R 5 is independently -CHF. In an embodiment, R 5 is independently -CHI. In embodiments, R 5 is independently —CN. In an embodiment, R 5 is independently —OH. In an embodiment, R 5 is independently —NH. In an embodiment, R 5is independently —COOH. In an embodiment, R 5 is independently -CONH. In an embodiment, R 5 is independently —NO. In an embodiment, R 5 is independently -SH. In an embodiment, R 5 is independently —SO3H. In an embodiment, R 5 is independently —OSO3H. In embodiments, R 5 is independently —SO 2 NH 2 . In an embodiment, R 5 is independently -NHNH. In embodiments, R 5 is independently -ONH. In embodiments, R 5 is independently —NHC(O)NHNH. In embodiments, R 5 is independently —NHC(O)NH. In embodiments, R 5 is independently —NHSO2H. In an embodiment, R 5 is independently —NHC(O)H. In an embodiment, R 5 is independently —NHC(O)OH. In embodiments, R 5 is independently —NHOH. In an embodiment, R 5 is independently —OCCl. In an embodiment, R 5 is independently —OCBr. In an embodiment, R 5 is independently -OCF. In an embodiment, R 5 is independently -OCI. In an embodiment, R 5 is independently —OCH2Cl. In an embodiment, R 5 is independently —OCHBr. In an embodiment, R 5 is independently —OCHF. In an embodiment, R 5 is independently -OCH2I. In embodiments, R 5 is independently —OCHCl. ​​In an embodiment, R 5 is independently —OCHBr. In embodiments, R 5 is independently -OCHF. In an embodiment, R 5is independently -OCHI. In embodiments, R 5 is independently unsubstituted C1-C4 alkyl. In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted ethyl. In embodiments, R 5 is independently unsubstituted propyl. In embodiments, R 5 is independently unsubstituted n-propyl. In embodiments, R 5 is independently unsubstituted isopropyl. In embodiments, R 5 is independently unsubstituted butyl. In embodiments, R 5 is independently unsubstituted n-butyl. In embodiments, R 5 is independently unsubstituted isobutyl. In embodiments, R 5 is independently unsubstituted tert-butyl. In embodiments, R 5 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 5 is independently unsubstituted methoxy. In embodiments, R 5 is independently unsubstituted ethoxy. In embodiments, R 5 is independently unsubstituted propoxy. In embodiments, R 5 is independently unsubstituted n-propoxy. In embodiments, R 5 is independently unsubstituted isopropoxy. In embodiments, R 5 is independently unsubstituted butoxy. In embodiments, R 5 is independently unsubstituted n-butoxy. In embodiments, R 5 is independently unsubstituted isobutoxy. In embodiments, R 5 is independently unsubstituted tert-butoxy. In embodiments, R 5 is independently substituted or unsubstituted phenyl. In embodiments, R 5 is independently substituted phenyl. In embodiments, R 5 is independently unsubstituted phenyl.

[0262] In an embodiment, z5 is 0. In an embodiment, z5 is 1. In an embodiment, z5 is 2. In an embodiment, z5 is 3. In an embodiment, z5 is 4. In an embodiment, z5 is 5. In an embodiment, z5 is 6. In an embodiment, z5 is 7.

[0263] In an embodiment,

[0264] [ka] teeth,

[0265] [ka] In an embodiment,

[0266] [ka] teeth,

[0267] [ka] In an embodiment,

[0268] [ka] teeth,

[0269] [ka] In an embodiment,

[0270] [ka] teeth,

[0271] [ka] In an embodiment,

[0272] [ka] teeth,

[0273] [ka] In an embodiment,

[0274] [ka] teeth,

[0275] [ka] is.

[0276] In embodiments, the substitution R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6 When R is substituted, it is substituted with at least one substituent. 6 When R is substituted, it is substituted with at least one size-limited substituent. 6 When is substituted, it is substituted with at least one lower substituent.

[0277] In embodiments, the substitution R 6A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6AWhen R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6A When substituted, R is substituted with at least one substituent. 6A When substituted, R is substituted with at least one size-limited substituent. 6A When substituted, it is substituted with at least one lower substituent.

[0278] In embodiments, the substitution R 6B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6B When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6B When substituted, R is substituted with at least one substituent. 6B When substituted, R is substituted with at least one size-limited substituent. 6B When substituted, it is substituted with at least one lower substituent.

[0279] In embodiments, R 6A and R 6B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent group, size-limited substituent group, or lower substituent group, and R 6A and R 6BWhen the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 6A and R 6B The substituted ring formed when the substituents are linked, if substituted, is substituted with at least one substituent group. In embodiments, R 6A and R 6B The substituted ring formed when the substituents are linked, if substituted, is substituted with at least one size-limited substituent group. In embodiments, R 6A and R 6B The substituted ring formed when the substituents are linked, if substituted, is substituted with at least one lower substituent group.

[0280] In embodiments, the substitution R 6C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6C When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6C When R is substituted, it is substituted with at least one substituent. 6C When R is substituted, it is substituted with at least one size-limited substituent. 6C When is substituted, it is substituted with at least one lower substituent.

[0281] In embodiments, the substitution R 6D (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6D When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6D When R is substituted, it is substituted with at least one substituent. 6D When R is substituted, it is substituted with at least one size-limited substituent. 6D When is substituted, it is substituted with at least one lower substituent.

[0282] In embodiments, R 6 is hydrogen, halogen, -CX 6 3. -CHX 6 2. -CH2X 6 , -OCX 6 3. -OCHX 6 2, -OCH2X 6 , -CN, -SO n6 R 6D , -SO v6 NR 6A R 6B , -NR 6C NR 6A R 6B , -ONR 6A R 6B , -NHC(O)NR 6C NR 6A R 6B , -NR 6C C(O)NR 6A R 6B , -N(O) m6 , -NR 6A R 6B , -C(O)R 6C , -C(O)OR 6C , -OC(O)R 6C , -OC(O)OR 6C , -C(O)NR 6AR 6B , -OR 6D , -SR 6D , -NR 6A SO2R 6D , -NR 6A C(O)R 6C , -NR 6A C(O)OR 6C , -OC(O)NR 6A R 6B , -NR 6A OR 6C , -P(O)R 6A R 6B , -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C6-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0283] In embodiments, R 6 is hydrogen, halogen, -CF3, -CHF2, -CH2F, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -OCF3, -OCHF2, -OCH2F, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 6 is a substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted 2- to 6-membered heteroalkyl.

[0284] In embodiments, R 6 is hydrogen. In embodiments, R 6 is halogen. In embodiments, R 6is -F. In an embodiment, R 6 is —Cl. In embodiments, R 6 is -Br. In embodiments, R 6 is -I. In an embodiment, R 6 is —CCl. In embodiments, R 6 is —CBr. In embodiments, R 6 is —CF. In embodiments, R 6 is -CI3. In embodiments, R 6 is —CH2Cl. In embodiments, R 6 is —CHBr. In embodiments, R 6 is —CHF. In embodiments, R 6 is -CH2I. In embodiments, R 6 is —CHCl. ​​In embodiments, R 6 is —CHBr. In embodiments, R 6 is -CHF2. In an embodiment, R 6 is -CHI2. In an embodiment, R 6 is -CN. In embodiments, R 6 is —OH. In embodiments, R 6 is —NH. In embodiments, R 6 is —COOH. In embodiments, R 6 is -CONH. In an embodiment, R 6 is —NO. In an embodiment, R 6 is -SH. In embodiments, R 6 is —SO3H. In embodiments, R 6 is —OSO3H. In embodiments, R 6 is —SO 2 NH 2 . In an embodiment, R 6 is -NHNH. In embodiments, R 6 is -ONH2. In embodiments, R 6 is —NHC(O)NHNH. In embodiments, R 6 is —NHC(O)NH. In embodiments, R 6 is —NHSO2H. In embodiments, R 6is —NHC(O)H. In embodiments, R 6 is —NHC(O)OH. In embodiments, R 6 is —NHOH. In embodiments, R 6 is —OCCl. In embodiments, R 6 is —OCBr. In embodiments, R 6 is -OCF3. In an embodiment, R 6 is -OCI3. In an embodiment, R 6 is —OCH2Cl. In embodiments, R 6 is —OCHBr. In embodiments, R 6 is -OCHF. In embodiments, R 6 is -OCH2I. In embodiments, R 6 is —OCHCl. ​​In embodiments, R 6 is —OCHBr. In embodiments, R 6 is -OCHF. In an embodiment, R 6 is -OCHI2. In embodiments, R 6 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 6 is a substituted C1-C4 alkyl. In embodiments, R 6 is a substituted methyl. In embodiments, R 6 is a substituted ethyl. In embodiments, R 6 is a substituted propyl. In embodiments, R 6 is substituted n-propyl. In embodiments, R 6 is substituted isopropyl. In embodiments, R 6 is a substituted butyl. In embodiments, R 6 is a substituted n-butyl. In embodiments, R 6 is substituted isobutyl. In embodiments, R 6 is a substituted tert-butyl. In embodiments, R 6 is unsubstituted C1-C4 alkyl. In embodiments, R 6 is unsubstituted methyl. In embodiments, R 6 is unsubstituted ethyl. In embodiments, R 6is unsubstituted propyl. In embodiments, R 6 is unsubstituted n-propyl. In embodiments, R 6 is unsubstituted isopropyl. In embodiments, R 6 is unsubstituted butyl. In embodiments, R 6 is unsubstituted n-butyl. In embodiments, R 6 is unsubstituted isobutyl. In embodiments, R 6 is unsubstituted tert-butyl. In embodiments, R 6 is a substituted or unsubstituted 2-4 membered heteroalkyl. In embodiments, R 6 is a substituted 2-4 membered heteroalkyl. In embodiments, R 6 is an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 6 is unsubstituted methoxy. In embodiments, R 6 is unsubstituted ethoxy. In embodiments, R 6 is unsubstituted propoxy. In embodiments, R 6 is unsubstituted n-propoxy. In embodiments, R 6 is unsubstituted isopropoxy. In embodiments, R 6 is unsubstituted butoxy. In embodiments, R 6 is unsubstituted n-butoxy. In embodiments, R 6 is unsubstituted isobutoxy. In embodiments, R 6 is unsubstituted tert-butoxy.

[0285] In embodiments, R 6 is an amino acid side chain. In embodiments, R 6 is a glycine side chain. In embodiments, R 6 is an alanine side chain. In embodiments, R 6 is a valine side chain. In embodiments, R 6 is a leucine side chain. In embodiments, R 6 is an isoleucine side chain. In embodiments, R 6 is a methionine side chain. In embodiments, R 6 is a serine side chain. In embodiments, R 6is the threonine side chain. In embodiments, R 6 is a cysteine ​​side chain. In embodiments, R 6 is an aspartic acid side chain. In embodiments, R 6 is a glutamic acid side chain. In embodiments, R 6 is an asparagine side chain. In embodiments, R 6 is a glutamine side chain. In embodiments, R 6 is a histidine side chain. In embodiments, R 6 is a phenylalanine side chain. In embodiments, R 6 is a tyrosine side chain. In embodiments, R 6 is a tryptophan side chain. In embodiments, R 6 is an arginine side chain. In embodiments, R 6 is the lysine side chain.

[0286] In embodiments, R 6 is an amino acid side chain. In embodiments, R 6 is the L-glycine side chain. In embodiments, R 6 is an L-alanine side chain. In embodiments, R 6 is the L-valine side chain. In embodiments, R 6 is an L-leucine side chain. In embodiments, R 6 is an L-isoleucine side chain. In embodiments, R 6 is the L-methionine side chain. In embodiments, R 6 is an L-serine side chain. In embodiments, R 6 is the L-threonine side chain. In embodiments, R 6 is the L-cysteine ​​side chain. In embodiments, R 6 is the L-aspartic acid side chain. In embodiments, R 6 is an L-glutamic acid side chain. In embodiments, R 6 is an L-asparagine side chain. In embodiments, R 6 is an L-glutamine side chain. In embodiments, R 6 is an L-histidine side chain. In embodiments, R 6is the L-phenylalanine side chain. In embodiments, R 6 is the L-tyrosine side chain. In embodiments, R 6 is an L-tryptophan side chain. In embodiments, R 6 is the L-arginine side chain. In embodiments, R 6 is the L-lysine side chain.

[0287] In embodiments, R 6 is an amino acid side chain. In embodiments, R 6 is a D-glycine side chain. In embodiments, R 6 is a D-alanine side chain. In embodiments, R 6 is a D-valine side chain. In embodiments, R 6 is a D-leucine side chain. In embodiments, R 6 is a D-isoleucine side chain. In embodiments, R 6 is a D-methionine side chain. In embodiments, R 6 is a D-serine side chain. In embodiments, R 6 is a D-threonine side chain. In embodiments, R 6 is a D-cysteine ​​side chain. In embodiments, R 6 is a D-aspartic acid side chain. In embodiments, R 6 is a D-glutamic acid side chain. In embodiments, R 6 is a D-asparagine side chain. In embodiments, R 6 is a D-glutamine side chain. In embodiments, R 6 is a D-histidine side chain. In embodiments, R 6 is a D-phenylalanine side chain. In embodiments, R 6 is a D-tyrosine side chain. In embodiments, R 6 is a D-tryptophan side chain. In embodiments, R 6 is a D-arginine side chain. In embodiments, R 6 is the D-lysine side chain.

[0288] In embodiments, R 6 is hydrogen, unsubstituted methyl, unsubstituted isopropyl,

[0289] [ka] is.

[0290] In embodiments, R 3 and R 6 The substituted ring formed when the substituents are linked (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and R 3 and R 6 When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, R 3 and R 6 If the substituted ring formed when the substituents are attached is substituted, it is substituted with at least one substituent. In embodiments, R 3 and R 6 If the substituted ring formed when the substituents are attached is substituted, it is substituted with at least one size-limited substituent. In embodiments, R 3 and R 6 If the substituted ring formed when a substituent is attached is substituted, it is substituted with at least one lower substituent.

[0291] In embodiments, R 3 and R 6 may optionally be linked to form an unsubstituted heterocycloalkyl (e.g., 3 to 8-membered, 3 to 6-membered, 4 to 6-membered, 4 to 5-membered, or 5 to 6-membered) or an unsubstituted heteroaryl (e.g., 5 to 10-membered, 5 to 9-membered, or 5 to 6-membered).

[0292] In embodiments, R 3 and R 6are linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. 3 and R 6 are linked to form a substituted or unsubstituted 4-8 membered heteroaryl. 3 and R 6 are linked to form an unsubstituted pyrrolidinyl. In embodiments, R 3 and R 6 are linked to form an unsubstituted piperidinyl.

[0293] R 1A , R 1B , R 1C , R 1D , R 6A , R 6B , R 6C , and R 6D are independently hydrogen, halogen, -CX, -CHX, -CHX, -CN, -COOH, -CONH, -N, unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 1A and R 1B The substituents may optionally be linked to form an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or an unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 6A and R 6B The substituents can be optionally linked to form an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or an unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0294] R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D are independently hydrogen, halogen, -CX, -CHX, -CHX, -CN, -COOH, -CONH, -N, unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C-C, C-C, C-C, or C-C), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C-C 10 or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 4A and R 4B The substituents may optionally be linked to form an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or an unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 5A and R 5B The substituents can be optionally linked to form an unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered) or an unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0295] In embodiments, the substitution R 7 (e.g., substituted alkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 7 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 7When R is substituted, it is substituted with at least one substituent. 7 When R is substituted, it is substituted with at least one size-limited substituent. 7 When is substituted, it is substituted with at least one lower substituent.

[0296] In embodiments, R 7 is hydrogen, halogen, —OH, —N, or substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C). 7 is hydrogen, halogen, —OH, —N, or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C). 7 is hydrogen. In embodiments, R 7 is halogen. In embodiments, R 7 is -F. In an embodiment, R 7 is —Cl. In embodiments, R 7 is -Br. In embodiments, R 7 is -I. In an embodiment, R 7 is —OH. In embodiments, R 7 is -N3. In an embodiment, R 7 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 7 is unsubstituted C1-C4 alkyl. In embodiments, R 7 is unsubstituted methyl. In embodiments, R 7 is unsubstituted ethyl. In embodiments, R 7 is unsubstituted propyl. In embodiments, R 7 is unsubstituted n-propyl. In embodiments, R 7 is unsubstituted isopropyl. In embodiments, R 7 is unsubstituted butyl. In embodiments, R 7 is unsubstituted n-butyl. In embodiments, R 7 is unsubstituted isobutyl. In embodiments, R 7 is unsubstituted tert-butyl.

[0297] In embodiments, the substitution R 8 (e.g., substituted alkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 8 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 8 When R is substituted, it is substituted with at least one substituent. 8 When R is substituted, it is substituted with at least one size-limited substituent. 8 When is substituted, it is substituted with at least one lower substituent.

[0298] In embodiments, R 8 is hydrogen, halogen, —OH, —N, or substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C). 8 is hydrogen, halogen, —OH, —N, or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C). 8 is hydrogen. In embodiments, R 8 is halogen. In embodiments, R 8 is -F. In an embodiment, R 8 is —Cl. In embodiments, R 8 is -Br. In embodiments, R 8 is -I. In an embodiment, R 8 is —OH. In embodiments, R 8 is -N3. In an embodiment, R 8 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 8 is unsubstituted C1-C4 alkyl. In embodiments, R 8 is unsubstituted methyl. In embodiments, R 8 is unsubstituted ethyl. In embodiments, R 8 is unsubstituted propyl. In embodiments, R8 is unsubstituted n-propyl. In embodiments, R 8 is unsubstituted isopropyl. In embodiments, R 8 is unsubstituted butyl. In embodiments, R 8 is unsubstituted n-butyl. In embodiments, R 8 is unsubstituted isobutyl. In embodiments, R 8 is unsubstituted tert-butyl.

[0299] In embodiments, the substitution R 9 (e.g., substituted alkyl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 9 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 9 When R is substituted, it is substituted with at least one substituent. 9 When R is substituted, it is substituted with at least one size-limited substituent. 9 When is substituted, it is substituted with at least one lower substituent.

[0300] In embodiments, R 9 is hydrogen, halogen, —OH, —N, or substituted or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C). 9 is hydrogen, halogen, —OH, —N, or unsubstituted alkyl (e.g., C-C, C-C, C-C, or C-C). 9 is hydrogen. In embodiments, R 9 is halogen. In embodiments, R 9 is -F. In an embodiment, R 9 is —Cl. In embodiments, R 9 is -Br. In embodiments, R 9 is -I. In an embodiment, R 9 is —OH. In embodiments, R9 is -N3. In an embodiment, R 9 is a substituted or unsubstituted C1-C4 alkyl. In embodiments, R 9 is unsubstituted C1-C4 alkyl. In embodiments, R 9 is unsubstituted methyl. In embodiments, R 9 is unsubstituted ethyl. In embodiments, R 9 is unsubstituted propyl. In embodiments, R 9 is unsubstituted n-propyl. In embodiments, R 9 is unsubstituted isopropyl. In embodiments, R 9 is unsubstituted butyl. In embodiments, R 9 is unsubstituted n-butyl. In embodiments, R 9 is unsubstituted isobutyl. In embodiments, R 9 is unsubstituted tert-butyl.

[0301] In embodiments, substituted ring A (e.g., substituted phenyl and / or substituted 5-6 membered heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when substituted ring A is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, when ring A is substituted, it is substituted with at least one substituent. In embodiments, when ring A is substituted, it is substituted with at least one size-limiting substituent. In embodiments, when ring A is substituted, it is substituted with at least one lower substituent.

[0302] In embodiments, Ring A is unsubstituted phenyl or unsubstituted 5-6 membered heteroaryl. In embodiments, Ring A is substituted phenyl. In embodiments, Ring A is unsubstituted 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 substituted thienyl. In embodiments, Ring A is unsubstituted thienyl. In embodiments, Ring A is substituted 2-thienyl. In embodiments, Ring A is unsubstituted 2-thienyl. In embodiments, Ring A is substituted 3-thienyl. In embodiments, Ring A is unsubstituted 3-thienyl. In embodiments, Ring A is substituted pyridyl. In embodiments, Ring A is unsubstituted pyridyl. In embodiments, Ring A is substituted 2-pyridyl. In embodiments, Ring A is unsubstituted 2-pyridyl. In embodiments, Ring A is substituted 3-pyridyl. In an embodiment, Ring A is unsubstituted 3-pyridyl. In an embodiment, Ring A is substituted 4-pyridyl. In an embodiment, Ring A is unsubstituted 4-pyridyl. In an embodiment, Ring A is substituted pyrrolyl. In an embodiment, Ring A is unsubstituted pyrrolyl. In an embodiment, Ring A is substituted furanyl. In an embodiment, Ring A is unsubstituted furanyl. In an embodiment, Ring A is substituted pyrazolyl. In an embodiment, Ring A is unsubstituted pyrazolyl. In an embodiment, Ring A is substituted imidazolyl. In an embodiment, Ring A is unsubstituted imidazolyl. In an embodiment, Ring A is substituted oxazolyl. In an embodiment, Ring A is unsubstituted oxazolyl. In an embodiment, Ring A is substituted isoxazolyl. In an embodiment, Ring A is unsubstituted isoxazolyl. In an embodiment, Ring A is substituted thiazolyl. In an embodiment, Ring A is unsubstituted thiazolyl. In embodiments, Ring A is substituted triazolyl.In embodiments, Ring A is unsubstituted triazolyl.

[0303] In embodiments, Ring A is phenyl. In embodiments, Ring A is a 5-6 membered heteroaryl. 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 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 pyrrolyl. In embodiments, Ring A is furanyl. In embodiments, Ring A is pyrazolyl. In embodiments, Ring A is imidazolyl. In embodiments, Ring A is oxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is triazolyl.

[0304] In an embodiment, ring A is

[0305] [ka] In an embodiment, ring A is

[0306] [ka] In an embodiment, ring A is

[0307] [ka] In an embodiment, ring A is

[0308] [ka] In an embodiment, ring A is

[0309] [ka] In an embodiment, ring A is

[0310] [ka] In an embodiment, ring A is

[0311] [ka] In an embodiment, ring A is

[0312] [ka] In an embodiment, ring A is

[0313] [ka] In an embodiment, ring A is

[0314] [ka] In an embodiment, ring A is

[0315] [ka] In an embodiment, ring A is

[0316] [ka] In an embodiment, ring A is

[0317] [ka] In an embodiment, ring A is

[0318] [ka] In an embodiment, ring A is

[0319] [ka] is.

[0320] In embodiments, substituted ring B (e.g., substituted phenyl, substituted naphthyl, substituted quinolinyl, and / or substituted isoquinolinyl) is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when substituted ring B is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. In embodiments, when ring B is substituted, it is substituted with at least one substituent. In embodiments, when ring B is substituted, it is substituted with at least one size-limiting substituent. In embodiments, when ring B is substituted, it is substituted with at least one lower substituent.

[0321] In embodiments, Ring B is unsubstituted phenyl, unsubstituted naphthyl, unsubstituted quinolinyl, or unsubstituted isoquinolinyl. In embodiments, Ring B is substituted phenyl. In embodiments, Ring B is unsubstituted phenyl. In embodiments, Ring B is substituted naphthyl. In embodiments, Ring B is unsubstituted naphthyl. In embodiments, Ring B is substituted 1-naphthyl. In embodiments, Ring B is unsubstituted 1-naphthyl. In embodiments, Ring B is substituted 2-naphthyl. In embodiments, Ring B is unsubstituted 2-naphthyl. In embodiments, Ring B is substituted quinolinyl. In embodiments, Ring B is unsubstituted quinolinyl. In embodiments, Ring B is substituted 2-quinolinyl. In embodiments, Ring B is unsubstituted 2-quinolinyl. In embodiments, Ring B is substituted 3-quinolinyl. In embodiments, Ring B is unsubstituted 3-quinolinyl. In embodiments, Ring B is substituted 4-quinolinyl. In embodiments, Ring B is unsubstituted 4-quinolinyl. In embodiments, Ring B is substituted isoquinolinyl. In embodiments, Ring B is unsubstituted isoquinolinyl. In embodiments, Ring B is substituted 1-isoquinolinyl. In embodiments, Ring B is unsubstituted 1-isoquinolinyl. In embodiments, Ring B is substituted 3-isoquinolinyl. In embodiments, Ring B is unsubstituted 3-isoquinolinyl. In embodiments, Ring B is substituted 4-isoquinolinyl. In embodiments, Ring B is unsubstituted 4-isoquinolinyl.

[0322] In embodiments, Ring B is phenyl. 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 2-quinolinyl. In embodiments, Ring B is 3-quinolinyl. In embodiments, Ring B is 4-quinolinyl. In embodiments, Ring B is isoquinolinyl. In embodiments, Ring B is 1-isoquinolinyl. In embodiments, Ring B is 3-isoquinolinyl. In embodiments, Ring B is 4-isoquinolinyl.

[0323] In an embodiment, ring B is

[0324] [ka] In an embodiment, ring B is

[0325] [ka] In an embodiment, ring B is

[0326] [ka] In an embodiment, ring B is

[0327] [ka] In an embodiment, ring B is

[0328] [ka] In an embodiment, ring B is

[0329] [ka] In an embodiment, ring B is

[0330] [ka] In an embodiment, ring B is

[0331] [ka] is.

[0332] In embodiments, m is 0. In embodiments, m is 1. In embodiments, m is 2. In embodiments, m is 3. In embodiments, m is 4. In embodiments, m is 5.

[0333] In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, n is 5. In embodiments, n is 6. In embodiments, n is 7. In embodiments, n is 8. In embodiments, n is 9. In embodiments, n is 10.

[0334] In embodiments, the compound has the formula:

[0335] [ka] R 1 , z1, R 2 , R 3 , R 4 , z4, and R 6 is as described herein, including the embodiments.

[0336] In embodiments, the compound has the formula:

[0337] [ka] R 1 , z1, R 2 , R 3 , R 4 , z4, and R 6 is as described herein, including the embodiments.

[0338] In embodiments, the compound has the formula:

[0339] [ka] R 2 , R 3 , R 4 , z4, and R 6 is as described herein, including the embodiments.

[0340] In embodiments, the compound has the formula:

[0341] [ka] R 2 , R 3 , R 4 , z4, and R 6 is as described herein, including the embodiments.

[0342] In embodiments, the compound has the formula:

[0343] [ka] R 4 , z4, and R 6 is as described herein, including the embodiments.

[0344] In embodiments, the compound has the formula:

[0345] [ka] R 4 , z4, and R 6 is as described herein, including the embodiments.

[0346] In embodiments, the compound has the formula:

[0347] [ka] R 4 , z4, and R 6 is as described herein, including the embodiments.

[0348] In embodiments, the compound has the formula:

[0349] [ka] R 4 , z4, and R 6is as described herein, including the embodiments.

[0350] In embodiments, the compound has the formula:

[0351] [ka] R 6 is as described herein, including the embodiments.

[0352] In embodiments, the compound has the formula:

[0353] [ka] R 6 is as described herein, including the embodiments.

[0354] In embodiments, the compound has the formula:

[0355] [ka] R 6 is as described herein, including the embodiments.

[0356] In embodiments, the compound has the formula:

[0357] [ka] R 6 is as described herein, including the embodiments.

[0358] In embodiments, the compound has the formula:

[0359] [ka] R 2 , R 3 , R 4 , z4, R 5, z5, and R 6 is as described herein, including the embodiments.

[0360] In embodiments, the compound has the formula:

[0361] [ka] R 2 , R 3 , R 4 , z4, R 5 , z5, and R 6 is as described herein, including the embodiments.

[0362] In embodiments, the compound has the formula:

[0363] [ka] R 4 , R 5 , z5, and R 6 is as described herein, including the embodiments.

[0364] In embodiments, the compound has the formula:

[0365] [ka] R 4 , R 5 , z5, and R 6 is as described herein, including the embodiments.

[0366] In embodiments, the compound has the formula:

[0367] [ka] R 4 , R 5 , z5, and R 6 is as described herein, including the embodiments.

[0368] In embodiments, the compound has the formula:

[0369] [ka] R 4 , R 5 , z5, and R 6 is as described herein, including the embodiments.

[0370] In embodiments, the compound has the formula:

[0371] [ka] R 5 , z5, and R 6 is as described herein, including the embodiments.

[0372] In embodiments, the compound has the formula:

[0373] [ka] R 5 , z5, and R 6 is as described herein, including the embodiments.

[0374] In embodiments, the compound has the formula:

[0375] [ka] R 5 , z5, and R 6 is as described herein, including the embodiments.

[0376] In embodiments, the compound has the formula:

[0377] [ka] R5 , z5, and R 6 is as described herein, including the embodiments.

[0378] In embodiments, the compound has the formula:

[0379] [ka] In embodiments, the compound has the formula:

[0380] [ka] In embodiments, the compound has the formula:

[0381] [ka] In embodiments, the compound has the formula:

[0382] [ka] In embodiments, the compound has the formula:

[0383] [ka] In embodiments, the compound has the formula:

[0384] [ka] In embodiments, the compound has the formula:

[0385] [ka] In embodiments, the compound has the formula:

[0386] [ka] In embodiments, the compound has the formula:

[0387] [ka] In embodiments, the compound has the formula:

[0388] [ka] In embodiments, the compound has the formula:

[0389] [ka] In embodiments, the compound has the formula:

[0390] [ka] In embodiments, the compound has the formula:

[0391] [ka] In embodiments, the compound has the formula:

[0392] [ka] In embodiments, the compound has the formula:

[0393] [ka] In embodiments, the compound has the formula:

[0394] [ka] In embodiments, the compound has the formula:

[0395] [ka] In embodiments, the compound has the formula:

[0396] [ka] In embodiments, the compound has the formula:

[0397] [ka] In embodiments, the compound has the formula:

[0398] [ka] In embodiments, the compound has the formula:

[0399] [ka] In embodiments, the compound has the formula:

[0400] [ka] In embodiments, the compound has the formula:

[0401] [ka] In embodiments, the compound has the formula:

[0402] [ka] In embodiments, the compound has the formula:

[0403] [ka] In embodiments, the compound has the formula:

[0404] [ka] In embodiments, the compound has the formula:

[0405] [ka] In embodiments, the compound has the formula:

[0406] [ka] In embodiments, the compound has the formula:

[0407] [ka] In embodiments, the compound has the formula:

[0408] [ka] In embodiments, the compound has the formula:

[0409] [ka] In embodiments, the compound has the formula:

[0410] [ka] In embodiments, the compound has the formula:

[0411] [ka] In embodiments, the compound has the formula:

[0412] [ka] In embodiments, the compound has the formula:

[0413] [ka] In embodiments, the compound has the formula:

[0414] [ka] In embodiments, the compound has the formula:

[0415] [ka] In embodiments, the compound has the formula:

[0416] [ka] In embodiments, the compound has the formula:

[0417] [ka] In embodiments, the compound has the formula:

[0418] [ka] In embodiments, the compound has the formula:

[0419] [ka] In embodiments, the compound has the formula:

[0420] [ka] In embodiments, the compound has the formula:

[0421] [ka] In embodiments, the compound has the formula:

[0422] [ka] In embodiments, the compound has the formula:

[0423] [ka] In embodiments, the compound has the formula:

[0424] [ka] In embodiments, the compound has the formula:

[0425] [ka] In embodiments, the compound has the formula:

[0426] [ka] In embodiments, the compound has the formula:

[0427] [ka] In embodiments, the compound has the formula:

[0428] [ka] In embodiments, the compound has the formula:

[0429] [ka] In embodiments, the compound has the formula:

[0430] [ka] In embodiments, the compound has the formula:

[0431] [ka] In embodiments, the compound has the formula:

[0432] [ka] In embodiments, the compound has the formula:

[0433] [ka] In embodiments, the compound has the formula:

[0434] [ka] In embodiments, the compound has the formula:

[0435] [ka] In embodiments, the compound has the formula:

[0436] [ka] In embodiments, the compound has the formula:

[0437] [ka] In embodiments, the compound has the formula:

[0438] [ka] In embodiments, the compound has the formula:

[0439] [ka] In embodiments, the compound has the formula:

[0440] [ka] In embodiments, the compound has the formula:

[0441] [ka] In embodiments, the compound has the formula:

[0442] [ka] In embodiments, the compound has the formula:

[0443] [ka] In embodiments, the compound has the formula:

[0444] [ka] In embodiments, the compound has the formula:

[0445] [ka] In embodiments, the compound has the formula:

[0446] [ka] In embodiments, the compound has the formula:

[0447] [ka] In embodiments, the compound has the formula:

[0448] [ka] In embodiments, the compound has the formula:

[0449] [ka] In embodiments, the compound has the formula:

[0450] [ka] In embodiments, the compound has the formula:

[0451] [ka] In embodiments, the compound has the formula:

[0452] [ka] In embodiments, the compound has the formula:

[0453] [ka] In embodiments, the compound has the formula:

[0454] [ka] In embodiments, the compound has the formula:

[0455] [ka] In embodiments, the compound has the formula:

[0456] [ka] In embodiments, the compound has the formula:

[0457] [ka] In embodiments, the compound has the formula:

[0458] [ka] In embodiments, the compound has the formula:

[0459] [ka] In embodiments, the compound has the formula:

[0460] [ka] In embodiments, the compound has the formula:

[0461] [ka] In embodiments, the compound has the formula:

[0462] [ka] In embodiments, the compound has the formula:

[0463] [ka] In embodiments, the compound has the formula:

[0464] [ka] In embodiments, the compound has the formula:

[0465] [ka] In embodiments, the compound has the formula:

[0466] [ka] In embodiments, the compound has the formula:

[0467] [ka] In embodiments, the compound has the formula:

[0468] [ka] In embodiments, the compound has the formula:

[0469] [ka] In embodiments, the compound has the formula:

[0470] [ka] In embodiments, the compound has the formula:

[0471] [ka] In embodiments, the compound has the formula:

[0472] [ka] In embodiments, the compound has the formula:

[0473] [ka] In embodiments, the compound has the formula:

[0474] [ka] In embodiments, the compound has the formula:

[0475] [ka] In embodiments, the compound has the formula:

[0476] [ka] In embodiments, the compound has the formula:

[0477] [ka] In embodiments, the compound has the formula:

[0478] [ka] In embodiments, the compound has the formula:

[0479] [ka] In embodiments, the compound has the formula:

[0480] [ka] In embodiments, the compound has the formula:

[0481] [ka] In embodiments, the compound has the formula:

[0482] [ka] In embodiments, the compound has the formula:

[0483] [ka] In embodiments, the compound has the formula:

[0484] [ka] In embodiments, the compound has the formula:

[0485] [ka] In embodiments, the compound has the formula:

[0486] [ka] In embodiments, the compound has R 2 In an embodiment, the compound is a compound in this paragraph wherein R 3 In an embodiment, the compound is a compound in this paragraph wherein R 2 and R 3 is a compound in this paragraph wherein each of the positions is methyl instead of hydrogen.

[0487] In embodiments, the compound has the formula:

[0488] [ka] R 1 , z1, R 2 , R 4 , and z4 are as described herein, including embodiments.

[0489] In embodiments, the compound has the formula:

[0490] [ka] R 1 , z1, R 2 , R 4, and z4 are as described herein, including embodiments.

[0491] In embodiments, the compound has the formula:

[0492] [ka] R 2 , R 4 , and z4 are as described herein, including embodiments.

[0493] In embodiments, the compound has the formula:

[0494] [ka] R 2 , R 4 , and z4 are as described herein, including embodiments.

[0495] In embodiments, the compound has the formula:

[0496] [ka] R 4 is as described herein, including the embodiments.

[0497] In embodiments, the compound has the formula:

[0498] [ka] R 4 is as described herein, including the embodiments.

[0499] In embodiments, the compound has the formula:

[0500] [ka] R 4is as described herein, including the embodiments.

[0501] In embodiments, the compound has the formula:

[0502] [ka] R 4 is as described herein, including the embodiments.

[0503] In embodiments, the compound has the formula:

[0504] [ka] In embodiments, the compound has the formula:

[0505] [ka] In embodiments, the compound has the formula:

[0506] [ka] In embodiments, the compound has the formula:

[0507] [ka] It has.

[0508] In embodiments, the compound has the formula:

[0509] [ka] R 1 , z1, R 2 , R 4 , and z4 are as described herein, including embodiments.

[0510] In embodiments, the compound has the formula:

[0511] [ka] R 1 , z1, R 2 , R 4 , and z4 are as described herein, including embodiments.

[0512] In embodiments, the compound has the formula:

[0513] [ka] R 2 , R 4 , and z4 are as described herein, including embodiments.

[0514] In embodiments, the compound has the formula:

[0515] [ka] R 2 , R 4 , and z4 are as described herein, including embodiments.

[0516] In embodiments, the compound has the formula:

[0517] [ka] R 4 is as described herein, including the embodiments.

[0518] In embodiments, the compound has the formula:

[0519] [ka] R 4 is as described herein, including the embodiments.

[0520] In embodiments, the compound has the formula:

[0521] [ka] R 4 is as described herein, including the embodiments.

[0522] In embodiments, the compound has the formula:

[0523] [ka] R 4 is as described herein, including the embodiments.

[0524] In embodiments, the compound has the formula:

[0525] [ka] In embodiments, the compound has the formula:

[0526] [ka] In embodiments, the compound has the formula:

[0527] [ka] In embodiments, the compound has the formula:

[0528] [ka] In embodiments, the compound has the formula:

[0529] [ka] In embodiments, the compound has the formula:

[0530] [ka] In embodiments, the compound has the formula:

[0531] [ka] In embodiments, the compound has the formula:

[0532] [ka] It has.

[0533] In one aspect, a compound, or a pharmaceutically acceptable salt thereof, is provided having the formula:

[0534] [ka] or a pharmaceutically acceptable salt thereof. 1 , ring A, R 1 , z1, R 2 , R 3 , R 6 , and m are as described herein, including embodiments.

[0535] In embodiments, the compound has the formula:

[0536] [ka] L 1 , ring A, R 1 , z1, R 2 , R 3 , R 4 , z4, R 6 , and m are as described herein, including embodiments.

[0537] In embodiments, the compound has the formula:

[0538] [ka] L 1 , ring A, R 1 , z1, R 2 , R 3 , R 4 , z4, and R 6 is as described herein, including the embodiments.

[0539] In embodiments, R 1 If is substituted, R 1 is R as explained in the description of "first substituent" in the definition paragraph above. 1.1 In an embodiment, R 1.1 If the substituent is substituted, R 1.1 The substituents are as described in the definitions section above under "first substituent," R 1.2 In an embodiment, R 1.2 If the substituent is substituted, R 1.2 The substituents are as described in the definitions section above under "first substituent," R 1.3 In the above embodiment, R 1 , R 1.1 , R 1.2 , and R 1.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 1 , R 1.1 , R 1.2 , and R 1.3 Corresponds to.

[0540] In an embodiment, two adjacent R 1When substituents are optionally linked to form a substituted moiety (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety may be selected from R 1.1 In an embodiment, R 1.1 If the substituent is substituted, R 1.1 The substituents are as described in the definitions section above under "first substituent," R 1.2 In an embodiment, R 1.2 If the substituent is substituted, R 1.2 The substituents are as described in the definitions section above under "first substituent," R 1.3 In the above embodiment, R 1 , R 1.1 , R 1.2 , and R 1.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 1 , R 1.1 , R 1.2 , and R 1.3 Corresponds to.

[0541] In embodiments, R 1A If is substituted, R 1A is R as explained in the description of "first substituent" in the definition paragraph above. 1A.1 In an embodiment, R 1A.1 If the substituent is substituted, R 1A.1 The substituents are as described in the definitions section above under "first substituent," R 1A.2In an embodiment, R 1A.2 If the substituent is substituted, R 1A.2 The substituents are as described in the definitions section above under "first substituent," R 1A.3 In the above embodiment, R 1A , R 1A.1 , R 1A.2 , and R 1A.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 1A , R 1A.1 , R 1A.2 , and R 1A.3 Corresponds to.

[0542] In embodiments, R 1B If is substituted, R 1B is R as explained in the description of "first substituent" in the definition paragraph above. 1B.1 In an embodiment, R 1B.1 If the substituent is substituted, R 1B.1 The substituents are as described in the definitions section above under "first substituent," R 1B.2 In an embodiment, R 1B.2 If the substituent is substituted, R 1B.2 The substituents are as described in the definitions section above under "first substituent," R 1B.3 In the above embodiment, R 1B , R 1B.1 , R 1B.2 , and R 1B.3 are each R as explained in the description of the "first substituent" in the definition paragraph above.WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 1B , R 1B.1 , R 1B.2 , and R 1B.3 Corresponds to.

[0543] In embodiments, R 1A and R 1B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be selected from R 1A.1 In an embodiment, R 1A.1 If the substituent is substituted, R 1A.1 The substituents are as described in the definitions section above under "first substituent," R 1A.2 In an embodiment, R 1A.2 If the substituent is substituted, R 1A.2 The substituents are as described in the definitions section above under "first substituent," R 1A.3 In the above embodiment, R 1A.1 , R 1A.2 , and R 1A.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 1A.1 , R 1A.2 , and R 1A.3 Corresponds to.

[0544] In embodiments, R1A and R 1B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be selected from R 1B.1 In an embodiment, R 1B.1 If the substituent is substituted, R 1B.1 The substituents are as described in the definitions section above under "first substituent," R 1B.2 In an embodiment, R 1B.2 If the substituent is substituted, R 1B.2 The substituents are as described in the definitions section above under "first substituent," R 1B.3 In the above embodiment, R 1B.1 , R 1B.2 , and R 1B.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 1B.1 , R 1B.2 , and R 1B.3 Corresponds to.

[0545] In embodiments, R 1C If is substituted, R 1C is R as explained in the description of "first substituent" in the definition paragraph above. 1C.1 In an embodiment, R 1C.1 If the substituent is substituted, R 1C.1 The substituents are as described in the definitions section above under "first substituent," R 1C.2 In an embodiment, R 1C.2 If the substituent is substituted, R1C.2 The substituents are as described in the definitions section above under "first substituent," R 1C.3 In the above embodiment, R 1C , R 1C.1 , R 1C.2 , and R 1C.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 1C , R 1C.1 , R 1C.2 , and R 1C.3 Corresponds to.

[0546] In embodiments, R 1D If is substituted, R 1D is R as explained in the description of "first substituent" in the definition paragraph above. 1D.1 In an embodiment, R 1D.1 If the substituent is substituted, R 1D.1 The substituents are as described in the definitions section above under "first substituent," R 1D.2 In an embodiment, R 1D.2 If the substituent is substituted, R 1D.2 The substituents are as described in the definitions section above under "first substituent," R 1D.3 In the above embodiment, R 1D , R 1D.1 , R 1D.2 , and R 1D.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 1D , R 1D.1 , R 1D.2 , and R 1D.3 Corresponds to.

[0547] In embodiments, R 2 If is substituted, R 2 is R as explained in the description of "first substituent" in the definition paragraph above. 2.1 In an embodiment, R 2.1 If the substituent is substituted, R 2.1 The substituents are as described in the definitions section above under "first substituent," R 2.2 In an embodiment, R 2.2 If the substituent is substituted, R 2.2 The substituents are as described in the definitions section above under "first substituent," R 2.3 In the above embodiment, R 2 , R 2.1 , R 2.2 , and R 2.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 2 , R 2.1 , R 2.2 , and R 2.3 Corresponds to.

[0548] In embodiments, R 3 If is substituted, R 3 is R as explained in the description of "first substituent" in the definition paragraph above.3.1 In an embodiment, R 3.1 If the substituent is substituted, R 3.1 The substituents are as described in the definitions section above under "first substituent," R 3.2 In an embodiment, R 3.2 If the substituent is substituted, R 3.2 The substituents are as described in the definitions section above under "first substituent," R 3.3 In the above embodiment, R 3 , R 3.1 , R 3.2 , and R 3.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 3 , R 3.1 , R 3.2 , and R 3.3 Corresponds to.

[0549] In embodiments, R 4 If is substituted, R 4 is R as explained in the description of "first substituent" in the definition paragraph above. 4.1 In an embodiment, R 4.1 If the substituent is substituted, R 4.1 The substituents are as described in the definitions section above under "first substituent," R 4.2 In an embodiment, R 4.2 If the substituent is substituted, R 4.2 The substituents are as described in the definitions section above under "first substituent," R 4.3In the above embodiment, R 4 , R 4.1 , R 4.2 , and R 4.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4 , R 4.1 , R 4.2 , and R 4.3 Corresponds to.

[0550] In an embodiment, two adjacent R 4 When substituents are optionally linked to form a substituted moiety (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety may be selected from R 4.1 In an embodiment, R 4.1 If the substituent is substituted, R 4.1 The substituents are as described in the definitions section above under "first substituent," R 4.2 In an embodiment, R 4.2 If the substituent is substituted, R 4.2 The substituents are as described in the definitions section above under "first substituent," R 4.3 In the above embodiment, R 4 , R 4.1 , R 4.2 , and R 4.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4 , R 4.1 , R 4.2 , and R 4.3 Corresponds to.

[0551] In embodiments, R 4A If is substituted, R 4A is R as explained in the description of "first substituent" in the definition paragraph above. 4A.1 In an embodiment, R 4A.1 If the substituent is substituted, R 4A.1 The substituents are as described in the definitions section above under "first substituent," R 4A.2 In an embodiment, R 4A.2 If the substituent is substituted, R 4A.2 The substituents are as described in the definitions section above under "first substituent," R 4A.3 In the above embodiment, R 4A , R 4A.1 , R 4A.2 , and R 4A.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4A , R 4A.1 , R 4A.2 , and R 4A.3 Corresponds to.

[0552] In embodiments, R 4B If is substituted, R 4B is R as explained in the description of "first substituent" in the definition paragraph above.4B.1 In an embodiment, R 4B.1 If the substituent is substituted, R 4B.1 The substituents are as described in the definitions section above under "first substituent," R 4B.2 In an embodiment, R 4B.2 If the substituent is substituted, R 4B.2 The substituents are as described in the definitions section above under "first substituent," R 4B.3 In the above embodiment, R 4B , R 4B.1 , R 4B.2 , and R 4B.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4B , R 4B.1 , R 4B.2 , and R 4B.3 Corresponds to.

[0553] In embodiments, R 4A and R 4B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be selected from R 4A.1 In an embodiment, R 4A.1 If the substituent is substituted, R 4A.1 The substituents are as described in the definitions section above under "first substituent," R 4A.2 In an embodiment, R 4A.2 If the substituent is substituted, R4A.2 The substituents are as described in the definitions section above under "first substituent," R 4A.3 In the above embodiment, R 4A.1 , R 4A.2 , and R 4A.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , R WW.2 , and R WW.3 are R 4A.1 , R 4A.2 , and R 4A.3 Corresponds to.

[0554] In embodiments, R 4A and R 4B When substituents are optionally linked to form a substituted moiety (e.g., substituted heterocycloalkyl or substituted heteroaryl), the moiety may be selected from R 4B.1 In an embodiment, R 4B.1 If the substituent is substituted, R 4B.1 The substituents are as described in the definitions section above under "first substituent," R 4B.2 In an embodiment, R 4B.2 If the substituent is substituted, R 4B.2 The substituents are as described in the definitions section above under "first substituent," R 4B.3 In the above embodiment, R 4B.1 , R 4B.2 , and R 4B.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW.1 , RWW.2 , and R WW.3 are R 4B.1 , R 4B.2 , and R 4B.3 Corresponds to.

[0555] In embodiments, R 4C If is substituted, R 4C is R as explained in the description of "first substituent" in the definition paragraph above. 4C.1 In an embodiment, R 4C.1 If the substituent is substituted, R 4C.1 The substituents are as described in the definitions section above under "first substituent," R 4C.2 In an embodiment, R 4C.2 If the substituent is substituted, R 4C.2 The substituents are as described in the definitions section above under "first substituent," R 4C.3 In the above embodiment, R 4C , R 4C.1 , R 4C.2 , and R 4C.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4C , R 4C.1 , R 4C.2 , and R 4C.3 Corresponds to.

[0556] In embodiments, R 4D If is substituted, R 4D is R as explained in the description of "first substituent" in the definition paragraph above. 4D.1 In an embodiment, R 4D.1If the substituent is substituted, R 4D.1 The substituents are as described in the definitions section above under "first substituent," R 4D.2 In an embodiment, R 4D.2 If the substituent is substituted, R 4D.2 The substituents are as described in the definitions section above under "first substituent," R 4D.3 In the above embodiment, R 4D , R 4D.1 , R 4D.2 , and R 4D.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 4D , R 4D.1 , R 4D.2 , and R 4D.3 Corresponds to.

[0557] In embodiments, R 5 If is substituted, R 5 is R as explained in the description of "first substituent" in the definition paragraph above. 5.1 In an embodiment, R 5.1 If the substituent is substituted, R 5.1 The substituents are as described in the definitions section above under "first substituent," R 5.2 In an embodiment, R 5.2 If the substituent is substituted, R 5.2 The substituents are as described in the definitions section above under "first substituent," R 5.3 In the above embodiment, R 5 , R 5.1, R 5.2 , and R 5.3 are each R as explained in the description of the "first substituent" in the definition paragraph above. WW , R WW.1 , R WW.2 , and R WW.3 has a value corresponding to the value of R WW , R WW.1 , R WW.2 , and R WW.3 are R 5 , R 5.1 , R 5.2 , and R 5.3 Corresponds to.

[0558] In an embodiment, two adjacent R 5 When substituents are optionally linked to form a substituted moiety (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl), the moiety may be selected from R 5.1 In an embodiment, R 5.1 If the substituent is substituted, R 5.1 The substituents are as described in the definitions section above under "first substituent," R 5.2 In an embodiment, R 5.2 If the substituent is substituted, R 5.2 The substituents are as described in the definitions section above under "first substituent," R 5.3 In the above embodiment, R 5 , R ...

Claims

1. 1. A compound, or a pharma- ceutically acceptable salt thereof, having the formula: 【Chemistry 1】 having During the ceremony, L １ is -O-, -NR ７ -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR ７ C(O)-, -C(O)NR ７ -, -NR ７ C(O)NR ８ -, -NR ７ S(O) ２ O-, -OS(O) ２ NR ７ -, -NR ７ S(O) ２ -, -S(O) ２ NR ７ -, -S(O)-, -S(O) ２ -, -OS(O) ２ O-, -S(O) ２ O-, -OS(O) ２ -, -P(O)(OR ７ ), -OP(O)(OR ７ ), -OP(O)(OR ７ ), -P(O)(OR ７ ), or -CR ８ R ９ -, and R ７ , R ８ , and R ９ are independently hydrogen, halogen, -OH, -N ３ or substituted or unsubstituted alkyl; Ring A is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- to 6-membered heteroaryl; Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl; R １ is independently halogen, -CX １ ３ , -CHX １ ２ , -CH ２ X １ , -OCX １ ３ , -OCHX １ ２ , -OCH ２ X １ , -CN, -SO ｎ１ R １Ｄ , -SO ｖ１ NR １Ａ R １Ｂ , -NR １Ｃ NR １Ａ R １Ｂ , -ONR １Ａ R １Ｂ , -NHC(O)NR １Ｃ NR １Ａ R １Ｂ , -NR １Ｃ C(O)NR １Ａ R １Ｂ , -N(O) ｍ１ , -NR １Ａ R １Ｂ , -C(O)R １Ｃ , -C(O)OR １Ｃ , -OC(O)R １Ｃ , -OC(O)OR １Ｃ , -C(O)NR １Ａ R １Ｂ , -OR １Ｄ , -SR １Ｄ , -NR １Ａ SO ２ R １Ｄ , -NR １Ａ C(O)R １Ｃ , -NR １Ａ C(O)OR １Ｃ , -OC(O)NR １Ａ R １Ｂ , -NR １Ａ OR １Ｃ , -P(O)R １Ａ R １Ｂ , -N 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, and two adjacent R １ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２ Hydrogen, halogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -CN, -COOH, -CONH ２ , -N 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; R ３ Hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -CN, -COOH, -CONH ２ , -N 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; R ６ is hydrogen, halogen, -CX ６ ３ , -CHX ６ ２ , -CH ２ X ６ , -OCX ６ ３ , -OCHX ６ ２ , -OCH ２ X ６ , -CN, -SO ｎ６ R ６Ｄ , -SO ｖ６ NR ６Ａ R ６Ｂ , -NR ６Ｃ NR ６Ａ R ６Ｂ , -ONR ６Ａ R ６Ｂ , -NHC(O)NR ６Ｃ NR ６Ａ R ６Ｂ , -NR ６Ｃ C(O)NR ６Ａ R ６Ｂ , -N(O) ｍ６ , -NR ６Ａ R ６Ｂ , -C(O)R ６Ｃ , -C(O)OR ６Ｃ , -OC(O)R ６Ｃ , -OC(O)OR ６Ｃ , -C(O)NR ６Ａ R ６Ｂ , -OR ６Ｄ , -SR ６Ｄ , -NR ６Ａ SO ２ R ６Ｄ , -NR ６Ａ C(O)R ６Ｃ , -NR ６Ａ C(O)OR ６Ｃ , -OC(O)NR ６Ａ R ６Ｂ , -NR ６Ａ OR ６Ｃ , -P(O)R ６Ａ R ６Ｂ , -N 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; R ３ and R ６ may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ , R ６Ａ , R ６Ｂ , R ６Ｃ , and R ６Ｄ are independently hydrogen, halogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -COOH, -CONH ２ , -N 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, and R １Ａ and R １Ｂ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R ６Ａ and R ６Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 4, m1, m6, v1, and v6 are independently 1 or 2; n1 and n6 are independently an integer from 0 to 4; X, X １ , X ２ , X ３ , and X ６ is independently -Cl, -Br, -I, or -F; m is an integer from 0 to 5; n is an integer from 0 to 10; However, L １ is -O-, m is 0, n is 0, and Ring B is substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl, R ６ is not hydrogen, or a pharma- ceutically acceptable salt thereof.

2. formula: 【Chemistry 2】 having During the ceremony, Ring A is phenyl or 5- to 6-membered heteroaryl; Ring B is phenyl, naphthyl, quinolinyl, or isoquinolinyl; R ４ is independently halogen, -CX ４ ３ , -CHX ４ ２ , -CH ２ X ４ , -OCX ４ ３ , -OCHX ４ ２ , -OCH ２ X ４ , -CN, -SO ｎ４ R ４Ｄ , -SO ｖ４ NR ４Ａ R ４Ｂ , -NR ４Ｃ NR ４Ａ R ４Ｂ , -ONR ４Ａ R ４Ｂ , -NHC(O)NR ４Ｃ NR ４Ａ R ４Ｂ , -NR ４Ｃ C(O)NR ４Ａ R ４Ｂ , -N(O) ｍ４ , -NR ４Ａ R ４Ｂ , -C(O)R ４Ｃ , -C(O)OR ４Ｃ , -OC(O)R ４Ｃ , -OC(O)OR ４Ｃ , -C(O)NR ４Ａ R ４Ｂ , -OR ４Ｄ , -SR ４Ｄ , -NR ４Ａ SO ２ R ４Ｄ , -NR ４Ａ C(O)R ４Ｃ , -NR ４Ａ C(O)OR ４Ｃ , -OC(O)NR ４Ａ R ４Ｂ , -NR ４Ａ OR ４Ｃ , -P(O)R ４Ａ R ４Ｂ , -N 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, and two adjacent R ４ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ５ is independently halogen, -CX ５ ３ , -CHX ５ ２ , -CH ２ X ５ , -OCX ５ ３ , -OCHX ５ ２ , -OCH ２ X ５ , -CN, -SO ｎ５ R ５Ｄ , -SO ｖ５ NR ５Ａ R ５Ｂ , -NR ５Ｃ NR ５Ａ R ５Ｂ , -ONR ５Ａ R ５Ｂ , -NHC(O)NR ５Ｃ NR ５Ａ R ５Ｂ , -NR ５Ｃ C(O)NR ５Ａ R ５Ｂ , -N(O) ｍ５ , -NR ５Ａ R ５Ｂ , -C(O)R ５Ｃ , -C(O)OR ５Ｃ , -OC(O)R ５Ｃ , -OC(O)OR ５Ｃ , -C(O)NR ５Ａ R ５Ｂ , -OR ５Ｄ , -SR ５Ｄ , -NR ５Ａ SO ２ R ５Ｄ , -NR ５Ａ C(O)R ５Ｃ , -NR ５Ａ C(O)OR ５Ｃ , -OC(O)NR ５Ａ R ５Ｂ , -NR ５Ａ OR ５Ｃ , -P(O)R ５Ａ R ５Ｂ , -N 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, and two adjacent R ５ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ４Ａ , R ４Ｂ , R ４Ｃ , R ４Ｄ , R ５Ａ , R ５Ｂ , R ５Ｃ , and R ５Ｄ are independently hydrogen, halogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -COOH, -CONH ２ , -N 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, and R ４Ａ and R ４Ｂ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R ５Ａ and R ５Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 5; z5 is 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 and X ５ The compound of claim 1, wherein is independently -Cl, -Br, -I, or -F.

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

4. formula: 【Chemistry 4】 4. The compound of claim 3 having the formula:

5. formula: 【Chemistry 5】 4. The compound of claim 3 having the formula:

6. formula: 【Chemistry 6】 4. The compound of claim 3 having the formula:

7. formula: 【Chemistry 7】 4. The compound of claim 3 having the formula:

8. formula: 【Chemistry 8】 4. The compound of claim 3 having the formula:

9. L １ is -O-, -NH-, -NCH ３ -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHSO ２ O-, -OS(O) ２ NH-, -NHSO ２ -, -SO ２ NH-, -SO-, -SO ２ -, -OS(O) ２ O-, -SO ２ O-, -OS(O) ２ -, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR ９ -, or -CR ８ R ９ -, and R ８ and R ９ The compound of claim 1 , wherein is independently halogen or unsubstituted methyl.

10. L １ The compound according to claim 1, wherein is -O-.

11. L １ The compound of claim 1, wherein is -S-.

12. L １ But -S(O) ２ The compound according to claim 1, wherein

13. 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 2-8 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 of claim 1 which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

14. R １ are independently halogen, -CF ３ , —OH, —NH ２ , -SH, substituted or unsubstituted C １ -C ４ Alkyl, substituted or unsubstituted 2-4 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.

15. R １ are independently a 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.

16. 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 R is F, unsubstituted methyl, or unsubstituted methoxy.

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

18. The compound according to claim 1 , wherein z1 is 0.

19. R ２ is hydrogen, -CX ２ ３ , -CHX ２ ２ , C.H. 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 2-6 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.

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

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

22. R ３ is 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 2-6 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.

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

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

25. R ６ is hydrogen, 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 2-8 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 of claim 1 which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

26. R ６ is a substituted or unsubstituted C １ -C ６ The compound of claim 1, which is alkyl or substituted or unsubstituted 2-6 membered heteroalkyl.

27. R ６ is hydrogen, unsubstituted methyl, unsubstituted isopropyl, 【Chemistry 9】 2. The compound of claim 1,

28. R ３ and R ６ The compound of claim 1 , wherein:

29. R ３ and R ６ The compound of claim 1, wherein:

30. R ３ and R ６ The compound of claim 1 , wherein:

31. R ３ and R ６ The compound of claim 1 , wherein:

32. R ４ are independently a 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 2-8 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 of claim 2, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

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

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

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

36. R ４ is independently -OR ４Ｄ 3. The compound of claim 2,

37. R ４Ｄ 37. The compound of claim 36, wherein is hydrogen or substituted or unsubstituted alkyl.

38. R ４Ｄ 37. The compound of claim 36, wherein is hydrogen or unsubstituted alkyl.

39. R ４Ｄ is hydrogen or unsubstituted C １ -C ５ 37. The compound of claim 36, which is alkyl.

40. R ４Ｄ 37. The compound of claim 36, wherein is hydrogen or unsubstituted methyl.

41. R ４Ｄ is unsubstituted methyl.

42. The compound of claim 2, wherein z4 is 1.

43. The compound according to claim 2, wherein z4 is 0.

44. R ５ are independently a 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 2-8 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 of claim 2, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

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

46. 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 2, which is alkyl, unsubstituted 2-4 membered heteroalkyl, or unsubstituted phenyl.

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

48. The compound of claim 2, wherein z5 is 1.

49. The compound of claim 2, wherein z5 is 0.

50. The compound of claim 1 , wherein Ring A is a substituted or unsubstituted phenyl.

51. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 5- to 6-membered heteroaryl.

52. The compound of claim 1 , wherein Ring A is a substituted or unsubstituted thienyl.

53. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 2-thienyl.

54. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 3-thienyl.

55. The compound of claim 1 , wherein Ring A is a substituted or unsubstituted pyridyl.

56. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 2-pyridyl.

57. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 3-pyridyl.

58. The compound of claim 1, wherein Ring A is a substituted or unsubstituted 4-pyridyl.

59. The compound of claim 1 , wherein Ring B is substituted or unsubstituted phenyl.

60. The compound of claim 1 , wherein Ring B is a substituted or unsubstituted naphthyl.

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

62. The compound of claim 1, wherein Ring B is a substituted or unsubstituted 2-naphthyl.

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

64. The compound of claim 1, wherein Ring B is a substituted or unsubstituted 2-quinolinyl.

65. The compound of claim 1, wherein Ring B is a substituted or unsubstituted 3-quinolinyl.

66. The compound of claim 1, wherein Ring B is a substituted or unsubstituted 4-quinolinyl.

67. The compound of claim 1 , wherein Ring B is a substituted or unsubstituted isoquinolinyl.

68. The compound of claim 1, wherein Ring B is a substituted or unsubstituted 1-isoquinolinyl.

69. The compound of claim 1, wherein Ring B is a substituted or unsubstituted 3-isoquinolinyl.

70. The compound of claim 1, wherein Ring B is a substituted or unsubstituted 4-isoquinolinyl.

71. formula: 【Chemistry 10】 3. The compound of claim 2 having the formula:

72. formula: 【Chemistry 11】 3. The compound of claim 2 having the formula:

73. formula: 【Chemistry 12】 3. The compound of claim 2 having the formula:

74. formula: 【Chemistry 13】 3. The compound of claim 2 having the formula:

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

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

77. formula: 【Chemistry 16】 3. The compound of claim 2 having the formula:

78. formula: 【Chemistry 17】 3. The compound of claim 2 having the formula:

79. formula: 【Chemistry 18】 3. The compound of claim 2 having the formula:

80. formula: 【Chemistry 19】 2. The compound of claim 1 having the formula:

81. formula: 【Chemistry 20】 3. The compound of claim 2 having the formula:

82. formula: 【Chemistry 21】 3. The compound of claim 2 having the formula:

83. formula: 【Chemical 22】 3. The compound of claim 2 having the formula:

84. formula: 【Chemistry 23】 3. The compound of claim 2 having the formula:

85. formula: 【Chemistry 24】 2. The compound of claim 1 having the formula:

86. formula: 【Chemistry 25】 2. The compound of claim 1 having the formula:

87. formula: 【Chemistry 26】 【Chemistry 27】 2. The compound of claim 1 having the formula:

88. 88. A pharmaceutical composition comprising a compound according to any one of claims 1 to 87, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

89. 89. The pharmaceutical composition of claim 88, further comprising an anti-cancer agent.

90. 90. The pharmaceutical composition of claim 89, wherein the anticancer agent is a platinum-based compound, a topoisomerase inhibitor, or a Chk1 inhibitor.

91. 90. The pharmaceutical composition of claim 89, wherein the anticancer drug is cisplatin.

92. 90. The pharmaceutical composition of claim 89, wherein the anticancer drug is etoposide, SN-38, camptothecin, or gemcitabine.

93. 90. The pharmaceutical composition of claim 89, wherein the anticancer agent is CHIR-124, debromohymenialdisine, SB218078, LY2603618, SCH900776, TCS2312, PF477736, UCN-01, or AZD7762.

94. A method for treating a disease associated with PCNA activity in a subject in need of such treatment, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 87 or a pharma- ceutically acceptable salt thereof.

95. 103. A method of treating cancer in a subject in need of such treatment, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 87, or a pharma- ceutically acceptable salt thereof.

96. 96. The method of claim 95, further comprising administering radiation.

97. 96. The method of claim 95, wherein the cancer is a sarcoma, adenocarcinoma, leukemia, or lymphoma.

98. 96. The method of claim 95, wherein the cancer is lung cancer, colon cancer, central nervous system cancer, brain cancer, neuroblastoma, skin cancer, head and neck cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, breast cancer, mesothelioma, liver cancer, gastric cancer, esophageal cancer, bladder cancer, cervical cancer, osteosarcoma, pancreatic cancer, adrenocortical carcinoma, adrenal cancer, colorectal cancer, testicular cancer, myeloma, B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, chronic leukemia, acute leukemia, glandular carcinoma, or hematoid cancer.

99. 88. A method of inhibiting PCNA activity, comprising contacting PCNA with an effective amount of a compound according to any one of claims 1 to 87, or a pharma- ceutically acceptable salt thereof.

100. 100. The method of claim 99, wherein the compound binds to His44, Val45, Leu47, Pro234, Tyr250, Leu251, Ala252, Met40, Leu47, Leu126, Leu128, Val233, Pro234, Ala252, Pro253, or Asp232 of PCNA.

101. 100. The method of claim 99, wherein the compound non-covalently binds to His44, Val45, Leu47, Pro234, Tyr250, Leu251, Ala252, Met40, Leu47, Leu126, Leu128, Val233, Pro234, Ala252, Pro253, or Asp232 of PCNA.

102. 1. A compound, or a pharma- ceutically acceptable salt thereof, having the formula: 【Chemistry 28】 having During the ceremony, L １ is -O-NR ７ -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR ７ C(O)-, -C(O)NR ７ -, -NR ７ C(O)NR ８ -, -NR ７ S(O) ２ O-, -OS(O) ２ NR ７ -, -NR ７ S(O) ２ -, -S(O) ２ NR ７ -, -S(O)-, -S(O) ２ -, -OS(O) ２ O-, -S(O) ２ O-, -OS(O) ２ -, -P(O)(OR ７ ), -OP(O)(OR ７ ), -OP(O)(OR ７ ), -P(O)(OR ７ ), or -CR ８ R ９ -, R ７ , R ８ , and R ９ are independently hydrogen, halogen, -OH, -N ３ or substituted or unsubstituted alkyl; Ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl; R １ is independently halogen, -CX １ ３ , -CHX １ ２ , -CH ２ X １ , -OCX １ ３ , -OCHX １ ２ , -OCH ２ X １ , -CN, -SO ｎ１ R １Ｄ , -SO ｖ１ NR １Ａ R １Ｂ , -NR １Ｃ NR １Ａ R １Ｂ , -ONR １Ａ R １Ｂ , -NHC(O)NR １Ｃ NR １Ａ R １Ｂ , -NR １Ｃ C(O)NR １Ａ R １Ｂ , -N(O) ｍ１ , -NR １Ａ R １Ｂ , -C(O)R １Ｃ , -C(O)OR １Ｃ , -OC(O)R １Ｃ , -OC(O)OR １Ｃ , -C(O)NR １Ａ R １Ｂ , -OR １Ｄ , -SR １Ｄ , -NR １Ａ , -NR ２ SO １Ｄ , -NR １Ａ C(O)R １Ｃ , -NR １Ａ C(O)OR １Ｃ , -OC(O)NR １Ａ R １Ｂ , -NR １Ａ OR １Ｃ , -P(O)R １Ａ R １Ｂ , -N 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, and two adjacent R １ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２ Hydrogen, halogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -CN, -COOH, -CONH ２ , -N 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; R ３ Hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -CN, -COOH, -CONH ２ , -N 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; R ６ is hydrogen, halogen, -CX ６ ３ , -CHX ６ ２ , -CH ２ X ６ , -OCX ６ ３ , -OCHX ６ ２ , -OCH ２ X ６ , -CN, -SO ｎ６ R ６Ｄ , -SO ｖ６ NR ６Ａ R ６Ｂ , -NR ６Ｃ NR ６Ａ R ６Ｂ , -ONR ６Ａ R ６Ｂ , -NHC(O)NR ６Ｃ NR ６Ａ R ６Ｂ , -NR ６Ｃ C(O)NR ６Ａ R ６Ｂ , -N(O) ｍ６ , -NR ６Ａ R ６Ｂ , -C(O)R ６Ｃ , -C(O)OR ６Ｃ , -OC(O)R ６Ｃ , -OC(O)OR ６Ｃ , -C(O)NR ６Ａ R ６Ｂ , -OR ６Ｄ , -SR ６Ｄ , -NR ６Ａ SO ２ R ６Ｄ , -NR ６Ａ C(O)R ６Ｃ , -NR ６Ａ C(O)OR ６Ｃ , -OC(O)NR ６Ａ R ６Ｂ , -NR ６Ａ OR ６Ｃ , -P(O)R ６Ａ R ６Ｂ , -N 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; R ３ and R ６ may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ , R ６Ａ , R ６Ｂ , R ６Ｃ , and R ６Ｄ are independently hydrogen, halogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -COOH, -CONH ２ , -N 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, and R １Ａ and R １Ｂ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R ６Ａ and R ６Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 4, m1, m6, v1, and v6 are independently 1 or 2; n1 and n6 are independently an integer from 0 to 4; X, X １ , X ２ , X ３ , and X ６ is independently -Cl, -Br, -I, or -F; A compound, or a pharma- ceutically acceptable salt thereof, wherein m is an integer of 0 to 5.

103. formula: 【Chemical 29】 having During the ceremony, R ４ is independently halogen, -CX ４ ３ , -CHX ４ ２ , -CH ２ X ４ , -OCX ４ ３ , -OCHX ４ ２ , -OCH ２ X ４ , -CN, -SO ｎ４ R ４Ｄ , -SO ｖ４ NR ４Ａ R ４Ｂ , -NR ４Ｃ NR ４Ａ R ４Ｂ , -ONR ４Ａ R ４Ｂ , -NHC(O)NR ４Ｃ NR ４Ａ R ４Ｂ , -NR ４Ｃ C(O)NR ４Ａ R ４Ｂ , -N(O) ｍ４ , -NR ４Ａ R ４Ｂ , -C(O)R ４Ｃ , -C(O)OR ４Ｃ , -OC(O)R ４Ｃ , -OC(O)OR ４Ｃ , -C(O)NR ４Ａ R ４Ｂ , -OR ４Ｄ , -SR ４Ｄ , -NR ４Ａ SO ２ R ４Ｄ , -NR ４Ａ C(O)R ４Ｃ , -NR ４Ａ C(O)OR ４Ｃ , -OC(O)NR ４Ａ R ４Ｂ , -NR ４Ａ OR ４Ｃ , -P(O)R ４Ａ R ４Ｂ , -N 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, and two adjacent R ４ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ are independently hydrogen, halogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -COOH, -CONH ２ , -N 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, and R ４Ａ and R ４Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 5; m4 and v4 are independently 1 or 2; n4 is an integer from 0 to 4; X ４ is independently -Cl, -Br, -I, or -F.

104. formula: 【Chemistry 30】 The compound of claim 103, having the formula:

105. L １ is -O-, -NH-, -NCH ３ -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)NH-, -NHSO ２ O-, -OS(O) ２ NH-, -NHSO ２ -, -SO ２ NH-, -SO-, -SO ２ -, -OS(O) ２ O-, -SO ２ O-, -OS(O) ２ -, -P(O)(OH)-, -OP(O)(OH)O-, -OP(O)(OH)-, -P(O)(OH)O-, -CHR ９ -, or -CR ８ R ９ -, and R ８ and R ９ is independently halogen or unsubstituted methyl.

106. L １ The compound of claim 102, wherein is -O-.

107. L １ The compound of claim 102, wherein is -S-.

108. L １ But -S(O) ２ The compound according to claim 102, wherein

109. 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 2-8 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 of claim 102, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

110. R １ are independently halogen, -OH, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ 103. The compound of claim 102, which is F, unsubstituted methyl, or unsubstituted methoxy.

111. The compound of claim 102, wherein z1 is 1.

112. The compound of claim 102, wherein z1 is 0.

113. R ２ 103. The compound of claim 102, wherein is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

114. R ３ 103. The compound of claim 102, wherein is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

115. R ６ is hydrogen, 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 2-8 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 of claim 102, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

116. R ６ is a substituted or unsubstituted C １ -C ６ 103. The compound of claim 102, which is alkyl or substituted or unsubstituted 2-6 membered heteroalkyl.

117. R ６ is hydrogen, unsubstituted methyl, unsubstituted isopropyl, 【Chemistry 31】 103. The compound of claim 102,

118. 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 2-8 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 of claim 103, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

119. R ４ are independently a halogen -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ 104. The compound of claim 103, which is F, -OH, unsubstituted methyl, or unsubstituted methoxy.

120. R ４ is independently -OR ４Ｄ 104. The compound of claim 103,

121. R ４Ｄ is hydrogen or substituted or unsubstituted alkyl.

122. R ４Ｄ is hydrogen or unsubstituted C １ -C ５ 121. The compound of claim 120, which is alkyl.

123. R ４Ｄ is unsubstituted methyl.

124. The compound of claim 103, wherein z4 is 1.

125. The compound of claim 103, wherein z4 is 0.

126. 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 2-8 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 of claim 103, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

127. R ５ are independently a halogen -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ 104. The compound of claim 103, which is F, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.

128. The compound of claim 103, wherein z5 is 1.

129. The compound of claim 103, wherein z5 is 0.

130. 103. The compound of claim 102, wherein Ring A is substituted or unsubstituted phenyl.

131. The compound of claim 102, wherein Ring A is a substituted or unsubstituted 5-6 membered heteroaryl.

132. 103. The compound of claim 102, wherein Ring A is substituted or unsubstituted thienyl.

133. 103. The compound of claim 102, wherein Ring A is substituted or unsubstituted pyridyl.

134. A process for making compound (I) or a pharma- ceutically acceptable salt thereof, comprising mixing compound (VII) and compound (X) together in a reaction vessel; Compound (I) has the formula: 【Chemistry 32】 having Compound (VII) has the formula: 【Chemical 33】 having Compound (X) is represented by the formula: 【Chemical 34】 having L １ is -O-NR ７ -, -S-, -C(O)-, -C(O)O-, -OC(O)-, -NR ７ C(O)-, -C(O)NR ７ -, -NR ７ C(O)NR ８ -, -NR ７ S(O) ２ O-, -OS(O) ２ NR ７ -, -NR ７ S(O) ２ -, -S(O) ２ NR ７ -, -S(O)-, -S(O) ２ -, -OS(O) ２ O-, -S(O) ２ O-, -OS(O) ２ -, -P(O)(OR ７ ), -OP(O)(OR ７ ), O-, -OP(O)(OR ７ ), -P(O)(OR ７ ), O-, or -CR ８ R ９ -, and R ７ , R ８ , and R ９ are independently hydrogen, halogen, -OH, -N ３ or substituted or unsubstituted alkyl; Ring A is a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl; Ring B is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl; R １ is independently halogen, -CX １ ３ , -CHX １ ２ , -CH ２ X １ , -OCX １ ３ , -OCHX １ ２ , -OCH ２ X １ , -CN, -SO ｎ１ R １Ｄ , -SO ｖ１ NR １Ａ R １Ｂ , -NR １Ｃ NR １Ａ R １Ｂ , -ONR １Ａ R １Ｂ , -NHC(O)NR １Ｃ NR １Ａ R １Ｂ , -NR １Ｃ C(O)NR １Ａ R １Ｂ , -N(O) ｍ１ , -NR １Ａ R １Ｂ , -C(O)R １Ｃ , -C(O)OR １Ｃ , -OC(O)R １Ｃ , -OC(O)OR １Ｃ , -C(O)NR １Ａ R １Ｂ , -OR １Ｄ , -SR １Ｄ , -NR １Ａ SO ２ R １Ｄ , -NR １Ａ C(O)R １Ｃ , -NR １Ａ C(O)OR １Ｃ , -OC(O)NR １Ａ R １Ｂ , -NR １Ａ OR １Ｃ , -P(O)R １Ａ R １Ｂ , -N 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, and two adjacent R １ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２ Hydrogen, halogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -CN, -COOH, -CONH ２ , -N 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; R ３ Hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -CN, -COOH, -CONH ２ , -N 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; R ６ is hydrogen, halogen, -CX ６ ３ , -CHX ６ ２ , -CH ２ X ６ , -OCX ６ ３ , -OCHX ６ ２ , -OCH ２ X ６ , -CN, -SO ｎ６ R ６Ｄ , -SO ｖ６ NR ６Ａ R ６Ｂ , -NR ６Ｃ NR ６Ａ R ６Ｂ , -ONR ６Ａ R ６Ｂ , -NHC(O)NR ６Ｃ NR ６Ａ R ６Ｂ , -NR ６Ｃ C(O)NR ６Ａ R ６Ｂ , -N(O) ｍ６ , -NR ６Ａ R ６Ｂ , -C(O)R ６Ｃ , -C(O)OR ６Ｃ , -OC(O)R ６Ｃ , -OC(O)OR ６Ｃ , -C(O)NR ６Ａ R ６Ｂ , -OR ６Ｄ , -SR ６Ｄ , -NR ６Ａ SO ２ R ６Ｄ , -NR ６Ａ C(O)R ６Ｃ , -NR ６Ａ C(O)OR ６Ｃ , -OC(O)NR ６Ａ R ６Ｂ , -NR ６Ａ OR ６Ｃ , -P(O)R ６Ａ R ６Ｂ , -N 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; R ３ and R ６ may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R １Ａ , R １Ｂ , R １Ｃ , R １Ｄ , R ６Ａ , R ６Ｂ , R ６Ｃ , and R ６Ｄ are independently hydrogen, halogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -COOH, -CONH ２ , -N 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, and R １Ａ and R １Ｂ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R ６Ａ and R ６Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z1 is an integer from 0 to 4, m1, m6, v1, and v6 are independently 1 or 2; n1 and n6 are independently an integer from 0 to 4; X, X １ , X ２ , X ３ , and X ６ is independently -Cl, -Br, -I, or -F; m is an integer from 0 to 5; n is an integer from 0 to 10; The method wherein LG is a leaving group.

135. 135. The method of claim 134, wherein LG is a halogen.

136. 135. The method of claim 134, wherein LG is -Cl.

137. 135. The method of claim 134, further comprising a base.

138. 138. The method of claim 137, wherein the base is N,N-diisopropylethylamine.

139. 135. The method of claim 134, wherein LG is -OH.

140. 135. The method of claim 134, further comprising a peptide coupling agent.

141. 141. The method of claim 140, wherein the peptide coupling agent is dicyclohexylcarbodiimide.

142. 141. The method of claim 140, wherein the peptide coupling agent is HBTU.

143. 141. The method of claim 140, wherein the peptide coupling agent is HOBt.

144. 141. The method of claim 140, wherein the peptide coupling agent is PyBOP.

145. Compound (I) is a compound of formula (II), 【Chemistry 35】 Compound (VII) is a compound of formula (VIII), 【Chemical 36】 Compound (X) is a compound of formula (XI), 【Chemical 37】 R ４ is independently halogen, -CX ４ ３ , -CHX ４ ２ , -CH ２ X ４ , -OCX ４ ３ , -OCHX ４ ２ , -OCH ２ X ４ , -CN, -SO ｎ４ R ４Ｄ , -SO ｖ４ NR ４Ａ R ４Ｂ , -NR ４Ｃ NR ４Ａ R ４Ｂ , -ONR ４Ａ R ４Ｂ , -NHC(O)NR ４Ｃ NR ４Ａ R ４Ｂ , -NR ４Ｃ C(O)NR ４Ａ R ４Ｂ , -N(O) ｍ４ , -NR ４Ａ R ４Ｂ , -C(O)R ４Ｃ , -C(O)OR ４Ｃ , -OC(O)R ４Ｃ , -OC(O)OR ４Ｃ , -C(O)NR ４Ａ R ４Ｂ , -OR ４Ｄ , -SR ４Ｄ , -NR ４Ａ , -NR ２ SO ４Ｄ , -NR ４Ａ C(O)R ４Ｃ , -NR ４Ａ C(O)OR ４Ｃ , -OC(O)NR ４Ａ R ４Ｂ , -NR ４Ａ OR ４Ｃ , -P(O)R ４Ａ R ４Ｂ , -N 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, and two adjacent R ４ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ５ is independently halogen, -CX ５ ３ , -CHX ５ ２ , -CH ２ X ５ , -OCX ５ ３ , -OCHX ５ ２ , -OCH ２ X ５ , -CN, -SO ｎ５ R ５Ｄ , -SO ｖ５ , -SONR ５Ａ R ５Ｂ , -NR ５Ｃ , -NR ５Ａ R ５Ｂ , -ONR ５Ａ R ５Ｂ , -NHC(O)NR ５Ｃ NR ５Ａ R ５Ｂ , -NR ５Ｃ , -NR ５Ａ R ５Ｂ , -N(O) ｍ５ , -NR ５Ａ R ５Ｂ , -C(O)R ５Ｃ , -C(O)OR ５Ｃ , -OC(O)R ５Ｃ , -OC(O)OR ５Ｃ , -C(O)NR ５Ａ R ５Ｂ , -OR ５Ｄ , -SR ５Ｄ , -NR ５Ａ , -NR ２ SO ５Ｄ , -NR ５Ａ , -NR ５Ｃ , -NR ５Ａ , -NR ５Ｃ , -OC(O)NR ５Ａ R ５Ｂ , -NR ５Ａ , -NR ５Ｃ , -P(O)R ５Ａ R ５Ｂ , -N 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, and two adjacent R ５ the substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ４Ａ , R ４Ｂ , R ４Ｃ , R ４Ｄ , R ５Ａ , R ５Ｂ , R ５Ｃ , and R ５Ｄ are independently hydrogen, halogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -COOH, -CONH ２ , -N 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, and R ４Ａ and R ４Ｂ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, and R ５Ａ and R ５Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z4 is an integer from 0 to 5; z5 is 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 and X ５ is independently -Cl, -Br, -I, or -F.

146. L １ is —O—, —NH—, —NCH ３ —, —S—, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)—, —C(O)NH—, —NHC(O)NH—, —NHSO ２ O—, —OS(O) ２ NH—, —NHSO ２ —, —S(O) ２ NH—, —S(O)—, —S(O) ２ —, —OS(O) ２ O—, —S(O) ２ O—, —OS(O) ２ —, —P(O)(OH)—, —OP(O)(OH)O—, —OP(O)(OH)—, —P(O)(OH)O—, —CHR ９ —, or —CR ８ R ９ —, and R ８ and R ９ 135. The method of claim 134, wherein is independently halogen or unsubstituted methyl.

147. L １ The method of claim 134, wherein is -O-.

148. L １ The method of claim 134, wherein is -S-.

149. L １ But -S(O) ２ The method of claim 134, wherein:

150. 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 2-8 membered heteroalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C ６ -C １０ 135. The method of claim 134, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

151. R １ are independently halogen, —OH, —CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ 135. The method of claim 134, wherein said aryl group is F, unsubstituted methyl, or unsubstituted methoxy.

152. The method of claim 134, wherein z1 is 1.

153. The method of claim 134, wherein z1 is 0.

154. R ２ 135. The method of claim 134, wherein is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

155. R ３ 135. The method of claim 134, wherein is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

156. R ６ is hydrogen, 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 2-8 membered heteroalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C ６ -C １０ 135. The method of claim 134, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

157. R ６ is a substituted or unsubstituted C １ -C ６ 135. The method of claim 134, wherein said alkyl is substituted or unsubstituted 2-6 membered heteroalkyl.

158. R ６ is hydrogen, unsubstituted methyl, unsubstituted isopropyl, 【Chemical Formula 38】 The method of claim 134, wherein:

159. 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 2-8 membered heteroalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C ６ -C １０ 146. The method of claim 145, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

160. R ４ are independently halogen, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ 146. The method of claim 145, wherein said alkyl group is F, -OH, unsubstituted methyl, or unsubstituted methoxy.

161. R ４ is independently -OR ４Ｄ The method of claim 145,

162. R ４Ｄ 162. The method of claim 161, wherein is hydrogen or substituted or unsubstituted alkyl.

163. R ４Ｄ is hydrogen or unsubstituted C １ -C ５ The method of claim 161, wherein said alkyl group is an alkyl group.

164. R ４Ｄ is unsubstituted methyl.

165. The method of claim 145, wherein z4 is 1.

166. The method of claim 145, wherein z4 is 0.

167. 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 2-8 membered heteroalkyl, substituted or unsubstituted C ３ -C ８ Cycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted or unsubstituted C ６ -C １０ 146. The method of claim 145, which is aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

168. R ５ are independently halogen, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ 146. The method of claim 145, wherein said alkyl group is F, -OH, unsubstituted methyl, unsubstituted methoxy, or unsubstituted phenyl.

169. The method of claim 145, wherein z5 is 1.

170. The method of claim 145, wherein z5 is 0.

171. 135. The method of claim 134, wherein Ring A is substituted or unsubstituted phenyl.

172. 135. The method of claim 134, wherein Ring A is a substituted or unsubstituted 5-6 membered heteroaryl.

173. 135. The method of claim 134, wherein Ring A is substituted or unsubstituted thienyl.

174. 135. The method of claim 134, wherein Ring A is substituted or unsubstituted pyridyl.

175. 135. The method of claim 134, wherein Ring B is substituted or unsubstituted phenyl.

176. 135. The method of claim 134, wherein Ring B is substituted or unsubstituted naphthyl.

177. 135. The method of claim 134, wherein Ring B is substituted or unsubstituted quinolinyl.

178. 135. The method of claim 134, wherein Ring B is substituted or unsubstituted isoquinolinyl.

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