Stabilization of MHC complexes

Abstract

To provide a method of identifying a candidate compound that stabilizes binding of an MHC protein to a peptide antigen.SOLUTION: A method disclosed herein comprises contacting an MHC protein with a peptide antigen and a candidate compound so as to form an MHC-peptide-compound complex, and detecting an increased stability of the MHC-peptide-compound complex relative to stability of an MHC-peptide complex without the candidate compound. Thus, the candidate compound is identified as a compound that stabilizes binding of the MHC protein to the peptide antigen.SELECTED DRAWING: Figure 12A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 952,800, filed December 23, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0002] Reference to a "Sequence Listing," table, or computer program listing appendix submitted as an ASCII file The sequence listing set forth in file 048536-671001WO_Sequence_Listing_ST25, 4,746 bytes, machine format IBM-PC, MS Windows operating system, created on December 18, 2020, is incorporated herein by reference. [Background technology]

[0003] Checkpoint blockade therapies are transforming the landscape of cancer treatment by unleashing tumor-specific T cells to attack tumors (1). An essential aspect of the cancer immune cycle is the availability of tumor-specific somatic mutations that serve as suitable MHC ligands for T cell recognition. Current checkpoint therapies are most effective in tumors with a high mutational burden, increasing the likelihood that a good MHC peptide neoantigen will provide a suitable T cell epitope. Ideal cancer-specific T cell epitopes would be recurrent mutations such as those found in common oncogenes (e.g., KRAS (G12D / V / C), BRAF (V600E), and PI3K (i.e., PIK3) (E545K / H1047R)). However, such peptides are generally poor peptide antigens, significantly limiting the ability of the immune system to mobilize and target the up to 50% of patient tumors containing these driver oncogenes. Therefore, there is a need in the art for better representation of the most common specific hotspot mutations. Solutions to these and other problems in the art are provided herein. Summary of the Invention

[0004] Provided herein, inter alia, are methods and compositions for treating cancer. In one aspect, provided herein is a method for identifying a candidate compound that stabilizes the binding of an MHC protein to a peptide antigen. The method includes contacting an MHC protein with a peptide antigen and a candidate compound, thereby forming an MHC-peptide-compound complex, and detecting increased stability of the MHC-peptide-compound complex compared to the stability of an MHC-peptide complex without the candidate compound. Thus, the candidate compound is identified as a compound that stabilizes the binding of an MHC protein to a peptide antigen.

[0005] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising: a. detecting an MHC allele of an MHC protein in the subject; b. detecting a driver cancer gene mutation in the subject; and c. administering an effective amount of an MHC-peptide antigen stabilizing compound.

[0006] In yet another aspect, provided herein is a method for identifying a modified peptide-MHC protein allele binding pair, the method comprising contacting a plurality of different modified peptides with a plurality of different MHC protein alleles, and detecting or computationally predicting binding of a first modified peptide to a first MHC protein allele. Thus, a modified peptide-MHC protein allele binding pair is identified.

[0007] In another aspect, provided herein is a method of vaccinating a subject against cancer, the method comprising administering a peptide cancer antigen and a compound that stabilizes binding of an MHC protein to the peptide cancer antigen.

[0008] In another aspect, provided herein is a method of vaccinating a subject against cancer, comprising administering a peptide-compound conjugate, wherein the peptide-compound conjugate comprises a peptide cancer antigen linked to a compound via a chemical bond.

[0009] In another aspect, provided herein is a composition comprising an MHC protein, a peptide antigen, and a compound, wherein the MHC protein, peptide antigen, and compound combine to form an MHC-peptide-compound complex, and the compound stabilizes binding of the MHC protein to the peptide antigen compared to the absence of the compound.

[0010] In another embodiment, a compound of the formula: [ka] or salts thereof are provided herein.

[0011] In another embodiment, a compound of the formula: [ka] [ka] [ka] or salts thereof are provided herein. [Brief explanation of the drawings]

[0012] [Figure 1] 1 shows drug screening of candidate compounds for stabilizing the binding of MHC proteins to peptide antigens. [Figure 2] 1 shows the screening of a kinase inhibitor library of candidate compounds for induction of K-Ras peptide presentation. [Figure 3A]Pazopanib-induced stabilization of presentation of mutant K-Ras peptides by HLA-B*57:01 (Figure 3A) and HLA-B*58:01 (Figure 3B) and peptide sequences G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)), G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2)), G12D 8-16 (VVGADGVGK (SEQ ID NO: 3)), G12D 7-16 (VVVGADGVGK (SEQ ID NO: 4)), and G12V 8-16 W16 (VVGAVGVGW (SEQ ID NO: 5)) (Figure 3C) are shown. [Figure 3B] Pazopanib-induced stabilization of presentation of mutant K-Ras peptides by HLA-B*57:01 (Figure 3A) and HLA-B*58:01 (Figure 3B) and peptide sequences G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)), G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2)), G12D 8-16 (VVGADGVGK (SEQ ID NO: 3)), G12D 7-16 (VVVGADGVGK (SEQ ID NO: 4)), and G12V 8-16 W16 (VVGAVGVGW (SEQ ID NO: 5)) (Figure 3C) are shown. [Figure 3C] Pazopanib-induced stabilization of presentation of mutant K-Ras peptides by HLA-B*57:01 (Figure 3A) and HLA-B*58:01 (Figure 3B) and peptide sequences G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)), G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2)), G12D 8-16 (VVGADGVGK (SEQ ID NO: 3)), G12D 7-16 (VVVGADGVGK (SEQ ID NO: 4)), and G12V 8-16 W16 (VVGAVGVGW (SEQ ID NO: 5)) (Figure 3C) are shown. [Figure 4]1 shows pazopanib-induced stabilization of presentation of wild-type and mutant K-Ras peptides and peptide sequences WT 8-16 (VVGAGGVGK (SEQ ID NO: 6)), WT 7-16 (VVVGAGGVGK (SEQ ID NO: 7)), G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)), G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2)), G12D 8-16 (VVGADGVGK (SEQ ID NO: 3)), and G12D 7-16 (VVVGADGVGK (SEQ ID NO: 4)) by HLA-B*57:01. [Figure 5A] Pazopanib- and pazopanib analog-induced stabilization of presentation of mutant K-Ras peptide (G12V 7-16) by HLA-B*57:01 (FIG. 5A) and after 72 hours (FIG. 5B) is shown. [Figure 5B] Pazopanib- and pazopanib analog-induced stabilization of presentation of mutant K-Ras peptide (G12V 7-16) by HLA-B*57:01 (FIG. 5A) and after 72 hours (FIG. 5B) is shown. [Figure 6]Four K-Ras peptides (G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)), G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2)), G12D 8-16 (VVGADGVGK (SEQ ID NO: 3)), G12D 9-16 (VVGADGVGK (SEQ ID NO: 4)), G12D 10-16 (VVGADGVGK (SEQ ID NO: 5)), G12D 11-16 (VVGADGVGK (SEQ ID NO: 6)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 7)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 8)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 9)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 1)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 1)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 2)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 3)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 4)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 5)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 6)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 1)), G12D 12-16 (VVGADGVGK (SEQ ID NO: 1)), G12D 12-16 (VVGADGVGK (SEQ 7-16 (VVVGADGVGK (SEQ ID NO: 4)). The 69 MHC class I alleles from left to right are A0201, A0206, A0301, A1101, A2301, A2402, A2501, A2601, A2902, A3001, A3002, A3101, A3201, A3303, A6801, A6802, A7401, B0702, B0801, B1301, B1302, B1402, B1501, B1502, B1525, B1801, B2702, B2705, B3501, B3503, B3701, B3801, B3901, B4001, B4002, B4402, B4403, B4601, B4801, B4901, B5001, B5101, B5201, B5301, B5501, B5601, B5701, B5801, B5802, C0102, C0202, C0209, C0302, C0303, C0304, C0401, C0501, C0602, C0701, C0702, C0704, C0801, C0802, C1202, C1203, C1402, C1502, C1601, C1701. [Figure 7A] Figure 7 shows W-scans of four K-Ras peptides (G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)), G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2)), G12D 8-16 (VVGADGVGK (SEQ ID NO: 3)), and G12D 7-16 (VVVGADGVGK (SEQ ID NO: 4)) against four common MHC class I alleles. Figure 7A shows the computational prediction of binding of a first modified peptide to a first MHC protein allele, and Figure 7B shows the experimental results of binding. [Figure 7B]Figure 7 shows W-scans of four K-Ras peptides (G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)), G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2)), G12D 8-16 (VVGADGVGK (SEQ ID NO: 3)), and G12D 7-16 (VVVGADGVGK (SEQ ID NO: 4)) against four common MHC class I alleles. Figure 7A shows the computational prediction of binding of a first modified peptide to a first MHC protein allele, and Figure 7B shows the experimental results of binding. [Figure 8] 1 shows pazopanib- and pazopanib analog-induced stabilization of presentation of mutant K-Ras peptides (VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14)) by HLA-B*57:01. [Figure 9] FIG. 1 shows abacavir- and abacavir analog-induced stabilization of presentation of mutant K-Ras peptides (VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14)) by HLA-B*57:01. [Figure 10] 1 shows a peptide-abacavir conjugate (G12V 8-16 (VVGAVGVGK (SEQ ID NO: 1)) refolded with the HLA-B*57:01 heavy chain. [Figure 11A] Vaccination strategies. Figure 11A shows the use of a mixture of small molecules and mutant peptides or proteins, and Figure 11B shows the use of covalent drug-peptide conjugates. [Figure 11B] Vaccination strategies. Figure 11A shows the use of a mixture of small molecules and mutant peptides or proteins, and Figure 11B shows the use of covalent drug-peptide conjugates. [Figure 12A] Small molecule modulation of antigen presentation. Figure 12A shows a non-cognate oncogene peptide forming a drug-stabilized MHC-peptide complex. Figure 12B shows the published crystal structure of a class I MHC-peptide complex stabilized by abacavir. The complex contains PepV: (HSITYLLPV, SEQ ID NO: 14). Figure 12C shows the published crystal structure of a class II MHC-peptide complex stabilized by sodium and beryllium cations. The complex contains the QAFWIDLFETIG peptide (SEQ ID NO: 21). [Figure 12B] Small molecule modulation of antigen presentation. Figure 12A shows a non-cognate oncogene peptide forming a drug-stabilized MHC-peptide complex. Figure 12B shows the published crystal structure of a class I MHC-peptide complex stabilized by abacavir. The complex contains PepV: (HSITYLLPV, SEQ ID NO: 14). Figure 12C shows the published crystal structure of a class II MHC-peptide complex stabilized by sodium and beryllium cations. The complex contains the QAFWIDLFETIG peptide (SEQ ID NO: 21). [Figure 12C] Small molecule modulation of antigen presentation. Figure 12A shows a non-cognate oncogene peptide forming a drug-stabilized MHC-peptide complex. Figure 12B shows the published crystal structure of a class I MHC-peptide complex stabilized by abacavir. The complex contains PepV: (HSITYLLPV, SEQ ID NO: 14). Figure 12C shows the published crystal structure of a class II MHC-peptide complex stabilized by sodium and beryllium cations. The complex contains the QAFWIDLFETIG peptide (SEQ ID NO: 21). [Figure 13A] Primary assay: Refolding ELISA. Capture ELISA (reaction mixture diluted 10-fold) is shown. [Figure 13B] Primary assay: Refolding ELISA. Capture ELISA (reaction mixture diluted 10-fold) is shown. [Figure 14A]W-scan: A computational method for identifying opportunities for drug-induced peptide presentation. Figure 14A shows a series of Trp-substituted peptides (W-scan peptides), and Figure 14B shows the prediction of binding affinity of W-scan peptides to common MHC class I alleles using the NetMHCpan 4.0 algorithm. Peptides in which the Trp substitution confers higher binding affinity are potential candidates for drug-induced presentation. [Figure 14B] W-scan: A computational method for identifying opportunities for drug-induced peptide presentation. Figure 14A shows a series of Trp-substituted peptides (W-scan peptides), and Figure 14B shows the prediction of binding affinity of W-scan peptides to common MHC class I alleles using the NetMHCpan 4.0 algorithm. Peptides in which the Trp substitution confers higher binding affinity are potential candidates for drug-induced presentation. [Figure 15] Engineering disulfide bridges to increase complex stability. [Figure 16A] Preferred disulfide bond positions were identified by design using disulfides (G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2) and G12C 7-16 (QAFWIDLFETIG (SEQ ID NO: 21)). Figure 16A shows that no preferred residues are found in the B5701-9mer complex, and Figure 16B shows disulfide formation confirmed by mass spectrometry of B*57:01 / K-Ras(G12C) 7-16. [Figure 16B] Preferred disulfide bond positions were identified by design using disulfides (G12V 7-16 (VVVGAVGVGK (SEQ ID NO: 2) and G12C 7-16 (QAFWIDLFETIG (SEQ ID NO: 21)). Figure 16A shows that no preferred residues are found in the B5701-9mer complex, and Figure 16B shows disulfide formation confirmed by mass spectrometry of B*57:01 / K-Ras(G12C) 7-16. [Figure 17]B5701●LF9 is a representative stable MHC complex without a small molecule drug, B5701●PepV●045B is a representative unstable MHC complex with a small molecule drug, and B5701-A67C●C7-16●045B is a representative disulfide-bridged MHC complex with a small molecule drug. The B5701●C7-16●045B complex, which would be an ideal control, is too unstable to prepare and test. LF9:LSSPVTKSF (SEQ ID NO: 15), PepV:HSITYLLPV (SEQ ID NO: 14), G12C 7-16:VVVGACGVGK (SEQ ID NO: 20). [Figure 18A] Unsuccessful disulfide engineering. Figure 18A shows HLA-B*27:05, which contains a native cysteine in the peptide-binding groove (ARAAAAAAA (SEQ ID NO: 22)). Figure 18B shows that cysteine- and homocysteine-containing peptides refold in HLA-B*27:05, but independently of Cys67. Mass spectrometry analysis of GXF9 showed no disulfide formation. [Figure 18B] Unsuccessful disulfide engineering. Figure 18A shows HLA-B*27:05, which contains a native cysteine in the peptide-binding groove (ARAAAAAAA (SEQ ID NO: 22)). Figure 18B shows that cysteine- and homocysteine-containing peptides refold in HLA-B*27:05, but independently of Cys67. Mass spectrometry analysis of GXF9 showed no disulfide formation. [Figure 19] Covalent immobilization of peptides with C-terminal cysteines. [Figure 20A]Design of a compound that stabilizes a peptide with a C-terminal cysteine by forming a covalent bond. Figure 20A shows the structure of B*57:01 / ABA / HSITYLLPV (SEQ ID NO: 14). Figure 20B shows the modeled structure of B*57:01 / ABA / HMTEVVRHC (SEQ ID NO: 16). Figure 20C shows a heat map of the ELISA assay signal (OD450) in an MHC refolding assay using HLA-B*57:01 to measure the amount of correctly folded MHC complexes. LF9 is a positive control. PepV is a peptide known to be stabilized by abacavir in HLA-B*57:01. Peptides shown: LSSPVTKSF (SEQ ID NO: 15), HSITYLLPV (SEQ ID NO: 14), HMTEVVRHC (SEQ ID NO: 16). [Figure 20B] Design of a compound that stabilizes a peptide with a C-terminal cysteine by forming a covalent bond. Figure 20A shows the structure of B*57:01 / ABA / HSITYLLPV (SEQ ID NO: 14). Figure 20B shows the modeled structure of B*57:01 / ABA / HMTEVVRHC (SEQ ID NO: 16). Figure 20C shows a heat map of the ELISA assay signal (OD450) in an MHC refolding assay using HLA-B*57:01 to measure the amount of correctly folded MHC complexes. LF9 is a positive control. PepV is a peptide known to be stabilized by abacavir in HLA-B*57:01. Peptides shown: LSSPVTKSF (SEQ ID NO: 15), HSITYLLPV (SEQ ID NO: 14), HMTEVVRHC (SEQ ID NO: 16). [Figure 20C]Design of a compound that stabilizes a peptide with a C-terminal cysteine by forming a covalent bond. Figure 20A shows the structure of B*57:01 / ABA / HSITYLLPV (SEQ ID NO: 14). Figure 20B shows the modeled structure of B*57:01 / ABA / HMTEVVRHC (SEQ ID NO: 16). Figure 20C shows a heat map of the ELISA assay signal (OD450) in an MHC refolding assay using HLA-B*57:01 to measure the amount of correctly folded MHC complexes. LF9 is a positive control. PepV is a peptide known to be stabilized by abacavir in HLA-B*57:01. Peptides shown: LSSPVTKSF (SEQ ID NO: 15), HSITYLLPV (SEQ ID NO: 14), HMTEVVRHC (SEQ ID NO: 16). [Figure 21] Covalent abacavir-peptide conjugates refold with HLA-B*57:01. [Figure 22] Structural modifications of abacavir result in changes in the peptide specificity of B*57:01 / ABA / HSITYLLPV (HSITYLLPV SEQ ID NO: 14). [Figure 23A] Stabilization of class I MHC-peptide complexes with abacavir analogs. Figure 23A: VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14). Figure 23B: VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14). Figure 23C: LSSPVTKSF (SEQ ID NO: 15), HSITYLLPV (SEQ ID NO: 14), VVVGAVGVGK (SEQ ID NO: 12), HMTEVVRRC (SEQ ID NO: 17), HMTEVVRRW (SEQ ID NO: 18), HMTEVVRHC (SEQ ID NO: 16), and HMTEVVRHW (SEQ ID NO: 19). [Figure 23B] Stabilization of class I MHC-peptide complexes with abacavir analogs. Figure 23A: VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14). Figure 23B: VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14). Figure 23C: LSSPVTKSF (SEQ ID NO: 15), HSITYLLPV (SEQ ID NO: 14), VVVGAVGVGK (SEQ ID NO: 12), HMTEVVRRC (SEQ ID NO: 17), HMTEVVRRW (SEQ ID NO: 18), HMTEVVRHC (SEQ ID NO: 16), and HMTEVVRHW (SEQ ID NO: 19). [Figure 23C] Stabilization of class I MHC-peptide complexes with abacavir analogs. Figure 23A: VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14). Figure 23B: VVVGAVGVGG (SEQ ID NO: 8), VVVGAVGVGA (SEQ ID NO: 9), VVVGAVGVGV (SEQ ID NO: 10), VVVGAVGVGI (SEQ ID NO: 11), VVVGAVGVGK (SEQ ID NO: 12), VVVGAVGVGW (SEQ ID NO: 13), and HSITYLLPV (SEQ ID NO: 14). Figure 23C: LSSPVTKSF (SEQ ID NO: 15), HSITYLLPV (SEQ ID NO: 14), VVVGAVGVGK (SEQ ID NO: 12), HMTEVVRRC (SEQ ID NO: 17), HMTEVVRRW (SEQ ID NO: 18), HMTEVVRHC (SEQ ID NO: 16), and HMTEVVRHW (SEQ ID NO: 19). DETAILED DESCRIPTION OF THE INVENTION

[0013] I. Definition The term "disease" or "condition" refers to an existing state or state of health of a patient or subject that can be treated with the compounds or methods provided herein. The disease can be cancer. The disease can be an autoimmune disease. The disease can be an inflammatory disease. The disease can be an infectious disease. In some further examples, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., such as solid and lymphoid cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer, e.g., hepatocellular carcinoma, lymphomas, e.g., B-acute lymphoblastic lymphoma, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell, and large cell lymphoma), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma.

[0014] As used herein, the term "cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, medulloblastoma, melanoma, cervical cancer, stomach cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's disease, and non-Hodgkin's lymphoma. Exemplary cancers that can 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, ovarian cancer, pancreatic cancer, rectal cancer, stomach cancer, and uterine cancer. Further examples include thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, squamous cell carcinoma of the head and neck, invasive carcinoma of the breast, lung adenocarcinoma, squamous cell carcinoma of the lung, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, 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.

[0015] The term "leukemia" refers broadly to progressive, malignant diseases of the blood-forming organs, generally characterized by 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 character of the disease—acute or chronic, (2) the type of cell involved—myeloid (myeloid), lymphatic (lymphoid), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood—leukemic or nonleukemic (subleukemic). Exemplary leukemias that may be treated using the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, and leukemia of the genotype. leukemia), histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic 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, or anaplastic cell leukemia.

[0016] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphatic tissues. It develops primarily in lymphocytes, which are blood cells found 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. Based on the type of cell involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that can 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 can 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.

[0017] The term "sarcoma" generally refers to tumors composed of a substance like embryonic connective tissue, and generally composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated using the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, and Ewing's sarcoma. sarcoma, fascial sarcoma, fibroblastic 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 sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0018] 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 melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0019] The term "carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that 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 carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid 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, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, 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, telangiectatic-like carcinoma, transitional cell carcinoma, carcinoma tuberosum, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0020] The term "treat" or "treatment" refers to any indication of success in treating or ameliorating an injury, disease, pathology, or condition, including any objective or subjective parameter, such as remission, remission; diminishing symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; or improving the patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric testing, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, disease, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0021] As used herein (and as is well understood in the art), "treating" or "treatment" broadly includes any approach to achieving beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether partial or total, and whether detectable or undetectable, reduction in the extent of disease, stabilization of disease conditions (i.e., not worsening), prevention of disease infection or spread, delay or slowing of disease progression, improvement or alleviation of disease conditions, reduction of disease recurrence, and remission. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of disease. Treatment can prevent the onset of disease, inhibit the spread of disease, alleviate symptoms of disease, completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination thereof.

[0022] As used herein, "treating" and "treatment" include prophylactic treatment. A therapeutic method involves administering a therapeutically effective amount of an active agent to a subject. The administration step can consist of a single administration or can include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the composition used for treatment, or a combination thereof. It will also be understood that the effective dosage of an agent used for treatment or prevention can increase or decrease during a particular treatment or prevention regimen. Dosage changes can be determined and made evident by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, a composition is administered to a subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment.

[0023] The term "preventing" refers to a reduction in the occurrence of disease symptoms in a patient. As noted above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely develop without treatment.

[0024] "Patient" or "subject in need of treatment" 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.

[0025] An "effective amount" is an amount of a compound sufficient to achieve its stated purpose compared to the absence of the compound (e.g., achieve the effect for which the compound is 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). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom of a disease, which may also be referred to as a "therapeutically effective amount." "Reduction" of a symptom (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of the symptom, or the 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 the intended preventative 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 preventative 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 can be administered in one or more administrations. As used herein, "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of antagonist. As used herein, "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 antagonist. The exact amount depends on the purpose of treatment and can be determined by those skilled in the art using known techniques (see, for example, 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).

[0026] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound that is capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0027] As is well known in the art, the therapeutically effective amount used in humans can also be determined from animal models.For example, human dosage can be formulated to achieve the concentration found to be effective in animals.As described above, human dosage can be adjusted by monitoring the effectiveness of compound and adjusting dosage upward or downward.Based on the above method and other methods, it is well within the ability of those skilled in the art to adjust dosage to achieve maximum effectiveness in humans.

[0028] The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent sufficient to improve a disorder, as described above. For example, for a given parameter, a therapeutically effective amount may exhibit an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness may also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount may be at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effective than a control.

[0029] Dosage may vary depending on the patient's requirements and the compound used. In light of the present disclosure, the dose administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the capabilities of those skilled in the art. Generally, treatment is initiated with a lower dosage that is less than the optimal dose of the compound. Thereafter, the dosage is gradually increased until the optimal effect is reached under the circumstances. Dosage amount and interval can be individually adjusted to provide an effective level of the administered compound for the specific clinical indication being treated. This will provide a treatment plan that is appropriate for the severity of the individual's condition.

[0030] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, 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. In embodiments, administration does not include administration of any active agent other than the listed active agent.

[0031] "Specific," "specifically," "specificity," and the like, of a compound refer to the ability of the compound to cause a particular effect, such as inhibition, on a particular molecular target with minimal or no effect on other proteins in the cell.

[0032] As used herein, "T cells" or "T lymphocytes" are a type of lymphocyte (a subtype of white blood cell) that plays a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of T cell receptors on the cell surface. T cells include, for example, natural killer T (NKT) cells, cytotoxic T lymphocytes (CTLs), regulatory T (Treg) cells, and T helper cells. Various types of T cells can be distinguished using T cell detection agents.

[0033] "Memory T cells" are T cells that have previously encountered and responded to a cognate antigen during a previous infection, cancer encounter, or previous vaccination. Upon a second encounter with the cognate antigen, memory T cells can replicate (divide) and mount a faster and stronger immune response than the immune system's first response to the pathogen.

[0034] "Regulatory T cells" or "suppressor T cells" are lymphocytes that regulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune diseases.

[0035] 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 known to the chemical arts.

[0036] Substituents, when specified 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-.

[0037] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and can include monovalent, divalent, and polyvalent radicals. An alkyl can contain the number of carbons specified (e.g., C-C 10means 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 the like, as well as 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. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated. An alkenyl can contain more than one double bond and / or one or more triple bonds in addition to one or more double bonds. In embodiments, an alkenyl contains one or more double bonds. An alkynyl can contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds. In embodiments, an alkynyl contains one or more triple bonds.

[0038] 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. 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.

[0039] 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., O, 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 is a non-cyclizing chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-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.

[0040] 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 —SOR′. When “heteroalkyl” is recited followed by a specific heteroalkyl group, e.g., —NR′R″, etc., it is understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term “heteroalkyl” should not be construed herein to exclude specific heteroalkyl groups, e.g., —NR′R″, etc. In embodiments, the term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from a heteroalkene. In embodiments, the term “heteroalkynylene,” by itself or as part of another substituent, means, unless otherwise specified, a divalent radical derived from a heteroalkyne. In embodiments, a heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. In embodiments, the heteroalkenylene contains one or more double bonds. In embodiments, the heteroalkynylene contains one or more triple bonds.

[0041] 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.

[0042] 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. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is a ring in which two non-adjacent carbon atoms of a monocyclic ring are joined by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., of the form (CH)). wwhere w is 1, 2, or 3. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, the fused bicyclic cycloalkyl ring system comprises a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. In embodiments, the cycloalkyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkyl ring system is (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) a monocyclic cycloalkyl ring (base ring) fused to either of two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the base ring.In embodiments, the polycyclic cycloalkyl ring system is a monocyclic cycloalkyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl, and perhydrophenoxazin-1-yl. In embodiments, 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 bonded to the parent molecular moiety through any carbon atom contained within the cycloalkyl ring of the multiple rings.

[0043] 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. In embodiments, a bicyclic or polycyclic cycloalkenyl ring system refers to multiple rings fused together, where at least one of the fused rings is a cycloalkenyl ring, and the multiple rings are attached to the parent molecular moiety through any carbon atom contained within the cycloalkenyl ring of the multiple rings. In embodiments, a monocyclic cycloalkenyl ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups are unsaturated (i.e., contain at least one cyclic carbon-carbon double bond) but are not aromatic. Examples of monocyclic cycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. In embodiments, a bicyclic cycloalkenyl ring is a bridged monocyclic ring or a fused bicyclic ring. In embodiments, a bridged monocyclic ring is one in which two non-adjacent carbon atoms of the monocyclic ring are joined by an alkylene bridge (i.e., of the form (CH)) between 1 to 3 additional carbon atoms. wwhere w is 1, 2, or 3. Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct2enyl. In embodiments, the fused bicyclic cycloalkenyl ring system comprises a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. In embodiments, the cycloalkenyl group is optionally substituted with one or two groups, independently oxo or thia. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. In embodiments, the polycyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the base ring. In embodiments, the polycyclic cycloalkenyl ring comprises a monocyclic cycloalkenyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.

[0044] In embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring, where the ring is saturated or unsaturated but not aromatic, and contains at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring can contain zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, Examples of heterocyclic heterocycles include, but are not limited to, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups, independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, optionally substituted by one or two groups that are independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, the polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl. In embodiments, the term "heterocycloalkyl" refers to a monocyclic, bicyclic, or polycyclic heterocycloalkyl ring system. In embodiments, the heterocycloalkyl group is fully saturated. In embodiments, a bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, wherein at least one of the fused rings is a heterocycloalkyl ring, and the rings are attached to the parent molecular moiety through any carbon atom contained within the heterocycloalkyl ring of the multiple rings.

[0045] 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.

[0046] The term "acyl," unless otherwise specified, means -C(O)R, in which 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.

[0047] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked together. Fused-ring aryl refers to multiple rings fused together, at least one of which is an aryl ring. In embodiments, 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 an aromatic heterocycle). In embodiments, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., at least one of the fused rings is a heteroaromatic ring, and the rings are bonded to the parent molecular moiety through any atom contained within the heteroaromatic ring of the rings). 5,6-fused-ring heteroarylene refers to two rings fused together, one having 5 members and the other having 6 members, and at least one ring is a heteroaryl ring. Similarly, 6,6-fused-ring heteroarylene refers to two rings fused together, one having 6 members and the other having 6 members, and at least one ring is a heteroaryl ring. Also, 6,5-fused-ring heteroarylene refers to two rings fused together, one having 6 members and the other having 5 members, and at least one ring is a heteroaryl ring. Heteroaryl groups can be bonded to the remainder 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.

[0048] A fused-ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused-ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Each fused-ring heterocycloalkyl-aryl, fused-ring heterocycloalkyl-heteroaryl, fused-ring heterocycloalkyl-cycloalkyl, or fused-ring heterocycloalkyl-heterocycloalkyl can independently be unsubstituted or substituted with one or more of the substituents described herein.

[0049] Spirocyclic rings are two or more rings in which adjacent rings are connected via a single atom. The individual rings in a spirocyclic ring can be the same or different. The individual rings in a spirocyclic ring can be substituted or unsubstituted, and can have different substituents from the other individual rings in a set of spirocyclic rings. The possible substituents of the individual rings in a spirocyclic ring are the possible substituents of the same ring (e.g., the substituents of a cycloalkyl ring or heterocycloalkyl ring) when they are not part of a spirocyclic ring. The spirocyclic ring can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings in a spirocyclic ring group can be any of the rings in the previous list, including all rings of one type (e.g., all rings are 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 can 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 can optionally be different.

[0050] symbol

number

[0051] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0052] As used herein, the term "alkylsulfonyl" refers to a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' can have a specified number of carbon atoms (e.g., "C1-C4 alkylsulfonyl").

[0053] 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: [ka]

[0054] The alkylarylene moiety can be substituted (e.g., by a substituent) at the alkylene portion or arylene linker (e.g., at carbons 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.

[0055] 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.

[0056] Substituents for the alkyl and heteroalkyl radicals (including those groups often 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, but are not limited to, -OR', ═O, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', It can be one or more of a variety of groups selected from: -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R'')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -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.).

[0057] Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups vary and include, for example, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′′, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′-C(O)NR″R′′′, —NR″C(O)R′, —NR-C(NR′R″R′′)═NR′″, —NR-C(NR′R″)═NR′″, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NRSOR′, —NR′ 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 for each R', R", R'", and R"" group when more than one of these groups is present.

[0058] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be shown as substituents on the ring (commonly 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) can 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 be optionally 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 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.

[0059] 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.

[0060] 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 may optionally form a ring of the formula -A-(CH2) r A and B may be optionally replaced with a substituent of the formula -B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') dwhere s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0061] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0062] As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI 2, -OCHF2, -N3, 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 10aryl, 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 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: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI 2, -OCHF2, -N3, 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 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: (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI 2, -OCHF2, -N3, 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) Oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI 2, -OCHF2, -N3, 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 alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 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).

[0063] As used herein, "size-limited substituent" or "size-limited substituent" 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 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 each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0064] 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.

[0065] 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-rank substituent.

[0066] 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.

[0067] 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 10 In some embodiments, each substituted or unsubstituted alkylene is substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is substituted or unsubstituted 2-8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is substituted or unsubstituted 3-7 membered heterocycloalkylene, and each substituted or unsubstituted arylene is 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.

[0068] 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).

[0069] 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.

[0070] 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 size-limiting 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.

[0071] 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 can optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0072] 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.

[0073] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds and can be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids, as (D)- or (L). 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0078] 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.

[0079] 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.

[0080] It should be noted that throughout this application, alternatives, 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.

[0081] 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, -C(O)OH, -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., via a covalent bond or linker (e.g., a first linker of a second linker), or indirect, e.g., via 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). 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, active esters), electrophilic substitution (e.g., enamine reaction), and addition to 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).

[0082] Useful bioconjugate reactive moieties for use in the bioconjugate chemistry herein include, for example: (a) Carboxyl groups and their various derivatives, including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyls, alkenyls, alkynyls, and esters (b) Hydroxyl groups that can be converted into esters, ethers, aldehydes, etc. (c) haloalkyl groups, in which the halide is subsequently replaced with a nucleophilic group, such as an amine, a carboxylate anion, a thiol anion, a carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom. (d) Dienophile groups capable of participating in Diels-Alder reactions, such as maleimide or maleimido groups (e) an aldehyde or ketone group that is capable of subsequent derivatization, for example, via formation of a carbonyl derivative such as an imine, hydrazone, semicarbazone, or oxime, or via mechanisms such as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines to form, for example, sulfonamides (g) Thiol groups that can be converted to disulfides, react with acyl halides, conjugated to metals such as gold, or reacted with maleimides. (h) amine or sulfhydryl groups (e.g., those present in cysteine), which may be, for example, acylated, alkylated, or oxidized. (i) Alkenes that can undergo, for example, cycloaddition, acylation, Michael addition, etc. (j) epoxides, which can react with, for example, amines and hydroxyl compounds. (k) Phosphoramidites and other standard functional groups useful in nucleic acid synthesis (l) Metal-silicon oxide bond (m) metal binding to a reactive phosphorus group (e.g., phosphine) to form, for example, a phosphodiester bond (n) Azides coupled to alkynes using copper-catalyzed cycloaddition click chemistry (o) The biotin conjugate can react with avidin or streptavidin to form an avidin-biotin complex or a streptavidin-biotin complex.

[0083] 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.

[0084] "Analog" or "analogue" 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 replacement of one atom with an atom of a different element, or the presence of a particular functional group, or the replacement 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.

[0085] 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 specified 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.

[0086] 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 13 When substituents are present, each R 13 The substituents are R 13A , R 13B , R 13C , R 13D can be distinguished from R 13A , R 13B , R 13C , R 13D Each of these is R 13are defined within the definition of and are arbitrarily different.

[0087] A "detectable agent" or "detectable moiety" is a composition that is detectable by appropriate means, such as spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. In embodiments, a "detectable agent" or "detectable moiety" is a composition, substance, element, or compound that is detectable by appropriate means, such as 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 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, 154-1581 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, 225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, 32 P, fluorophores (such as fluorescent dyes), electron-dense reagents, enzymes (e.g., those commonly used in ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron 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, biological chorioalbuminuria, thiazolinone ... These include microbubbles (e.g., microbubble shells comprising albumin, galactose, lipids, and / or polymers; microbubble gas cores comprising air, heavy gases, perfluorocarbons, nitrogen, octafluoropropane, perflexane lipid microspheres, 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, for example, by incorporating a radioactive label into a peptide or antibody that specifically reacts with a target peptide. Detectable moieties are monovalent detectable agents or detectable agents that can form a bond with another composition.

[0088] 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, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 These include, but are not limited to, 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, 154-1581 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 225Paramagnetic ions that can be used as additional imaging agents in accordance with 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.

[0089] The description of the compound of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when group can be substituted with one or more of several substituents, such substitution is 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.

[0090] 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 moiety (e.g., organotin heteroalkyl), halogen (e.g., Br), perfluoroalkylsulfonate (e.g., triflate), tosylate, mesylate, water, alcohol, nitrate, phosphate, thioether, amine, ammonia, fluoride, carboxylate, phenoxide, boronic acid, boronic ester, and alkoxide. In embodiments, two molecules having leaving groups can be brought into contact, and upon reaction and / or bond formation (e.g., acyloin condensation, aldol condensation, Claisen condensation, Stille reaction), the leaving groups separate from each molecule. In embodiments, the leaving groups are bioconjugate reactive moieties. In embodiments, at least two leaving groups (e.g., R 1 and R 13 ) can be contacted such that the leaving group is in sufficient proximity to react, interact, or physically contact. In embodiments, the leaving group is designed to facilitate reaction.

[0091] 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).

[0092] Those of skill in the art will understand that when a variable (e.g., a moiety or linker) of a compound or compound genus (e.g., a genus described herein) is described by the name or formula of a stand-alone compound with all valences satisfied, the unsatisfied valences of that variable will be determined by the context in which the variable is used. For example, when a variable of a compound described herein is connected (e.g., bonded) to the remainder of the compound via a single bond, that variable will be understood to represent the monovalent form of the stand-alone compound (i.e., capable of forming a single bond due to unsatisfied valences). (For example, if a variable is named "methane" in one embodiment, but that variable is known to be connected to the remainder of the compound by a single bond, those of skill in the art will understand that that variable is actually the monovalent form of methane, i.e., methyl or -CH3.) Similarly, linker variables (e.g., L as described herein) will be understood to represent the monovalent form of the stand-alone compound (i.e., capable of forming a single bond due to unsatisfied valences).1 , L 2 , or L 3 ), one of skill in the art will understand that the variable is a divalent form of the stand-alone compound (e.g., if a variable is assigned to "PEG" or "polyethylene glycol" in one embodiment, but that variable is connected to the remainder of the compound by two separate bonds, one of skill in the art will understand that the variable is a divalent (i.e., capable of forming two bonds via two unsatisfied valences) form of PEG, rather than the stand-alone compound PEG.

[0093] The term "exogenous" refers to a molecule or substance (e.g., a compound, nucleic acid, or protein) that originates from outside a given cell or organism. For example, an "exogenous promoter" as referred to herein is a promoter that does not originate from the plant in which it is expressed. Conversely, the terms "endogenous" or "endogenous promoter" refer to a molecule or substance that is naturally present in or originates from within a given cell or organism.

[0094] The term "lipid moiety" is used according to its ordinary meaning in chemistry and generally refers to a hydrophobic molecule characterized by an aliphatic hydrocarbon chain. In embodiments, the lipid moiety comprises a carbon chain of 3 to 100 carbons. In embodiments, the lipid moiety comprises a carbon chain of 5 to 50 carbons. In embodiments, the lipid moiety comprises a carbon chain of 5 to 25 carbons. In embodiments, the lipid moiety comprises a carbon chain of 8 to 525 carbons. The lipid moiety may comprise a saturated or unsaturated carbon chain and may be optionally substituted. In embodiments, the lipid moiety is optionally substituted at its terminal with a charged moiety. In embodiments, the lipid moiety is an alkyl or heteroalkyl optionally substituted at its terminal with a carboxylic acid moiety.

[0095] Charged moieties refer to functional groups that have abundant electron density (i.e., electronegative) or lack electron density (i.e., electropositive). Non-limiting examples of charged moieties include carboxylic acids, alcohols, phosphates, aldehydes, and sulfonamides. In embodiments, charged moieties are capable of forming hydrogen bonds.

[0096] The term "coupling reagent" is used according to its plain and ordinary meaning in the art to refer to a substance (e.g., a compound or solution) that participates in a chemical reaction and results in the formation of a covalent bond (e.g., between bioconjugate reactive moieties, between a bioconjugate reactive moiety and a coupling reagent). In embodiments, the reagent level is depleted during the course of a chemical reaction. This is in contrast to a solvent, which is not typically consumed during a chemical reaction. Non-limiting examples of coupling reagents include benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU).

[0097] The term "solution" is used in accor to refer to a liquid mixture in which a minor component (e.g., a solute or compound) is uniformly distributed within a major component (e.g., a solvent).

[0098] As used herein, the term "organic solvent" is used according to its ordinary meaning in chemistry and refers to a solvent containing carbon. Non-limiting examples of organic solvents include acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether, diglyme (diethylene glycol, dimethyl ether), 1,2-dimethoxyethane (glyme, DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, and the like. Examples of suitable organic solvents include ethanol, ethylene glycol, glycerin, heptane, hexamethylphosphoramide (HMPA), hexamethylphosphorus triamide (HMPT), hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride, N-methyl-2-pyrrolidinone (NMP), nitromethane, pentane, petroleum ether (ligroin), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethylamine, o-xylene, m-xylene, or p-xylene. In embodiments, the organic solvent is or includes chloroform, dichloromethane, methanol, ethanol, tetrahydrofuran, or dioxane.

[0099] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present invention. Illustrative examples of acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, and phosphoric acid), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, and citric acid), and salts of quaternary ammonium salts (such as methyl iodide and ethyl iodide).

[0100] As used herein, the terms "bind" and "bound" are used according to their plain and ordinary meaning to refer to an association between atoms or molecules. The association can be direct or indirect. For example, the bound atoms or molecules can be direct, e.g., through a covalent bond or linker (e.g., a first linker or 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 forces), ring stacking (π effect), hydrophobic interactions, etc.). In embodiments, the bound atoms or molecules may be bound, for example, by a covalent linker (e.g., a first linker or a second linker) or by 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 forces), ring stacking (π effect), hydrophobic interactions, etc.).

[0101] As used herein, the term "capable of binding" refers to a moiety (e.g., a compound described herein) that can measurably bind to a target (e.g., NF-κB, Toll-like receptor). In embodiments where a moiety is capable of binding to a target, the moiety can bind with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM.

[0102] As used herein, the term "conjugated" when referring to two moieties means that the two moieties are attached, and the bond(s) connecting the two moieties can be covalent or non-covalent. In embodiments, the two moieties are covalently attached to one another (e.g., directly or through a covalently attached intermediate). In embodiments, the two moieties are non-covalently attached (e.g., through an ionic bond, a van der Waals bond / interaction, a hydrogen bond, a polar bond, or a combination or mixture thereof).

[0103] As used herein, the term "non-nucleophilic base" refers to any sterically hindered base that is a poor nucleophile.

[0104] As used herein, the term "nucleophile" refers to a chemical species that donates an electron pair to an electrophile to form a chemical bond in the context of a reaction. Any molecule or ion with a free electron pair or at least one pi bond can function as a nucleophile.

[0105] 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.

[0106] 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 different 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.

[0107] 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.

[0108] 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 a moiety 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. A "fusion protein" refers to a chimeric protein encoding two or more separate protein sequences that are recombinantly expressed as a single moiety.

[0109] As used herein, the terms "nucleic acid," "nucleic acid molecule," "nucleic acid oligomer," "oligonucleotide," "nucleic acid sequence," "nucleic acid fragment," and "polynucleotide" are used interchangeably and are intended to include, but are not limited to, polymeric forms of nucleotides covalently linked to one another, either deoxyribonucleotides or ribonucleotides, or analogs, derivatives, or modifications thereof, which may be of various lengths. Different polynucleotides may have different three-dimensional structures and perform various functions, known or unknown. Non-limiting examples of polynucleotides include genes, gene fragments, exons, introns, intergenic DNA (including, but not limited to, heterochromatic DNA), messenger RNA (mRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA sequences, isolated RNA sequences, nucleic acid probes, and primers. Polynucleotides useful in the methods of the present disclosure may include naturally occurring nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or combinations of such sequences.

[0110] Polynucleotides are typically composed of a specific sequence of four nucleotide bases: adenine (A), cytosine (C), guanine (G), and thymine (T) (if the polynucleotide is RNA, uracil (U) is substituted for thymine (T)). Thus, the term "polynucleotide sequence" is the alphabetical representation of a polynucleotide molecule; alternatively, the term can apply to the polynucleotide molecule itself. This alphabetical representation can be input into a database on a computer with a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. A polynucleotide can optionally contain one or more non-standard nucleotides, nucleotide analogs, and / or modified nucleotides.

[0111] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to a particular nucleic acid sequence, "conservatively modified variants" refers to nucleic acids that encode identical or essentially identical amino acid sequences. Due to the degeneracy of the genetic code, many nucleic acid sequences encode any given protein. For example, the codons GCA, GCC, GCG, and GCU all encode the amino acid alanine. Thus, at every position where alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," a type of conservatively modified variation. Every nucleic acid sequence herein that encodes a polypeptide also describes every possible silent variation of the nucleic acid. Those skilled in the art will understand that each codon in a nucleic acid (except AUG, which is usually the only codon for methionine, and TGG, which is usually the only codon for tryptophan) can be modified to produce a functionally identical molecule. Thus, each silent variation of a nucleic acid that encodes a polypeptide is implicit in each described sequence.

[0112] With respect to amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions, or additions to nucleic acid, peptide, polypeptide, or protein sequences that alter, add, or delete a single amino acid or a small portion of the amino acids in the coding sequence are "conservatively modified variants," in that these changes result in the substitution of amino acids with chemically similar amino acids. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to, and do not exclude, polymorphic variants, interspecies homologs, and alleles of the present disclosure.

[0113] The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G), 2) Aspartic acid (D), glutamic acid (E), 3) Asparagine (N), Glutamine (Q), 4) Arginine (R), Lysine (K), 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V), 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W), 7) serine (S), threonine (T), and 8) Cysteine (C), Methionine (M) (See, e.g., Creighton, Proteins (1984)).

[0114] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, where the portion of the polynucleotide or polypeptide sequence in the comparison window may contain additions or deletions (i.e., gaps) compared to the reference sequence (which does not contain additions or deletions) for optimal alignment of the two sequences. This percentage is calculated by determining the number of positions where the same nucleic acid base or amino acid residue is present in both sequences to generate the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to generate the percentage of sequence identity.

[0115] The terms "identical" or "percent identity" in the context of two or more nucleic acid or polypeptide sequences refer to two or more sequences or subsequences that are identical or have a specified percentage of identical amino acid residues or nucleotides (i.e., about 60% identity over a specified region, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity or greater when compared and aligned for maximum correspondence over a comparison window or designated region, as measured using the BLAST or BLAST 2.0 sequence comparison algorithm with the default parameters described below, or by manual alignment and visual inspection (see, e.g., the NCBI website http: / / www.ncbi.nlm.nih.gov / BLAST / ). Such sequences are then said to be "substantially identical." This definition also refers to or can apply to the complement of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as sequences that have substitutions. As explained below, preferred algorithms are able to account for gaps, etc. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, and more preferably over a region that is 50-100 amino acids or nucleotides in length.

[0116] 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, no amino acid in the variant will correspond to the position in the reference sequence at the deletion site. 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. Thus, in embodiments, and as detailed in the following paragraphs, a position may correspond to a differently numbered position in a corresponding protein, e.g., that is homologous and / or contains one or more deletions, insertions, truncations, or condensations.

[0117] 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.

[0118] The term "amino acid side chain" refers to a functional substituent found on an amino acid. For example, the amino acid side chain can be the side chain of a naturally occurring amino acid. Naturally occurring amino acids are those encoded by the genetic code (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine), as well as amino acids that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. In embodiments, the amino acid side chain can be a non-natural amino acid side chain. In embodiments, the amino acid side chain can be H, [ka] is.

[0119] The term "unnatural amino acid side chain" refers to a functional substituent of a compound having the same basic chemical structure as a naturally occurring amino acid, i.e., an alpha carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium, allylalanine, and 2-aminoisobutyric acid. Unnatural amino acids are non-proteinogenic amino acids that occur naturally or are chemically synthesized. 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. Non-limiting examples include exo-cis-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid hydrochloride, cis-2-aminocycloheptanecarboxylic acid hydrochloride, cis-6-amino-3-cyclohexene-1-carboxylic acid hydrochloride, cis-2-amino-2-methylcyclohexanecarboxylic acid hydrochloride, cis-2-amino-2-methylcyclopentanecarboxylic acid hydrochloride, 2-(Boc-aminomethyl)benzoic acid, 2-(Boc-amino)octanedioic acid, Boc-4,5-dehydro-Leu-OH(dicyclohexylammonium), Boc-4-(Fmoc-amino)-L-phenylalanine, Boc-β-homopyl-OH, Boc-(2-indanyl)-Gly-OH, 4-Boc-3-morpholineacetic acid, 4-Boc-3-morpholineacetic acid, Boc-pentafluoro-D-phenylalanine, Boc-pentafluoro-L-phenylalanine, Boc-Phe(2-Br)-OH, Boc-Phe(4-Br)-OH, Boc-D-Phe(4-Br)-OH, Boc-D-Phe(3-Cl)-OH, Boc-Phe(4-NH2)-OH, Boc-Phe(3-NO2)-OH, Boc-Phe(3,5-F2)-OH, 2-(4-Boc-piperazino)-2-(3,4-Dimethoxyphenyl)acetic acid (purum), 2-(4-Boc-piperazino)-2-(2-fluorophenyl)acetic acid (pure), 2-(4-Boc-piperazino)-2-(3-fluorophenyl)acetic acid (pure), 2-(4-Boc-piperazino)-2-(4-fluorophenyl)acetic acid (pure), 2-(4-Boc-piperazino)-2-(4-methoxyphenyl)-acetic acid (pure), 2-(4-Boc-piperazino)-2-phenylacetic acid (pure), 2-(4-Boc-piperazino)-2-(3-pyridyl)acetic acid (pure), 2-(4-Boc-piperazino)-2-[4-(trifluoromethyl)phenyl]-acetic acid (pure), Boc-β-(2-quinolyl)-Ala-OH, N-Boc-1,2,3,6-tetrahydro-2-pyridinecarboxamide Boc-β-(4-thiazolyl)-Ala-OH, Boc-β-(2-thienyl)-D-Ala-OH, Fmoc-N-(4-Boc-aminobutyl)-Gly-OH, Fmoc-N-(2-Boc-aminoethyl)-Gly-OH, Fmoc-N-(2,4-dimethoxybenzyl)-Gly-OH, Fmoc-(2-indanyl)-Gly-OH, Fmoc- Fmoc-Pen(Trt)-OH, Fmoc-Phe(2-Br)-OH, Fmoc-Phe(4-Br)-OH, Fmoc-Phe(3,5-F2)-OH, Fmoc-β-(4-thiazolyl)-Ala-OH, Fmoc-β-(2-thienyl)-Ala-OH, and 4-(hydroxymethyl)-D-phenylalanine.

[0120] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof, or their complements, or nucleosides (e.g., deoxyribonucleosides or ribonucleosides), in either single-, double-, or multi-stranded form. In embodiments, "nucleic acid" does not include nucleosides. The terms "polynucleotide," "oligonucleotide," "oligo," and the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term "nucleoside" refers, in the usual and customary sense, to a glycosylamine containing a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non-limiting examples of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine, and inosine. The term "nucleotide," in the usual and customary sense, refers to a single polynucleotide unit, i.e., monomer. A nucleotide may be a ribonucleotide, a deoxyribonucleotide, or a modified form thereof. Examples of polynucleotides contemplated herein include single-stranded and double-stranded DNA, single-stranded and double-stranded RNA, and hybrid molecules containing a mixture of single-stranded and double-stranded DNA and RNA. Examples of nucleic acids, e.g., polynucleotides, contemplated herein include all types of RNA, such as mRNA, siRNA, miRNA, and guide RNA, as well as all types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term "double-stranded" in the context of polynucleotides refers to double-strandedness in the usual and conventional sense. Nucleic acids can be linear or branched. For example, nucleic acids can be linear chains of nucleotides, or nucleic acids can be branched, for example, such that the nucleic acid contains one or more arms or branches of nucleotides. Optionally, branched nucleic acids are repeatedly branched to form higher-order structures such as dendrimers.

[0121] For example, nucleic acids containing nucleic acids with phosphothioate backbones can contain one or more reactive moieties.As used herein, the term reactive moiety includes any group that can react with another molecule, such as a nucleic acid or a polypeptide, through covalent, non-covalent, or other interactions.For example, nucleic acids can contain amino acid reactive moieties that react with amino acids on proteins or polypeptides through covalent, non-covalent, or other interactions.

[0122] This term also encompasses the nucleic acid that contains known nucleotide analogues or modified backbone residues or bonds, which are synthetic, naturally occurring, and non-naturally occurring, and have the same binding properties as reference nucleic acid, and are metabolized in the same manner as reference nucleotide.Examples of such analogues include, but are not limited to, for example, phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate, which replaces the oxygen in phosphate with double-bond sulfur), phosphorodithioate, phosphonocarboxylic acid, phosphonocarboxylate, phosphonoacetic acid, phosphonoformic acid, methylphosphonate, boronphosphonate, or O-methylphosphoramidite bond (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press), and phosphodiester derivatives, including modifications to nucleotide bases such as 5-methylcytidine or pseudouridine, and peptide nucleic acid backbone and bond. Other analog nucleic acids include those with cationic backbones, non-ionic backbones, modified sugars, and non-ribose backbones (e.g., phosphorodiamidate morpholino oligonucleotides or bridged nucleic acids (LNA) known in the art), including those described in U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acid. Modifications of the ribose-phosphate backbone can be made for various reasons, such as to increase the stability and half-life of such molecules in physiological environments or as probes on biochips. Mixtures of naturally occurring nucleic acids and analogs can be made, or alternatively, mixtures of different nucleic acid analogs and mixtures of naturally occurring nucleic acids and analogs can be made. In embodiments, the internucleotide linkages in the DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0123] Nucleic acid can contain non-specific sequence.As used herein, the term "non-specific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary or only partially complementary to any other nucleic acid sequence.For example, a non-specific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[0124] The term "gene" refers to the segment of DNA involved in producing a protein, including the regions preceding and following the coding region (leader and trailer), as well as the intervening sequences (introns) between individual coding segments (exons). The leader, trailer, and introns contain regulatory elements required during transcription and translation of a gene. Furthermore, a "protein gene product" is a protein expressed from a particular gene.

[0125] In the case of certain proteins described herein, the designated protein includes any of the naturally occurring forms of the protein, variants, or homologs that maintain protein transcription factor activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the native protein). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to the naturally occurring form. In other embodiments, the protein is a protein identified by its NCBI sequence reference. In other embodiments, the protein is a protein identified by its NCBI sequence reference, a homolog, or a functional fragment thereof.

[0126] The term "B-Raf protein" or "B-Raf" as provided herein includes any recombinant or naturally occurring form of the human protein encoded by the BRAF gene, or a variant or homolog thereof, that maintains B-Raf activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to B-Raf). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring B-Raf protein. The term "B-Raf" XYZ refers to a mutant B-Raf nucleotide sequence or protein in which the Y-numbered amino acid of B-Raf that has an X amino acid in the wild-type has a Z amino acid instead in the mutant (e.g., B-Raf V600E has a V in the wild-type protein but an E in the B-Raf V600E mutant protein). In some embodiments, the B-Raf protein is substantially identical to the protein identified by UniProt reference number P15056, or a variant or homolog having substantial identity thereto. In embodiments, the B-Raf protein encoded by the BRAF gene has an amino acid sequence set forth in or corresponding to Entrez 673, UniProt P15056, RefSeq(protein)NP_004324, RefSeq(protein)NP_001341538, RefSeq(protein)NP_001361173, RefSeq(protein)NP_001361187, or RefSeq(protein)NP_001365396. In embodiments, the BRAF gene has a nucleic acid sequence set forth in RefSeq(mRNA)NM_004324, RefSeq(mRNA)NM_001341538, RefSeq(mRNA)NM_001361173, RefSeq(mRNA)NM_001361187, or RefSeq(mRNA)NM_001365396.In embodiments, the amino acid or nucleic acid sequence is a sequence known at the time of filing this application. In embodiments, when a B-Raf amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / . In embodiments, when a B-Raf amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / cancer.sanger.ac.uk / cosmic.

[0127] As used herein, the term "BRAF gene" or "BRAF" refers to any recombinant or naturally occurring form of the BRAF gene, or a variant or homolog thereof, that encodes a B-Raf polypeptide that is capable of maintaining the activity of the B-Raf polypeptide (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the B-Raf polypeptide). In embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous nucleic acid portion) compared to the naturally occurring BRAF gene.

[0128] The term "EGFR protein" as provided herein includes any recombinant or naturally occurring form of epidermal growth factor receptor (EGFR), also known as ErbB-1 or HER1 in humans, or a variant or homolog thereof, that maintains EGFR protein activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the EGFR protein). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to the naturally occurring EGFR protein. The term "EGFR" XYZ refers to a mutant EGFR nucleotide sequence or protein in which the Y-numbered amino acid of EGFR, which has an X amino acid in the wild-type, instead has a Z amino acid in the mutant (e.g., EGFR L858R has an L in the wild-type protein but an R in the EGFR L858R mutant protein). In some embodiments, the EGFR protein is substantially identical to the protein identified by UniProt reference number P00533, or a variant or homolog having substantial identity thereto. In embodiments, the EGFR protein has the amino acid sequence set forth in or corresponding to Entrez 1956, UniProt P00533, RefSeq(protein)NP_001333826, RefSeq(protein)NP_001333827, RefSeq(protein)NP_001333828, RefSeq(protein)NP_01333829, or RefSeq(protein)NP_0001333870. In embodiments, the EGFR gene has the nucleic acid sequence set forth in RefSeq(mRNA)NM_001346897, RefSeq(mRNA)NM_001346898, RefSeq(mRNA)NM_001346899, RefSeq(mRNA)NM_001346900, or RefSeq(mRNA)NM_001346941.In embodiments, the amino acid or nucleic acid sequence is a sequence known at the time of filing this application. In embodiments, when an EGFR amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / . In embodiments, when an EGFR amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / cancer.sanger.ac.uk / cosmic.

[0129] As used herein, the term "EGFR gene" refers to any recombinant or naturally occurring form of the EGFR gene, or a variant or homolog thereof, that encodes an EGFR polypeptide that is capable of maintaining the activity of the EGFR polypeptide (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to a B-Raf polypeptide). In embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous nucleic acid portion) compared to a naturally occurring EGFR gene.

[0130] As used herein, the term "Her2 protein" or "Her2" includes any of the recombinant or naturally occurring forms of the receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), the proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), or a variant or homolog thereof, that maintains Her2 activity (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% compared to Her2). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring Her2 protein. In some embodiments, the Her2 protein is substantially identical to the protein identified by UniProt reference number P04626, or a variant or homolog having substantial identity thereto. In embodiments, when a Her2 amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / . In embodiments, when a Her2 amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / cancer.sanger.ac.uk / cosmic.

[0131] The term "Ras" refers to one or more of the family of human Ras GTPase proteins (e.g., K-Ras, H-Ras, N-Ras).

[0132] The term "K-Ras" refers to the nucleotide sequence or protein of human K-Ras (e.g., human K-Ras4A (NP_203524.1), human K-Ras4B (NP_004976.2), or both K-Ras4A and K-Ras4B). The term "K-Ras" includes both the wild-type form of the nucleotide sequence or protein and any mutant forms thereof. In some embodiments, "K-Ras" is wild-type K-Ras. In some embodiments, "K-Ras" is one or more mutant forms. The term "K-Ras" XYZ refers to the nucleotide sequence or protein of a mutant K-Ras in which the Y-numbered amino acid of K-Ras that has an X amino acid in the wild-type form instead has a Z amino acid in the mutant (e.g., K-Ras G12C has a G in the wild-type protein but a C in the K-Ras G12C mutant protein). In some embodiments, the K-Ras protein is substantially identical to the protein identified by UniProt reference number P01116, or a variant or homolog having substantial identity thereto. In embodiments, the K-Ras protein encoded by the KRAS gene has an amino acid sequence set forth in or corresponding to Entrez 3845, UniProt P01116, RefSeq(protein) NP_004976, RefSeq(protein) NP_203524, RefSeq(protein) NP_001356715, RefSeq(protein) NP_001356716, or RefSeq(protein) NP_004976.2. In embodiments, the KRAS gene has the nucleic acid sequence set forth in RefSeq(mRNA)NM_004985, RefSeq(mRNA)NM_033360, RefSeq(mRNA)NM_001369786, or RefSeq(mRNA)NM_001369787. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In embodiments, when a K-Ras amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / .In embodiments, when a K-Ras amino acid position is referenced, the position corresponds to the numbering system set out at https: / / cancer.sanger.ac.uk / cosmic.

[0133] As used herein, the term "KRAS gene" or "KRAS" refers to any recombinant or naturally occurring form of a KRAS gene encoding a K-Ras polypeptide, or a variant or homolog thereof, that can maintain the activity of the K-Ras polypeptide (e.g., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the K-Ras polypeptide). In embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity over the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 contiguous nucleic acid segments) compared to a naturally occurring KRAS gene.

[0134] The term "H-Ras" includes both the wild-type form of a nucleotide sequence or protein and any mutants thereof. In some embodiments, "H-Ras" refers to wild-type H-Ras. In some embodiments, "H-Ras" refers to one or more mutant forms. The term "H-Ras" XYZ refers to a mutant H-Ras nucleotide sequence or protein in which the Y-numbered amino acid of H-Ras that has an X amino acid in the wild-type form has a Z amino acid instead in the mutant (e.g., H-Ras G12C has a G in the wild-type protein but a C in the H-Ras G12C mutant protein). In some embodiments, the H-Ras protein is substantially identical to the protein identified by UniProt reference number P01112, or a variant or homolog having substantial identity thereto. In embodiments, the H-Ras protein encoded by the HRAS gene has an amino acid sequence described in or corresponding to Entrez 3265, UniProt P01112, RefSeq(protein) NP_001123914, RefSeq(protein) NP_001123915, RefSeq(protein) NP_001123916, RefSeq(protein) NP_001304983, RefSeq(protein) NP_005334, RefSeq(protein) NP_032310, or RefSeq(protein) NP_789765. In embodiments, the HRAS gene has the nucleic acid sequence set forth in RefSeq(mRNA)NM_001130442, NM_001130443, NM_001130444, RefSeq(mRNA)NM_NM_005343, RefSeq(mRNA)NM_176795, RefSeq(mRNA)NM_0013618054, or RefSeq(mRNA)NM_008284. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In some embodiments, H-Ras refers to the protein NP_005334.1. In embodiments, when an H-Ras amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / .In embodiments, when an H-Ras amino acid position is referenced, the position corresponds to the numbering system set out at https: / / cancer.sanger.ac.uk / cosmic.

[0135] The term "N-Ras" includes both the wild-type and any mutant forms of a nucleotide sequence or protein. In some embodiments, "N-Ras" refers to wild-type N-Ras. In some embodiments, "N-Ras" refers to one or more mutant forms. The term "N-Ras" XYZ refers to a mutant N-Ras nucleotide sequence or protein in which the Y-numbered amino acid of N-Ras that has an X amino acid in the wild-type protein has a Z amino acid instead in the mutant (e.g., N-Ras G12C has a G in the wild-type protein but a C in the N-Ras G12C mutant protein). In some embodiments, the N-Ras protein is substantially identical to the protein identified by UniProt reference number P01111, or a variant or homolog having substantial identity thereto. In embodiments, the N-Ras protein encoded by the NRAS gene has an amino acid sequence described in or corresponding to Entrez 4893, UniProt P01111, or RefSeq(protein) NP_002515. In embodiments, the NRAS gene has a nucleic acid sequence as set forth in RefSeq(mRNA) NM_002524, NM_010937, NM_001368638. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In embodiments, when an N-Ras amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / . In embodiments, when an N-Ras amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / cancer.sanger.ac.uk / cosmic.

[0136] The term "PI3K protein" or "PI3K" as provided herein includes any recombinant or naturally occurring form of the human protein encoded by the PI3K gene, or a variant or homolog thereof, that maintains PIK3 activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to PI3K). A "PIK3 gene" or "PIK3," as used in the context of a nucleic acid encoding a PI3K polypeptide, as described above and herein, may alternatively be referred to herein as a PI3K gene or PI3K. In some embodiments, a variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring PI3K protein. The term "PI3K" XYZ refers to a mutant PI3K nucleotide sequence or protein in which the Y-numbered amino acid of PI3K that has an X amino acid in the wild-type has a Z amino acid instead in the mutant (e.g., PI3K E545K has an E in the wild-type protein but a K in the PI3K E545K mutant protein). In embodiments, the PI3K protein is PK3CA. In some embodiments, the PI3K protein is substantially identical to the protein identified by UniProt reference number P42336, or a variant or homolog having substantial identity thereto. In embodiments, when a PI3K amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / . In embodiments, when a PI3K amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / cancer.sanger.ac.uk / cosmic.

[0137] As used herein, the term "PIK3 gene" or "PIK3" refers to any recombinant or naturally occurring form of a PI3K gene encoding a PI3K polypeptide, or a variant or homolog thereof, that is capable of maintaining the activity of the PI3K polypeptide (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the PIK3 polypeptide). In embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity over the entire sequence or a portion of the sequence (e.g., 50, 100, 150, or 200 contiguous nucleic acid portions) compared to a naturally occurring PIK3 (i.e., PI3K) gene.

[0138] As used herein, the term "p53" or "tumor protein p53" includes any recombinant or naturally occurring form of the human protein encoded by the TP53 gene, or a variant or homolog thereof, that maintains p53 activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to p53). In some embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to the naturally occurring p53 protein. The term "p53" XYZ refers to a mutant p53 nucleotide sequence or protein in which the Y-numbered amino acid of p53 that has an X amino acid in the wild-type has a Z amino acid instead in the mutant (e.g., p53 R175H has an R in the wild-type protein but an H in the p53 E545K mutant protein). In some embodiments, the p53 protein is substantially identical to the protein identified by UniProt reference number P04637, or a variant or homolog having substantial identity thereto. In embodiments, the p53 protein encoded by the TP53 gene has an amino acid sequence set forth in or corresponding to Entrez 7157, UniProt P04637, RefSeq(protein)NP_000537, RefSeq(protein)NP_001119584, RefSeq(protein)NP_001119585, RefSeq(protein)NP_001119586, or RefSeq(protein)NP_001119587. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of this application. In embodiments, when a p53 amino acid position is referenced, the position corresponds to the numbering system set forth at https: / / www.cbioportal.org / .In embodiments, when a p53 amino acid position is referenced, the position corresponds to the numbering system set out at https: / / cancer.sanger.ac.uk / cosmic.

[0139] As used herein, the term "TP53 gene" or "TP53" refers to any recombinant or naturally occurring form of the TP53 gene encoding a p53 polypeptide, or a variant or homolog thereof, that is capable of retaining the activity of the p53 polypeptide (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to the p53 polypeptide). In embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% nucleic acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous nucleic acid portion) compared to a naturally occurring TP53 gene.

[0140] 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 directly 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 directly 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 amino acid salts such as arginate salts, and organic acid salts such as glucuronic acid or galacturonic 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.

[0141] 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, 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.

[0142] 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.

[0143] In addition to salt forms, the present disclosure provides compounds in prodrug form.Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to produce the compounds of the present disclosure.Prodrugs of the compounds described herein can be converted in vivo after administration.In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, for example, when contacted with suitable enzymes or chemical reagents.

[0144] Certain compounds of the present disclosure can exist in unsolvated form and solvated form, including hydrated form.In general, solvated form is equivalent to unsolvated form and is included within the scope of the present disclosure.Certain compounds of the present disclosure can exist in polycrystalline form or amorphous form.In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0145] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the administration and absorption of active agents by a subject and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, 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 disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0146] The term "preparation" is intended to include the combination of active compound and 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 thus associated with it.Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0147] The term "antibody" refers to a polypeptide encoded by immunoglobulin genes or functional fragments thereof that specifically binds to and recognizes an antigen. Recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively.

[0148] The terms "antigen" and "epitope" refer synonymously to that portion of a molecule (e.g., a polypeptide) that is specifically recognized by a component of the immune system, e.g., an antibody, T cell receptor, or other immune receptor, such as a receptor on a natural killer (NK) cell. As used herein, the term "antigen" encompasses antigenic epitopes and antigenic fragments thereof.

[0149] The term "vaccine" refers to a composition capable of providing active acquired immunity and / or a therapeutic effect (e.g., treatment) against a particular disease or pathogen. Vaccines typically contain one or more agents capable of inducing an immune response in a subject against a pathogen or disease, i.e., a target pathogen or target disease. An immunogenic agent stimulates the body's immune system to recognize the agent as a threat or indicator of the presence of the target pathogen or target disease, thereby inducing immunological memory so that the immune system can more easily recognize and destroy any pathogen upon subsequent exposure. Vaccines can be prophylactic (e.g., preventing or ameliorating the effects of any future infection by a natural or pathogenic agent, or the anticipated development of cancer in a predisposed subject) or therapeutic (e.g., treating cancer in a subject diagnosed with cancer). Administration of a vaccine is referred to as vaccination. In some examples, a vaccine composition can be provided to a subject with a nucleic acid, e.g., an mRNA encoding an antigenic molecule (e.g., a peptide). In a subject, the nucleic acid delivered via the vaccine composition can be expressed into an antigen molecule, allowing the subject to acquire immunity against the antigen molecule. In the context of vaccination against infectious diseases, the vaccine composition can provide mRNA encoding an antigen molecule associated with a specific pathogen, for example, one or more peptides known to be expressed in the pathogen (e.g., pathogenic bacteria or pathogenic viruses). In the context of cancer vaccines, the vaccine composition can provide mRNA encoding a specific peptide associated with cancer, for example, a peptide that is expressed substantially only in cancer cells or more highly expressed in cancer cells than in normal cells. After vaccination with the cancer vaccine composition, the subject will have immunity against the cancer-associated peptide and be able to specifically kill cancer cells.

[0150] As used herein, the term "immune response" includes, but is not limited to, an "adaptive immune response" (also known as an "acquired immune response"), which elicits an initial response to a specific pathogen or type of cell that the immune response targets, followed by an enhanced response against the target when the target is subsequently encountered. Induction of immune memory can provide the basis for vaccination.

[0151] The terms "immunogenic" or "antigenic" refer to a compound or composition that, when administered to an immunocompetent subject, induces an immune response, such as a cytotoxic T lymphocyte (CTL) response, a B cell response (e.g., the production of antibodies that specifically bind to an epitope), an NK cell response, or any combination thereof. Thus, an immunogenic or antigenic composition is a composition that can elicit an immune response in an immunocompetent subject. For example, an immunogenic or antigenic composition can contain one or more immunogenic epitopes associated with a pathogen or specific cell type that is the target of the immune response. In addition, an immunogenic composition can include an isolated nucleic acid construct (DNA or RNA) that encodes one or more immunogenic epitopes of an antigenic polypeptide and can be used to express the epitope (and thus can be used to elicit an immune response against the polypeptide or related polypeptides associated with the target pathogen or cell type).

[0152] The term "MHC protein" refers to a protein encoded by one of the genes that make up the major histocompatibility complex (MHC). In embodiments, the MHC protein is an MHC class I protein or an MHC class II protein. In embodiments, the MHC protein is an MHC class I protein. In embodiments, the MHC protein is an MHC class II protein.

[0153] The term "driver oncogene mutation" refers to a mutation in a normal gene that predisposes a cell to cancer. In embodiments, a driver oncogene mutation is a mutation in a gene that alters the activity of a protein gene product in a manner that increases the likelihood that a cell harboring the driver oncogene mutation will become cancerous. In embodiments, a driver oncogene mutation is a tumor suppressor gene mutation that results in the production of a mutant tumor suppressor protein with reduced tumor suppressor activity, thereby increasing the likelihood that a cell harboring the tumor suppressor gene mutation will become cancerous. In embodiments, a driver oncogene mutation is not limited to point mutations. In embodiments, the driver oncogene mutation is in the EGFR gene. In embodiments, the driver oncogene mutation is in the PDGFR gene. In embodiments, the driver oncogene mutation is in the VEGFR gene. In embodiments, the driver oncogene mutation is in the HER2 / neu gene. In embodiments, the driver oncogene mutation is in the BRAF gene. In embodiments, the driver oncogene mutation is in the K-Ras gene. In embodiments, the driver oncogene mutation is in the PI3K (i.e., PIK3) gene.

[0154] The term "driver oncogene protein" refers to a protein that is expressed as a result of a driver oncogene mutation (i.e., the protein gene product of a driver oncogene mutation). In an embodiment, the driver oncogene protein is an EGFR protein. In an embodiment, the driver oncogene protein is a PDGFR protein. In an embodiment, the driver oncogene protein is a VEGFR protein. In an embodiment, the driver oncogene protein is a HER2 / neu protein. In an embodiment, the driver oncogene protein is a B-Raf protein. In an embodiment, the driver oncogene protein is a K-Ras protein. In an embodiment, the driver oncogene protein is KRAS p.G12V. In an embodiment, the driver oncogene protein is a PI3K protein.

[0155] The term "tumor suppressor gene" refers to a gene that regulates cells during cell division and replication. Thus, in embodiments, a tumor suppressor gene encodes a protein with tumor suppressor activity and is also referred to herein as a tumor suppressor protein or tumor suppressor (e.g., p53). In embodiments, a tumor suppressor gene contains one or more mutations that result in the loss or reduction of its function as a tumor suppressor. Thus, in embodiments, a tumor suppressor gene contains one or more mutations that encode a mutant tumor suppressor protein with reduced or eliminated tumor suppressor function. In embodiments, the tumor suppressor gene mutation is in the tumor protein p53 (p53). In embodiments, the mutant p53 protein is R175H, R175G, R175L, R175C, Y220C, G245S, G245D, G245V, G245R, R248Q, R248W, R248L, R273H, R273C, R273L, R282W, or R282G.

[0156] As used herein, the term "EC50" or "half maximal effective concentration" refers to the concentration of a molecule (e.g., an antibody, chimeric antigen receptor, or bispecific antibody) that can induce a response that is between the baseline response and the maximal response after a specified exposure time. In embodiments, the EC50 is the concentration of a molecule (e.g., an antibody, chimeric antigen receptor, or bispecific antibody) that produces 50% of the molecule's maximum possible effect.

[0157] 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 specified value. In embodiments, about includes the specified value.

[0158] In this disclosure, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," etc. "Consisting essentially of" or "consists essentially" likewise have the meaning ascribed to them in U.S. patent law, and the term is open-ended and allows for the presence of more than what is recited, but does not include prior art embodiments, so long as the basic or novel characteristics of what is recited are not changed by the presence of more than what is recited.

[0159] An "inhibitor" refers to a compound (e.g., a compound described herein) that reduces activity compared to a control, such as the absence of the compound or a compound with known inactivity.

[0160] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two different species (e.g., compounds, including biomolecules or cells) to come into sufficient proximity to react, interact, or physically contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate derived from one or more of the added reagents that may be produced in the reaction mixture.

[0161] The term "contacting" can include allowing two species to react, interact, or come into physical contact, and the two species can be a compound described herein and a protein or enzyme. In some embodiments, contacting includes allowing a compound described herein to interact with a protein or enzyme involved in a signal transduction pathway.

[0162] As defined herein, the terms "activation," "activate," "activating," "activator," and the like, with respect to protein-inhibitor interactions, refer to positively affecting (e.g., increasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the activator. In embodiments, activation refers to positively affecting (e.g., increasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the activator. These terms may refer to activating, activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein that is decreased in a disease. Thus, activation may include, at least in part, partially or fully increasing stimulation, increasing signal transduction or enzymatic activity, or the amount of a protein associated with a disease (e.g., a protein that is decreased in a disease compared to an unaffected control), or enabling activation, activating, sensitizing, or upregulating signal transduction or enzymatic activity, or the amount of a protein. Activation may include, at least in part, partially or fully increasing stimulation, increasing signal transduction or enzymatic activity, or the amount of a protein, or enabling activation, activating, sensitizing, or upregulating.

[0163] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to a protein-inhibitor interaction, refer to adversely affecting (e.g., reducing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to negatively affecting (e.g., decreasing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptoms. In embodiments, inhibition refers to the reduction of the activity of a specific protein target. Thus, inhibition includes at least partially or completely blocking a stimulus, reducing, preventing, or delaying activation of signaling or enzymatic activity or the amount of a protein, or inactivating, desensitizing, or downregulating. In embodiments, inhibition refers to the reduction of the activity of a target protein due to a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to the reduction of the activity of a target protein due to an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0164] The terms "inhibitor," "suppressor," "antagonist," or "down-regulator" refer interchangeably to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more 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 expression or activity in the absence of the antagonist.

[0165] The term "expression" includes any step involved in polypeptide production, 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.).

[0166] 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 a molecular target compared to the absence of the modulator.

[0167] The term "modulate" is used according to its plain and ordinary meaning and refers 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.

[0168] In the context of a substance or activity or function of a substance that is associated with a disease (e.g., a protein-related disease, a cancer (e.g., a cancer, an inflammatory disease, an autoimmune disease, or an infectious disease)), the term "associated" or "related to" means that the disease (e.g., a cancer, an inflammatory disease, an autoimmune disease, or an infectious disease) is caused (in whole or in part) or a symptom of the disease is caused (in whole or in part) by the substance or activity or function of the substance. As used herein, something that is described as associated with a disease, if it is a causative agent, may be a target for disease treatment.

[0169] As used herein, "stabilize" means reducing the Kd of an MHC protein that binds to a peptide antigen. Thus, a compound stabilizes the binding of an MHC protein to a peptide antigen by reducing the Kd of the MHC protein that binds to the peptide antigen compared to the absence of the compound.

[0170] The term "irreversible covalent bond" is used according to its plain and ordinary meaning in the art to refer to an association obtained between atoms or molecules that have a low probability of dissociation (e.g., an electrophilic chemical moiety and a nucleophilic moiety). In embodiments, an irreversible covalent bond does not readily dissociate under normal biological conditions. In embodiments, an irreversible covalent bond is formed through a chemical reaction between two species (e.g., an electrophilic chemical moiety and a nucleophilic moiety).

[0171] The term "electrophilic moiety" is used according to its plain and ordinary meaning to refer to a chemical group (e.g., a monovalent chemical group) that is electrophilic. In embodiments, an electrophilic chemical moiety is referred to herein as "E." In embodiments, E is [ka] where R 26 , R 27 , R 28 , R 29 , and X 27 is as described herein, including embodiments. In embodiments, the electrophilic moiety is a covalent cysteine modifying moiety.

[0172] As used herein, the term "covalent cysteine modifier moiety" refers to a monovalent electrophilic moiety capable of measurably binding to a cysteine amino acid. In embodiments, the covalent cysteine modifier moiety is attached via an irreversible covalent bond. In embodiments, the covalent cysteine modifier moiety can bind with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM. In embodiments, the covalent cysteine modifier moiety is attached via a covalent bond.

[0173] The term "nucleophilic moiety" is used according to its plain and ordinary meaning to refer to a chemical group (eg, a monovalent chemical group) that is nucleophilic.

[0174] II. Usage In one aspect, provided herein is a method for identifying a candidate compound that stabilizes the binding of an MHC protein to a peptide antigen. The method includes contacting an MHC protein with a peptide antigen and a candidate compound, thereby forming an MHC-peptide-compound complex, and detecting increased stability of the MHC-peptide-compound complex compared to the stability of an MHC-peptide complex without the candidate compound. The candidate compound is thus identified as a compound that stabilizes the binding of an MHC protein to a peptide antigen. This method can be performed in vitro.

[0175] In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 1 μM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 10 nM, 100 nM, 500 nM, 1 μM, 10 μM, 50 μM, 100 μM, 500 μM, or 1 mM (in the presence of the candidate compound). The Kd can be a specific value in the range of 10 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1 μM, 1 μM to 10 μM, 10 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, or 500 μM to 1 mM (in the presence of the candidate compound). The specific value can be selected from any 1 nM increment within the selected range (in the presence of the candidate compound). The Kd can be selected from any subrange within the aforementioned Kd range (in the presence of the candidate compound). The lower limit of a partial range can be any value selected from the lower limit of the range, or a 1 nM increment from the lower limit of the range to 1 nM less than the upper limit of the maximum range (in the presence of the candidate compound). The upper limit of a partial range can be any value selected from the upper limit of the range, or a 1 nM increment from the upper limit of the range to 1 nM more than the lower limit of the maximum range (in the presence of the candidate compound).

[0176] In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 10 nM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 100 nM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 500 nM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 1 μM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 10 μM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 50 μM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 100 μM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 500 μM (in the presence of the candidate compound). In embodiments, the MHC protein binds to the peptide antigen with a Kd of greater than 1 mM (in the presence of the candidate compound).

[0177] In embodiments, the MHC protein contacted with the peptide antigen and candidate compound is folded, partially folded, or unfolded. In embodiments, the MHC protein contacted with the peptide antigen and candidate compound is folded or unfolded. In embodiments, the MHC protein contacted with the peptide antigen and candidate compound is folded. In embodiments, the MHC protein contacted with the peptide antigen and candidate compound is partially folded. In embodiments, the MHC protein contacted with the peptide antigen and candidate compound is unfolded.

[0178] In embodiments, the MHC protein is an MHC class I protein or an MHC class II protein. In embodiments, the MHC protein is an MHC class I protein. In embodiments, the MHC protein is an MHC class II protein.

[0179] In embodiments, the MHC class I proteins are MHC class I heavy and light chain proteins. In embodiments, the light chain protein is β-microglobulin. In embodiments, the heavy chain protein is an alpha chain. In embodiments, the alpha chain is an alpha polypeptide chain. In embodiments, the alpha chain consists of three extracellular regions or domains called α1, α2, and α3. In embodiments, the α1 and α2 domains form the site for binding of antigen-derived peptides. In embodiments, the three genetic loci encoding classical (major) MHC class I molecules in humans are called HLA-A, HLA-B, and HLA-C. In embodiments, there are five non-classical (minor) MHC class I molecules in humans called HLA-E, HLA-F, HLA-G, HLA-K, and HLA-L.

[0180] In embodiments, the MHC protein is HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLA-K, or HLA-L. In embodiments, the MHC protein is HLA-A, HLA-B, or HLA-C. In embodiments, the MHC protein is HLA-A. In embodiments, the MHC protein is HLA-B. In embodiments, the MHC protein is HLA-C. In embodiments, the MHC protein is HLA-E. In embodiments, the MHC protein is HLA-F. In embodiments, the MHC protein is HLA-G. In embodiments, the MHC protein is HLA-K. In embodiments, the MHC protein is HLA-L.

[0181] In embodiments, the MHC protein is HLA-B. In embodiments, the MHC protein is HLA-B*57:01. In embodiments, the MHC protein is HLA-B*58:01.

[0182] In embodiments, the peptide antigen is a peptide derived from a driver oncogene. A driver oncogene-derived peptide is a peptide antigen derived from a driver oncogene protein and may be referred to herein as a peptide cancer antigen. In embodiments, a driver oncogene-derived peptide (peptide cancer antigen) comprises an amino acid sequence containing a mutation that alters the activity of the driver oncogene protein in a manner that increases the likelihood that a cell harboring a driver oncogene mutation will become cancerous. In embodiments, the peptide antigen is a peptide derived from a common driver oncogene. In embodiments, the peptide antigen comprises an amino acid sequence encoded by a driver oncogene mutation. Thus, the peptide antigen may comprise an amino acid sequence containing a mutation that alters the activity of the driver oncogene protein in a manner that increases the likelihood that a cell harboring a driver oncogene mutation will become cancerous. In embodiments, the peptide antigen is a peptide derived from an altered driver oncogene. In embodiments, the driver oncogenic alteration comprises a mutation, truncation, gene fusion, and / or splice variant. In embodiments, common driver oncogenes are KRAS(G12D / V / C), BRAF(V600E), and PI3K (i.e., PIK3)(E545K / H1047R). In embodiments, a common driver oncogene is KRAS(G12D / V / C). In embodiments, a common driver oncogene is BRAF(V600E). In embodiments, a common driver oncogene is PI3K (i.e., PIK3)(E545K / H1047R). Thus, in embodiments, the peptide antigen comprises an amino acid sequence comprising KRAS(G12D / V / C), BRAF(V600E), or PI3K(E545K / H1047R).

[0183] In embodiments, the peptide antigen is 5 to 100 amino acids in length. In embodiments, the peptide antigen is 5 to 50 amino acids in length. In embodiments, the peptide antigen is 5 to 25 amino acids in length. In embodiments, the peptide antigen is 5 to 20 amino acids in length. In embodiments, the peptide antigen is 5 to 15 amino acids in length. In embodiments, the peptide antigen is 5 to 14 amino acids in length. In embodiments, the peptide antigen is 5 to 13 amino acids in length. In embodiments, the peptide antigen is 5 to 12 amino acids in length. In embodiments, the peptide antigen is 5 to 11 amino acids in length. In embodiments, the peptide antigen is 5 to 10 amino acids in length.

[0184] In embodiments, the peptide antigen is 6 to 20 amino acids in length. In embodiments, the peptide antigen is 6 to 15 amino acids in length. In embodiments, the peptide antigen is 6 to 14 amino acids in length. In embodiments, the peptide antigen is 6 to 13 amino acids in length. In embodiments, the peptide antigen is 6 to 12 amino acids in length. In embodiments, the peptide antigen is 6 to 11 amino acids in length. In embodiments, the peptide antigen is 6 to 10 amino acids in length.

[0185] In embodiments, the peptide antigen is 7 to 20 amino acids in length. In embodiments, the peptide antigen is 7 to 15 amino acids in length. In embodiments, the peptide antigen is 7 to 14 amino acids in length. In embodiments, the peptide antigen is 7 to 13 amino acids in length. In embodiments, the peptide antigen is 7 to 12 amino acids in length. In embodiments, the peptide antigen is 7 to 11 amino acids in length. In embodiments, the peptide antigen is 7 to 10 amino acids in length.

[0186] In embodiments, the peptide antigen is 8 to 20 amino acids in length. In embodiments, the peptide antigen is 8 to 15 amino acids in length. In embodiments, the peptide antigen is 8 to 14 amino acids in length. In embodiments, the peptide antigen is 8 to 13 amino acids in length. In embodiments, the peptide antigen is 8 to 12 amino acids in length. In embodiments, the peptide antigen is 8 to 11 amino acids in length. In embodiments, the peptide antigen is 8 to 10 amino acids in length.

[0187] In embodiments, the peptide antigen is 9 to 20 amino acids in length. In embodiments, the peptide antigen is 9 to 15 amino acids in length. In embodiments, the peptide antigen is 9 to 14 amino acids in length. In embodiments, the peptide antigen is 9 to 13 amino acids in length. In embodiments, the peptide antigen is 9 to 12 amino acids in length. In embodiments, the peptide antigen is 9 to 11 amino acids in length. In embodiments, the peptide antigen is 9 to 10 amino acids in length.

[0188] In embodiments, the driver oncogene-derived peptide is presented by an MHC protein. In embodiments, the driver oncogene-derived peptide is not sufficiently presented by an MHC protein for T cell recognition. In embodiments, the driver oncogene-derived peptide is not presented by an MHC protein. In embodiments, the driver oncogene-derived peptide is an intracellular antigen. In embodiments, the MHC-peptide antigen stabilizing compound increases MHC presentation of driver oncogene-derived peptides, bringing them into visibility for T cell surveillance. Thus, the MHC-peptide antigen stabilizing compound can increase MHC presentation of peptide antigens (e.g., driver oncogene-derived peptides) compared to the absence of the MHC-peptide antigen stabilizing compound. In embodiments, the MHC-peptide antigen stabilizing compound induces presentation of KRAS(G12D)-derived peptides by HLA-B*57:01. In embodiments, the MHC-peptide antigen stabilizing compound induced presentation of KRAS(G12V)-derived peptides by HLA-B*57:01. In embodiments in which MHC presentation is increased or induced, the MHC-peptide antigen is stabilized by the MHC-peptide antigen stabilizing compound compared to the absence of the MHC-peptide antigen stabilizing compound.

[0189] In embodiments, the candidate compound is the compound being tested. In embodiments, the candidate compound is an MHC-peptide antigen stabilizing compound. In embodiments, provided herein are MHC-peptide antigen stabilizing compounds having a molecular weight of less than 2000 g / mol. In embodiments, the MHC-peptide antigen stabilizing compound has a molecular weight of less than 1500 g / mol. In embodiments, the MHC-peptide antigen stabilizing compound has a molecular weight of less than 1000 g / mol. In embodiments, the MHC-peptide antigen stabilizing compound has a molecular weight of less than 750 g / mol. In embodiments, the MHC-peptide antigen stabilizing compound has a molecular weight of less than 500 g / mol. In embodiments, the MHC-peptide antigen stabilizing compound has a molecular weight of less than 100 g / mol.

[0190] In embodiments, provided herein are MHC-peptide antigen stabilizing compounds having the structure of Formula I or II below, or a salt thereof: [ka]

[0191] W, X, Y, and Z are each independently C or N.

[0192] R 1 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO n1 R 1A , -SO v1 NR 1A R 1B , -PO m1 R 1A , -PO r1 NR 1A R 1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0193] R 2 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, SO n2 R 2A , -SO v2 NR 2A R 2B , -PO m2 R 2A , -PO r2 NR 2A R 2B, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0194] R 3 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0195] R 4 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 4A , -NR 4A R 4B , -COOR 4A , -CONR 4A R 4B , -NO2, -SR 4A , -SO n4 R 4A , -SO v4 NR 4A R 4B , -PO(OH)2, -PO m4 R 4A , -PO r4 NR 4A R 4B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0196] R 5 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 5A , -NR 5A R 5B , -COOH, -CONH2, -NO2, -SH, -SO n5 R 5A , -PO(OH)2, -PO m5 R 5A , -PO r5 NR 5A R 5B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0197] R 6 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 6A , -NH2, -COOH, -CONH2, -NO2, -SH, -SO n6 R 6A , -SO v6 NR 6A R 6B , -PO(OH)2, -PO m6 R 6A , -PO r6 NR 6A R 6B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0198] R 7 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 7A , -NH2, -COOH, -CONH2, -NO2, -SH, -SO n7 R 7A , -SO v7 NR 7A R 7B , -PO(OH)2, -PO m7 R 7A , -PO r7 NR 7A R 7B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0199] R 8 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO n8 R 8A , -SO v8 NR 8A R 8B , -PO(OH)2, -PO m8 R 8A , -PO r8 NR 8A R 8B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl.

[0200] Each R 1A , R 1B , R 2A , R 2B , R4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , and R 8B are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SOH, -SOH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSOH, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0201] In embodiments, R 1A Substituents and R 1B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. In embodiments, R 2A Substituents and R 2B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. In embodiments, R 4A Substituents and R 4B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. In embodiments, R 5A Substituents and R 5B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. In embodiments, R 6A Substituents and R 6BThe substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. In embodiments, R 7A Substituents and R 7B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. In embodiments, R 8A Substituents and R 8B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0202] X is -Cl, -Br, -I, or -F.

[0203] Each of n1, n2, n4, n5, n6, n7, and n8 is independently an integer from 0 to 4.

[0204] Each of v1, v2, v4, v5, v6, v7, and v8 is independently 1 or 2.

[0205] Each of m1, m2, m4, m5, m6, m7, and m8 is independently an integer of 0 to 3.

[0206] Each of r1, r2, r4, r5, r6, r7, and r8 is independently 1 or 2.

[0207] Each z1 and z3 is independently 0 to 5. In an embodiment, z2 is 0 to 4. In an embodiment, z4 is 0 to 3.

[0208] In embodiments, R 1 is hydrogen or unsubstituted alkyl, and R 3 is hydrogen or unsubstituted alkyl, and R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R 5is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NR 5A R 5B , -COOH, -CONH2, -NO2, -SH, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted alkyl; R 4 is hydrogen, substituted or unsubstituted alkyl, or -SO2NR 4A R 4B and R 6 is hydrogen, halogen, or substituted or unsubstituted alkyl, and R 7 is hydrogen or substituted or unsubstituted alkyl, and R 8 is hydrogen or substituted or unsubstituted alkyl, and each R 4A , R 4B , R 5A , and R 5B are independently hydrogen or substituted or unsubstituted alkyl.

[0209] In embodiments, R 1 is hydrogen or methyl, and R 3 is hydrogen or methyl, and R 2 is methyl, unsubstituted cycloalkyl, unsubstituted aryl, or substituted heteroaryl, and R 5 is hydrogen, oxo, methyl, halogen, unsubstituted heteroalkyl, or -NR 5A R 5B and R 4 is hydrogen, methyl, or -SO2NR 4A R 4B and R 6 is hydrogen or methyl, and R 7 is hydrogen or methyl, and R 8 is hydrogen or methyl, and each R 4A , R 4B , R 5A , and R 5B is independently hydrogen or methyl.

[0210] In embodiments, R 1is hydrogen or methyl, and R 3 is hydrogen or methyl, and R 2 is methyl, cyclopropyl, phenyl, or substituted 2H-indazole, and R 5 is hydrogen, oxo, halogen, ethoxy, or -NR 5A R 5B and R 4 is hydrogen, methyl, or -SO2NR 4A R 4B and R 6 is hydrogen or methyl, and R 7 is methyl and R 8 is methyl, and each R 4A , R 4B , R 5A , and R 5B is independently hydrogen or methyl.

[0211] In embodiments, W, X, Y, and Z are each independently C or N. In embodiments, W is C or N. In embodiments, X is C or N. In embodiments, Y is C or N. In embodiments, Z is C or N. In embodiments, Y and Z are N. In embodiments, X and W are C. In embodiments, X and Y are N. In embodiments, W and Z are C. In embodiments, X, Y, W, and Z are N. In embodiments, X, Y, W, and Z are C. In embodiments, X is N. In embodiments, Y, W, and Z are C. In embodiments, Y is N. In embodiments, W is N. Z is N. In embodiments, X and W are N. In embodiments, X and Z are N. In embodiments, Y and W are N.

[0212] In an embodiment, Y and Z are N and W and X are C. In an embodiment, X and Y are N and W and Z are C.

[0213] In embodiments, R 1is hydrogen or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 1 is hydrogen. In embodiments, R 1 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 1 is hydrogen, methyl, ethyl, propyl, butyl, or pentyl. 1 is hydrogen or methyl. In embodiments, R 1 is hydrogen. In embodiments, R 1 is methyl. In embodiments, R 1 is ethyl. In embodiments, R 1 is propyl. In embodiments, R 1 is butyl. In an embodiment, R 1 is pentyl.

[0214] In embodiments, R 3 is hydrogen or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 3 is hydrogen. In embodiments, R 3 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 3 is hydrogen, methyl, ethyl, propyl, butyl, or pentyl. 3 is hydrogen or methyl. In embodiments, R 3 is hydrogen. In embodiments, R 3 is methyl. In embodiments, R 3 is ethyl. In embodiments, R 3 is propyl. In embodiments, R 3 is butyl. In an embodiment, R 3 is pentyl.

[0215] In embodiments, R 2is hydrogen, substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0216] In embodiments, R 2 is hydrogen, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0217] In embodiments, R 2 is hydrogen. In embodiments, R 2 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 2 is unsubstituted cycloalkyl (e.g., C-C cycloalkyl, C-C cycloalkyl, or C-C cycloalkyl). In embodiments, R2 is a substituted (e.g., substituted, size-limited, or lower substituted) aryl (e.g., C-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 2 is an unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl). In embodiments, R 2 is a substituted (e.g., substituted, size-limited, or lower substituted) heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). 2 is an unsubstituted heteroaryl (eg, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0218] In embodiments, R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0219] In embodiments, R 2 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or substituted (e.g., having a substituted, size-limited, or lower substituted) heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0220] In embodiments, R 2 is methyl, cyclopropyl, phenyl, 1H-indazole, or 2H-indazole.2 is methyl. In embodiments, R 2 is cyclopropyl. In embodiments, R 2 is phenyl. In embodiments, R 2 is a substituted (e.g., substituted, size-limited, or lower substituted) 1H-indazole. 2 is a substituted (eg, substituted, size-limited, or lower substituted) 2H-indazole.

[0221] In embodiments, R 2 teeth, [ka] In an embodiment, R 2 teeth, [ka] In an embodiment, R 2 teeth, [ka] In an embodiment, R 2 teeth, [ka] In an embodiment, R 2 teeth, [ka] is.

[0222] In embodiments, R 7 is hydrogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 7 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, or tert-butyl. 7is hydrogen. In embodiments, R 7 is methyl. In embodiments, R 7 is methyl. In embodiments, R 7 is propyl. In embodiments, R 7 is butyl. In an embodiment, R 7 is isobutyl. In embodiments, R 7 is tert-butyl.

[0223] In embodiments, R 8 is hydrogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 8 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, or tert-butyl. 8 is hydrogen. In embodiments, R 8 is methyl. In embodiments, R 8 is methyl. In embodiments, R 8 is propyl. In embodiments, R 8 is butyl. In an embodiment, R 8 is isobutyl. In embodiments, R 8 is tert-butyl.

[0224] In embodiments, R 4 is hydrogen, substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), or -SO2NR 4A R 4B In an embodiment, R 4 is hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, or -SO2NR 4A R 4B In an embodiment, R 4 is hydrogen. In embodiments, R 4is methyl. In embodiments, R 4 is methyl. In embodiments, R 4 is propyl. In embodiments, R 4 is butyl. In an embodiment, R 4 is isobutyl. In embodiments, R 4 is tert-butyl.

[0225] In embodiments, R 4 is -SO2NR 4A R 4B where each R 4A and R 4B are independently as described herein, including embodiments. In embodiments, R 4 is -SO2NR 4A R 4B where each R 4A and R 4B are independently hydrogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In embodiments, R 4 is -SO2NR 4A R 4B where each R 4A and R 4B are independently hydrogen. In embodiments, R 4 is -SO2NR 4A R 4B where each R 4A and R 4B is independently a substituted (e.g., substituted, size-limited, or lower substituted) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 4 is -SO2NR 4A R 4B where each R 4A and R 4B is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 4 is -SO2NR4A R 4B where each R 4A and R 4B is independently hydrogen or methyl. In an embodiment, R 4 is -SO2NR 4A R 4B where each R 4A and R 4B are independently hydrogen. In embodiments, R 4 is -SO2NR 4A R 4B where each R 4A and R 4B is independently methyl.

[0226] In embodiments, R 4 is —SO 2 NH 2 . In an embodiment, R 4 is —SO 2 NHCH 3 . In an embodiment, R 4 is -SO2N(CH3)2.

[0227] In embodiments, R 5 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 5A , -NR 5A R 5B , -COOH, -CONH2, -NO2, -SH, substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., a 2- to 8-membered heteroalkyl, a 2- to 6-membered heteroalkyl, or a 2- to 4-membered heteroalkyl), or substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0228] In embodiments, R 5is hydrogen, methyl, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NR 5A R 5B , -COOH, -CONH, -NO, or -SH. In embodiments, R 5 is hydrogen, methyl, halogen, oxo, -NR 5A R 5B , or unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). 5 is hydrogen. In embodiments, R 5 is methyl. In embodiments, R 5 is halogen. In embodiments, R 5 is —Cl. In embodiments, R 5 is Br. In an embodiment, R 5 is F. In an embodiment, R 5 is I. In an embodiment, R 5 is oxo. In embodiments, R 5 is -NR 5A R 5B In an embodiment, R 5 is unsubstituted alkoxy. In embodiments, R 5 is methoxy, ethoxy, propoxy, butoxy, or pentoxy. 5 is methoxy. In embodiments, R 5 is ethoxy. In embodiments, R 5 is propoxy. In embodiments, R 5 is butoxy. In embodiments, R 5 is pentoxy.

[0229] In embodiments, R 5 is -NR 5A R 5B where each R 5A and R 5Bare independently as described herein, including embodiments. In embodiments, R 5 is -NR 5A R 5B where each R 5A and R 5B are independently hydrogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 5 is -NR 5A R 5B where each R 5A and R 5B are independently hydrogen. In embodiments, R 5 is -NR 5A R 5B where each R 5A and R 5B is independently substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 5 is -NR 5A R 5B where each R 5A and R 5B is independently a substituted (e.g., substituted, size-limited, or lower substituted) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 5 is -NR 5A R 5B where each R 5A and R 5B is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 5 is -NR 5A R 5B where each R 5A and R 5B is independently hydrogen or methyl. In an embodiment, R 5 is -NR 5A R5B where each R 5A and R 5B are independently hydrogen. In embodiments, R 5 is -NR 5A R 5B where each R 5A and R 5B is independently methyl.

[0230] In embodiments, R 5 is —NH. In embodiments, R 5 is -NHCH3. In embodiments, R 5 is -N(CH3)2.

[0231] In embodiments, R 6 is hydrogen, halogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 6 is hydrogen. In embodiments, R 6 is halogen. In embodiments, R 6 is F. In an embodiment, R 6 is Cl. In an embodiment, R 6 is Br. In an embodiment, R 6 is I. In an embodiment, R 6 is a substituted (e.g., substituted, size-limited, or lower substituted) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 6 is unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 6 is methyl, ethyl, propyl, butyl, isopropyl, isobutyl, or tert-butyl. 6 is methyl. In embodiments, R 6 is ethyl. In embodiments, R 6 is propyl. In embodiments, R 6is butyl. In an embodiment, R 6 is isopropyl. In embodiments, R 6 is isobutyl. In embodiments, R 6 is tert-butyl.

[0232] In embodiments, provided herein are MHC-peptide antigen stabilizing compounds having the structure of Formula III below, or a salt thereof: [ka] R 1 , R 2 , R 4 , R 5 , X, Y, W, Z, and z2 are as described herein, including embodiments. 3 is hydrogen or methyl. z1 is 0 to 4. Each R 4C and R 4D are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -SONH, -NHNH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, 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 are attached to the same nitrogen atom 4C and R 4D The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[0233] In embodiments, R 3 is hydrogen or methyl. 3 is hydrogen. 3 is methyl.

[0234] 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.

[0235] In embodiments, each R 4C and R 4D are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, a substitution (e.g., a substituent, a size-limited substituent, or a lower substituent), or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl). 4C and R 4DThe substituents can be optionally linked to form a substituted (e.g., having a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl) or a substituted (e.g., having a substituent, a size-limiting substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0236] In embodiments, each R 4C and R 4D are independently hydrogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl). In embodiments, each R 4C and R 4D is independently hydrogen or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 4C and R 4D is independently hydrogen. In an embodiment, each R 4C and R 4D is independently unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, each R 4C and R 4D is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. 4C and R 4D is independently hydrogen. In an embodiment, each R 4C and R 4D is independently methyl. In an embodiment, each R 4C and R 4D is independently ethyl. In an embodiment, each R 4C and R 4D is independently propyl. In an embodiment, each R 4C and R 4Dis independently butyl. In an embodiment, each R 4C and R 4D is independently pentyl. In an embodiment, each R 4C and R 4D but independently, is hexyl.

[0237] In embodiments, R 4C are independently hydrogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 4C are independently hydrogen or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 4C are independently hydrogen. In embodiments, R 4C is independently substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 4C is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. 4C are independently hydrogen. In embodiments, R 4C is independently methyl. In an embodiment, R 4C is independently ethyl. In an embodiment, R 4C is independently propyl. In an embodiment, R 4C is independently butyl. In an embodiment, R 4C is independently pentyl. In embodiments, R 4C is independently hexyl.

[0238] In embodiments, R 4D are independently hydrogen, or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). 4Dare independently hydrogen or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 4D are independently hydrogen. In embodiments, R 4D is independently substituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In embodiments, R 4D is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. 4D are independently hydrogen. In embodiments, R 4D is independently methyl. In an embodiment, R 4D is independently ethyl. In an embodiment, R 4D is independently propyl. In an embodiment, R 4D is independently butyl. In an embodiment, R 4D is independently pentyl. In embodiments, R 4D is independently hexyl.

[0239] In embodiments, provided herein are MHC-peptide antigen stabilizing compounds having the structure of Formula IV below, or a salt thereof: [ka] R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 4C , R 4D , X, Y, W, Z, z1, z2, and z4 are as described herein, including embodiments.

[0240] In embodiments, provided herein are MHC-peptide antigen stabilizing compounds having the structure of Formula IV below, or a salt thereof: [ka] R1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 4C , R 4D , X, Y, W, Z, z1, z2, and z4 are as described herein, including embodiments.

[0241] In embodiments, an MHC-peptide antigen stabilizing compound has the formula: [ka] or salts thereof are provided herein.

[0242] R 11 is hydrogen, halogen, -CX 11 3. -CHX 11 2. -CH2X 11 , -OCX 11 3. -OCH2X 11 , -OCHX 11 2, -CN, -SO n11 R 11D , -SO v11 NR 11A R 11B , -NHC(O)NR 11A R 11B , -N(O) m11 , -NR 11A R 11B , -C(O)R 11C , -C(O)-OR 11C , -C(O)NR 11A R 11B , -OR 11D , -NR 11A CH2C(O)R 11C , -NR 11A CH2SO2R 11D , -NR 11A SO2R 11D , -NR 11A C(O)R 11C , -NR 11A C(O)OR 11C , -NR 11A OR 11C , -NR11A OSO2R 11D , -NR 11A OCH2C(O)R 11C , -NR 11A CH2P(O)R 11C R 11D , -PO q11 R 11A , -PO r11 R 11C R 11D , -PO r11 NR 11A R 11B , 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.

[0243] R 12 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, 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.

[0244] R 13 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, 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.

[0245] R 14 is -CH2OR 14A , -C(O)OR 14B, or -CH2OC(=NH)R 14C is.

[0246] R 15 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCHI, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, 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.

[0247] R 16 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCHI, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, 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.

[0248] R 17 is =O, =S, or =NR 17A is.

[0249] Each R 11A , R 11B , R 11C , and R 11Dare independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -OSOH, -NH2, -COOH, -CONH2, -NO2, -SH, 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 are attached to the same nitrogen atom 11A and R 11B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl.

[0250] R 14A and R 14B are independently hydrogen or unsubstituted C1-C5 alkyl.

[0251] R 14C is an unsubstituted C1-C5 alkyl.

[0252] R 17A are independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —OSOH, —NH2, —COOH, —CONH2, —NO2, —SH, 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.

[0253] X 11 is -Cl, -Br, -I, or -F.

[0254] n11 is an integer of 0 to 4.

[0255] v11 is either 1 or 2.

[0256] m11 is an integer of 0 to 3.

[0257] Each q11 and r11 is independently 1 or 2.

[0258] z16 is independently an integer of 0 to 8.

[0259] In embodiments, an MHC-peptide antigen stabilizing compound has the formula: [ka] or a salt thereof is provided herein. 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and z16 are as described herein, including embodiments. In embodiments, the MHC-peptide antigen stabilization compound has the formula: [ka] or a salt thereof. 11 , R 12 , R 13 , R 14 , R 15 , R 16 and z16 are as described herein, including embodiments. In embodiments, the MHC-peptide antigen stabilization compound has the formula: [ka] or a salt thereof. 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and z16 are as described herein, including embodiments.

[0260] In embodiments, an MHC-peptide antigen stabilizing compound has the formula: [ka] or salts thereof are provided herein, R 11 However, hydrogen, halogen, -CX 11 3. -CHX 11 2. -CH2X 11 , -OCX 11 3. -OCH2X 11 , -OCHX 11 2, -CN, -SO n11 R 11D , -SO v11 NR 11A R 11B , -NHC(O)NR 11A R 11B , -N(O) m11 , -NR 11A R 11B , -C(O)R 11C , -C(O)-OR 11C , -C(O)NR 11A R 11B , -OR 11D , -NR 11A CH2C(O)R 11C , -NR 11A CH2SO2R 11D , -NR 11A SO2R 11D , -NR 11A C(O)R 11C , -NR 11A C(O)OR 11C , -NR 11A OR 11C , -NR 11A OSO2R 11D , -NR 11A OCH2C(O)R 11C , -NR 11A CH2P(O)R 11C R 11D , -PO q11 R 11A , -PO r11 R 11C R 11D , -PO r11 NR 11A R 11B, 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 12 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, 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 13 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, 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 14 But -CH2OR 14A , -C(O)OR 14B , or -CH2OC(=NH)R 14C and R 15 is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCH2I, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, 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 R16 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCH2I, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, 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 17 but =O, =S, or =NR 17A and each R 11A , R 11B , R 11C , and R 11D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -OSOH, -NH2, -COOH, -CONH2, -NO2, -SH, 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 are attached to the same nitrogen atom 11A and R 11B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, R 14A and R 14B are independently hydrogen or unsubstituted C1-C5 alkyl, and R 14C is unsubstituted C1-C5 alkyl, and R 17Aare independently hydrogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —OSO3H, —NH2, —COOH, —CONH2, —NO2, —SH, 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 X 11 is -Cl, -Br, -I, or -F; n11 is independently an integer of 0 to 4; v11 is independently 1 or 2; m11 is independently an integer of 0 to 3; each q11 and r11 is independently 1 or 2; and z16 is independently an integer of 0 to 8.

[0261] In embodiments, R 12 is hydrogen.

[0262] In embodiments, R 13 is hydrogen.

[0263] In embodiments, R 15 is hydrogen.

[0264] In embodiments, R 14 is -CH2OR 14A is.

[0265] In embodiments, R 14A is hydrogen. In embodiments, R 14A is unsubstituted C1-C5 alkyl. In embodiments, R 14A is unsubstituted methyl. In embodiments, R 14A is unsubstituted ethyl. In embodiments, R 14A is unsubstituted propyl.

[0266] In embodiments, R 14B is hydrogen. In embodiments, R 14B is unsubstituted C1-C5 alkyl. In embodiments, R 14Bis unsubstituted methyl. In embodiments, R 14B is unsubstituted ethyl. In embodiments, R 14B is unsubstituted propyl.

[0267] In embodiments, R 14C is unsubstituted methyl. In embodiments, R 14C is unsubstituted ethyl. In embodiments, R 14C is unsubstituted propyl.

[0268] In embodiments, the MHC-peptide antigen stabilization compound has the formula: [ka] or a salt thereof. 11 , R 16 , R 17 , and z16 are as described herein, including embodiments.

[0269] In embodiments, the MHC-peptide antigen stabilization compound has the formula: [ka] or a salt thereof. 11 , R 16 , R 17 , and z16 are as described herein, including embodiments.

[0270] In embodiments, the MHC-peptide antigen stabilization compound has the formula: [ka] or a salt thereof. 11 , R 16 , R 17 , and z16 are as described herein, including embodiments.

[0271] In embodiments, the MHC-peptide antigen stabilization compound has the formula: [ka] or a salt thereof. 11 , R 16 , R 17 , and z16 are as described herein, including embodiments.

[0272] In embodiments, R 16 are independently hydrogen or —OH.

[0273] In an embodiment, z16 is 1 or 2.

[0274] In an embodiment, z16 is 0.

[0275] In embodiments, R 11 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -ONH2, -NR 11A R 11B , -COOH, -COO(C1-C4 alkyl), -CONH2, -NO2, -SH, -SO2OH, -SO4NH, -PO(OH)2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N 3、 It is 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.

[0276] In embodiments, R 11 is -NR 11A R 11B is.

[0277] In embodiments, R 11 is 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.

[0278] In embodiments, R 11A and R 11B are independently hydrogen, 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 11A and R 11B The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0279] In embodiments, R 11A and R 11B are independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C3-C6 cycloalkyl.

[0280] In embodiments, R 11A and R 11B The substituents are linked to form a substituted or unsubstituted 4- to 6-membered heterocycloalkyl or a substituted or unsubstituted 5- to 6-membered heteroaryl.

[0281] In embodiments, R 11A and R 11B are independently hydrogen, —COCHCH2, —CH2COOH, —CH2SO2OH, —OSO2OH, —CH2P(O)(OH)2, or —OCH2COOH.

[0282] In embodiments, R 1 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO n1 R 1A , -SO v1 NR 1A R 1B , -POm1 R 1A , -PO r1 NR 1A R 1B , substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 1 is substituted with one or more substituents. In embodiments, R 1 is substituted with one or more size-limited substituents. In embodiments, R 1 is substituted with one or more lower substituents.

[0283] 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 1When 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 substituted, R is substituted with at least one substituent. 1 When substituted, R is substituted with at least one size-limited substituent. 1 When substituted, it is substituted with at least one lower substituent.

[0284] In embodiments, R 2 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO n2 R 2A , -SO v2 NR 2A R 2B , -PO m2 R 2A , -PO r2 NR 2A R 2B , -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 2 is substituted with one or more substituents. In embodiments, R 2 is substituted with one or more size-limited substituents. In embodiments, R 2 is substituted with one or more lower substituents.

[0285] 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 substituted, R is substituted with at least one substituent. 2 When substituted, R is substituted with at least one size-limited substituent. 2 When substituted, it is substituted with at least one lower substituent.

[0286] In embodiments, R 3is hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CH2Cl, —CH2Br, —CH2F, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 3 is substituted with one or more substituents. In embodiments, R 3 is substituted with one or more size-limited substituents. In embodiments, R 3 is substituted with one or more lower substituents.

[0287] 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 substituted, R is substituted with at least one substituent. 3 When substituted, R is substituted with at least one size-limited substituent. 3 When substituted, it is substituted with at least one lower substituent.

[0288] In embodiments, R 4 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 4A , -NR 4A R 4B , -COOR 4A , -CONR 4A R 4B , -NO2, -SR 4A , -SO n4 R 4A , -SO v4 NR 4A R 4B , -PO(OH)2, -PO m4 R 4A , -PO r4 NR 4A R 4B, substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 4 is substituted with one or more substituents. In embodiments, R 4 is substituted with one or more size-limited substituents. In embodiments, R 4 is substituted with one or more lower substituents.

[0289] 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 substituted, R is substituted with at least one substituent. 4 When substituted, R is substituted with at least one size-limited substituent. 4 When substituted, it is substituted with at least one lower substituent.

[0290] In embodiments, R 5 is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 5A , -NR 5A R 5B , -COOH, -CONH2, -NO2, -SH, -SO n5 R 5A , -PO(OH)2, -PO m5 R 5A , -PO r5 NR 5A R 5B , substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 5 is substituted with one or more substituents. In embodiments, R 5 is substituted with one or more size-limited substituents. In embodiments, R 5 is substituted with one or more lower substituents.

[0291] 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 substituted, R is substituted with at least one substituent. 5 When substituted, R is substituted with at least one size-limited substituent. 5 When substituted, it is substituted with at least one lower substituent.

[0292] In embodiments, R 6is hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 6A , -NH2, -COOH, -CONH2, -NO2, -SH, -SO n6 R 6A , -SO v6 NR 6A R 6B , -PO(OH)2, -PO m6 R 6A , -PO r6 NR 6A R 6B , substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 6 is substituted with one or more substituents. In embodiments, R 6 is substituted with one or more size-limited substituents. In embodiments, R 6is substituted with one or more lower substituents.

[0293] 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 substituted, R is substituted with at least one substituent. 6 When substituted, R is substituted with at least one size-limited substituent. 6 When substituted, it is substituted with at least one lower substituent.

[0294] In embodiments, R 7 represents hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OR 7A , -NH2, -COOH, -CONH2, -NO2, -SH, -SO n7 R 7A , -SO v7 NR 7A R 7B , -PO(OH)2, -PO m7 R 7A , -PO r7 NR 7A R 7B, substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 7 is substituted with one or more substituents. In embodiments, R 7 is substituted with one or more size-limited substituents. In embodiments, R 7 is substituted with one or more lower substituents.

[0295] In embodiments, the substitution R 7 (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 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 substituted, R is substituted with at least one substituent. 7 When substituted, R is substituted with at least one size-limited substituent. 7 When substituted, it is substituted with at least one lower substituent.

[0296] In embodiments, R 8 are hydrogen, halogens, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO n8 R 8A , -SO v8 NR 8A R 8B , -PO(OH)2, -PO m8 R 8A , -PO r8 NR 8A R 8B , substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl, or phenyl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heteroaryl (e.g., a 5-10 membered heteroaryl, a 5-9 membered heteroaryl, or a 5-6 membered heteroaryl), substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., a C3-C8 cycloalkyl, a C3-C6 cycloalkyl, or a C5-C6 cycloalkyl), or substituted (e.g., having a substituent, size-limiting substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3-8 membered heterocycloalkyl, a 3-6 membered heterocycloalkyl, or a 5-6 membered heterocycloalkyl). 8 is substituted with one or more substituents. In embodiments, R 8 is substituted with one or more size-limited substituents. In embodiments, R 8 is substituted with one or more lower substituents.

[0297] In embodiments, the substitution R 8 (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 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 substituted, R is substituted with at least one substituent. 8 When substituted, R is substituted with at least one size-limited substituent. 8 When substituted, it is substituted with at least one lower substituent.

[0298] In embodiments, R 1A , R 1B , R 2A , R 2B , R 4A , R4B , R 5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , and R 8B are independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 1A , R 1B , R 2A , R 2B , R 4A , R 4B , R5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , and R 8B is independently substituted with one or more substituents. In embodiments, each R 1A , R 1B , R 2A , R 2B , R 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , and R 8B is independently substituted with one or more size-limited substituents. In embodiments, each R 1A , R 1B , R 2A , R 2B , R 4A , R 4B , R 5A , R 5B , R 6A , R 6B , R 7A , R 7B , R 8A , and R 8B is independently substituted with one or more lower substituents.

[0299] In embodiments, R 1Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 1A is independently substituted with one or more substituents. In embodiments, each R 1A is independently substituted with one or more size-limited substituents. In embodiments, each R 1A is independently substituted with one or more lower substituents.

[0300] 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 substituted, R is substituted with at least one substituent. 1A When substituted, R is substituted with at least one size-limited substituent. 1A When substituted, it is substituted with at least one lower substituent.

[0301] In embodiments, R 1Bare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 1B is independently substituted with one or more substituents. In embodiments, each R 1B is independently substituted with one or more size-limited substituents. In embodiments, each R 1B is independently substituted with one or more lower substituents.

[0302] 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 substituted, R is substituted with at least one substituent. 1B When substituted, R is substituted with at least one size-limited substituent. 1B When substituted, it is substituted with at least one lower substituent.

[0303] In embodiments, R 2Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 2A is independently substituted with one or more substituents. In embodiments, each R 2A is independently substituted with one or more size-limited substituents. In embodiments, each R 2A is independently substituted with one or more lower substituents.

[0304] In embodiments, the substitution R 2A(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 2A 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. 2A When substituted, R is substituted with at least one substituent. 2A When substituted, R is substituted with at least one size-limited substituent. 2A When substituted, it is substituted with at least one lower substituent.

[0305] In embodiments, R 2Bare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 2B is independently substituted with one or more substituents. In embodiments, each R 2B is independently substituted with one or more size-limited substituents. In embodiments, each R 2B is independently substituted with one or more lower substituents.

[0306] In embodiments, the substitution R 2B(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 2B 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. 2B When substituted, R is substituted with at least one substituent. 2B When substituted, R is substituted with at least one size-limited substituent. 2B When substituted, it is substituted with at least one lower substituent.

[0307] In embodiments, R 4Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4A is independently substituted with one or more substituents. In embodiments, each R 4A is independently substituted with one or more size-limited substituents. In embodiments, each R 4A is independently substituted with one or more lower substituents.

[0308] 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 substituted, R is substituted with at least one substituent. 4A When substituted, R is substituted with at least one size-limited substituent. 4A When substituted, it is substituted with at least one lower substituent.

[0309] In embodiments, R 4Bare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4B is independently substituted with one or more substituents. In embodiments, each R 4B is independently substituted with one or more size-limited substituents. In embodiments, each R 4B is independently substituted with one or more lower substituents.

[0310] 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 substituted, R is substituted with at least one substituent. 4B When substituted, R is substituted with at least one size-limited substituent. 4B When substituted, it is substituted with at least one lower substituent.

[0311] In embodiments, R 4Care independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4C is independently substituted with one or more substituents. In embodiments, each R 4C is independently substituted with one or more size-limited substituents. In embodiments, each R 4C is independently substituted with one or more lower substituents.

[0312] 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 substituted, R is substituted with at least one substituent. 4C When substituted, R is substituted with at least one size-limited substituent. 4C When substituted, it is substituted with at least one lower substituent.

[0313] In embodiments, R 4Dare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 4D is independently substituted with one or more substituents. In embodiments, each R 4D is independently substituted with one or more size-limited substituents. In embodiments, each R 4D is independently substituted with one or more lower substituents.

[0314] 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 substituted, R is substituted with at least one substituent. 4D When substituted, R is substituted with at least one size-limited substituent. 4D When substituted, it is substituted with at least one lower substituent.

[0315] In embodiments, R 5Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 5A is independently substituted with one or more substituents. In embodiments, each R 5A is independently substituted with one or more size-limited substituents. In embodiments, each R 5A is independently substituted with one or more lower substituents.

[0316] 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 substituted, R is substituted with at least one substituent. 5A When substituted, R is substituted with at least one size-limited substituent. 5A When substituted, it is substituted with at least one lower substituent.

[0317] In embodiments, R 5Bare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 5B is independently substituted with one or more substituents. In embodiments, each R 5B is independently substituted with one or more size-limited substituents. In embodiments, each R 5B is independently substituted with one or more lower substituents.

[0318] 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 substituted, R is substituted with at least one substituent. 5B When substituted, R is substituted with at least one size-limited substituent. 5B When substituted, it is substituted with at least one lower substituent.

[0319] In embodiments, R 6Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 6A is independently substituted with one or more substituents. In embodiments, each R 6A is independently substituted with one or more size-limited substituents. In embodiments, each R 6A is independently substituted with one or more lower substituents.

[0320] 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 6A 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. 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.

[0321] In embodiments, R 6Bare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 6B is independently substituted with one or more substituents. In embodiments, each R 6B is independently substituted with one or more size-limited substituents. In embodiments, each R 6B is independently substituted with one or more lower substituents.

[0322] 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.

[0323] In embodiments, R 7Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 7A is independently substituted with one or more substituents. In embodiments, each R 7A is independently substituted with one or more size-limited substituents. In embodiments, each R 7A is independently substituted with one or more lower substituents.

[0324] In embodiments, the substitution R 7A(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 7A 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. 7A When substituted, R is substituted with at least one substituent. 7A When substituted, R is substituted with at least one size-limited substituent. 7A When substituted, it is substituted with at least one lower substituent.

[0325] In embodiments, R 7Bare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 7B is independently substituted with one or more substituents. In embodiments, each R 7B is independently substituted with one or more size-limited substituents. In embodiments, each R 7B is independently substituted with one or more lower substituents.

[0326] In embodiments, the substitution R 7B(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 7B 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. 7B When substituted, R is substituted with at least one substituent. 7B When substituted, R is substituted with at least one size-limited substituent. 7B When substituted, it is substituted with at least one lower substituent.

[0327] In embodiments, R 8Aare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 8A is independently substituted with one or more substituents. In embodiments, each R 8A is independently substituted with one or more size-limited substituents. In embodiments, each R 8A is independently substituted with one or more lower substituents.

[0328] In embodiments, the substitution R 8A(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 8A 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. 8A When substituted, R is substituted with at least one substituent. 8A When substituted, R is substituted with at least one size-limited substituent. 8A When substituted, it is substituted with at least one lower substituent.

[0329] In embodiments, R 8Bare independently hydrogen, -CX, -CHX, -CHX, -CN, -OH, -NH, -COOH, -CONH, -NO, -SH, -SO, -SO, -SO, -NH, -ONH, -NHC=(O)NHNH, -NHC=(O)NH, -NHSO, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX, -OCHX, -OCHX, substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted alkyl (e.g., C-C alkyl, C-C alkyl, or C-C alkyl), substituted (e.g., with a substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaromatic group. alkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted (e.g., having a substituent, size-limited substituent, or lower substituent) or unsubstituted aryl (e.g., C6-C 10 Aryl, C 10 aryl, or phenyl), or substituted (e.g., with a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). 8B is independently substituted with one or more substituents. In embodiments, each R 8B is independently substituted with one or more size-limited substituents. In embodiments, each R 8B is independently substituted with one or more lower substituents.

[0330] In embodiments, the substitution R 8B(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 8B 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. 8B When substituted, R is substituted with at least one substituent. 8B When substituted, R is substituted with at least one size-limited substituent. 8B When substituted, it is substituted with at least one lower substituent.

[0331] In embodiments, R 1A and R 1B The substituents may optionally be linked to form a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), or a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In embodiments, R 1A and R 1B The substituted heterocycloalkyl or substituted heteroaryl formed by linking substituents is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkyl or substituted heteroaryl 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, R 1A and R 1BThe heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one substituent. In embodiments, R 1A and R 1B The heterocycloalkyl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 1A and R 1B The heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one lower substituent. In embodiments, R 1A and R 1B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 1A and R 1B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 1A and R 1B When substituted, the heteroaryl formed by linking the substituents is substituted with at least one lower substituent.

[0332] In embodiments, R 2A and R 2B The substituents may optionally be linked to form a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), or a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In embodiments, R 2A and R 2BThe substituted heterocycloalkyl or substituted heteroaryl formed by linking substituents is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkyl or substituted heteroaryl 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, R 2A and R 2B The heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one substituent. In embodiments, R 2A and R 2B The heterocycloalkyl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 2A and R 2B The heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one lower substituent. In embodiments, R 2A and R 2B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 2A and R 2B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 2A and R 2B When substituted, the heteroaryl formed by linking the substituents is substituted with at least one lower substituent.

[0333] In embodiments, R 4A and R 4BThe substituents may optionally be linked to form a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), or a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In embodiments, R 4A and R 4B The substituted heterocycloalkyl or substituted heteroaryl formed by linking substituents is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkyl or substituted heteroaryl 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, R 4A and R 4B The heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one substituent. In embodiments, R 4A and R 4B The heterocycloalkyl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 4A and R 4B The heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one lower substituent. In embodiments, R 4A and R 4B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 4A and R 4BThe heteroaryl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 4A and R 4B When substituted, the heteroaryl formed by linking the substituents is substituted with at least one lower substituent.

[0334] In embodiments, R 5A and R 5B The substituents may optionally be linked to form a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), or a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In embodiments, R 5A and R 5B The substituted heterocycloalkyl or substituted heteroaryl formed by linking substituents is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkyl or substituted heteroaryl 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, R 5A and R 5B The heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one substituent. In embodiments, R 5A and R 5B The heterocycloalkyl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 5A and R 5BThe heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one lower substituent. In embodiments, R 5A and R 5B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 5A and R 5B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 5A and R 5B When substituted, the heteroaryl formed by linking the substituents is substituted with at least one lower substituent.

[0335] In embodiments, R 6A and R 6B The substituents may optionally be linked to form a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heterocycloalkyl (e.g., a 3- to 8-membered heterocycloalkyl, a 3- to 6-membered heterocycloalkyl, or a 5- to 6-membered heterocycloalkyl), or a substituted (e.g., having a substituent, a size-limited substituent, or a lower substituent) or unsubstituted heteroaryl (e.g., a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl). In embodiments, R 6A and R 6B The substituted heterocycloalkyl or substituted heteroaryl formed by linking substituents is substituted with at least one substituent, size-limiting substituent, or lower substituent, and when the substituted heterocycloalkyl or substituted heteroaryl 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, R 6A and R 6BThe heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one substituent. In embodiments, R 6A and R 6B The heterocycloalkyl formed by linking the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 6A and R 6B The heterocycloalkyl formed by linking the substituents, when substituted, is substituted with at least one lower substituent. In embodiments, R 6A and R 6B The heteroaryl formed by linking the substituents, if substituted, is substituted with at least one substituent. In embodiments, R 6A and R 6B The moiety formed by the joining of the substituents, if substituted, is substituted with at least one size-limited substituent. In embodiments, R 6A and R 6B When substituted, the heteroaryl formed by linki...

Claims

1. 1. A method for identifying a candidate compound that stabilizes binding of an MHC protein to a peptide antigen, comprising: a. contacting an MHC protein with a peptide antigen and a candidate compound, thereby forming an MHC-peptide-compound complex; b. detecting an increased stability of the MHC-peptide-compound complex relative to the stability of the MHC-peptide complex, wherein the MHC-peptide complex comprises the MHC protein and the peptide antigen in the absence of the candidate compound, thereby identifying the candidate compound as one that stabilizes binding of the MHC protein to the peptide antigen.

2. 2. The method of claim 1, wherein the MHC protein binds to the peptide antigen with a Kd of greater than 1 micromolar.

3. 2. The method of claim 1, wherein the MHC protein of step a is unfolded.

4. 2. The method of claim 1, wherein the MHC protein is an MHC class I protein or an MHC class II protein.

5. 2. The method of claim 1, wherein the MHC protein is an MHC class I heavy chain protein.

6. 2. The method of claim 1, wherein the MHC protein is HLA-B*57:

01.

7. 1. A method of treating cancer in a subject in need thereof, comprising: (a) detecting an MHC allele of an MHC protein of said subject; (b) detecting a driver oncogene mutation in the subject; and (c) administering an effective amount of an MHC-peptide antigen stabilizing compound.

8. the MHC-peptide antigen stabilizing compound (i) contacting the MHC protein with a peptide cancer antigen and the MHC-peptide antigen stabilizing compound in vitro, thereby forming an MHC-peptide-compound complex; (ii) detecting an increased stability of the MHC-peptide-compound complex compared to the stability of the MHC-peptide complex comprising the MHC protein and the peptide cancer antigen in the absence of the MHC-peptide antigen stabilizing compound.

9. 8. The method of claim 7, wherein the MHC-peptide antigen stabilizing compound has a molecular weight of less than 750 g / mol.

10. 1. A method for identifying modified peptide-MHC protein allele binding pairs, comprising: a. contacting a plurality of different modified peptides with a plurality of different MHC protein alleles; b. detecting or computationally predicting binding of a first modified peptide to a first MHC protein allele, thereby identifying a modified peptide-MHC protein allele binding pair.

11. 11. The method of claim 10, wherein the first modified peptide is modified with tryptophan.

12. 11. The method of claim 10, wherein the plurality of different modified peptides are modified with tryptophan at the last residue.

13. 11. The method of claim 10, wherein the plurality of different modified peptides is derived from a driver oncogene protein.

14. The method of claim 10, wherein the plurality of different modified peptides is derived from a K-Ras protein.

15. The method of claim 10, wherein the plurality of different modified peptides is derived from a mutant K-Ras protein.

16. 16. The method of claim 15, wherein the mutant K-Ras protein is KRAS p.G12V.

17. The MHC-peptide antigen stabilizing compound has the following formula: 【Chemical 1】 or a salt thereof, During the ceremony, W, X, Y, and Z are each independently C or N; R １ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ｎ１ R １Ａ , -SO ｖ１ NR １Ａ R １Ｂ , -PO ｍ１ R １Ａ , -PO ｒ１ NR １Ａ R １Ｂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R ２ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, SO ｎ２ R ２Ａ , -SO ｖ２ NR ２Ａ R ２Ｂ , -PO ｍ２ R ２Ａ , -PO ｒ２ NR ２Ａ R ２Ｂ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -N ３ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R ３ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OR, -NH ２ , -COOH, -CONH ２ , -NO ２ , —SH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R ４ is hydrogen, oxo, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OR ４Ａ , -NR ４Ａ R ４Ｂ , -COOR ４Ａ , -CONR ４Ａ R ４Ｂ , -NO ２ , -SR ４Ａ , -SO ｎ４ R ４Ａ , -SO ｖ４ NR ４Ａ R ４Ｂ , -PO(OH) ２ , -PO ｍ４ R ４Ａ , -PO ｒ４ NR ４Ａ R ４Ｂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R ５ is hydrogen, oxo, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OR ５Ａ , -NR ５Ａ R ５Ｂ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ｎ５ R ５Ａ , -SO ｖ５ NR ５Ａ R ５Ｂ , -PO(OH) ２ , -PO ｍ５ R ５Ａ , -PO ｒ５ NR ５Ａ R ５Ｂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R ６ is hydrogen, oxo, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OR ６Ａ , -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ｎ６ R ６Ａ , -SO ｖ６ NR ６Ａ R ６Ｂ , -PO(OH) ２ , -PO ｍ６ R ６Ａ , -PO ｒ６ NR ６Ａ R ６Ｂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R ７ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OR ７Ａ , -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ｎ７ R ７Ａ , -SO ｖ７ NR ７Ａ R ７Ｂ , -PO(OH) ２ , -PO ｍ７ R ７Ａ , -PO ｒ７ NR ７Ａ R ７Ｂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R ８ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ｎ８ R ８Ａ , -SO ｖ８ NR ８Ａ R ８Ｂ , -PO(OH) ２ , -PO ｍ８ R ８Ａ , -PO ｒ８ NR ８Ａ R ８Ｂ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; Each R １Ａ , R １Ｂ , R ２Ａ , R ２Ｂ , R ４Ａ , R ４Ｂ , R ５Ａ , R ５Ｂ , R ６Ａ , R ６Ｂ , R ７Ａ , R ７Ｂ , R ８Ａ , and R ８Ｂ are independently hydrogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -SO ４ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC=(O)NHNH ２ , -NHC=(O)NH ２ , -NHSO ２ H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX ３ , -OCHX ２ , -OCH ２ X, 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 are attached to the same nitrogen atom. １Ａ and R １Ｂ The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl, and R ２Ａ and R ２Ｂ The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a 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, 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, 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, and R ７Ａ and R ７Ｂ The substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl, and R ８Ａ and R ８Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; X is independently —Cl, —Br, —I, or —F; each n1, n2, n4, n5, n6, n7, and n8 is independently an integer from 0 to 4; each v1, v2, v4, v5, v6, v7, and v8 is independently 1 or 2; each m1, m2, m4, m5, m6, m7, and m8 is independently an integer from 0 to 3; each r1, r2, r4, r5, r6, r7, and r8 is independently 1 or 2; each z1 and z3 is independently an integer from 0 to 5; z2 is an integer from 0 to 4, 2. The method of claim 1, wherein z4 is an integer from 0 to 3.

18. R １ is hydrogen or unsubstituted alkyl; R ３ is hydrogen or unsubstituted alkyl; R ２ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R ５ are independently hydrogen, oxo, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NR ５Ａ R ５Ｂ , -COOH, -CONH ２ , -NO ２ , —SH, substituted or unsubstituted heteroalkyl, or substituted or unsubstituted alkyl; R ４ is hydrogen, substituted or unsubstituted alkyl, or —SO ２ NR ４Ａ R ４Ｂ and R ６ is hydrogen, halogen, or substituted or unsubstituted alkyl; R ７ is hydrogen, or substituted or unsubstituted alkyl; R ８ is hydrogen, or substituted or unsubstituted alkyl; Each R ４Ａ , R ４Ｂ , R ５Ａ , and R ５Ｂ 18. The method of claim 17, wherein is independently hydrogen or substituted or unsubstituted alkyl.

19. R １ is hydrogen or methyl, R ３ is hydrogen or methyl, R ２ is methyl, unsubstituted cycloalkyl, unsubstituted aryl, or substituted heteroaryl; R ５ is hydrogen, oxo, methyl, halogen, unsubstituted heteroalkyl, or —NR ５Ａ R ５Ｂ and R ４ is hydrogen, methyl, or —SO ２ NR ４Ａ R ４Ｂ and R ６ is hydrogen or methyl, R ７ is hydrogen or methyl, R ８ is hydrogen or methyl, Each R ４Ａ , R ４Ｂ , R ５Ａ , and R ５Ｂ 18. The method of claim 17, wherein is independently hydrogen or methyl.

20. R １ is hydrogen or methyl, R ３ is hydrogen or methyl, R ２ is methyl, cyclopropyl, phenyl, or substituted 2H-indazole; R ５ is hydrogen, oxo, halogen, ethoxy, or —NR ５Ａ R ５Ｂ and R ４ is hydrogen, methyl, or —SO ２ NR ４Ａ R ４Ｂ and R ６ is hydrogen or methyl, R ７ is methyl, R ８ is methyl, Each R ４Ａ , R ４Ｂ , R ５Ａ , and R ５Ｂ 18. The method of claim 17, wherein is independently hydrogen or methyl.

21. Y and Z are N; 18. The method of claim 17, wherein W and X are C.

22. X and Y are N; 18. The method of claim 17, wherein W and Z are C.

23. The MHC-peptide antigen stabilizing compound has the following formula: 【Chemistry 2】 and During the ceremony, Each R ４Ｃ and R ４Ｄ are independently hydrogen, -CX ３ , -CHX ２ , -CH ２ X, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ３ H, -SO ４ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC=(O)NHNH ２ , -NHC=(O)NH ２ , -NHSO ２ H, -NHC=(O)H, -NHC(O)OH, -NHOH, -OCX ３ , -OCHX ２ , -OCH ２ X, 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 are attached to the same nitrogen atom. ４Ｃ and R ４Ｄ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R ３ is hydrogen or methyl, 18. The method of claim 17, wherein z1 is an integer from 0 to 4.

24. The MHC-peptide antigen stabilizing compound has the following formula: 【Chemistry 3】 24. The method of claim 23, comprising:

25. the MHC-peptide antigen stabilizing compound 【Chemistry 4】 or a salt thereof.

26. The MHC-peptide antigen stabilizing compound has the following formula: 【Chemistry 5】 or a salt thereof, During the ceremony, R １１ is hydrogen, halogen, -CX １１ ３ , -CHX １１ ２ , -CH ２ X １１ , -OCX １１ ３ , -OCH ２ X １１ , -OCHX １１ ２ , -CN, -SO ｎ１１ R １１Ｄ , -SO ｖ１１ NR １１Ａ R １１Ｂ , -NHC(O)NR １１Ａ R １１Ｂ , -N(O) ｍ１１ , -NR １１Ａ R １１Ｂ , -C(O)R １１Ｃ , -C(O)-OR １１Ｃ , -C(O)NR １１Ａ R １１Ｂ , -OR １１Ｄ , -NR １１Ａ CH ２ C(O)R １１Ｃ , -NR １１Ａ CH ２ , -SO ２ R １１Ｄ , -NR １１Ａ SO ２ R １１Ｄ , -NR １１Ａ C(O)R １１Ｃ , -NR １１Ａ C(O)OR １１Ｃ , -NR １１Ａ OR １１Ｃ , -NR １１Ａ OSO ２ R １１Ｄ , -NR １１Ａ OCH ２ C(O)R １１Ｃ , -NR １１Ａ CH ２ P(O)R １１Ｃ R １１Ｄ , -PO ｑ１１ R １１Ａ , -PO ｒ１１ R １１Ｃ R １１Ｄ , -PO ｒ１１ NR １１Ａ R １１Ｂ , 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 １２ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , —SH, 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 １３ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , —SH, 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 １４ But -CH ２ OR １４Ａ , -C(O)OR １４Ｂ , or -CH ２ OC(=NH)R １４Ｃ and R １５ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R １６ are independently hydrogen, halogen, or —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -OCCl ３ , -OCBr ３ , -OCF ３ , -OCI ３ , -OCH ２ Cl, —OCH ２ Br, —OCH ２ F, -OCH ２ I, —OCHCl ２ , -OCHBr ２ , -OCHF ２ , -OCHI ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R １７ is ═O, ═S, or ═NR １７Ａ and Each R １１Ａ , R １１Ｂ , R １１Ｃ , and R １１Ｄ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -OSO ３ H, —NH ２ , -COOH, -CONH ２ , -NO ２ , —SH, 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 are attached to the same nitrogen atom １１Ａ and R １１Ｂ the substituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R １４Ａ and R １４Ｂ are independently hydrogen or unsubstituted C １ -C ５ is alkyl, R １４Ｃ is unsubstituted C １ -C ５ is alkyl, R １７Ａ are independently hydrogen, —CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -OSO ３ H, —NH ２ , -COOH, -CONH ２ , -NO ２ , —SH, 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; X １１ is —Cl, —Br, —I, or —F; n11 is independently an integer of 0 to 4; v11 is independently 1 or 2; m11 independently represents an integer of 0 to 3; each q11 and r11 is independently 1 or 2; 2. The method of claim 1, wherein z16 is an integer from 0 to 8.

27. R １２ 27. The method of claim 26, wherein is hydrogen.

28. R １３ 27. The method of claim 26, wherein is hydrogen.

29. R １５ 27. The method of claim 26, wherein is hydrogen.

30. R １４ But -CH ２ OR １４Ａ 27. The method of claim 26, wherein:

31. R １４Ａ 31. The method of claim 30, wherein is hydrogen.

32. 27. The method of claim 26, wherein the MHC-peptide antigen stabilizing compound has the formula: 【Chemistry 6】

33. 27. The method of claim 26, wherein the MHC-peptide antigen stabilizing compound has the formula: 【Chemistry 7】

34. R １６ is independently hydrogen or —OH.

35. 33. The method of claim 32, wherein z16 is 1 or 2.

36. 33. The method of claim 32, wherein z16 is 0.

37. R １１ is hydrogen, halogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CH ２ Cl, —CH ２ Br, —CH ２ F, -CH ２ I, -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CN, -OH, -ONH ２ , -NR １１Ａ R １１Ｂ , -COOH, -COO(C １ -C ４ alkyl), -CONH ２ , -NO ２ , -SH, -SO ２ OH, -SO ２ NH ２ , -PO(OH) ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , —OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF 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.

38. R １１ But, -NR １１Ａ R １１Ｂ The method according to any one of claims 26 to 36, wherein

39. R １１ 37. The method of claims 26-36, wherein is hydrogen, 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.

40. R １１Ａ and R １１Ｂ are independently hydrogen, 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 are attached to the same nitrogen atom １１Ａ and R １１Ｂ 39. The method of claim 38, wherein the substituents can be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

41. R １１Ａ and R １１Ｂ are independently hydrogen, substituted or unsubstituted C １ -C ４ Alkyl, or substituted or unsubstituted C ３ -C ６ 39. The method of claim 38, wherein the alkyl is cycloalkyl.

42. R attached to the same nitrogen atom １１Ａ and R １１Ｂ 39. The method of claim 38, wherein the substituents are linked to form a substituted or unsubstituted 4- to 6-membered heterocycloalkyl or a substituted or unsubstituted 5- to 6-membered heteroaryl.

43. R １１Ａ and R １１Ｂ are independently hydrogen, -COCHCH ２ , -CH ２ COOH, -CH ２ SO ２ OH, -OSO ２ OH, -CH ２ P(O)(OH) ２ , or -OCH ２ 39. The method of claim 38, wherein the alkyl group is COOH.

44. the MHC-peptide antigen stabilizing compound 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 27. The method of claim 26, selected from the group consisting of:

45. 1. A method of vaccinating a subject against cancer, comprising: a. peptide cancer antigens, and b) administering a compound that stabilizes the binding of an MHC protein to said peptidic cancer antigen.

46. 1. A method of vaccinating a subject against cancer, comprising administering a peptide-compound conjugate, wherein the peptide-compound conjugate comprises a peptide cancer antigen linked to a compound via a chemical bond.

47. 1. A method of vaccinating a subject against cancer, comprising: a. peptide cancer antigens, and b) A method comprising administering a compound that stabilizes binding of an MHC protein to the peptide cancer antigen, wherein the MHC-peptide cancer antigen stabilizing compound is identified by the method of claim 1.

48. 46. The method of claim 45, wherein the vaccine is administered in a single formulation.

49. 1. A composition comprising an MHC protein, a peptide antigen, and a compound, wherein the MHC protein, the peptide antigen, and the compound combine to form an MHC-peptide-compound complex, and the compound stabilizes binding of the MHC protein to the peptide antigen compared to the absence of the compound.

50. 50. The composition of claim 49, wherein the MHC protein is covalently linked to the peptide antigen.

51. 50. The composition of claim 49, wherein the MHC protein is covalently linked to the peptide antigen via a disulfide bond.

52. 52. The composition of claim 51, wherein a cysteine amino acid in the MHC protein forms part of the disulfide bond.

53. 50. The composition of claim 49, wherein the compound is covalently attached to the peptide antigen.

54. 54. The composition of claim 53, wherein the compound is covalently attached to the peptidic antigen via a reaction between an electrophilic moiety on the compound and a nucleophilic moiety on the peptidic antigen.

55. 55. The composition of claim 54, wherein the nucleophilic moiety is a cysteine sulfhydryl group.

56. 55. The composition of claim 54, wherein the nucleophilic group is a lysine amine group.

57. A composition comprising an MHC protein covalently linked to a peptide antigen.

58. 58. The composition of claim 57, wherein the MHC protein is covalently linked to the peptide antigen via a disulfide bond.

59. 59. The composition of claim 58, wherein a cysteine amino acid in the MHC protein forms part of the disulfide bond.

60. A composition comprising a peptide antigen covalently attached to a compound.

61. 61. The composition of claim 60, wherein the compound is covalently attached to the peptidic antigen via a reaction between an electrophilic moiety on the compound and a nucleophilic moiety on the peptidic antigen.

62. 62. The composition of claim 61, wherein the nucleophilic moiety is a cysteine sulfhydryl group.

63. 62. The composition of claim 61, wherein the nucleophilic group is a lysine amine group.

64. A compound having the formula: 【Chemistry 9】 Or their salts.

65. A compound having the formula: 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 Or their salts.

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