Covalent inhibitors of the G12S, G12D, and / or G12E mutants of K-RAS GTPase

Abstract

Described herein are, among other things, GTPase inhibitors and uses thereof.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 322,528, filed March 22, 2022, U.S. Provisional Application No. 63 / 313,040, filed February 23, 2022, and U.S. Provisional Application No. 63 / 292,910, filed December 22, 2021, which are incorporated by reference in their entireties for all purposes.

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (048536-724001WO_Sequence_Listing_ST26.xml; size: 75,428 bytes; creation date: December 14, 2022) are incorporated herein by reference in their entirety. [Background technology]

[0003] Drugs that directly interfere with the function of driver oncogenes offer exceptional efficacy and therapeutic window for the treatment of cancer. The recently approved mutant-selective small molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, offers an immediate answer. KRAS is the most frequently mutated proto-oncogene in human cancers, but despite the success of targeting the G12C allele, targeted therapies against other hotspot mutants of KRAS have never been described. Oncogenic mutations of Ras are among the most common genetic alterations in human cancers, with an estimated disease burden of more than 3 million patients per year worldwide. In the KRAS gene, a nucleotide transition from GGT to GAT at codon 12 (c.35 G>A) gives rise to KRAS G12D, the most frequent Ras mutation accounting for approximately 23% of Ras-driven cancers. Selective targeting of KRAS G12D while sparing wild-type KRAS is a highly desirable therapeutic goal pursued by many research groups as it would enable a large therapeutic window for cancer treatment. Disclosed herein, inter alia, are solutions to these and other problems in the art. Summary of the Invention

[0004] In one aspect, a compound having the formula:

[0005] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0006] R 1 is the Switch II binding pocket binding moiety.

[0007] L 1 is a bond or a bivalent linker.

[0008] E 1is an electrophilic moiety capable of forming a covalent bond with a switch II GTPase protein serine residue or a switch II GTPase protein threonine residue.

[0009] In one aspect, a compound having the formula:

[0010] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0011] R 1 is the Switch II binding pocket binding moiety.

[0012] L 1 is a bond or a bivalent linker.

[0013] E 2 is an electrophilic moiety capable of forming a covalent bond with a Switch II GTPase protein aspartic acid residue or a Switch II GTPase protein glutamic acid residue.

[0014] In one aspect, a pharmaceutical composition is provided comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0015] In one aspect, a method of treating cancer in a subject in need thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0016] In one aspect, a method is provided for treating a K-Ras(G12S) associated disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0017] In one aspect, a method is provided for treating an H-Ras(G12S) associated disease in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0018] In one aspect, a method is provided for treating an N-Ras(G12S) associated disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0019] In one aspect, a method of treating a K-Ras(G12D) associated disease in a subject in need thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0020] In one aspect, a method of treating an H-Ras(G12D) associated disease in a subject in need thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0021] In one aspect, a method is provided for treating an N-Ras(G12D) associated disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0022] In one aspect, a method of modulating the level of activity of a K-Ras protein in a cell is provided, the method comprising contacting the cell with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0023] In one aspect, a method of modulating the level of activity of an H-Ras protein in a cell is provided, the method comprising contacting the cell with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0024] In one aspect, a method of modulating the level of activity of an N-Ras protein in a cell is provided, comprising contacting the cell with an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof.

[0025] In one aspect, there is provided a K-Ras protein covalently bound to a compound described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is covalently bound to a serine residue in the K-Ras protein.

[0026] In one aspect, there is provided an H-Ras protein covalently linked to a compound described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is covalently linked to a serine residue in the H-Ras protein.

[0027] In one aspect, there is provided an N-Ras protein covalently linked to a compound described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is covalently linked to a serine residue in the N-Ras protein.

[0028] In one aspect, there is provided a K-Ras protein covalently linked to a compound described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is covalently linked to an aspartic acid residue of the K-Ras protein.

[0029] In one aspect, there is provided an H-Ras protein covalently linked to a compound described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is covalently linked to an aspartic acid residue of the H-Ras protein.

[0030] In one aspect, there is provided an N-Ras protein covalently linked to a compound described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is covalently linked to an aspartic acid residue of the N-Ras protein. [Brief description of the drawings]

[0031] [Figure 1A] Immunoblots of Ba / F3 cells expressing wild-type K-Ras, K-Ras(G12S), or K-Ras(G12C). Cells were lysed and analyzed 10 min after IL-3 was removed from the culture medium. Data are representative of two experiments using independently generated Ba / F3 transfectants. [Figure 1B] Growth of Ba / F3 transductants in the absence of IL-3. Data are representative of two experiments using independently generated Ba / F3 transductants. Error bars represent standard deviation. [Figure 1C] Intrinsic and NF1-mediated single-turnover GTPase activity of wild-type K-Ras (circles), K-Ras(G12S) (squares), and K-Ras(G12C) (triangles) (n=3). Error bars represent standard deviation. [Figure 2A] Structure of β-lactones 1' and 2'. [Figure 2B] Covalent modification of 4 μM recombinant K-Ras(G12S)·GDP or wild-type K-Ras·GDP proteins treated with 10 μM 1' (first bar in each set of two) or 2' (second bar in each set of two) as assessed by total protein mass spectrometry (n=3). [Figure 2C] Differential scanning fluorimetry of unmodified K-Ras(G12S)·GDP (black) and the K-Ras(G12S)·GDP·1' complex (gray) (n=3). [Figure 2D] Schematic illustration of a biochemical assay that uses fluorescent-GDP analogues to monitor nucleotide exchange. [Figure 2E] Nucleotide exchange of wild-type K-Ras (circles), K-Ras(G12S) (squares), or K-Ras(G12S)·1' adduct (triangles) in the presence of magnesium (endogenous), Sos, or EDTA (n=3). [Figure 2F] X-ray cocrystal structure of the K-Ras(G12S)·GDP·1' complex. The 2Fo-Fc map for ligand 1' and serine 12 is shown in grey shading (1.0σ). [Figure 2G] Scheme representation of the nucleophilic ring opening of the β-lactone in 1′ by serine 12. [Figure 3A] Structure of K-Ras (G12S) ligand 3'-5'. [Figure 3B] Time-dependent covalent modification of recombinant K-Ras(G12S)·GDP protein by 10 μM compounds (ADA: circles; compound 3': squares; compound 4: up triangles; compound 5': down triangles) at 23 °C assessed by total protein mass spectrometry (n = 3, replicates are plotted as individual data points). [Figure 3C] Immunoblot of A549 cells treated with 10 μM adagrasib 3', 4', or 5' for 2 hours. Data are representative of two independent experiments. [Figure 3D] Immunoblot of A549 cells treated for 2 hours with various concentrations of 5'. Data are representative of two independent experiments. [Figure 3E] Immunoblots of A549, A375, SW1990, and H358 cells treated with DMSO or 10 μM 5' for 2 hours. Data are representative of two independent experiments. [Figure 3F] Relative growth of Ba / F3 parental cells (+10 ng / mL IL-3) (circles) and Ba / F3:K-Ras(G12S) cells (no IL-3) (squares) after treatment with adagrasib or 5' for 72 hours. Data are representative of three independent experiments. [Figure 4] Measurement of Ki and kinact for the reaction between K-Ras(G12S)·GDP and compound 1. [Diagram 5] Compound 1' does not react with GppNHp-loaded K-Ras(G12S). [Figure 6A] Comparison of the structure of the K-Ras(G12S)·GDP·compound 1' adduct bound by an electrophilic ligand with the reported crystal structure of K-Ras(G12C)·GDP. Crystal structure of K-Ras(G12S)·GDP·compound 1' adduct. [Figure 6B]Comparison of the structure of the K-Ras(G12S)·GDP·compound 1' adduct bound by an electrophilic ligand with the reported crystal structure of K-Ras(G12C)·GDP. Crystal structure of K-Ras(G12C)·GDP·adaglasib adduct (PDB: 6USZ). [Figure 6C] Comparison of the structure of the K-Ras(G12S)·GDP·compound 1' adduct bound by an electrophilic ligand with the reported crystal structure of K-Ras(G12C)·GDP. Switch II pocket: Conformational superposition of the covalent ligands compound 1', adagrasib (PDB:6USZ), sotorasib (PDB:6OIM), and ARS1620 (PDB:5V9U). [Figure 7] Phospho-ERK levels in BaF3 parental cells (+10 ng / mL IL-3) (circles) and BaF3 / K-Ras(G12S) cells (no IL-3) (squares) after treatment with adagrasib or 5' for 1 hour. [Figure 8] Sanger sequencing of KRAS exon 2 of G12S-mutant cell lines. Genomic DNA sequence is presented as the antisense strand. Arrow indicates c.34G>A mutation. A549 and KMS20 ​​were determined to carry homozygous KRAS p.G12S mutations, and HKA-1 and LS123 were determined to carry heterozygous KRAS p.G12S mutations. Sequence: K-Ras GASGVGKS (residues 10-17 of SEQ ID NO:4) or GAGGVGKS (residues 10-17 of SEQ ID NO:1). gDNA (antisense): ACTCTTGCCTACGCCACTAGCTCCA (SEQ ID NO:5). [Figure 9] Validation of mutant-specific Ras(G12S) antibodies. Pan-Ras (abcam108602) and mutant-specific Ras(G12S) (NewEast Bio26186) were used to detect recombinant K-Ras wild-type, K-Ras(G12S), and K-Ras(G12S)·1' adducts. [Figure 10] Uncropped immunoblot image of Figure 1A. [Figure 11] Uncropped immunoblot image in Figure 3C. [Figure 12]Uncropped immunoblot image in Figure 3D. NOTE: Due to limitations in gel size (12 wells), samples (1–10 and 11–14) were run on two separate gels and transferred onto a single membrane in a single transfer sandwich. Due to technical difficulties in perfectly aligning the gels during transfer, some bands are vertically offset between the two gels. [Figure 13]Examples of GTPases that contain a serine at position 12 or an equivalent position (i.e., corresponding to position 12): human KRas (UniProt P01116): MTEYKLVVVGASGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSA (residues 1-66 of SEQ ID NO: 4), human ERas (UniProt Q7Z444): MELPTKPGTFDLGLATWSPSFQGETHRAQARRRDVGRQLPEYKAVVVGASGVGKSALTIQLNHQCFVEDHDPTIQDSYWKELTLDSGDCILNVLDTAGQAIHRA (SEQ ID NO: 6), human RASD1 (UniProt Q9Y272):MKLAAMIKKMCPSDSELSIPAKNCYRMVILGSSKVGKTAIVSRFLTGRFEDAYTPTIEDFHRKFYSIRGEVYQLDILDTSGNHPFPA (SEQ ID NO: 7), human Rhes (UniProt Q96D21):MMKTLSSGNCTLSVPAKNSYRMVVLGASRVGKSSIVSRFLNGRFEDQYTPTIEDFHRKVYNIRGDMYQLDILDTSGNHPFPA (SEQ ID NO: 8), human RASL11B (UniProt Q9BPW5):MRLIQNMCTIAEYPAPGNAAASDCCVGAAGRRLVKIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVQIEGETLALQVQDTPGIQVHENSL (SEQ ID NO: 9), human REM2 (UniProt Q8IYK8):GAPRRRGSMPVPYKHQLRRAQAVDELDWPPQASSSGSSDSLGSGEAAPAQKDGIFKVMLVGESGVGKSTLAGTFGGLQGDSAHEPENPEDTYERRIMVDKEEVTLVVYDIWEQGD (SEQ ID NO: 10). Only a partial sequence alignment is shown. The K-Ras sequence (RASK_HUMAN) is shown as the G12S mutant. [Figure 14]Examples of GTPases that contain a serine at position 12 or an equivalent position (i.e., corresponding to position 12): human KRas (UniProt P01116): MTEYKLVVVGASGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQ (residues 1-99 of SEQ ID NO: 4), human RHOH (UniProt Q15669): MLSSIKCVLVGDSAVGKTSLLVRFTSETFPEAYKPTVYENTGVDVFMDGIQISLGLWDTAGNDAFRSIRPLSYQQADVVLMCYSVANHNSFLNLKNKWIGE (SEQ ID NO: 11), human RND3 (UniProt P61587):MKERRASQKLSSKSIMDPNQNVKCKIVVVGDSQCGKTALLHVFAKDCFPENYVPTVFENYTASFEIDTQRIELSLWDTSGSPYYDNVRPLSYPDSDAVLICFDISRPETLDSVLKKWKGE (SEQ ID NO: 12). Only partial sequence alignment is shown. K-Ras sequence (RASK_HUMAN) is shown as G12S mutant. [Figure 15]Examples of GTPases that contain a serine at position 12 or an equivalent position (i.e., corresponding to position 12): human KRas (UniProt P01116): MTEYKLVVVGASGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPM (residues 1-111 of SEQ ID NO: 4), human RAB1A (UniProt P62820): MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNK (SEQ ID NO: 13), human RAB1B (UniProt P62820): MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNK (SEQ ID NO: 13), Q9H0U4): MNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESYANVKQWLQEIDRYASENVNK (SEQ ID NO: 14), human RAB2A (UniProt P61019): MAYAYLFKYIIIGDTGVGKSCLLLQFTDKRFQPVHDLTIGVEFGARMITIDGKQIKLQIWDTAGQESFRSITRSYYRGAAGALLVYDITRRDTFNHLTTWLEDARQHSNSNMVI (SEQ ID NO: 15), human RAB2B (UniProt Q8WUD1):MTYAYLFKYIIIGDTGVGKSCLLLQFTDKRFQPVHDLTIGVEFGARMVNIDGKQIKLQIWDTAGQESFRSITRSYYRGAAGALLVYDITRRETFNHLTSWLEDARQHSSSNMVI (SEQ ID NO: 16). Only partial sequence alignment is shown. K-Ras sequence (RASK_HUMAN) is shown as G12S mutant. [Figure 16]Examples of GTPases that contain a serine at position 12 or an equivalent position (i.e., corresponding to position 12): human KRas (UniProt P01116): MTEYKLVVVGASGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVP (residues 1-110 of SEQ ID NO: 4), human GNAZ (UniProt P19086): MGCRQSSEEKEAARRSRRIDRHLRSESQRQRREIKLLLLGTSNSGKSTIVKQMKIIHSGGFNLEACKEYKPLIIYNAIDSLTRIIRALAALRIDFHNPDRAYDAVQLFALTGPAESKGEITPELLGVMRRLWADPGAQACFSRSSEYHLEDNAAYYLNDLERIAAADYIP (SEQ ID NO: 17). Only a partial sequence alignment is shown. The K-Ras sequence (RASK_HUMAN) is shown as the G12S mutant. [Figure 17] Examples of GTPases that contain a serine at position 12 or an equivalent position (i.e., corresponding to position 12): human KRas (UniProt P01116): MTEYKLVVVGASGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQR (SEQ ID NO: 4), human LRRK2 ... Q5S007):FLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQIRDKRKRDLVLNWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNAT (SEQ ID NO: 18). Only partial sequence alignment is shown. K-Ras sequence (RASK_HUMAN) is shown as G12S mutant. [Figure 18A]β-Propiolactone covalently modifies mutant aspartates in K-Ras(G12D). Schematic showing the reaction between aspartate residues and β-propiolactone. [Figure 18B] β-propiolactone covalently modifies the mutant aspartic acid in K-Ras(G12D). MS / MS spectrum of β-propiolactone modified K-Ras(G12D) peptide. Sequence: LVVVGADGVGK (SEQ ID NO: 19). [Figure 18C] β-Propiolactone covalently modifies mutant aspartates in K-Ras(G12D). Intensity of modified peptides shown in FIG. 18B under different treatment conditions. [Figure 19A] Compound 1 is a selective covalent ligand of K-Ras(G12D). Chemical structure of β-lactone Compound 1. [Figure 19B] Compound 1 is a selective covalent ligand of K-Ras(G12D). Covalent modification of recombinant K-Ras protein with 10 μM compound 1 at 23° C. [Figure 19C] Compound 1 is a selective covalent ligand of K-Ras(G12D). Time-dependent covalent modification of K-Ras(G12D)·GDP and K-Ras(G12D)·GppNHp by 10 μM compound 1 at 23 °C. [Figure 19D] Compound 1 is a selective covalent ligand of K-Ras(G12D). Differential scanning fluorimetry of K-Ras(G12D)·GDP, K-Ras(G12D)·GppNHp, and their covalent adducts with compound 1. [Figure 19E] Compound 1 is a selective covalent ligand of K-Ras(G12D). Binding of GST-Raf1-RBD to immobilized K-Ras(G12D)·GppNHp and K-Ras(G12D)·GppNHp·1 measured by biolayer interferometry. [Figure 19F] Compound 1 is a selective covalent ligand of K-Ras(G12D). Intact protein mass spectra of K-Ras(G12D) with and without (RS)-1 treatment. [Figure 19G] Compound 1 is a selective covalent ligand of K-Ras(G12D). Kinetics of covalent modification of K-Ras(G12D) by (RS)-1. [Figure 19H] Compound 1 is a selective covalent ligand of K-Ras(G12D). Compound (RS)-1 disrupted Ras-RafRBD binding. [Figure 20A] The reaction between compound 1 and K-Ras(G12D) is stereoselective. Crystal structure of the covalent adduct between K-Ras(G12D)·GDP and compound 1. [Figure 20B] The reaction between compound 1 and K-Ras(G12D) is stereoselective. Fo-Fc omit map of the ligand and Asp12 contoured at 2.0σ. [Figure 20C] The reaction between compound 1 and K-Ras(G12D) is stereoselective. Chemical structure of the adduct formed between the ligand and Asp12 after opening of the β-lactone ring. [Figure 20D] The reaction between compound 1 and K-Ras(G12D) is stereoselective. Two possible reaction pathways lead to the stereochemistry of the observed adduct. [Figure 20E] The reaction between compound 1 and K-Ras(G12D) is stereoselective. Chemical structures of enantiopure (S)-2 and (R)-2. [Figure 20F] The reaction between compound 1 and K-Ras(G12D) is stereoselective. Time-dependent covalent modification of K-Ras(G12D)·GDP by 10 μM (S)-2 or 10 μM (R)-2. [Figure 21A] Compound 1, also referred to as 14-049, inhibits p-ERK signaling in KRAS G12D mutant cells. Growth inhibition of BaF3 / K-Ras(G12D) cells by Compound 1 in the presence or absence of IL-3. [Figure 21B] Compound 1, also known as 14-049, inhibits p-ERK signaling in KRAS G12D mutant cells. Compound 1 inhibited the growth of KRAS G12D cancer cell lines. [Figure 21C] Compound 1, also referred to as 14-049, inhibits p-ERK signaling in KRAS G12D mutant cells. Growth inhibition of K-Ras(G12D) cell lines by Compound 1. [Figure 22A] Covalent adduct formation stabilizes K-Ras(G12D) in both the GDP and GTP states. Differential scanning fluorimetry of K-Ras(G12D)·GDP, K-Ras(G12D)·GppNHp, and their covalent adducts with compound 14-005. β-Lactone 14-005 stabilizes K-Ras(G12D)·GDP. [Figure 22B] Covalent adduct formation stabilizes K-Ras(G12D) in both the GDP and GTP states. Differential scanning fluorimetry of K-Ras(G12D)·GDP, K-Ras(G12D)·GppNHp, and their covalent adducts with compound 14-005. β-Lactone 14-005 stabilizes K-Ras(G12D)·GppNHp. [Figure 23] β-Lactones covalently modify K-Ras(G12D). Time-dependent covalent modification of K-Ras(G12D)·GDP and K-Ras(G12D)·GppNHp by 10 μM 14-005, 14-036, and 14-049 at 23 °C. [Figure 24] Compound 1, also referred to as 14-049, inhibits proliferation of K-Ras(G12D) mutant cells. Growth inhibition of AsPc-1 and SW1990 cells by 14-005, 14-036, and 14-049. [Diagram 25] Inhibition of the interaction between K-Ras and Raf1-RBD by compound 1. [Figure 26A] Chemical structures of substituted β-lactones. [Figure 26B] Time-dependent covalent modification of K-Ras(G12D)·GDP. [Figure 26C] Stability of substituted β-lactones in PBS 7.4 at 23 °C. [Figure 26D] Growth inhibition of BaF3 / K-Ras(G12D) cells by substituted β-lactones. [Figure 26E]Chemical structures of the two enantiomers of compound 4. [Figure 26F] Time-dependent covalent modification of K-Ras(G12D)·GDP. [Figure 26G] Growth inhibition of BaF3 / K-Ras(G12D) cells by each enantiomer of compound 4. [Fig. 26H] Inhibition of K-Ras(G12D) signaling in SW1990 cells. [Figure 27]Examples of GTPases that contain an aspartic acid at position 12 or an equivalent position (i.e., corresponding to position 12): ARF1 (e.g., UniProt P84077): MGNIFANLFKGLFGKKEMRILMVGLDAAGKTTILYKLKLG (SEQ ID NO: 20), ARF3 (e.g., UniProt P61204): MGNIFGNLLKSLIGKKEMRILMVGLDAAGKTTILYKLKLG (SEQ ID NO: 21), ARF4 (e.g., UniProt P18085): MGLTISSLFSRLFGKKQMRILMVGLDAAGKTTILYKLKLG (SEQ ID NO: 22), ARF5 (e.g., UniProt P84085): MGLTLTVSALFSRIFGKKQMRILMVGLDAAGKTTILYKLKLG (SEQ ID NO: 23), ARF6 (e.g., UniProt P62330): MGKVLSKIFGNKEMRILMLGLDAAGKTTILYKLKLG (SEQ ID NO: 24), TRIM23 (e.g., UniProt P36406): MAFTKDNRVHIGPKMEIRVVTLGLDGAGKTTILFKLKQD (SEQ ID NO: 25), ARL1 (e.g., UniProt P40616): MGGFFSSIFSSLFGTREMRILILGLDGAGKTTILYRLQVG (SEQ ID NO: 26), ARL2 (e.g., UniProt P36404): MGLLTILKKMKQKERELRLLMLGLDNAGKTTILKK (SEQ ID NO: 27), ARL3 (e.g., UniProt P36405): MGLLSILRKLKSAPDQEVRILLLGLDNAGKTTLLKQ (SEQ ID NO: 28), ARL4A (e.g., UniProt P40617): MGDQTSILSNLPSFQSFHIVILGLDCAGKTTVLYRLQFN (SEQ ID NO: 29), ARL4B: MGDQTSILSSLPSFQSFHIVMLGLDCAGKTTVLYRLQFN (SEQ ID NO: 30), ARL5: MGILFTRIWRLFNHQEHKVIIVGLDNAGKTTILYQFSMN (SEQ ID NO: 31), ARL6 (e.g., UniProtQ9H0F7): MGLLDRLSVLLGLKKKEVHVLCLGLDNSGKTTIINKLKPSN (SEQ ID NO: 32), ARL7: MGNISSNISAFQSLHIVMLGLDSAGKTTVLYRLKFN (SEQ ID NO: 33), ARL8: MGLIFAKLWSLFCNQEHKVIIVGLDNAGKTTILYQFLMN (SEQ ID NO: 34), ARL9 (e.g., UniProt Q6T311): MRWKALSHPAWPEEKNKQILVLGLDGAGKTSVLHSLASN (SEQ ID NO: 35), ARL12: MGQLIAKLMSIFGNQEHTVIIVGLDNEGKTTILYRFLTN (SEQ ID NO: 36), ARF4L: MGMAPTASSFLPHFQALHVVVIGLDSAGKTSLLYRLKFK (SEQ ID NO: 37), ARL11 (e.g., UniProt Q969Q4): MGSVNSRGHKAEAQVVMMGLDSAGKTTLLYKLKGH (SEQ ID NO: 38), ARF7: MGSLGSKNPQTKQAQVLLLGLDSAGKSTLLYKLKLA (SEQ ID NO: 39), 339231 (e.g., UniProt QPN6): MCLLLGATGVGKTLLVKRLQEV (SEQ ID NO: 40), DKFZp761: MFCCGWFKRWREPVRKVTLLMVGLDNAGKTATAKGIQGE (SEQ ID NO: 41), ARFRP1 (e.g., UniProt Q13795): MYTLLSGLYKYMFQKDEYCILILGLDNAGKTTFLEQSKTRF (SEQ ID NO: 42), ARFRP2 (e.g., UniProt Q9NXU5): MSRALCCKGPPPARPEYDLVCIGLTGSGKTSLLSKLCSE (SEQ ID NO: 43), ARL10A (e.g., UniProt Q8N8L6): MADEEDEEPALEELEQREVLVLGLDGAGKSTFLRVLSGKP (SEQ ID NO: 44), ARL10B (e.g., UniProtQ96BM9):MIKLLDWFKALFWKEEMELTLVGLQYSGKTTFVNVIASGQ (SEQ ID NO: 45), ARL10C:MLRLLDWFRSLFWKEEMELTLVGLQYSGKTTFVNVIASGQ (SEQ ID NO: 46), 344988:MSFSSVPQFLGLNKKSGKLLFVGLNNTDKTILLHMIKDD (SEQ ID NO: 47), SARA1 (e.g., UniProt Q6FID4):MSFSSVLQFLGLYKKSGKLVFLGLDNAGKTTLLHMLKDD (SEQ ID NO: 48), SARA2:MSFSSVLQFLGLYKKTGKLVFLGLDNAGKTTLLHMLKDD (SEQ ID NO: 49). Only partial sequence alignments are shown. [Figure 28A] Chemical structures of (2R,3S)-4, (2R,3S)-5, and (2R,3S)-6. [Figure 28B] GTP state-responsive β-lactone K-Ras(G12D) inhibitors. Pseudo-first order kinetics of K-Ras(G12D) labeling with isopropyl-substituted β-lactones. [Figure 28C] The Western blot time course is consistent with the observed kinetics of recombinant K-Ras(G12D) labeling. [Figure 29A] Chemical structure of compound (R)-7. [Figure 29B] Labeling kinetics of recombinant K-Ras(G12D) with (R)-7. [Figure 29C] Second-order kinetics of recombinant K-Ras(G12D) with (R)-7. [Figure 29D] Compound (R)-7 selectively modified recombinant K-Ras(G12D) in both nucleotide states. [Figure 29E] Compound (R)-7 selectively modified cellular K-Ras(G12D) and inhibited the signaling pathway. [Figure 29F] Compound (R)-7 potently inhibited Ba / F3 KRAS G12D cell line growth via on-target inhibition of K-Ras(G12D). [Figure 29G]Compound (R)-7 selectively inhibited the growth of cancer cell lines harboring the K-Ras(G12D) mutation. [Fig. 29H] The difference in compound (R)-7-induced apoptosis was striking between K-Ras(G12D) and non-K-Ras(G12D) cell lines. [Diagram 30] Compound 6 fully labels K-Ras(G12D) in cells at submicromolar concentrations. [Diagram 31] Selective covalent engagement of K-Ras(G12D) in cells for compound 6. [Figure 32A] Complete intracellular covalent labeling can be achieved by repeated administration of as little as 40 nM compound 6. Time course of (2R,3S)-6-induced intracellular K-Ras(G12D) labeling and downstream signaling pathway inhibition. [Figure 32B] Complete intracellular covalent labeling can be achieved by repeated administration of as little as 40 nM of compound 6. Medium exchange allowed complete labeling of endogenous K-Ras(G12D) by (2R,3S)-6 at 40 nM. [Figure 33A] On-target growth inhibition assessed in BaF3 / K-Ras(G12D) cells. Growth inhibition of Ba / F3 KRAS G12D cells by (2R,3S)-5. [Figure 33B] On-target growth inhibition assessed in BaF3 / K-Ras(G12D) cells. Growth inhibition of Ba / F3 KRAS G12D cells by (2R,3S)-6. [Figure 33C] On-target growth inhibition assessed in BaF3 / K-Ras(G12D) cells. Growth inhibition of Ba / F3 KRAS G12D cells by (RS)-7. [Diagram 34] Stereospecific synthesis of the β-lactone K-Ras(G12D) warhead. [Diagram 35] An example of a method for synthesizing compound 7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] I. Definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known to the chemical arts.

[0033] 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., -CH 2 O-OCH 2 -Equal to.

[0034] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and which may include monovalent, divalent, and polyvalent radicals. An alkyl may contain the specified number of carbons (e.g., C 1 ~C 10 means 1 to 10 carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl (e.g., C 1 ~C 10 , C 1 ~C 6 , or C 1 ~C 4The alkyl radicals are fully saturated. In embodiments, the alkyl radicals are monounsaturated. In embodiments, the alkyl radicals are polyunsaturated. The alkyl radicals are non-cyclized chains. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl linked to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. In embodiments, the alkyl moiety is an alkenyl moiety (e.g., C 2 ~C 10 Alkenyl, C 2 ~C 6 Alkenyl, or C 2 ~C 4 The alkyl moiety may be an alkynyl moiety (e.g., C 2 ~C 10 Alkynyl, C 2 ~C 6 Alkynyl, or C 2 ~C 4 Alkenyl can be one or more double bonds. Alkenyl can be one or more triple bonds.

[0035] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, including, but not limited to, -CH 2 CH 2 CH 2 CH 2-. Typically, alkyl (or alkylene) groups 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 a divalent radical derived from an alkene, unless otherwise stated. The term "alkynylene", by itself or as part of another substituent, means a divalent radical derived from an alkyne, unless otherwise stated. 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.

[0036] The term "heteroalkyl", alone 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), where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom (e.g., N, S, Si, or P) may be located 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-cyclized chain. Examples include, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -S-CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O)2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , -CH=CH-N(CH 3 )-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 For example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 Up to two or three heteroatoms may be consecutive, such as: A heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may 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 a heteroalkyl containing at least one double bond, unless otherwise specified. Heteroalkenyl may optionally contain, in addition to one or more double bonds, more than one double bond and / or one or more triple bonds. The term "heteroalkynyl", alone or in combination with another term, means, unless otherwise specified, a heteroalkyl containing at least one triple bond. Heteroalkynyl may optionally contain, in addition to one or more triple bonds, more than one triple bond and / or one or more double bonds. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated.

[0037] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyl, including but not limited to, -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). 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, a group of the formula -C(O) 2 R'- is -C(O) 2 R'- and -R'C(O) 2 As noted above, heteroalkyl groups as used herein include both -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO. 2

[0033] In some embodiments, the heteroalkyl group is a substituted or unsubstituted alkyl group, and the heteroalkyl group is a substituted or unsubstituted alkyl group. In some embodiments, ...

[0038] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, mean cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise specified. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, in the case of heterocycloalkyl, a heteroatom may 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. In an embodiment, the heterocycloalkyl is hexahydro-1H-pyrrolidin-7a-yl. In an embodiment, the heterocycloalkyl is 2-pyrrolidinyl. "Cycloalkylene" and "heterocycloalkylene", alone or as part of another substituent, refer to a divalent radical derived from a cycloalkyl and a heterocycloalkyl, respectively. In an embodiment, the cycloalkyl is fully saturated. In an embodiment, the cycloalkyl is monounsaturated. In an embodiment, the cycloalkyl is polyunsaturated. In an embodiment, the heterocycloalkyl is fully saturated. In an embodiment, the heterocycloalkyl is monounsaturated. In an embodiment, the heterocycloalkyl is polyunsaturated.

[0039] 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, and such groups can be saturated or unsaturated, but are not aromatic. In embodiments, a cycloalkyl group is fully saturated. A bicyclic or polycyclic cycloalkyl ring system refers to multiple rings fused together, at least one of the fused rings being a cycloalkyl ring, and the multiple rings being attached to the parent molecular moiety through any carbon atom contained within the cycloalkyl ring of the multiple rings.

[0040] In embodiments, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its plain and ordinary meaning. In embodiments, cycloalkenyl is a monocyclic, bicyclic or polycyclic cycloalkenyl ring system. A bicyclic or polycyclic cycloalkenyl ring system refers to multiple rings fused together, at least one of the fused rings being a cycloalkenyl ring, and the multiple rings are bonded to the parent molecular moiety through any carbon atom contained within the cycloalkenyl ring of the multiple rings.

[0041] 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, the heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, 5-6 membered, or 5-8 membered) group is fully saturated. A bicyclic or polycyclic heterocycloalkyl ring system refers to multiple rings fused together, at least one of the fused rings is a heterocycloalkyl ring, and the multiple rings are attached to the parent molecular moiety through any atom contained within the heterocycloalkyl ring of the multiple rings.

[0042] The terms "halo" or "halogen," alone 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, "halo(C 1 ~C 4 The term "alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0043] The term "acyl," unless otherwise specified, means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0044] The term "aryl", unless otherwise specified, means a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1-3 rings) fused together (i.e., fused-ring aryl) or covalently bonded together. Fused-ring aryl refers to multiple rings fused together, at least one of the fused rings being an aryl ring, and the multiple rings being 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, where 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 the fused rings being a heteroaromatic ring, and the multiple rings being bonded to the parent molecular moiety through any atom contained within the heteroaromatic ring of the multiple rings). 5,6-fused ring heteroarylene refers to two rings fused together, one ring having 5 members and the other ring having 6 members, at least one ring being a heteroaryl ring. Similarly, 6,6-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 6 members, at least one ring being a heteroaryl ring. Also, 6,5-fused ring heteroarylene refers to two rings fused together, one ring having 6 members and the other ring having 5 members, at least one ring being a heteroaryl ring. Heteroaryl groups can be bonded to the rest of the molecule via 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, 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 aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. The heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0045] A spirocyclic ring is two or more rings in which adjacent rings are linked through a single atom. The individual rings in a spirocyclic ring may be the same or different. The individual rings in a spirocyclic ring may be substituted or unsubstituted and may have different substitutions from the other individual rings in a set of spirocyclic rings. The possible substitutions of the individual rings in a spirocyclic ring are the possible substitutions of the same ring (e.g., substitutions of a cycloalkyl ring or a heterocycloalkyl ring) when they are not part of a spirocyclic ring. A spirocyclic ring may be a 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 may be any of the previous lists, including all rings of one kind (e.g., all rings may be substituted heterocycloalkylene, and each ring may 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 a heterocyclic ring, and each ring may be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted, and each substitution may optionally be different.

[0046] symbol

[0047] [ka] indicates the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0048] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0049] 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:

[0050] [ka] has.

[0051] The alkylarylene moiety may contain halogen, oxo, -N at the alkylene portion or at the arylene linker (e.g., at carbons 2, 3, 4, or 6). 3 , -CF 3 , -CCl 3 , -CBr 3 , -CI 3 , -CN, -CHO, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 2 CH 3 , -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , substituted or unsubstituted C 1 ~C 5 In an embodiment, the alkylarylene is unsubstituted.

[0052] 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.

[0053] Substituents on alkyl and heteroalkyl radicals (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) range in number from zero to (2m'+1), where m' is the total number of carbon atoms in such radical, and include -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R''', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'C(O)NR"R''', -NR"C(O) 2 R', -NRC(NR'R"R''')=NR''', -NRC(NR'R")=NR''', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", -NRSO 2 R', -NR'NR"R''', -ONR'R", -NR'C(O)NR"NR'''R''', -CN, -NO 2 , -NR'SO 2It can be one or more of a variety of groups selected from, but not limited to, -R", -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 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When the compounds described herein contain 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 substitution, one of skill in the art will recognize that the term "alkyl" can be used in conjunction with haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 It will be understood that this is intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as aryl, aryloxy ...

[0054] Similar to the substituents described for the alkyl radicals, 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', -CO 2 R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'C(O)NR"R''', -NR"C(O) 2R', -NR-C(NR'R"R''')=NR''', -NR-C(NR'R")=NR''', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", -NRSO 2 R', -NR'NR"R''', -ONR'R", -NR'C(O)NR"NR'''R''', -CN, -NO 2 , -R', -N 3 , -CH(Ph) 2 , Fluoro(C 1 ~C 4 ) alkoxy, and fluoro (C 1 ~C 4 ) alkyl, -NR'SO 2 R", -NR'C(O)R", -NR'C(O)OR", -NR'OR", where R', R", R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", and R'''' groups when more than one of these groups is present.

[0055] Substituents of a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be shown as substitutions on the ring (commonly referred to as floating substitutions) rather than on a specific atom of the ring. In such cases, the substitutions may be attached (according to the rules of chemical valence) to any of the ring atoms, and in the case of a fused or spirocyclic ring, a substitution shown as attached to a member of the fused or spirocyclic ring (floating substitutions on a single ring) may also be a substitution on any of the fused or spirocyclic rings (floating substitutions on a polycyclic ring). When a substitution is attached to a ring rather than to a specific atom (floating substitutions) and the subscript of the substitution is an integer greater than 1, the multiple substitutions may be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substitution may optionally be different. If the point of attachment of the ring to the rest of the molecule is not limited to a single atom (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 either of the fused or spirocyclic rings, according to the rules of chemical valence. If a ring, fused or spirocyclic ring contains one or more ring heteroatoms, and the ring, fused 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. If a ring heteroatom is shown to be attached to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to a ring atom 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.

[0056] Two or more substituents may be optionally 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.

[0057] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are optionally represented by the formula -TC(O)-(CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can form a ring of the formula -A-(CH 2 ) r -B- (wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 Optionally, one of the single bonds of the new ring so formed may be replaced with a substituent of the formula -(CRR') s -X'-(C”R”R'') d In the formula, s and d are independently an integer of 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 - or -S(O) 2The 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.

[0058] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0059] As used herein, "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 ,-SCIENCE FICTION 5 , unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 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., C 6 ~C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (B) Alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5~C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 ~C 10 Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 ,-SCIENCE FICTION 5 , unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 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., C 6 ~C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (ii) alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 ~C 10Aryl, C 10 aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 ,-SCIENCE FICTION 5 , unsubstituted alkyl (e.g., C 1 ~C 8Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 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., C 6 ~C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), and (b) Alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 cycloalkyl), heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), aryl (e.g., C 6 ~C 10 Aryl, C 10aryl, or phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl), each of which is substituted with at least one substituent selected from the following: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl: oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 ,-SCIENCE FICTION 5 , unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6Alkyl or C 1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl, or C 5 ~C 6 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., C 6 ~C 10 Aryl, C 10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0060] As used herein, "size-limited substituents" or "size-limited substituents" refers to a group selected from all of the substituents described above for "substituents," and each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 ~C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 ~C 8 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 C 6 ~C 10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-10 membered heteroaryl.

[0061] "Lower substituted" or "lower substituent" as used herein means a group selected from all of the substituents described above for "substituent", and each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 ~C8 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl; and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 ~C 7 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.

[0062] In some embodiments, each of the substituents described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each of the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0063] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is substituted or unsubstituted C 1 ~C 20 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl; and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 ~C 8 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 C 6 ~C 10aryl, 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 1 ~C 20 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene; and each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 ~C 8 each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene; each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 ~C 10 arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0064] In some embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C 1 ~C 8 each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 membered heteroalkyl; and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 ~C 7 each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl; and each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 ~C 10 In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted 5- to 9-membered heteroaryl. 1 ~C 8 each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene; and each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 ~C 7each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene; and each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 ~C 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.

[0065] 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).

[0066] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one 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.

[0067] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limiting substituent, and when a substituted moiety is substituted with multiple substituents, each size-limiting substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple size-limiting substituents, each size-limiting substituent is different.

[0068] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent, and when a substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In embodiments, when a substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0069] 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, and 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.

[0070] In any of the claims or formula descriptions cited herein, each R substituent or L linker described as being "substituted" (also referred to herein as an "open substitution" for an R substituent or L linker or an "openly substituted" R substituent or L linker), without reference to the identity of any chemical moieties that make up the "substituted" group, the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituents, as defined below.

[0071] The first substituent can be, for example, R 1 But R 1.1 and R 2 But R 2.1 and R 3 But R 3.1 and R 4 But R 4.1 and R 5 But R 5.1 and may be substituted with one or more first substituents represented by up to or corresponding R 100 But R 100.1As a further example, R 1A But R 1A.1 and R 2A But R 2A.1 and R 3A But R 3A.1 and R 4A But R 4A.1 and R 5A But R 5A.1 and may be substituted with one or more first substituents represented by up to or corresponding R 100A But R 100A.1 As a further example, L may be substituted with one or more first substituents represented by 1 But R L1.1 and L may be substituted with one or more first substituents represented by 2 But R L2.1 and L may be substituted with one or more first substituents represented by 3 But R L3.1 and L may be substituted with one or more first substituents represented by 4 But R L4.1 and L may be substituted with one or more first substituents represented by 5 But R L5.1 and may be substituted with one or more first substituents represented by the formula: 100 But R L100.1 Thus, each numbered R or L group described herein (alternatively, R WW Or L WW and "WW" represents the listed superscript number of the subject R or L group), are generally referred to herein as R WW.1 or R LWW.1 Each of the first substituents (e.g., R 1.1 , R 2.1 , R 3.1 , R4.1 , R 5.1 ...R 100.1 ;R 1A.1 , R 2A.1 , R 3A.1 , R 4A.1 , R 5A.1 ...R 100A.1 ;R L1.1 , R L2.1 , R L3.1 , R L4.1 , R L5.1 ...R L100.1 ) may be substituted with one or more second substituents (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ...R 100.2 ;R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ...R 100A.2 ;R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ...R L100.2 ) may be further substituted. Thus, as used herein, R WW.1 Each first substituent may alternatively be represented herein as R WW.2 The alkyl group may be further substituted with one or more second substituents, which may alternatively be represented as:

[0072] Finally, each second substituent (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ...R 100.2 ;R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ...R 100A.2 ;R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ...R L100.2) may each be selected from one or more third substituents (e.g., R 1.3 , R 2.3 , R 3.3 , R 4.3 , R 5.3 ...R 100.3 ;R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.3 ...R 100A.3 ;R L1.3 , R L2.3 , R L3.3 , R L4.3 , R L5.3 ...R L100.3 ) may be further substituted. Thus, as used herein, R WW.2 Each second substituent may alternatively be represented herein as R WW.3 Each of the first substituents may be optionally different. Each of the second substituents may be optionally different. Each of the third substituents may be optionally different.

[0073] Thus, as used herein, R WW represents an openly substituted substituent as recited in the claims or in the description of the formula herein. "WW" represents the superscript number of the R group of interest (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Similarly, L WW is an open-substituted linker as described in the claims or formula description herein. Additionally, "WW" represents the listed superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As noted above, in embodiments, each R WW may be unsubstituted or as defined herein as R WW.1 Each of the first substituents R WW.1 may be unsubstituted or as defined herein as R WW.2 Each of the second substituents may be independently substituted with one or more second substituents, referred to herein as RWW.3 Similarly, each L may be independently substituted with one or more third substituents, referred to as WW The linker may be unsubstituted or may be defined herein as R LWW.1 Each of the first substituents R LWW.1 may be unsubstituted or as defined herein as R LWW.2 Each of the second substituents may be independently substituted with one or more second substituents, referred to herein as R LWW.3 Each of the first substituents is optionally different. Each of the second substituents is optionally different. Each of the third substituents is optionally different. For example, R WW When is phenyl, the phenyl group may be one or more R WW.1 Optionally substituted with groups, such as R WW.1 R WW.2 In the case of substituted or unsubstituted alkyl, examples of the groups so formed include one or more R WW.2 R itself, optionally substituted by WW.2 is one or more R WW.3 For example, R WW R is a methyl group WW.1 When the methyl group is phenyl substituted by

[0074] [ka] The groups may include, but are not limited to,

[0075] R WW.1 are independently oxo, halogen, -CX WW.1 3 , -CHX WW.1 2 , -CH 2 X WW.1 , -OCX WW.1 3 , -OCH 2 XWW.1 , -OCHX WW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R WW.2 Substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), R WW.2 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.2 Substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), R WW.2 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.2 Substituted or unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or R WW.2 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW.1 are independently oxo, halogen, -CXWW.1 3 , -CHX WW.1 2 , -CH 2 X WW.1 , -OCX WW.1 3 , -OCH 2 X WW.1 , -OCHX WW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 members, 5 to 10 members, 5 to 9 members, or 5 to 6 members). WW.1is independently -F, -Cl, -Br, or -I.

[0076] R WW.2 are independently oxo, halogen, -CX WW.2 3 , -CHX WW.2 2 , -CH 2 X WW.2 , -OCX WW.2 3 , -OCH 2 X WW.2 , -OCHX WW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R WW.3 Substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), R WW.3 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.3 Substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), R WW.3substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.3 Substituted or unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or R WW.3 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW.2 are independently oxo, halogen, -CX WW.2 3 , -CHX WW.2 2 , -CH 2 X WW.2 , -OCX WW.2 3 , -OCH 2 X WW.2 , -OCHX WW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6, C 4 ~C 6 , or C 5 ~C 6 ), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 members, 5 to 10 members, 5 to 9 members, or 5 to 6 members). WW.2 is independently -F, -Cl, -Br, or -I.

[0077] R WW.3 are independently oxo, halogen, -CX WW.3 3 , -CHX WW.3 2 , -CH 2 X WW.3 , -OCX WW.3 3 , -OCH 2 X WW.3 , -OCHX WW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 members, 5 to 10 members, 5 to 9 members, or 5 to 6 members). WW.3 is independently -F, -Cl, -Br, or -I.

[0078] Two different R WW When the substituents are linked together to form an open substituted ring (e.g., a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, or a substituted heteroaryl), in embodiments, the open substituted ring is defined herein as R WW.1 Each of the first substituents R WW.1 may be unsubstituted or as defined herein as R WW.2 Each of the second substituents R WW.2 may be unsubstituted or as defined herein as R WW.3 Each third substituent R WW.3 is unsubstituted. Each first substituent is optionally different. Each second substituent is optionally different. Each third substituent is optionally different. Two different R WW In the context where the substituents are linked together to form an open substituted ring, R WW.1 , R WW.2 , and R WW.3 The "WW" symbol in WWRefers to a specified number of one of the substitutions. For example, R 100A and R 100B are optionally linked together to form an open substituted ring, R WW.1 is R 100A.1 and R WW.2 is R 100A.2 and R WW.3 is R 100A.3 Alternatively, R 100A and R 100B are optionally linked together to form an open substituted ring, R WW.1 is R 100B.1 and R WW.2 is R 100B.2 and R WW.3 is R 100B.3 R in this paragraph WW.1 , R WW.2 , and R WW.3 is as defined in the previous paragraph.

[0079] R LWW.1 are independently oxo, halogen, -CX LWW.1 3 , -CHX LWW.1 2 , -CH 2 X LWW.1 , -OCX LWW.1 3 , -OCH 2 X LWW.1 , -OCHX LWW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , RLWW.2 Substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), R LWW.2 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R LWW.2 Substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), R LWW.2 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.2 Substituted or unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or R LWW.2 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). LWW.1 are independently oxo, halogen, -CX LWW.1 3 , -CHX LWW.1 2 , -CH 2 X LWW.1 , -OCX LWW.1 3 , -OCH 2 X LWW.1 , -OCHX LWW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 members, 5 to 10 members, 5 to 9 members, or 5 to 6 members). LWW.1 is independently -F, -Cl, -Br, or -I.

[0080] R LWW.2 are independently oxo, halogen, -CX LWW.2 3 , -CHX LWW.2 2 , -CH 2 X LWW.2 , -OCX LWW.2 3 , -OCH 2 X LWW.2 , -OCHX LWW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R LWW.3 Substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), R LWW.3 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.3 Substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), R LWW.3 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.3 Substituted or unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or R LWW.3 In embodiments, R is a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). LWW.2 are independently oxo, halogen, -CX LWW.2 3 , -CHX LWW.2 2 , -CH 2 X LWW.2 , -OCX LWW.23 , -OCH 2 X LWW.2 , -OCHX LWW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 members, 5 to 10 members, 5 to 9 members, or 5 to 6 members). LWW.2 is independently -F, -Cl, -Br, or -I.

[0081] R LWW.3 are independently oxo, halogen, -CX LWW.33 , -CHX LWW.3 2 , -CH 2 X LWW.3 , -OCX LWW.3 3 , -OCH 2 X LWW.3 , -OCHX LWW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 members, 5 to 10 members, 5 to 9 members, or 5 to 6 members). LWW.3is independently -F, -Cl, -Br, or -I.

[0082] Any R group (R WW If an R group (R WW The groups are each independently oxo, halogen, -CX WW 3 , -CHX WW 2 , -CH 2 X WW , -OCX WW 3 , -OCH 2 X WW , -OCHX WW 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R WW.1 Substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), R WW.1 substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R WW.1 Substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C6 , or C 5 ~C 6 ), R WW.1 substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R WW.1 Substituted or unsubstituted aryl (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or R WW.1 X is defined herein as a substituted or unsubstituted heteroaryl (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). WW are independently -F, -Cl, -Br, -I. Again, "WW" represents the listed superscript number of the R group of interest (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R WW.1 , R WW.2 , and R WW.3 is as defined above.

[0083] Any of the L linker groups listed in the chain or formula descriptions herein (i.e., L WW If the L group (L WW group) are independently a bond, -O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO 2 -, -SO 2 NH-, R LWW.1 Substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), R LWW.1 substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), R LWW.1 Substituted or unsubstituted cycloalkylene (e.g., C 3 ~C 8 , C3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), R LWW.1 substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), R LWW.1 Substituted or unsubstituted arylene (e.g., C 6 ~C 12 , C 6 ~C 10 , or phenyl), or R LWW.1 R is defined herein as a substituted or unsubstituted heteroarylene (e.g., 5-12 membered, 5-10 membered, 5-9 membered, or 5-6 membered). Additionally, "WW" represents the listed superscript numbers (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.) of the subject L group. LWW.1 , and R LWW.2 and R LWW.3 is as defined above.

[0084] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds, and in terms of absolute stereochemistry, may be defined as (R)- or (S)- or (D)- or (L) for amino acids, including enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers 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 asymmetric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified.

[0085] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but differ with regard to the structural or stereochemical arrangement of the atoms.

[0086] 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.

[0087] 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.

[0088] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0089] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-enriched carbon, are within the scope of this disclosure.

[0090] 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, for example, 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.

[0091] It should be noted that throughout this application, options, e.g., each amino acid position that contains more than one possible amino acid, are described in Markush groups. 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.

[0092] As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the resulting association between the atoms or molecules of a bioconjugate reactive group or bioconjugate reactive moiety. The association can be direct or indirect. For example, a first bioconjugate reactive group (e.g., -NH 2, -COOH, -N-hydroxysuccinimide, or -maleimide) and the second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine side chain containing amino acid, or carboxylic acid) can be direct, for example, via a covalent bond or linker (e.g., the first linker to the second linker), or indirect, for example, 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, etc.). In embodiments, bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups), including, but not limited to, nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, 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 attached to a second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently attached to a second bioconjugate reactive group (e.g., a sulfhydryl).In embodiments, the first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., a -N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., a maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., a -sulfo-N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).

[0093] Useful bioconjugate reactive groups 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-hydroxybenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl, and aromatic esters; (b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, and the like; (c) haloalkyl groups, where the halide can be subsequently displaced with a nucleophilic group, such as, for example, 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, such as, for example, maleimide or maleimido groups, which can participate in Diels-Alder reactions; (e) dienophile groups, such as, for example, maleimide or maleimido groups, which can subsequently be reacted with a carbonyl derivative, such as, for example, an imine, hydrazone, semicarbazone, or oxime, or via mechanisms such as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups, for example, for subsequent reaction with amines to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, attached to metals such as gold, or reacted with maleimides; (h) amine or sulfhydryl groups (such as those present in cysteine), which can be, for example, acylated, alkylated, or oxidized; (i) alkenes, which can undergo, for example, cycloaddition, acylation, Michael addition, etc.; (j) amines and sulfhydryl groups, which can be, for example, acylated, alkylated, or oxidized; These include epoxides, which can react with hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal-silicon oxide linkages; (m) metal linkages to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphodiester linkages; (n) azides coupled to alkynes using copper-catalyzed cycloaddition click chemistry; and (o) biotin conjugates that can react with avidin or streptavidin to form avidin-biotin or streptavidin-biotin complexes.

[0094] Bioconjugate reactive groups can be selected such that they do not participate in 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 a protecting group. In embodiments, bioconjugates include molecular entities resulting from the reaction of an unsaturated bond, such as a maleimide, with a sulfhydryl group.

[0095] "Analog," "analogue," or "derivative" is used according to its plain and ordinary meaning within chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the replacement of one atom by an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group by 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.

[0096] 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 particular 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 a heteroaryl group is an "unsubstituted C 1 ~C 20 When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is selected from the group consisting of one or more unsubstituted C 1 ~C 20 It may contain alkyl and / or one or more unsubstituted 2-20 membered heteroalkyl.

[0097] Additionally, 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 is present in a description of a chemical species (such as formula (I)), the Roman alphabet symbol may be used to distinguish each occurrence of that particular R group. For example, multiple R 13 When substituents are present, each R 13 The substituent is R 13.A , R 13.B , R 13.C , R 13.D etc., and R 13.A , R 13.B , R 13.C , R 13.D Each of the above is R 13 Within the scope of the definition, it may be defined differently at will.

[0098] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of several substitutes, such substitutions are selected to follow the principles of chemical bonding and to bring about compounds that are not inherently unstable and / or are 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 heteroatoms according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0099] The term "pharmaceutically acceptable salts" is meant 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 a neutral form of such a compound with a sufficient amount of a desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galactunoric acid (see, for example, 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.

[0100] Therefore, the compounds of the present disclosure may exist as salts with pharma- ceutically acceptable acids and the like. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof, including racemic mixtures), 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.

[0101] 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.

[0102] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that undergo easy 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 invention by chemical or biochemical methods in an ex vivo environment, for example, when contacted with a suitable enzyme or chemical reagent.

[0103] Certain compounds of the present disclosure may exist in unsolvated and solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0104] A polypeptide or cell is "recombinant" if it is artificially or engineered, or if it is derived from or contains an artificially or engineered protein or nucleic acid (e.g., non-naturally occurring or non-wild type). For example, a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in the genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as found in nature is a recombinant polynucleotide. A protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide. Similarly, a polynucleotide sequence not found in nature, e.g., a variant of a naturally occurring gene, is recombinant.

[0105] "Co-administered" means that the compositions described herein are administered simultaneously, immediately before, or immediately after the administration of one or more additional therapeutic agents. The compounds of the present invention can be administered to a patient alone or simultaneously. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparations can also be combined with other active substances if desired (e.g., to reduce metabolic degradation).

[0106] As used herein, a "cell" refers to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. Cells may be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a particular dye, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian cells, insect cells (e.g., spodoptera), and human cells. Cells may be useful if they are naturally non-adherent or have been treated to prevent them from adhering to surfaces, for example, by trypsinization.

[0107] The term "treating" or "treatment" refers to any indication of success in treating or improvement of an injury, disease, condition, or state, including any objective or subjective parameters, such as alleviation, remission, reduction of symptoms, or making the injury, condition, or state more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, improving the patient's physical or mental health, etc. The treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of a physical exam, a neuropsychiatric exam, and / or a psychiatric evaluation. For example, certain methods provided herein successfully treat cancer by reducing the incidence of cancer and / or by causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer includes slowing the rate of growth or spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term "treating" and conjugations thereof include prevention of injury, condition, state, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In an embodiment, the treating or treatment is not a prophylactic treatment.

[0108] An "effective amount" is an amount sufficient for the compound to achieve a given purpose (e.g., achieve the effect of being administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, alleviate one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of a symptom or symptoms of a disease, which may also be referred to as a "therapeutically effective amount" when referred to in this context. "Alleviation" of a symptom or symptoms (and grammatical equivalents of this phrase) means a reduction in the severity or frequency of a symptom, or the elimination of a symptom. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have an intended prophylactic effect, for example, an amount of a drug that prevents or delays the onset (or recurrence) of an injury, disease, condition, or condition, or reduces the likelihood of the onset (or recurrence) of an injury, disease, condition, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more doses. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme compared to the absence of the antagonist. As used herein, an "amount that interferes with function" refers to the amount of antagonist required to interfere with the function of an enzyme or protein compared to the absence of the antagonist. As used herein, an "activity-increasing amount" refers to the amount of agonist required to increase the activity of an enzyme compared to the absence of the agonist. As used herein, an "amount that increases function" refers to the amount of agonist required to increase the function of an enzyme or protein compared to the absence of the agonist.The exact amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0109] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which an experimental subject or agent is treated the same as a parallel experiment except for the omission of an experimental procedure, agent, or variable. In some cases, a control is used as a standard of comparison in evaluating the efficacy of an experiment. In some embodiments, a control is a measurement of a protein activity (e.g., a signaling pathway) in the absence of a compound described herein (including in any embodiment, example, figure, or table).

[0110] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two distinct species (e.g., chemical compounds, including biological molecules or cells) to come into sufficient proximity to react, interact, or be in physical contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or may be produced from an intermediate from one or more of the added reagents that may be produced in the reaction mixture.

[0111] The term "contacting" may include allowing two species to react, interact, or come into physical contact, where the two species may be a compound described herein and a cellular component (e.g., a protein, an ion, a lipid, a nucleic acid, a nucleotide, an amino acid, a protein, a particle, an organelle, a subcellular compartment, a microorganism, a virus, a lipid droplet, a vesicle, a small molecule, a protein complex, a protein aggregate, or a macromolecule). In some embodiments, contacting includes allowing a compound described herein to interact with a cellular component (e.g., a protein, an ion, a lipid, a nucleic acid, a nucleotide, an amino acid, a protein, a particle, a virus, a lipid droplet, an organelle, a subcellular compartment, a microorganism, a vesicle, a small molecule, a protein complex, a protein aggregate, or a macromolecule) involved in a signaling pathway.

[0112] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to a protein, refer to the conversion of a protein from an initial inactive or inactivated state to a biologically active derivative. These terms refer to activating, or activating, sensitizing, or upregulating signal transduction or enzymatic activity, or the amount of a protein that is decreased in a disease.

[0113] The terms "agonist," "activator," "upregulator," and the like refer to a substance capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the agonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more, higher than expression or activity in the absence of the agonist.

[0114] As defined herein, the terms "inhibit," "inhibit," "inhibiting," and the like, with respect to cellular component-inhibitor interactions, refer to adversely affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing a signal transduction pathway stimulated by the cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, subcellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) compared to the activity or function of the cellular component in the absence of the inhibitor. In embodiments, inhibition refers to adversely affecting (e.g., decreasing) the concentration or level of the cellular component compared to the concentration or level of the cellular component in the absence of the inhibitor. In embodiments, inhibition refers to the alleviation of a disease or disease symptom. In some embodiments, inhibition refers to a reduction in the activity of a signal transduction or signal transduction pathway (e.g., a reduction in a pathway in which the cellular component is involved). Thus, inhibiting includes, at least in part, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating a signaling pathway or enzymatic activity or the amount of a cellular component.

[0115] The terms "inhibitor", "suppressor", "antagonist" or "down-regulator" refer synonymously to a substance capable of detectably decreasing the expression or activity of a given gene or protein. An antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% compared to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more lower than expression or activity in the absence of the antagonist.

[0116] 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 target of the molecule relative to the absence of the composition (e.g., the target can be a cellular component (e.g., a protein, an ion, a lipid, a virus, a lipid droplet, a nucleic acid, a nucleotide, an amino acid, a protein, a particle, an organelle, a subcellular compartment, a microorganism, a vesicle, a small molecule, a protein complex, a protein aggregate, or a macromolecule)).

[0117] The term "expression" includes any step involved in the production of a polypeptide, including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0118] The term "modulate" is used according to its plain and ordinary meaning to refer to the act of changing or varying one or more properties. "Modulation" refers to the process of changing or varying one or more properties. For example, as applied to the effect of a modulator on a target protein, modulating means altering by increasing or decreasing the property or function of the target molecule or the amount of the target molecule.

[0119] "Patient", "patient in need thereof", "subject" or "subject in need thereof" refers to an organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human. In embodiments, the patient in need thereof is a human. In embodiments, the subject is a human. In embodiments, the subject in need thereof is a human.

[0120] "Disease" or "condition" refers to a state of existence or health of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease is a disease associated with (e.g., caused by) a cellular component (e.g., a protein, an ion, a lipid, a nucleic acid, a nucleotide, an amino acid, a protein, a particle, an organelle, a subcellular compartment, a microorganism, a vesicle, a small molecule, a protein complex, a protein aggregate, or a macromolecule). In embodiments, the disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In embodiments, the disease is Costello syndrome.

[0121] As used herein, the term "cancer" refers to all types of cancer, neoplasms, or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. Further examples may include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0122] The term "leukemia" refers broadly to progressive, malignant diseases of the hematopoietic 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 characteristics of the disease - acute or chronic, (2) the type of cells involved, myeloid (myeloid), lymphatic (lymphoid), or monocytic, and (3) the increase or absence of an increase in the number of abnormal cells in the blood - leukemia or non-leukemia (subleukemia). Exemplary leukemias that may be treated with the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, and leukemia. leukemia), leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblast ... Examples of leukemia include lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic 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, and anaplastic cell leukemia.

[0123] As used herein, the term "lymphoma" refers to a group of cancers that affect the 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 represents approximately 15% of all lymphomas diagnosed. It is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphomas (NHL) can be classified based on how fast the cancer grows and the type of cells involved. There are aggressive (high-grade) and indolent (low-grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHL. Exemplary B-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytic B-cell) lymphoma, splenic lymphoma, diffuse large cell B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

[0124] The term "sarcoma" generally refers to tumors composed of embryonic connective tissue-like material and generally composed of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chlorosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, and sarcoma of the sarcoma family. These include alveolar sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0125] 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 lentigo melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0126] The term "carcinoma" refers to a malignant new growth composed of epithelial cells that tend to invade 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, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid cell carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, compact carcinoma, and endothelial carcinoma. durum, embryonal carcinoma, encephalomyeloma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, carcinoma in situ, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, mucin-secreting carcinoma muciparum, mucous cell carcinoma, mucoepidermoid carcinoma, 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, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinomacarcinoma, globular cell carcinoma, spindle cell carcinoma, cellular carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectasia carcinoma, telangiectasia-like carcinoma, transitional cell carcinoma, carcinoma tuberosum, nodular carcinoma, warty carcinoma, or choriocarcinoma.

[0127] As used herein, the terms "metastasis", "metastatic" and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or part of the body. "Metastatic cancer" is also referred to as "stage IV cancer". Cancer begins at a site of origin, e.g., the breast, referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or site of origin acquire the ability to penetrate and invade surrounding normal tissues in the local area and / or penetrate the walls of the lymphatic or vascular system and circulate through the system to other sites and tissues of the body. A clinically detectable second tumor formed from cancer cells of the primary tumor is called a metastatic or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, when lung cancer metastasizes to the breast, the secondary tumor at the breast site is composed of abnormal lung cells, not abnormal breast cells. A secondary tumor in the breast is referred to as metastatic lung cancer. Thus, the phrase metastatic cancer refers to a disease in which a subject has or has had a primary tumor, and has one or more secondary tumors.The phrase non-metastatic cancer or a subject with non-metastatic cancer refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors.For example, metastatic lung cancer refers to a disease in a subject who has or has had a history of a primary lung tumor, and has one or more secondary tumors, for example, in a second location in the breast or in multiple locations.

[0128] The terms "skin metastasis" and "cutaneous metastasis" refer to secondary malignant cell growth in the skin, where the malignant cells originate from a primary cancer site (e.g., breast). In skin metastasis, cancerous cells from the primary cancer site migrate to the skin, where they can divide and cause lesions. Skin metastasis can result from the migration of cancer cells from a breast cancer tumor to the skin.

[0129] The term "visceral metastasis" refers to secondary malignant cell growth in an organ (e.g., heart, lung, liver, pancreas, intestine) or body cavity (e.g., pleura, peritoneum) where the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast). In visceral metastasis, cancerous cells from the primary cancer site migrate to a viscera where they may divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from a liver cancer tumor or a head and neck tumor to a viscera.

[0130] As used herein, the term "RASopathy" refers to a disease caused by a germline mutation in a gene encoding a component of the RAS / MAPK signaling pathway. In an embodiment, the RASopathy is a mosaic RASopathy. In an embodiment, the RASopathy is a germline RASopathy. In an embodiment, the RASopathy is a developmental syndrome. In an embodiment, the RASopathy is Noonan syndrome. In an embodiment, the RASopathy is an epidermal nevus. In an embodiment, the RASopathy is Schimmelpenning syndrome. In an embodiment, the RASopathy is a sebaceous nevus. In an embodiment, the RASopathy is equinovarus (e.g., congenital equinovarus). In an embodiment, the RASopathy is PIK3CA-related overgrowth syndrome (PROS). In an embodiment, the RASopathy is a PTEN-Hamartoma of the soft tissue (PHOST). In an embodiment, the RASopathy is fibrolipid overgrowth, hemihypertrophic multiple lipomatosis, congenital lipomatous overgrowth, vascular malformation, epidermal nevus, spinal and skeletal syndrome, macrodactyly syndrome, megalocephaly syndrome, or congenital diffuse infiltrating lipomatosis. In an embodiment, the RASopathy is Klippel-Trenaunay syndrome (KTS), venous malformation, or lymphatic malformation. In an embodiment, the RASopathy is capillary malformation-AV malformation syndrome. In an embodiment, the RASopathy is autoimmune lymphoproliferative syndrome. In an embodiment, the RASopathy is cardio-facio-cutaneous syndrome. In an embodiment, the RASopathy is hereditary gingival fibromatosis type 1. In an embodiment, the RASopathy is neurofibromatosis type 1. In an embodiment, the RASopathy is Costello syndrome. In an embodiment, the RASopathy is Regius syndrome.

[0131] As used herein, the term "switch II GTPase protein-associated disease" refers to any disease or condition caused by abnormal activity or signaling of a switch II GTPase protein. In an embodiment, the switch II GTPase protein-associated disease is cancer (e.g., colon cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the switch II GTPase protein-associated disease is a RASopathy.

[0132] As used herein, the term "K-Ras(G12S)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G12S). In an embodiment, the K-Ras(G12S)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the K-Ras(G12S)-associated disease is a RASopathy.

[0133] As used herein, the term "H-Ras(G12S)-associated disease" refers to any disease or condition caused by abnormal activity or signaling of H-Ras(G12S). In an embodiment, the H-Ras(G12S)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the H-Ras(G12S)-associated disease is Costello syndrome. In an embodiment, the H-Ras(G12S)-associated disease is a RASopathy.

[0134] As used herein, the term "N-Ras(G12S)-associated disease" refers to any disease or condition caused by abnormal activity or signaling of N-Ras(G12S). In an embodiment, the N-Ras(G12S)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the N-Ras(G12S)-associated disease is a RASopathy.

[0135] As used herein, the term "K-Ras(G13S)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G13S). In an embodiment, the K-Ras(G13S)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the K-Ras(G13S)-associated disease is a RASopathy.

[0136] As used herein, the term "H-Ras(G13S)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G13S). In an embodiment, the H-Ras(G13S)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the H-Ras(G13S)-associated disease is a RASopathy.

[0137] As used herein, the term "N-Ras(G13S)-associated disease" refers to any disease or condition caused by abnormal activity or signaling of N-Ras(G13S). In an embodiment, the N-Ras(G13S)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the N-Ras(G13S)-associated disease is a RASopathy.

[0138] As used herein, the term "K-Ras(G12T)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G12T). In an embodiment, the K-Ras(G12T)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the K-Ras(G12T)-associated disease is a RASopathy.

[0139] As used herein, the term "H-Ras(G12T)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G12T). In an embodiment, the H-Ras(G12T)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the H-Ras(G12T)-associated disease is a RASopathy.

[0140] As used herein, the term "N-Ras(G12T)-associated disease" refers to any disease or condition caused by abnormal activity or signaling of N-Ras(G12T). In an embodiment, the N-Ras(G12T)-associated disease is cancer (e.g., rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia). In an embodiment, the N-Ras(G12T)-associated disease is a RASopathy.

[0141] As used herein, the term "K-Ras(G12D)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G12D). In an embodiment, the K-Ras(G12D)-associated disease is cancer. In an embodiment, the K-Ras(G12D)-associated disease is a RASopathy.

[0142] As used herein, the term "H-Ras(G12D)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G12D). In an embodiment, the H-Ras(G12D)-associated disease is cancer. In an embodiment, the H-Ras(G12D)-associated disease is a RASopathy.

[0143] As used herein, the term "N-Ras(G12D)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of N-Ras(G12D). In an embodiment, the N-Ras(G12D)-associated disease is cancer. In an embodiment, the N-Ras(G12D)-associated disease is a RASopathy.

[0144] As used herein, the term "K-Ras(G13D)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G13D). In an embodiment, the K-Ras(G13D)-associated disease is cancer. In an embodiment, the K-Ras(G13D)-associated disease is a RASopathy.

[0145] As used herein, the term "H-Ras(G13D)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G13D). In an embodiment, the H-Ras(G13D)-associated disease is cancer. In an embodiment, the H-Ras(G13D)-associated disease is a RASopathy.

[0146] As used herein, the term "N-Ras(G13D)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of N-Ras(G13D). In an embodiment, the N-Ras(G13D)-associated disease is cancer. In an embodiment, the N-Ras(G13D)-associated disease is a RASopathy.

[0147] As used herein, the term "K-Ras(G12E)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of K-Ras(G12E). In an embodiment, the K-Ras(G12E)-associated disease is a cancer. In an embodiment, the K-Ras(G12E)-associated disease is a RASopathy.

[0148] As used herein, the term "H-Ras(G12E)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of H-Ras(G12E). In an embodiment, the H-Ras(G12E)-associated disease is cancer. In an embodiment, the H-Ras(G12E)-associated disease is a RASopathy.

[0149] As used herein, the term "N-Ras(G12E)-associated disease" refers to any disease or condition caused by aberrant activity or signaling of N-Ras(G12E). In an embodiment, the N-Ras(G12E)-associated disease is cancer. In an embodiment, the N-Ras(G12E)-associated disease is a RASopathy.

[0150] The term "drug" is used according to its ordinary meaning to refer to a substance that has a physiological effect (e.g., a beneficial effect, useful to treat a subject) when introduced into or to a subject (e.g., into or on the body of a subject or patient). The drug moiety is the radical of the drug.

[0151] A "detectable agent," "detectable compound," "detectable label," or "detectable moiety" is a substance (e.g., an element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means. For example, 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 Mr. 89 Zr、 94 Tc 94 Tc 99m Tc 99 For 105 pd 105 Rh、 111 Ag 111 in 123 I 124 I 125 I 131 I 142 Mr. 143 Mr. 149 PM 153 Sm、 154-158 God 161 Tb 166 Dy 166 Ho 169 Err 175 sun 177 sun 186 Re 188 Re 189 Re 194 Ir 198 I 199 I 211 And 211 Pb、 212 Hello 212 Pb、 213 Hello 223 Ra 225 Ac、Cr、V、Mn、Fe、Co、Ni、Cu、La、Ce、Pr、Nd、Pm、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb、Lu、 32P, fluorophores (e.g., fluorescent dyes), modified oligonucleotides (e.g., portions described in International Application No. PCT / US2015 / 022063, incorporated herein by reference), electron-dense reagents, enzymes (e.g., commonly used in ELISAs), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SU ... oxide, "SPIO") nanoparticles, SPIO nanoparticle aggregates, single crystal iron oxide nanoparticles, single crystal iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing gadolinium chelate ("Gd-chelate") molecules, gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma emitting radionuclide, positron emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., microbubble shells comprising albumin, galactose, lipids, and / or polymers, air, heavy gases, perfluorocarbons, nitrogen, octafluoropropane, perflexane lipid microspheres, microbubble gas cores including perflutren, etc., iodine 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 an antibody that specifically reacts with a target peptide.

[0152] 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 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra, and 225Paramagnetic ions that can be used as additional imaging agents according to aspects 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.

[0153] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids in the administration and absorption of an active agent by a subject and can be included in the composition of the present invention without causing significant adverse toxic effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, saline (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0154] The term "preparation" is intended to include the formulation of the active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier and is therefore associated with the carrier. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0155] As used herein, the term "about" refers to a range of values ​​that includes the particular value and that one of ordinary skill in the art would consider to be reasonably similar to the particular value. In embodiments, about refers to within a standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range that covers + / - 10% of the particular value. In embodiments, about includes the particular value.

[0156] As used herein, the term "administering" is used according to its plain and ordinary meaning and means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or implantation of a sustained release device, such as a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. "Concomitant administration" means that the compositions described herein are administered simultaneously with, immediately prior to, or immediately following the administration of one or more additional therapies, such as cancer therapies, such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered to a patient alone or simultaneously. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound) individually or in combination. Thus, the preparations can be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention can be delivered transdermally or by topical routes, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, nanoparticles, pastes, jellies, paints, powders, and aerosols.

[0157] The compounds described herein can be used in combination with each other, in combination with other active agents known to be useful in the treatment of diseases associated with cells expressing disease-associated cellular components, or in combination with adjunct agents that may not be effective alone but may contribute to the effectiveness of the active agent.

[0158] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes administering two active agents simultaneously, at about the same time (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjuncts may be combined or conjugated to each other.

[0159] In therapeutic use for the treatment of disease, the compounds utilized in the pharmaceutical compositions of the present invention may be administered at an initial dosage of about 0.001 mg / kg to about 1000 mg / kg daily. A daily dosage range of about 0.01 mg / kg to about 500 mg / kg, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 mg / kg to about 50 mg / kg can be used. However, dosages may vary depending on the requirements of the patient, the severity of the condition being treated, and the compound or drug being used. For example, dosages can be empirically determined taking into account the type and stage of disease (e.g., cancer, RASopathy, or Costello syndrome) diagnosed in a particular patient. In light of the present invention, the dosage administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects accompanying the administration of the compound in a particular patient. The determination of the appropriate dosage for a particular situation is within the ability of a person skilled in the art.Generally, treatment is started with a smaller dosage that is less than the optimal dose of compound.Then, dosage is gradually increased until the optimal effect is reached under the circumstances.For convenience, if desired, the total daily dosage can be divided and administered in portions throughout the day.

[0160] In the context of a substance or a substance activity or function related to a disease (e.g., a protein-related disease, a disease associated with a cellular constituent), the term "related to" or "associated with" means that the substance or the substance activity or function causes (in whole or in part) the disease (e.g., cancer, RASopathy, or Costello syndrome) or causes (in whole or in part) a symptom of the disease, or the symptom of the disease can be treated by modulating (e.g., inhibiting or activating) the substance (e.g., a cellular constituent). As used herein, something that is described as associated with a disease may be a target for the treatment of the disease if it is a causative agent.

[0161] The term "abnormal" as used herein refers to something that is different from normal. When used to describe enzyme activity, abnormal refers to activity that is greater or less than the average of normal control or normal non-disease control samples. Abnormal activity may refer to an amount of activity that results in disease, and restoring the abnormal activity to a normal or non-disease associated amount (e.g., by administering a compound or using the methods described herein) results in the alleviation of the disease or one or more disease symptoms.

[0162] The term "electrophilic" as used herein refers to a chemical group that can accept electron density. "Electrophilic substituent", "electrophilic chemical moiety", or "electrophilic moiety" refers to an electron-deficient chemical group, substituent, or moiety (a monovalent chemical group) that can react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.

[0163] As used herein, "nucleophile" refers to a chemical group capable of donating electron density.

[0164] The term "isolated," as applied to a nucleic acid or protein, means that the nucleic acid or protein is essentially free of other cellular components with which it is naturally associated. It can be, for example, in a homogeneous state, either dry or in an aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is present as the predominant species in a preparation is substantially purified.

[0165] 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, for example, 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 attached to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refer to compounds that have a structure that differs from the general chemical structure of an amino acid, but that 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.

[0166] 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.

[0167] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, which may, in embodiments, be conjugated to moieties not composed of amino acids. The terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of a corresponding naturally occurring amino acid, as well as to naturally occurring and non-naturally occurring amino acid polymers.

[0168] The "position" of an amino acid or nucleotide base is indicated by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-terminus). In general, the number of amino acid residues in a test sequence, determined by simply counting from the N-terminus, is not necessarily the same as the number of corresponding positions in the reference sequence, due to deletions, insertions, truncations, fusions, etc., that must be considered when determining optimal alignment. For example, if a variant has a deletion compared to the aligned reference sequence, there will be no amino acid in the variant that corresponds to the position in the reference sequence at the site of the deletion. If there is an insertion in the aligned reference sequence, the insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of a truncation or fusion, there may be a stretch of amino acids in either the reference sequence or the aligned sequence that does not correspond to any amino acid in the corresponding sequence.

[0169] 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 the residues of a particular reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

[0170] An amino acid residue of a protein "corresponds" to a given residue if it occupies the same essential structural position in the protein as the given residue. For example, a selected residue in a selected protein corresponds to G12 of K-Ras if the selected residue occupies the same essential spatial or other structural relationship as G12 of K-Ras. In some embodiments, when the selected protein is aligned for maximum homology with K-Ras, the position in the aligned selected protein that aligns with G12 is said to correspond to G12. Instead of a primary sequence alignment, a three-dimensional structural alignment can also be used, for example, when the structure of the selected protein is aligned for maximum agreement with K-Ras and the overall structures are compared. In this case, the amino acid that occupies the same essential position in the structural model as G12 is said to correspond to the G12 residue.

[0171] The term "protein complex" is used according to its plain and ordinary meaning and refers to a protein associated with an additional substance (e.g., another protein, a protein subunit, or a compound). A protein complex typically has a defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between the protein and the additional substance (e.g., a compound) is via a non-covalent interaction. In embodiments, a protein complex refers to a group of two or more polypeptide chains. The proteins in a protein complex are linked by non-covalent protein-protein interactions. A non-limiting example of a protein complex is the proteasome.

[0172] The term "protein aggregate" is used according to its plain and ordinary meaning and refers to an abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with disease (e.g., amyloidosis). Typically, a protein misfolds as a result of a change in amino acid sequence or a change in the native environment that disrupts normal non-covalent interactions, and if the misfolded protein is not corrected or degraded, the unfolded / misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In an embodiment, the protein aggregates are referred to as aggresomes.

[0173] The term "switch II" as used herein refers to a protein domain of a GTPase protein (e.g., Ras, K-Ras, H-Ras, or N-Ras) formed by residues corresponding to residues 60-76 of K-Ras, H-Ras, or N-Ras (e.g., K-Ras switch II refers to residues 60-76 of K-Ras, H-Ras switch II refers to residues 60-76 of H-Ras, and N-Ras switch II refers to residues 60-76 of N-Ras). A "switch II binding pocket" is a cavity bounded, at least in part, by the amino acid residues that form switch II. In some embodiments, a "switch II binding pocket" is a cavity in the GDP-bound form of a GTPase protein (e.g., Ras, K-Ras, H-Ras, or N-Ras) that is bounded, at least in part, by the amino acid residues that form switch II. A "switch II binding pocket binding moiety" is a portion of a compound (eg, as described herein) that binds to the switch II binding pocket.

[0174] The term "switch II GTPase protein" as used herein refers to a GTPase protein that comprises a switch II. In embodiments, the switch II GTPase protein comprises a switch II binding pocket. In embodiments, the switch II GTPase protein is a Ras protein. In embodiments, the switch II GTPase protein is K-Ras. In embodiments, the switch II GTPase protein is H-Ras. In embodiments, the switch II GTPase protein is N-Ras. In embodiments, the switch II GTPase protein is E-Ras. In embodiments, the switch II GTPase protein is RASD1. In embodiments, the switch II GTPase protein is Rhes. In embodiments, the switch II GTPase protein is RASL11B. In embodiments, the switch II GTPase protein is REM2. In embodiments, the switch II GTPase protein is RHOH. In embodiments, the switch II GTPase protein is RND3. In embodiments, the switch II GTPase protein is RAB1A. In embodiments, the switch II GTPase protein is RAB1B. In embodiments, the switch II GTPase protein is RAB2A. In embodiments, the switch II GTPase protein is RAB2B. In embodiments, the switch II GTPase protein is GNAZ. In embodiments, the switch II GTPase protein is LRRK2. In embodiments, the switch II GTPase protein is a GTPase protein listed in Colicelli, J. Sci STKE, 2004, (250), RE13, which is incorporated by reference in its entirety for all purposes. In embodiments, the switch II GTPase protein is ARF1 (e.g., UniProt P84077). In embodiments, the switch II GTPase protein is ARF3 (e.g., UniProt P61204). In embodiments, the switch II GTPase protein is ARF4 (e.g., UniProt P18085).In embodiments, the switch II GTPase protein is ARF5 (e.g., UniProt P84085). In embodiments, the switch II GTPase protein is ARF6 (e.g., UniProt P62330). In embodiments, the switch II GTPase protein is TRIM23 (e.g., UniProt P36406). In embodiments, the switch II GTPase protein is ARL1 (e.g., UniProt P40616). In embodiments, the switch II GTPase protein is ARL2 (e.g., UniProt P36404). In embodiments, the switch II GTPase protein is ARL3 (e.g., UniProt P36405). In embodiments, the switch II GTPase protein is ARL4A (e.g., UniProt P40617). In embodiments, the switch II GTPase protein is ARL4B. In embodiments, the switch II GTPase protein is ARL5. In embodiments, the switch II GTPase protein is ARL6 (e.g., UniProt Q9H0F7). In embodiments, the switch II GTPase protein is ARL7. In embodiments, the switch II GTPase protein is ARL8. In embodiments, the switch II GTPase protein is ARL9 (e.g., UniProt Q6T311). In embodiments, the switch II GTPase protein is ARL12. In embodiments, the switch II GTPase protein is ARL11 (e.g., UniProt Q969Q4). In embodiments, the switch II GTPase protein is ARF7. In embodiments, the switch II GTPase protein is 339231 (e.g., UniProt Q0P5N6). In embodiments, the switch II GTPase protein is DKFZp761. In embodiments, the switch II GTPase protein is ARFRP1 (e.g., UniProt Q13795). In an embodiment, the Switch II GTPase protein is ARFRP2 (e.g., UniProt Q9NXU5).In embodiments, the switch II GTPase protein is ARL10A (e.g., UniProt Q8N8L6). In embodiments, the switch II GTPase protein is ARL10B (e.g., UniProt Q96BM9). In embodiments, the switch II GTPase protein is ARL10C. In embodiments, the switch II GTPase protein is 344988. In embodiments, the switch II GTPase protein is SARA1 (e.g., UniProt Q6FID4). In embodiments, the switch II GTPase protein is SARA2.

[0175] The term "switch II GTPase protein serine residue" as used herein refers to a serine residue of a switch II GTPase protein. In embodiments, the switch II GTPase protein serine residue is a serine residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein serine residue is a native switch II GTPase protein serine residue. In embodiments, the switch II GTPase protein serine residue is a mutant switch II GTPase protein serine residue. In embodiments, the mutant switch II GTPase protein serine residue is K-Ras(G12S), H-Ras(G12S), or N-Ras(G12S).

[0176] The term "switch II GTPase protein threonine residue" as used herein refers to a threonine residue of a switch II GTPase protein. In embodiments, the switch II GTPase protein threonine residue is a threonine residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein threonine residue is a native switch II GTPase protein threonine residue. In embodiments, the switch II GTPase protein threonine residue is a mutant switch II GTPase protein threonine residue. In embodiments, the mutant switch II GTPase protein threonine residue is K-Ras(G12T), H-Ras(G12T), or N-Ras(G12T).

[0177] The term "switch II GTPase protein aspartic acid residue" as used herein refers to an aspartic acid residue of a switch II GTPase protein. In embodiments, the switch II GTPase protein aspartic acid residue is an aspartic acid residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein aspartic acid residue is an aspartic acid residue corresponding to position 13 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein aspartic acid residue is a native switch II GTPase protein aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is a mutant switch II GTPase protein aspartic acid residue. In embodiments, the mutant switch II GTPase protein aspartate residue is aspartate residue 12 of K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D). In embodiments, the mutant switch II GTPase protein aspartate residue is aspartate residue 13 of K-Ras(G13D), H-Ras(G13D), or N-Ras(G13D).

[0178] The term "switch II GTPase protein glutamate residue" as used herein refers to a glutamate residue of a switch II GTPase protein. In embodiments, the switch II GTPase protein glutamate residue is a glutamate residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein glutamate residue is a native switch II GTPase protein glutamate residue. In embodiments, the switch II GTPase protein glutamate residue is a mutant switch II GTPase protein glutamate residue. In embodiments, the mutant switch II GTPase protein glutamate residue is glutamate residue 12 of K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D).

[0179] The term "Ras" refers to one or more of the family of human Ras GTPase proteins (e.g., K-Ras, H-Ras, N-Ras), including homologs, isoforms, and functional fragments thereof.

[0180] The term "K-Ras" refers to the protein encoded by the KRAS gene in humans. The K-Ras protein is a GTPase that converts guanosine triphosphate to guanosine diphosphate. Mutations (e.g., amino acid substitutions) in the K-Ras protein can result in various malignancies (e.g., lung adenocarcinoma, pancreatic cancer, or colorectal cancer). The term "K-Ras" can refer to the nucleotide sequence or protein sequence of human KRAS (e.g., Entrez 3845, UniProt P01116, RefSeq NM_004985.4, RefSeq NM_033360.3, RefSeq NP_004976.2, or RefSeq NP_203524.1). In an embodiment, K-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM (SEQ ID NO: 1).

[0181] In embodiments, the K-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQGVDDAFYTLVREIRKHKEKMSKDGKKKKKKSKTKCVIM (sequence number 56).

[0182] The term "H-Ras" refers to an enzyme that in humans is encoded by the HRAS gene. The H-Ras protein is a GTPase that converts guanosine triphosphate to guanosine diphosphate. Mutations (e.g., amino acid substitutions) in the H-Ras protein can result in a variety of malignancies (e.g., bladder, thyroid, salivary duct, epithelial, or renal cancers). The term "H-Ras" may refer to the nucleotide or protein sequence of human HRAS (e.g., Entrez 3265, UniProt P01112, RefSeq NM_001130442.2, RefSeq NM_001318054.1, RefSeq NM_005343.3, RefSeq NM_00176795.4, RefSeq NP_001123914.1, RefSeq NP_001304983.1, RefSeq NP_005334.1, or RefSeq NP_789765.1). In embodiments, H-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRVKDSDDVPMVLVGNKCDLAARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRKLNPPDESGPGCMSCKCVLS (SEQ ID NO: 2).

[0183] The term "N-Ras" refers to the enzyme encoded by the NRAS gene in humans. The N-Ras protein is a GTPase that converts guanosine triphosphate to guanosine diphosphate. The term "N-Ras" may refer to the nucleotide sequence or protein sequence of human NRAS (e.g., Entrez 4893, UniProt P01111, RefSeq NM_002524.4, or RefSeq NP_002515.1). In embodiments, N-Ras has the following amino acid sequence: MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDLPTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQGCMGLPCVVM (SEQ ID NO: 3).

[0184] In embodiments, the switch II binding pocket is bound at least in part by one or more of V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and / or I100 of K-Ras, or equivalent residues in a homologous related Ras protein (e.g., H-Ras or N-Ras) or mutant Ras protein. Compounds described herein (including embodiments, examples, and figures) that bind to or contact amino acids that form the switch II binding pocket are "switch II binding pocket binding compounds," and portions of compounds that bind to or contact amino acids that form the switch II binding pocket are "switch II binding pocket binding moieties."

[0185] In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts one amino acid forming the switch II binding pocket. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts multiple amino acids forming the switch II binding pocket. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts one amino acid selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts a plurality of K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts two K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts three K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts four K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts five K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts six K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts seven K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts eight K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts nine K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts ten K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts eleven K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 12 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 13 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 14 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety is directed against a mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), a related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N-Ras(G12T)), or amino acids in homologues of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.

[0186] In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts one amino acid selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), a related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts a plurality of K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), a related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts two K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts three K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), a related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts four K-Ras amino acids selected from amino acids in mutant K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E), a related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts five K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), a related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts six K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), a related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts seven K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts eight K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts nine K-Ras amino acids selected from amino acids in mutant K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), a related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts ten K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts eleven K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 12 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 13 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100. In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 14 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.In embodiments, the switch II binding pocket binding compound or switch II binding pocket binding moiety binds to or contacts 15 K-Ras amino acids selected from amino acids in mutant K-Ras (e.g., K-Ras(G12D), K-Ras(G13D), or K-Ras(G12E)), related Ras (e.g., H-Ras, H-Ras(G12D), H-Ras(G13D), H-Ras(G12E), N-Ras, N-Ras(G12D), N-Ras(G13D), or N-Ras(G12E)), or a homologue of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.

[0187] Terms such as "selective" or "selectivity" with respect to a compound or agent refer to the ability of the compound or agent to cause an increase or decrease in the activity of a particular molecular target (e.g., a protein, enzyme, etc.) preferentially over one or more different molecular targets (e.g., a compound having selectivity for mutant K-Ras(G12S) will preferentially inhibit K-Ras(G12S) over other K-Ras proteins (e.g., wild-type K-Ras), or a compound having selectivity for mutant K-Ras(G12D) will preferentially inhibit K-Ras(G12D) over other K-Ras proteins (e.g., wild-type K-Ras). In embodiments, a "Ras(G12S)-selective compound" refers to a compound (e.g., a compound described herein) that has selectivity for Ras(G12S). In embodiments, a "Ras(G12D)-selective compound" refers to a compound (e.g., a compound described herein) that has selectivity for Ras(G12D).

[0188] The term "β-lactone" is used according to its plain and ordinary meaning in organic chemistry to refer to a four-membered heterocycloalkyl ring containing a -C(O)O- moiety. In embodiments, a β-lactone has the formula

[0189] [ka] has.

[0190] The term "β-lactam" is used according to its plain and ordinary meaning in organic chemistry to refer to a four-membered heterocycloalkyl ring containing a -C(O)NR- moiety. In embodiments, a β-lactam has the formula

[0191] [ka] has.

[0192] II. Compounds In one aspect, a compound having the formula:

[0193] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0194] R 1 is the Switch II binding pocket binding moiety.

[0195] L 1 is a bond or a bivalent linker.

[0196] E 1 is an electrophilic moiety capable of forming a covalent bond with a switch II GTPase protein serine residue or a switch II GTPase protein threonine residue.

[0197] In an embodiment, E 1 is an electrophilic moiety capable of forming a covalent bond with a switch II GTPase protein serine residue. 1is an electrophilic moiety capable of forming a covalent bond with a switch II GTPase protein threonine residue. In embodiments, the switch II GTPase protein serine residue is a serine residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the switch II GTPase protein serine residue is a native switch II GTPase protein serine residue. In embodiments, the switch II GTPase protein serine residue is a mutant switch II GTPase protein serine residue. In embodiments, the mutant switch II GTPase protein serine residue is serine residue 12 of K-Ras(G12S), H-Ras(G12S), or N-Ras(G12S). In embodiments, the mutant switch II GTPase protein serine residue is serine residue 13 of K-Ras(G13S), H-Ras(G13S), or N-Ras(G13S). In embodiments, the switch II GTPase protein threonine residue is a native switch II GTPase protein threonine residue. In embodiments, the switch II GTPase protein threonine residue is a mutant switch II GTPase protein threonine residue. In embodiments, the mutant switch II GTPase protein threonine residue is threonine residue 12 of K-Ras(G12T), H-Ras(G12T), or N-Ras(G12T).

[0198] In embodiments, the switch II GTPase protein serine residue is a Ras protein serine residue. In embodiments, the switch II GTPase protein serine residue is a K-Ras serine residue. In embodiments, the switch II GTPase protein serine residue is an H-Ras serine residue. In embodiments, the switch II GTPase protein serine residue is an N-Ras serine residue. In embodiments, the switch II GTPase serine residue protein is an E-Ras serine residue. In embodiments, the switch II GTPase protein serine residue is a RASD1 serine residue. In embodiments, the switch II GTPase protein serine residue is a Rhes serine residue. In embodiments, the switch II GTPase protein serine residue is a RASL11B serine residue. In embodiments, the switch II GTPase protein serine residue is a REM2 serine residue. In embodiments, the switch II GTPase protein serine residue is a RHOH serine residue. In embodiments, the switch II GTPase protein serine residue is an RND3 serine residue. In embodiments, the switch II GTPase protein serine residue is a RAB1A serine residue. In embodiments, the switch II GTPase protein serine residue is a RAB1B serine residue. In embodiments, the switch II GTPase protein serine residue is a RAB2A serine residue. In embodiments, the switch II GTPase protein serine residue is a RAB2B serine residue. In embodiments, the switch II GTPase protein serine residue is a GNAZ serine residue. In embodiments, the switch II GTPase protein serine residue is an LRRK2 serine residue. In embodiments, the switch II GTPase protein threonine residue is an LRRK2 threonine residue. In embodiments, the switch II GTPase protein serine residue is a serine residue of a GTPase protein listed in Colicelli, J. Sci STKE, 2004, (250), RE13, which is incorporated by reference in its entirety for all purposes.

[0199] In embodiments, the switch II GTPase protein threonine residue is a Ras protein threonine residue. In embodiments, the switch II GTPase protein threonine residue is a K-Ras threonine residue. In embodiments, the switch II GTPase protein threonine residue is an H-Ras threonine residue. In embodiments, the switch II GTPase protein threonine residue is an N-Ras threonine residue.

[0200] In an embodiment, E 1 is an electrophilic moiety capable of forming a covalent bond with a K-Ras serine residue. 1 is an electrophilic moiety capable of forming a covalent bond with an H-Ras serine residue. 1 is an electrophilic moiety capable of forming a covalent bond with an N-Ras serine residue. 1 is an electrophilic moiety capable of forming a covalent bond with a K-Ras threonine residue. 1 is an electrophilic moiety capable of forming a covalent bond with an H-Ras threonine residue. 1 is an electrophilic moiety capable of forming a covalent bond with an N-Ras threonine residue. 1 In embodiments, E 1 contains a β-lactam.

[0201] In embodiments, the compound has the formula:

[0202] [ka] R 1 , L 1 , and E 1 as described herein, including the embodiments.

[0203] In embodiments, the compound has the formula:

[0204] [ka] R 1 and L 1 as described herein, including the embodiments.

[0205] Ring A is a cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), or heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered).

[0206] X is O or S.

[0207] Y is O, S, or NR 2 It is.

[0208] 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 3 H, -OSO 3 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0209] R 3 are independently 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 , -CHF2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two R 3 The substituents may be optionally linked to substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0210] The symbol z3 is an integer from 0 to 10.

[0211] R 4 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 3 H, -OSO 3 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, -OCCl3 , -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0212] R 5 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, -NH2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0213] In an embodiment, ring A is C 3 ~C 8 In an embodiment, ring A is cycloalkyl. In an embodiment, ring A is cyclobutyl. In an embodiment, ring A is cyclopentyl. In an embodiment, ring A is cyclohexyl. In an embodiment, ring A is cycloheptyl. In an embodiment, ring A is cyclooctyl. In an embodiment, ring A is 3-8 membered heterocycloalkyl. In an embodiment, ring A is 5-6 membered heterocycloalkyl. In an embodiment, ring A is piperidinyl, pyrrolidinyl, or piperazinyl. In an embodiment, ring A is piperidinyl. In an embodiment, ring A is pyrrolidinyl. In an embodiment, ring A is piperazinyl.

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

[0215] [ka] X, Y, R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0216] [ka] wherein X, Y, R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0217] [ka] wherein X, Y, R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0218] [ka] wherein X, Y, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0219] In embodiments, the compound has the formula:

[0220] [ka] R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0221] [ka] wherein R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0222] [ka] wherein R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0223] [ka] wherein R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0224] In embodiments, the compound has the formula:

[0225] [ka] X, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0226] In embodiments, the compound has the formula:

[0227] [ka] R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0228] In embodiments, the compound has the formula:

[0229] [ka] X, Y, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0230] In embodiments, the compound has the formula:

[0231] [ka] R 1 , L 1 , R 2 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0232] [ka] wherein R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0233] [ka] wherein R 1 , L 1 , R 2 , R 3 , and z3 are as described herein, including embodiments.

[0234] In embodiments, the compound has the formula:

[0235] [ka] X, Y, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0236] In embodiments, the compound has the formula:

[0237] [ka] R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0238] In embodiments, the compound has the formula:

[0239] [ka] X, Y, R 1 , L 1 , R 3, and z3 are as described herein, including embodiments.

[0240] In embodiments, the compound has the formula:

[0241] [ka] R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0242] In embodiments, the compound has the formula:

[0243] [ka] R 1 and L 1 as described herein, including the embodiments.

[0244] In embodiments, the compound has the formula:

[0245] [ka] R 1 and L 1 as described herein, including the embodiments.

[0246] In one aspect, a compound having the formula:

[0247] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0248] R 1 is the Switch II binding pocket binding moiety.

[0249] L 1is a bond or a bivalent linker.

[0250] E 2 is an electrophilic moiety capable of forming a covalent bond with a Switch II GTPase protein aspartic acid residue or a Switch II GTPase protein glutamic acid residue.

[0251] In an embodiment, E 2 is an electrophilic moiety capable of forming a covalent bond with an aspartic acid residue of a Switch II GTPase protein. 2is an electrophilic moiety capable of forming a covalent bond with a switch II GTPase protein glutamic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is a native switch II GTPase protein aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is a mutant switch II GTPase protein aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an aspartic acid residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the mutant switch II GTPase protein aspartic acid residue is aspartic acid residue 12 of K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D). In embodiments, the switch II GTPase protein aspartic acid residue is an aspartic acid residue corresponding to position 13 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the mutant switch II GTPase protein aspartic acid residue is aspartic acid residue 13 of K-Ras(G13D), H-Ras(G13D), or N-Ras(G13D). In embodiments, the switch II GTPase protein glutamic acid residue is a glutamic acid residue corresponding to position 12 of a Ras protein (e.g., K-Ras, H-Ras, or N-Ras). In embodiments, the mutant switch II GTPase protein glutamic acid residue is glutamic acid residue 12 of K-Ras(G12E), H-Ras(G12E), or N-Ras(G12E).

[0252] In embodiments, the switch II GTPase protein aspartic acid residue is a Ras protein aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is a K-Ras aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an H-Ras aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an N-Ras aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARF1 (e.g., UniProt P84077) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARF3 (e.g., UniProt P61204) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARF4 (e.g., UniProt P18085) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARF5 (e.g., UniProt P84085) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARF6 (e.g., UniProt P62330) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is a TRIM23 (e.g., UniProt P36406) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL1 (e.g., UniProt P40616) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL2 (e.g., UniProt P36404) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL3 (e.g., UniProt P36405) aspartic acid residue. In embodiments, the Switch II GTPase protein aspartic acid residue is an ARL4A (eg, UniProt P40617) aspartic acid residue.In embodiments, the switch II GTPase protein aspartic acid residue is an ARL4B aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL5 aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL6 (e.g., UniProt Q9H0F7) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL7 aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL8 aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL9 (e.g., UniProt Q6T311) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL12 aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARL11 (e.g., UniProt Q969Q4) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARF7 aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is a 339231 (e.g., UniProt Q0P5N6) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is a DKFZp761 aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARFRP1 (e.g., UniProt Q13795) aspartic acid residue. In embodiments, the switch II GTPase protein aspartic acid residue is an ARFRP2 (e.g., UniProt Q9NXU5) aspartic acid residue. In embodiments, the Switch II GTPase protein aspartic acid residue is an ARL10A (e.g., UniProt Q8N8L6) aspartic acid residue. In embodiments, the Switch II GTPase protein aspartic acid residue is an ARL10B (e.g., UniProt Q96BM9) aspartic acid residue.In embodiments, the Switch II GTPase protein aspartic acid residue is an ARL10C aspartic acid residue. In embodiments, the Switch II GTPase protein aspartic acid residue is a 344988 aspartic acid residue. In embodiments, the Switch II GTPase protein aspartic acid residue is a SARA1 (e.g., UniProt Q6FID4) aspartic acid residue. In embodiments, the Switch II GTPase protein aspartic acid residue is a SARA2 aspartic acid residue.

[0253] In embodiments, the switch II GTPase protein glutamic acid residue is a Ras protein glutamic acid residue. In embodiments, the switch II GTPase protein glutamic acid residue is a K-Ras glutamic acid residue. In embodiments, the switch II GTPase protein glutamic acid residue is a H-Ras glutamic acid residue. In embodiments, the switch II GTPase protein glutamic acid residue is a N-Ras glutamic acid residue.

[0254] In an embodiment, E 2 is an electrophilic moiety capable of forming a covalent bond with a K-Ras aspartic acid residue. 2 is an electrophilic moiety capable of forming a covalent bond with an H-Ras aspartic acid residue. 2 is an electrophilic moiety capable of forming a covalent bond with an N-Ras aspartic acid residue. 2 is an electrophilic moiety capable of forming a covalent bond with a K-Ras glutamic acid residue. 2 is an electrophilic moiety capable of forming a covalent bond with an H-Ras glutamic acid residue. 2 is an electrophilic moiety capable of forming a covalent bond with an N-Ras glutamic acid residue. 2 In embodiments, E 2 contains a β-lactam.

[0255] In embodiments, the compound has the formula:

[0256] [ka] R 1 , L 1 , and E 2 as described herein, including the embodiments.

[0257] In embodiments, the compound has the formula:

[0258] [ka] R 1 and L 1 as described herein, including the embodiments.

[0259] Ring A is a cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), or heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered).

[0260] L 2 is unsubstituted C 1 ~C 4 It is alkylene.

[0261] X is O or S.

[0262] Y is O, S, or NR 2 It is.

[0263] R 2 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2Cl, -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 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0264] R 3 are independently 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, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two R 3 The substituents may be optionally linked to substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0265] The symbol z3 is an integer from 0 to 10.

[0266] R 4 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0267] R 5 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 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0268] R 9 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 3 H, -OSO 3 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, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH2 Br, -OCH 2 F, -OCH 2 I, -OCHCl 2 , -OCHBr 2 , -OCHF 2 , -OCHI 2 , substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0269] R 10 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 3 H, -OSO 3H, -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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0270] In an embodiment, ring A is C 3 ~C 8In an embodiment, ring A is cycloalkyl. In an embodiment, ring A is cyclobutyl. In an embodiment, ring A is cyclopentyl. In an embodiment, ring A is cyclohexyl. In an embodiment, ring A is cycloheptyl. In an embodiment, ring A is cyclooctyl. In an embodiment, ring A is 3-8 membered heterocycloalkyl. In an embodiment, ring A is 5-6 membered heterocycloalkyl. In an embodiment, ring A is piperidinyl, pyrrolidinyl, or piperazinyl. In an embodiment, ring A is piperidinyl. In an embodiment, ring A is pyrrolidinyl. In an embodiment, ring A is piperazinyl.

[0271] In embodiments, the compound has the formula:

[0272] [ka] Rings A, X, Y, and R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0273] In embodiments, the compound has the formula:

[0274] [ka] X, Y, R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0275] [ka] wherein X, Y, R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0276] [ka] wherein X, Y, R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0277] [ka] wherein X, Y, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0278] In embodiments, the compound has the formula:

[0279] [ka] R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0280] [ka] wherein R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0281] [ka] wherein R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0282] [ka] wherein R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0283] In embodiments, the compound has the formula:

[0284] [ka] Rings A, X, and R 1 , L 1 , R 3 , z3, R 4 , and R 5 as described herein, including the embodiments.

[0285] In embodiments, the compound has the formula:

[0286] [ka] X, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0287] In embodiments, the compound has the formula:

[0288] [ka] R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0289] In embodiments, the compound has the formula:

[0290] [ka] Rings A, X, Y, and R 1 , L 1 , R 3 , z3, R 4 , and R 5 as described herein, including the embodiments.

[0291] In embodiments, the compound has the formula:

[0292] [ka] X, Y, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0293] In embodiments, the compound has the formula:

[0294] [ka] R 1 , L 1 , R 2 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0295] [ka] wherein R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0296] [ka] wherein R 1 , L 1 , R2 , R 3 , and z3 are as described herein, including embodiments.

[0297] In embodiments, the compound has the formula:

[0298] [ka] Rings A, X, Y, and R 1 , L 1 , R 3 , z3, R 4 , and R 5 as described herein, including the embodiments.

[0299] In embodiments, the compound has the formula:

[0300] [ka] X, Y, R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0301] In embodiments, the compound has the formula:

[0302] [ka] R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0303] In embodiments, the compound has the formula:

[0304] [ka] Rings A, X, Y, and R 1 , L 1 , R 3 , z3, R4 , R 5 , and R 10 as described herein, including the embodiments.

[0305] In embodiments, the compound has the formula:

[0306] [ka] X, Y, R 1 , L 1 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0307] In embodiments, the compound has the formula:

[0308] [ka] R 1 , L 1 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0309] In embodiments, the compound has the formula:

[0310] [ka] Rings A, X, Y, and R 1 , L 1 , R 3 , z3, R 4 , and R 5 as described herein, including the embodiments.

[0311] In embodiments, the compound has the formula:

[0312] [ka] R 1 , L1 , R 3 , z3, R 4 , and R 5 as described herein, including the embodiments.

[0313] In embodiments, the compound has the formula:

[0314] [ka] R 1 , L 1 , and R 4 as described herein, including the embodiments.

[0315] In embodiments, the compound has the formula:

[0316] [ka] R 1 , L 1 , R 4 , and R 5 as described herein, including the embodiments.

[0317] In embodiments, the compound has the formula:

[0318] [ka] Rings A, X, Y, and R 1 , L 1 , R 3 , z3, R 4 , R 5 , and R 10 as described herein, including the embodiments.

[0319] In embodiments, the compound has the formula:

[0320] [ka] X, Y, R1 , L 1 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0321] In embodiments, the compound has the formula:

[0322] [ka] R 1 , L 1 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0323] In embodiments, the compound has the formula:

[0324] [ka] Rings A, X, Y, and R 1 , L 1 , L 2 , R 3 , z3, R 4 , R 5 , and R 10 is as described herein, including the embodiments.

[0325] In embodiments, the compound has the formula:

[0326] [ka] X, Y, R 1 , L 1 , L 2 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0327] In embodiments, the compound has the formula:

[0328] [ka] R 1 , L 1 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0329] In embodiments, the compound has the formula:

[0330] [ka] Rings A, X, Y, and R 1 , L 1 , L 2 , R 3 , z3, R 4 , R 5 , and R 10 is as described herein, including the embodiments.

[0331] In embodiments, the compound has the formula:

[0332] [ka] X, Y, R 1 , L 1 , L 2 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0333] In embodiments, the compound has the formula:

[0334] [ka] R 1 , L 1 , R 3 , z3, and R 4 as described herein, including the embodiments.

[0335] In embodiments, the compound has the formula:

[0336] [ka] Rings A, X, Y, and R 1 , L 1 , R 3 , z3, R 4 , R 5 , and R 9 as described herein, including the embodiments.

[0337] In embodiments, the compound has the formula:

[0338] [ka] X, Y, R 1 , L 1 , R 3 , z3, and R 9 is as described herein, including embodiments. In embodiments, the compound has the formula:

[0339] [ka] wherein X, Y, R 1 , L 1 , R 3 , z3, and R 9 as described herein, including in embodiments. In embodiments, the compound has the formula:

[0340] [ka] wherein X, Y, R 1 , L 1 , R 3 , z3, and R 9 as described herein, including the embodiments.

[0341] In embodiments, the compound has the formula:

[0342] [ka] R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0343] [ka] wherein R 1 , L 1 , R 3 and z3 are as described herein, including embodiments. In embodiments, the compound has the formula:

[0344] [ka] wherein R 1 , L 1 , R 3 , and z3 are as described herein, including embodiments.

[0345] In embodiments, the compound has the formula:

[0346] [ka] X, Y, R 1 , L 1 , R 4 , R 5 , and R 10 as described herein, including the embodiments.

[0347] In embodiments, the compound has the formula:

[0348] [ka] R 1 and L 1 as described herein, including the embodiments.

[0349] In embodiments, the compound has the formula:

[0350] [ka] X, Y, R 1 , L 1 , R 4 , R 5 , and R 10 as described herein, including the embodiments.

[0351] In embodiments, the compound has the formula:

[0352] [ka] R 1 and L 1 as described herein, including the embodiments.

[0353] In an embodiment, the substitution R 2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 2 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 2 When R is substituted, it is substituted with at least one substituent. 2 When R is substituted, it is substituted with at least one size-limited substituent. 2 When is substituted, it is substituted with at least one lower substituent.

[0354] In embodiments, R 2 is hydrogen, -CF 3 , -CH 2 F, -CHF2 , 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.

[0355] In embodiments, R 2 is hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 2 is hydrogen. In embodiments, R 2 is unsubstituted C 1 ~C 4 In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is unsubstituted ethyl. In embodiments, R 2 is unsubstituted propyl. In embodiments, R 2 is unsubstituted n-propyl. In embodiments, R 2 is unsubstituted isopropyl. In embodiments, R 2 is unsubstituted butyl. In embodiments, R 2 is unsubstituted n-butyl. In embodiments, R 2 is unsubstituted isobutyl. In embodiments, R 2 is unsubstituted tert-butyl.

[0356] In an embodiment, the substitution R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 3 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 3 When R is substituted, it is substituted with at least one substituent. 3When R is substituted, it is substituted with at least one size-limited substituent. 3 When is substituted, it is substituted with at least one lower substituent.

[0357] In an embodiment, two R 3 The substituted ring formed when the substituents are linked (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent, and two R 3 When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-class substituents, each of the substituents, size-limiting substituents, and / or lower-class substituents may optionally be different. 3 When the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. 3 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. In embodiments, two R 3 If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0358] In embodiments, R 3 are independently 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 3 H, -OSO 3H, -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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and two R 3 The substituents may be optionally linked to substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or a substituted or unsubstituted heteroaryl (eg, 5-10 membered, 5-9 membered, or 5-6 membered).

[0359] In embodiments, R 3 is independently oxo. In embodiments, R 3 is independently halogen. In an embodiment, R 3 is independently -F. In embodiments, R 3 is independently -Cl. In embodiments, R 3 is independently -Br. In embodiments, R 3 is independently -I. In embodiments, R 3 are independently -CCl 3 In an embodiment, R 3 are independently -CBr 3 In an embodiment, R 3 are independently -CF 3 In an embodiment, R 3 is independently -CI 3 In an embodiment, R 3 are independently -CH 2 In an embodiment, R 3 are independently -CH 2 In an embodiment, R 3 are independently -CH 2 F. In embodiments, R 3 are independently -CH 2 In an embodiment, R 3 are independently -CHCl 2 In an embodiment, R 3 are independently -CHBr 2 In an embodiment, R 3 are independently -CHF 2In an embodiment, R 3 is independently -CHI 2 In an embodiment, R 3 is independently -CN. In embodiments, R 3 is independently -OH. In embodiments, R 3 are independently -NH 2 In an embodiment, R 3 is independently -COOH. In embodiments, R 3 independently, -CONH 2 In an embodiment, R 3 independently, -NO 2 In an embodiment, R 3 is independently -SH. In embodiments, R 3 independently, -SO 3 H. In embodiments, R 3 is independently -OSO 3 H. In embodiments, R 3 independently, -SO 2 NH 2 In an embodiment, R 3 are independently -NHNH 2 In an embodiment, R 3 independently, -ONH 2 In an embodiment, R 3 are independently -NHC(O)NHNH 2 In an embodiment, R 3 are independently -NHC(O)NH 2 In an embodiment, R 3 are independently -NHSO 2 H. In embodiments, R 3 is independently -NHC(O)H. In embodiments, R 3 is independently -NHC(O)OH. In embodiments, R 3 is independently -NHOH. In embodiments, R 3 are independently -OCCl 3 In an embodiment, R 3 are independently -OCBr 3 In an embodiment, R 3can be used independently, -OCF 3 In an embodiment, R 3 can be used independently. 3 In an embodiment, R 3 are independently -OCH 2 In an embodiment, R 3 are independently -OCH 2 In an embodiment, R 3 are independently -OCH 2 F. In embodiments, R 3 are independently -OCH 2 In an embodiment, R 3 are independently -OCHCl 2 In an embodiment, R 3 are independently -OCHBr 2 In an embodiment, R 3 are independently -OCHF 2 In an embodiment, R 3 is, independently, -OCHI 2 In an embodiment, R 3 are independently unsubstituted C 1 ~C 4 In embodiments, R 3 is independently unsubstituted methyl. In embodiments, R 3 is independently unsubstituted ethyl. In embodiments, R 3 is independently unsubstituted propyl. In embodiments, R 3 is independently unsubstituted n-propyl. In embodiments, R 3 is independently unsubstituted isopropyl. In embodiments, R 3 is independently unsubstituted butyl. In embodiments, R 3 is independently unsubstituted n-butyl. In embodiments, R 3 is independently unsubstituted isobutyl. In embodiments, R 3 is independently unsubstituted tert-butyl. In embodiments, R 3 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 3 is independently unsubstituted methoxy. In embodiments, R3 is independently unsubstituted ethoxy. In embodiments, R 3 is independently unsubstituted propoxy. In embodiments, R 3 is independently unsubstituted n-propoxy. In embodiments, R 3 is independently unsubstituted isopropoxy. In embodiments, R 3 is independently unsubstituted butoxy. In embodiments, R 3 is independently unsubstituted n-butoxy. In embodiments, R 3 is independently unsubstituted isobutoxy. In embodiments, R 3 is independently unsubstituted tert-butoxy.

[0360] In an embodiment, two R 3 The substituents may be linked to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl. In embodiments, two R 3 The substituents are linked to substituted or unsubstituted C 3 ~C 8 In one embodiment, two R 3 The substituents are linked to form a substituted or unsubstituted 3- to 8-membered heterocycloalkyl.

[0361] In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3 is 5. In embodiments, z3 is 6. In embodiments, z3 is 7. In embodiments, z3 is 8. In embodiments, z3 is 9. In embodiments, z3 is 10.

[0362] In an embodiment, 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 4When 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. 4 When R is substituted, it is substituted with at least one substituent. 4 When R is substituted, it is substituted with at least one size-limited substituent. 4 When is substituted, it is substituted with at least one lower substituent.

[0363] In embodiments, R 4 is hydrogen. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In embodiments, R 4 In embodiments, R 4 In an embodiment, R 4 In an embodiment, R 4 -CCl 3 In an embodiment, R 4 -CBr 3 In an embodiment, R 4 -CF 3 In an embodiment, R 4 -CI 3 In an embodiment, R 4 is -CH 2 In an embodiment, R 4 is -CH 2 In an embodiment, R 4 is -CH 2 F. In embodiments, R 4 is -CH 2 In an embodiment, R 4 -CHCl 2 In an embodiment, R 4 -CHBr 2 In an embodiment, R 4 -CHF 2 In an embodiment, R 4 -CHI 2 In an embodiment, R4 In embodiments, R 4 is -OH. In embodiments, R 4 is -NH 2 In an embodiment, R 4 is -COOH. In embodiments, R 4 -CONH 2 In an embodiment, R 4 -NO 2 In an embodiment, R 4 is -SH. In embodiments, R 4 -SO 3 H. In embodiments, R 4 -OSO 3 H. In embodiments, R 4 -SO 2 NH 2 In an embodiment, R 4 is -NHNH 2 In an embodiment, R 4 -ONH 2 In an embodiment, R 4 is -NHC(O)NHNH 2 In an embodiment, R 4 is -NHC(O)NH 2 In an embodiment, R 4 -NHSO 2 H. In embodiments, R 4 is -NHC(O)H. In embodiments, R 4 is -NHC(O)OH. In embodiments, R 4 is -NHOH. In embodiments, R 4 -OCCl 3 In an embodiment, R 4 -OCBr 3 In an embodiment, R 4 -OCF 3 In an embodiment, R 4 -OCI 3 In an embodiment, R 4 -OCH 2 In an embodiment, R 4 -OCH 2In an embodiment, R 4 -OCH 2 F. In embodiments, R 4 -OCH 2 In an embodiment, R 4 -OCHCl 2 In an embodiment, R 4 -OCHBr 2 In an embodiment, R 4 , -OCHF 2 In an embodiment, R 4 -OCHI 2 In an embodiment, R 4 is unsubstituted C 1 -C 4 In embodiments, R 4 is unsubstituted methyl. In embodiments, R 4 is unsubstituted ethyl. In embodiments, R 4 is unsubstituted propyl. In embodiments, R 4 is unsubstituted n-propyl. In embodiments, R 4 is unsubstituted isopropyl. In embodiments, R 4 is unsubstituted butyl. In embodiments, R 4 is unsubstituted n-butyl. In embodiments, R 4 is unsubstituted isobutyl. In embodiments, R 4 is unsubstituted tert-butyl. In embodiments, R 4 is an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 4 is unsubstituted methoxy. In embodiments, R 4 is unsubstituted ethoxy. In embodiments, R 4 is unsubstituted propoxy. In embodiments, R 4 is unsubstituted n-propoxy. In embodiments, R 4 is unsubstituted isopropoxy. In embodiments, R 4 is unsubstituted butoxy. In embodiments, R 4 is unsubstituted n-butoxy. In embodiments, R 4 is unsubstituted isobutoxy. In embodiments, R 4is unsubstituted tert-butoxy.

[0364] In an embodiment, the substitution R 5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 5 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 5 When R is substituted, it is substituted with at least one substituent. 5 When R is substituted, it is substituted with at least one size-limited substituent. 5 When is substituted, it is substituted with at least one lower substituent.

[0365] In embodiments, R 5 is hydrogen. In embodiments, R 5 is halogen. In embodiments, R 5 is -F. In embodiments, R 5 In embodiments, R 5 In an embodiment, R 5 In an embodiment, R 5 -CCl 3 In an embodiment, R 5 -CBr 3 In an embodiment, R 5 -CF 3 In an embodiment, R 5 -CI 3 In an embodiment, R 5 is -CH 2 In an embodiment, R 5 is -CH 2 In an embodiment, R 5 is -CH 2 F. In embodiments, R 5 is -CH2 In an embodiment, R 5 -CHCl 2 In an embodiment, R 5 -CHBr 2 In an embodiment, R 5 -CHF 2 In an embodiment, R 5 -CHI 2 In an embodiment, R 5 In embodiments, R 5 is -OH. In embodiments, R 5 is -NH 2 In an embodiment, R 5 is -COOH. In embodiments, R 5 -CONH 2 In an embodiment, R 5 -NO 2 In an embodiment, R 5 is -SH. In embodiments, R 5 -SO 3 H. In embodiments, R 5 -OSO 3 H. In embodiments, R 5 -SO 2 NH 2 In an embodiment, R 5 is -NHNH 2 In an embodiment, R 5 -ONH 2 In an embodiment, R 5 is -NHC(O)NHNH 2 In an embodiment, R 5 is -NHC(O)NH 2 In an embodiment, R 5 -NHSO 2 H. In embodiments, R 5 is -NHC(O)H. In embodiments, R 5 is -NHC(O)OH. In embodiments, R 5 is -NHOH. In embodiments, R 5 -OCCl 3 In an embodiment, R 5-OCBr 3 In an embodiment, R 5 -OCF 3 In an embodiment, R 5 -OCI 3 In an embodiment, R 5 -OCH 2 In an embodiment, R 5 -OCH 2 In an embodiment, R 5 -OCH 2 F. In embodiments, R 5 -OCH 2 In an embodiment, R 5 -OCHCl 2 In an embodiment, R 5 -OCHBr 2 In an embodiment, R 5 , -OCHF 2 In an embodiment, R 5 -OCHI 2 In an embodiment, R 5 is unsubstituted C 1 ~C 4 In embodiments, R 5 is unsubstituted methyl. In embodiments, R 5 is unsubstituted ethyl. In embodiments, R 5 is unsubstituted propyl. In embodiments, R 5 is unsubstituted n-propyl. In embodiments, R 5 is unsubstituted isopropyl. In embodiments, R 5 is unsubstituted butyl. In embodiments, R 5 is unsubstituted n-butyl. In embodiments, R 5 is unsubstituted isobutyl. In embodiments, R 5 is unsubstituted tert-butyl. In embodiments, R 5 is an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 5 is unsubstituted methoxy. In embodiments, R 5 is unsubstituted ethoxy. In embodiments, R 5is unsubstituted propoxy. In embodiments, R 5 is unsubstituted n-propoxy. In embodiments, R 5 is unsubstituted isopropoxy. In embodiments, R 5 is unsubstituted butoxy. In embodiments, R 5 is unsubstituted n-butoxy. In embodiments, R 5 is unsubstituted isobutoxy. In embodiments, R 5 is unsubstituted tert-butoxy.

[0366] In embodiments, R 4 is hydrogen and R 5 is not hydrogen. In embodiments, R 5 is hydrogen and R 4 is not hydrogen.

[0367] In embodiments, R 5 is hydrogen and R 4 is a substituted or unsubstituted C 1 ~C 4 In embodiments, R 5 is hydrogen and R 4 is unsubstituted C 1 ~C 4 In embodiments, R 5 is hydrogen and R 4 is substituted or unsubstituted methyl, or substituted or unsubstituted isopropyl. 4 is hydrogen and R 5 is unsubstituted methyl. In embodiments, R 5 is hydrogen and R 4 is unsubstituted methyl. In embodiments, R 4 is hydrogen and R 5 is unsubstituted isopropyl. In embodiments, R 5 is hydrogen and R 4 is unsubstituted isopropyl. In embodiments, R 4 and R 5 are independently substituted or unsubstituted C 1 ~C 3 In embodiments, R 4and R 5 are independently unsubstituted C 1 ~C 3 In embodiments, R 4 and R 5 is unsubstituted methyl.

[0368] In an embodiment, the substitution R 9 (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 9 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 9 When R is substituted, it is substituted with at least one substituent. 9 When R is substituted, it is substituted with at least one size-limited substituent. 9 When is substituted, it is substituted with at least one lower substituent.

[0369] In embodiments, R 9 is hydrogen, -CF 3 , -CH 2 F, -CHF 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.

[0370] In embodiments, R 9 is hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 9 is hydrogen. In embodiments, R 9 is unsubstituted C 1 ~C 4 In embodiments, R 9 is unsubstituted methyl. In embodiments, R9 is unsubstituted ethyl. In embodiments, R 9 is unsubstituted propyl. In embodiments, R 9 is unsubstituted n-propyl. In embodiments, R 9 is unsubstituted isopropyl. In embodiments, R 9 is unsubstituted butyl. In embodiments, R 9 is unsubstituted n-butyl. In embodiments, R 9 is unsubstituted isobutyl. In embodiments, R 9 is unsubstituted tert-butyl.

[0371] In an embodiment, the substitution R 10 (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 10 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. 10 When R is substituted, it is substituted with at least one substituent. 10 When R is substituted, it is substituted with at least one size-limited substituent. 10 When is substituted, it is substituted with at least one lower substituent.

[0372] In embodiments, R 10 is hydrogen. In embodiments, R 10 is halogen. In embodiments, R 10 is -F. In embodiments, R 10 is -Cl. In embodiments, R 10 In an embodiment, R 10 In an embodiment, R 10 -CCl 3 In an embodiment, R 10 -CBr 3In an embodiment, R 10 -CF 3 In an embodiment, R 10 -CI 3 In an embodiment, R 10 is -CH 2 In an embodiment, R 10 is -CH 2 In an embodiment, R 10 is -CH 2 F. In embodiments, R 10 is -CH 2 In an embodiment, R 10 -CHCl 2 In an embodiment, R 10 -CHBr 2 In an embodiment, R 10 -CHF 2 In an embodiment, R 10 -CHI 2 In an embodiment, R 10 In embodiments, R 10 is -OH. In embodiments, R 10 is -NH 2 In an embodiment, R 10 is -COOH. In embodiments, R 10 -CONH 2 In an embodiment, R 10 -NO 2 In an embodiment, R 10 is -SH. In embodiments, R 10 -SO 3 H. In embodiments, R 10 -OSO 3 H. In embodiments, R 10 -SO 2 NH 2 In an embodiment, R 10 is -NHNH 2 In an embodiment, R 10 -ONH 2 In an embodiment, R 10 is -NHC(O)NHNH 2 In an embodiment, R10 is -NHC(O)NH 2 In an embodiment, R 10 -NHSO 2 H. In embodiments, R 10 is -NHC(O)H. In embodiments, R 10 is -NHC(O)OH. In embodiments, R 10 is -NHOH. In embodiments, R 10 -OCCl 3 In an embodiment, R 10 -OCBr 3 In an embodiment, R 10 -OCF 3 In an embodiment, R 10 -OCI 3 In an embodiment, R 10 -OCH 2 In an embodiment, R 10 -OCH 2 In an embodiment, R 10 -OCH 2 F. In embodiments, R 10 -OCH 2 In an embodiment, R 10 -OCHCl 2 In an embodiment, R 10 -OCHBr 2 In an embodiment, R 10 , -OCHF 2 In an embodiment, R 10 -OCHI 2 In an embodiment, R 10 is unsubstituted C 1 ~C 4 In embodiments, R 10 is unsubstituted methyl. In embodiments, R 10 is unsubstituted ethyl. In embodiments, R 10 is unsubstituted propyl. In embodiments, R 10 is unsubstituted n-propyl. In embodiments, R 10 is unsubstituted isopropyl. In embodiments, R 10is unsubstituted butyl. In embodiments, R 10 is unsubstituted n-butyl. In embodiments, R 10 is unsubstituted isobutyl. In embodiments, R 10 is unsubstituted tert-butyl. In embodiments, R 10 is an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 10 is unsubstituted methoxy. In embodiments, R 10 is unsubstituted ethoxy. In embodiments, R 10 is unsubstituted propoxy. In embodiments, R 10 is unsubstituted n-propoxy. In embodiments, R 10 is unsubstituted isopropoxy. In embodiments, R 10 is unsubstituted butoxy. In embodiments, R 10 is unsubstituted n-butoxy. In embodiments, R 10 is unsubstituted isobutoxy. In embodiments, R 10 is unsubstituted tert-butoxy.

[0373] In an embodiment, L 2 is unsubstituted methylene. In embodiments, L 2 is unsubstituted ethylene. In embodiments, L 2 is unsubstituted propylene. In embodiments, L 2 is unsubstituted n-propylene. In embodiments, L 2 is unsubstituted isopropylene. In embodiments, L 2 is unsubstituted butylene. In embodiments, L 2 is unsubstituted n-butylene. In embodiments, L 2 is unsubstituted isobutylene. In embodiments, L 2 is unsubstituted tert-butylene.

[0374] In an embodiment, L 1 -L 101 -L 102 -L 103 -It is.

[0375] L101 E 1 Or E 2 is directly connected to the

[0376] In an embodiment, L 101 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 101 -, -C(O)NR 101 -, -NR 101 C(O)-, -NR 101 C(O)O-, -OC(O)NR 101 -, -NR 101 C(O)NR 101 -, -NR 101 C(NH)NR 101 -, -S(O) 2 -, -NR 101 S(O) 2 -, -S(O) 2 NR 101 -, substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C 6 ~C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0377] In an embodiment, L 102is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 102 -, -C(O)NR 102 -, -NR 102 C(O)-, -NR 102 C(O)O-, -OC(O)NR 102 -, -NR 102 C(O)NR 102 -, -NR 102 C(NH)NR 102 -, -S(O) 2 -, -NR 102 S(O) 2 -, -S(O) 2 NR 102 -, substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C 6 ~C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0378] In an embodiment, L 103 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 103 -, -C(O)NR 103 -, -NR 103 C(O)-, -NR 103 C(O)O-, -OC(O)NR 103-, -NR 103 C(O)NR 103 -, -NR 103 C(NH)NR 103 -, -S(O) 2 -, -NR 103 S(O) 2 -, -S(O) 2 NR 103 -, substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C 6 ~C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0379] Each R 101 , R 102 , and R 103 are independently 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 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0380] In an embodiment, the substitution L 101 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 101 When L 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. 101 When L is substituted, it is substituted with at least one substituent. 101 When L is substituted, it is substituted with at least one size-limited substituent. 101 When is substituted, it is substituted with at least one lower substituent.

[0381] In an embodiment, L 101 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O) 2 -,-NHS(O) 2 -, -S(O) 2 NH-, substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C 6 ~C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0382] In an embodiment, L 101 is a bond. In embodiments, L 101 is -C(O)-. In embodiments, L 101 is -C(O)O-. In embodiments, L 101 is -OC(O)-. In embodiments, L 101 In embodiments, L 101 In an embodiment, L 101 -NR 101 In an embodiment, L 101 In embodiments, L 101 is -C(O)NR 101 In an embodiment, L 101 is -C(O)NH-. In embodiments, L 101 -NR 101 In embodiments, L 101 is -NHC(O)-. In embodiments, L 101 -NR 101 In an embodiment, L 101 is -NHC(O)O-. In embodiments, L 101 is -OC(O)NR 101 In an embodiment, L 101 is -OC(O)NH-. In embodiments, L 101 -NR 101 C(O)NR 101 In an embodiment, L 101 is -NHC(O)NH-. In embodiments, L 101 -NR 101 C(NH)NR 101 In an embodiment, L 101is -NHC(NH)NH-. In embodiments, L 101 is -S(O) 2 In an embodiment, L 101 -NR 101 S(O) 2 In an embodiment, L 101 -NHS(O) 2 In an embodiment, L 101 is -S(O) 2 NR 101 In an embodiment, L 101 is -S(O) 2 In embodiments, L is 101 is a substituted (e.g., oxo-substituted) or unsubstituted C 1 ~C 6 In embodiments, L is an alkylene. 101 is substituted (e.g., oxo-substituted) or unsubstituted methylene. 101 is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L 101 is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L 101 is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. 101 is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L 101 is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L 101 is a substituted (e.g., oxo-substituted) unsubstituted n-butylene. 101 is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L 101 is a substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. 101 is substituted (e.g., oxo-substituted) or unsubstituted pentylene. 101 is substituted (e.g., oxo-substituted) or unsubstituted hexylene. 101 is a substituted (e.g., oxo-substituted) or unsubstituted 2-6 membered heteroalkylene. 101 teeth,

[0383] [ka] It is.

[0384] In an embodiment, the substitution R 101 (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 101 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. 101 When R is substituted, it is substituted with at least one substituent. 101 When R is substituted, it is substituted with at least one size-limited substituent. 101 When is substituted, it is substituted with at least one lower substituent.

[0385] In embodiments, R 101 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 101 is independently hydrogen. In embodiments, R 101 are independently unsubstituted C 1 ~C 4 In embodiments, R 101 is independently unsubstituted methyl. In embodiments, R 101 is independently unsubstituted ethyl. In embodiments, R 101 is independently unsubstituted propyl. In embodiments, R 101 is independently unsubstituted n-propyl. In embodiments, R 101 is independently unsubstituted isopropyl. In embodiments, R 101 is independently unsubstituted butyl. In embodiments, R 101is independently unsubstituted n-butyl. In embodiments, R 101 is independently unsubstituted isobutyl. In embodiments, R 101 is independently unsubstituted tert-butyl.

[0386] In an embodiment, the substitution L 102 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 102 When L 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. 102 When L is substituted, it is substituted with at least one substituent. 102 When L is substituted, it is substituted with at least one size-limited substituent. 102 When is substituted, it is substituted with at least one lower substituent.

[0387] In an embodiment, L 102 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O) 2 -,-NHS(O) 2 -, -S(O) 2 NH-, substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 ~C8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C 6 ~C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0388] In an embodiment, L 102 is a bond. In embodiments, L 102 is -C(O)-. In embodiments, L 102 is -C(O)O-. In embodiments, L 102 is -OC(O)-. In embodiments, L 102 In embodiments, L 102 In an embodiment, L 102 -NR 102 In an embodiment, L 102 In embodiments, L 102 is -C(O)NR 102 In an embodiment, L 102 is -C(O)NH-. In embodiments, L 102 -NR 102 In embodiments, L 102 is -NHC(O)-. In embodiments, L 102 -NR 102 In an embodiment, L 102 is -NHC(O)O-. In embodiments, L 102 is -OC(O)NR 102 In an embodiment, L 102 is -OC(O)NH-. In embodiments, L 102 -NR 102 C(O)NR 102 In an embodiment, L 102is -NHC(O)NH-. In embodiments, L 102 -NR 102 C(NH)NR 102 In an embodiment, L 102 is -NHC(NH)NH-. In embodiments, L 102 -S(O) 2 In an embodiment, L 102 -NR 102 S(O) 2 In an embodiment, L 102 -NHS(O) 2 In an embodiment, L 102 -S(O) 2 NR 102 In an embodiment, L 102 -S(O) 2 In embodiments, L is 102 is a substituted (e.g., oxo-substituted) or unsubstituted C 1 ~C 6 In embodiments, L is an alkylene. 102 is substituted (e.g., oxo-substituted) or unsubstituted methylene. 102 is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L 102 is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L 102 is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L 102 is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L 102 is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L 102 is a substituted (e.g., oxo-substituted) unsubstituted n-butylene. 102 is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L 102 is a substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. 102 is substituted (e.g., oxo-substituted) or unsubstituted pentylene. 102is substituted (e.g., oxo-substituted) or unsubstituted hexylene. 102 is a substituted (e.g., oxo-substituted) or unsubstituted 2-6 membered heteroalkylene. 102 teeth,

[0389] [ka] It is.

[0390] In an embodiment, the substitution R 102 (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 102 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. 102 When R is substituted, it is substituted with at least one substituent. 102 When R is substituted, it is substituted with at least one size-limited substituent. 102 When is substituted, it is substituted with at least one lower substituent.

[0391] In embodiments, R 102 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 102 is independently hydrogen. In embodiments, R 102 are independently unsubstituted C 1 ~C 4 In embodiments, R 102 is independently unsubstituted methyl. In embodiments, R 102 is independently unsubstituted ethyl. In embodiments, R 102 is independently unsubstituted propyl. In embodiments, R 102is independently unsubstituted n-propyl. In embodiments, R 102 is independently unsubstituted isopropyl. In embodiments, R 102 is independently unsubstituted butyl. In embodiments, R 102 is independently unsubstituted n-butyl. In embodiments, R 102 is independently unsubstituted isobutyl. In embodiments, R 102 is independently unsubstituted tert-butyl.

[0392] In an embodiment, the substitution L 103 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 103 When L 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. 103 When L is substituted, it is substituted with at least one substituent. 103 When L is substituted, it is substituted with at least one size-limited substituent. 103 When is substituted, it is substituted with at least one lower substituent.

[0393] In an embodiment, L 103 is a bond. In embodiments, L 103 is -C(O)-. In embodiments, L 103 is -C(O)O-. In embodiments, L 103 is -OC(O)-. In embodiments, L 103 In embodiments, L 103 In an embodiment, L 103 -NR 103 In an embodiment, L 103 In embodiments, L 103 is -C(O)NR 103In an embodiment, L 103 is -C(O)NH-. In embodiments, L 103 -NR 103 In embodiments, L 103 is -NHC(O)-. In embodiments, L 103 -NR 103 In an embodiment, L 103 is -NHC(O)O-. In embodiments, L 103 is -OC(O)NR 103 In an embodiment, L 103 is -OC(O)NH-. In embodiments, L 103 -NR 103 C(O)NR 103 In an embodiment, L 103 is -NHC(O)NH-. In embodiments, L 103 -NR 103 C(NH)NR 103 In an embodiment, L 103 is -NHC(NH)NH-. In embodiments, L 103 is -S(O) 2 In an embodiment, L 103 -NR 103 S(O) 2 In an embodiment, L 103 -NHS(O) 2 In an embodiment, L 103 is -S(O) 2 NR 103 In an embodiment, L 103 is -S(O) 2 In embodiments, L is 103 is a substituted (e.g., oxo-substituted) or unsubstituted C 1 ~C 6 In embodiments, L is an alkylene. 103 is substituted (e.g., oxo-substituted) or unsubstituted methylene. 103 is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L 103 is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L103 is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. 103 is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L 103 is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L 103 is a substituted (e.g., oxo-substituted) unsubstituted n-butylene. 103 is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L 103 is a substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. 103 is substituted (e.g., oxo-substituted) or unsubstituted pentylene. 103 is substituted (e.g., oxo-substituted) or unsubstituted hexylene. 103 is a substituted (e.g., oxo-substituted) or unsubstituted 2-6 membered heteroalkylene. 103 teeth,

[0394] [ka] It is.

[0395] In an embodiment, the substitution R 103 (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 103 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. 103 When R is substituted, it is substituted with at least one substituent. 103 When R is substituted, it is substituted with at least one size-limited substituent. 103 When is substituted, it is substituted with at least one lower substituent.

[0396] In embodiments, R 103 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 103 is independently hydrogen. In embodiments, R 103 are independently unsubstituted C 1 ~C 4 In embodiments, R 103 is independently unsubstituted methyl. In embodiments, R 103 is independently unsubstituted ethyl. In embodiments, R 103 is independently unsubstituted propyl. In embodiments, R 103 is independently unsubstituted n-propyl. In embodiments, R 103 is independently unsubstituted isopropyl. In embodiments, R 103 is independently unsubstituted butyl. In embodiments, R 103 is independently unsubstituted n-butyl. In embodiments, R 103 is independently unsubstituted isobutyl. In embodiments, R 103 is independently unsubstituted tert-butyl.

[0397] In an embodiment, L 1 is a bond. In embodiments, L 1 is -C(O)-. In embodiments, L 1 is a substituted 2-6 membered heteroalkylene. 1 teeth,

[0398] [ka] It is.

[0399] In embodiments, the compound contacts a residue of K-Ras switch II. In embodiments, the compound contacts a residue of H-Ras switch II. In embodiments, the compound contacts a residue of N-Ras switch II. In embodiments, the compound contacts a residue of K-Ras (e.g., K-Ras(G12S), human K-Ras(G12S)), R 1 is in contact with V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, or I100. 1 In embodiments, the compound does not contact residues of K-Ras (e.g., K-Ras(G12S), human K-Ras(G12S)) that contact GTP. In embodiments, the compound does not contact residues of K-Ras (e.g., K-Ras(G12S), human K-Ras(G12S)) that contact GTP or a guanine of GDP. In embodiments, the compound does not contact residues of K-Ras (e.g., K-Ras(G12S), human K-Ras(G12S)) that contact GDP. In embodiments, the compound does not contact residues of K-Ras (e.g., K-Ras(G12S), human K-Ras(G12S)). 1 contacts a residue that contacts switch II in the GTP-bound form of K-Ras (e.g., K-Ras(G12S), human K-Ras(G12S)). 1 contacts residues that contact switch II in the GDP-bound form of K-Ras (e.g., K-Ras(G12S), human K-Ras(G12S)).

[0400] In embodiments, the compound contacts a residue of K-Ras switch II. In embodiments, the compound contacts a residue of H-Ras switch II. In embodiments, the compound contacts a residue of N-Ras switch II. In embodiments, the compound contacts a residue of K-Ras (e.g., K-Ras(G12D), human K-Ras(G12D), K-Ras(G13D), human K-Ras(G13D), K-Ras(G12E), human K-Ras(G12E)), R 1is in contact with V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, or I100. 1 contacts at least one of G60, E62, or E63 of K-Ras (e.g., K-Ras(G12D), human K-Ras(G12D), K-Ras(G13D), human K-Ras(G13D), K-Ras(G12E), human K-Ras(G12E)). In embodiments, the compound does not contact a residue of K-Ras (e.g., K-Ras(G12D), human K-Ras(G12D), K-Ras(G13D), human K-Ras(G13D), K-Ras(G12E), human K-Ras(G12E)) that contacts GTP. In embodiments, the compound does not contact residues of K-Ras (e.g., K-Ras(G12D), human K-Ras(G12D), K-Ras(G13D), human K-Ras(G13D), K-Ras(G12E), human K-Ras(G12E)) that contact guanines of GTP or GDP. In embodiments, the compound does not contact residues of K-Ras (e.g., K-Ras(G12D), human K-Ras(G12D), K-Ras(G13D), human K-Ras(G13D), K-Ras(G12E), human K-Ras(G12E)) that contact GDP. In embodiments, R 1 contacts a residue that contacts switch II in the GTP-bound form of K-Ras (e.g., K-Ras(G12D), human K-Ras(G12D), K-Ras(G13D), human K-Ras(G13D), K-Ras(G12E), human K-Ras(G12E)). 1 contacts residues that contact switch II in the GDP-bound form of K-Ras (e.g., K-Ras(G12D), human K-Ras(G12D), K-Ras(G13D), human K-Ras(G13D), K-Ras(G12E), human K-Ras(G12E)).

[0401] In embodiments, R 1 -L 20 -R 20 It is.

[0402] In an embodiment, L20 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 200 -, -C(O)NR 200 -, -NR 200 C(O)-, -NR 200 C(O)O-, -OC(O)NR 200 -, -NR 200 C(O)NR 200 -, -NR 200 C(NH)NR 200 -, -S(O) 2 -, -NR 200 S(O) 2 -, -S(O) 2 NR 200 -, substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C 6 ~C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0403] R 200 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0404] R 20 is hydrogen, halogen, -CX 20 3 , -CHX 20 2 , -CH 2 X 20 , -OCX 20 3 , -OCH 2 X 20 , -OCHX 20 2 , -CN, -SO n20 R 20D , -SO v20 NR 20A R 20B , -NR 20C NR 20A R 20B , -ONR 20A R 20B , -NHC(O)NR 20C NR 20A R 20B , -NHC(O)NR 20A R 20B , -N(O) m20 , -NR 20A R 20B , -C(O)R 20C , -C(O)OR 20C , -C(O)NR 20A R 20B , -OR 20D , -SR 20D , -NR 20A SO 2 R 20D , -NR 20A C(O)R 20C , -NR 20A C(O)OR 20C , -NR 20A OR 20C ,-SCIENCE FICTION 5 , -N 3, substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0405] R 20A , R 20B , R 20C , and R 20D are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, substituted or unsubstituted alkyl (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered), and R 20A and R 20B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0406] X 20 is independently -F, -Cl, -Br, or -I.

[0407] The symbol n20 is an integer from 0 to 4.

[0408] The symbols m20 and v20 are independently 1 or 2.

[0409] In an embodiment, the substitution L 20(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted L 20 When L 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. 20 When L is substituted, it is substituted with at least one substituent. 20 When L is substituted, it is substituted with at least one size-limited substituent. 20 When is substituted, it is substituted with at least one lower substituent.

[0410] In an embodiment, L 20 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)O-, -OC(O)NH-, -NHC(O)NH-, -NHC(NH)NH-, -S(O) 2 -,-NHS(O) 2 -, -S(O) 2 NH-, substituted or unsubstituted alkylene (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkylene (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6), substituted or unsubstituted heterocycloalkylene (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted arylene (e.g., C 6 ~C 10 or phenylene), or substituted or unsubstituted heteroarylene (eg, 5 to 10 members, 5 to 9 members, or 5 to 6 members).

[0411] In an embodiment, L 20 is a bond. In embodiments, L 20 is -C(O)-. In embodiments, L 20 is -C(O)O-. In embodiments, L 20 is -OC(O)-. In embodiments, L 20 In embodiments, L 20 In an embodiment, L 20 -NR 200 In an embodiment, L 20 In embodiments, L 20 is -C(O)NR 200 In an embodiment, L 20 is -C(O)NH-. In embodiments, L 20 -NR 200 In embodiments, L 20 is -NHC(O)-. In embodiments, L 20 -NR 200 In an embodiment, L 20 is -NHC(O)O-. In embodiments, L 20 is -OC(O)NR 200 In an embodiment, L 20 is -OC(O)NH-. In embodiments, L 20 -NR 200 C(O)NR 200 In an embodiment, L 20 is -NHC(O)NH-. In embodiments, L 20 -NR 200 C(NH)NR 200 In an embodiment, L 20is -NHC(NH)NH-. In embodiments, L 20 -S(O) 2 In an embodiment, L 20 -NR 200 S(O) 2 In an embodiment, L 20 -NHS(O) 2 In an embodiment, L 20 -S(O) 2 NR 200 In an embodiment, L 20 -S(O) 2 In embodiments, L is 20 is a substituted (e.g., oxo-substituted) or unsubstituted C 1 ~C 6 In embodiments, L is an alkylene. 20 is substituted (e.g., oxo-substituted) or unsubstituted methylene. 20 is substituted (e.g., oxo-substituted) or unsubstituted ethylene. In embodiments, L 20 is substituted (e.g., oxo-substituted) or unsubstituted propylene. In embodiments, L 20 is substituted (e.g., oxo-substituted) or unsubstituted n-propylene. In embodiments, L 20 is substituted (e.g., oxo-substituted) or unsubstituted isopropylene. In embodiments, L 20 is substituted (e.g., oxo-substituted) or unsubstituted butylene. In embodiments, L 20 is a substituted (e.g., oxo-substituted) unsubstituted n-butylene. 20 is substituted (e.g., oxo-substituted) or unsubstituted isobutylene. In embodiments, L 20 is a substituted (e.g., oxo-substituted) or unsubstituted tert-butylene. 20 is substituted (e.g., oxo-substituted) or unsubstituted pentylene. 20 is substituted (e.g., oxo-substituted) or unsubstituted hexylene. 20 is a substituted (eg, oxo-substituted) or unsubstituted 2-6 membered heteroalkylene.

[0412] In an embodiment, the substitution R 200 (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 200 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. 200 When R is substituted, it is substituted with at least one substituent. 200 When R is substituted, it is substituted with at least one size-limited substituent. 200 When is substituted, it is substituted with at least one lower substituent.

[0413] In embodiments, R 200 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 200 is independently hydrogen. In embodiments, R 200 are independently unsubstituted C 1 ~C 4 In embodiments, R 200 is independently unsubstituted methyl. In embodiments, R 200 is independently unsubstituted ethyl. In embodiments, R 200 is independently unsubstituted propyl. In embodiments, R 200 is independently unsubstituted n-propyl. In embodiments, R 200 is independently unsubstituted isopropyl. In embodiments, R 200 is independently unsubstituted butyl. In embodiments, R 200 is independently unsubstituted n-butyl. In embodiments, R 200 is independently unsubstituted isobutyl. In embodiments, R 200 is independently unsubstituted tert-butyl.

[0414] In an embodiment, the substitution R 20 (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 20 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. 20 When R is substituted, it is substituted with at least one substituent. 20 When R is substituted, it is substituted with at least one size-limited substituent. 20 When is substituted, it is substituted with at least one lower substituent.

[0415] In an embodiment, the substitution R 20A (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 20A 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. 20A When R is substituted, it is substituted with at least one substituent. 20A When R is substituted, it is substituted with at least one size-limited substituent. 20A When is substituted, it is substituted with at least one lower substituent.

[0416] In an embodiment, the substitution R 20B (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 R20B 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. 20B When R is substituted, it is substituted with at least one substituent. 20B When R is substituted, it is substituted with at least one size-limited substituent. 20B When is substituted, it is substituted with at least one lower substituent.

[0417] In an embodiment, R 20A and R 20B If the substituted ring formed when the substituents are linked (e.g., substituted heterocycloalkyl and / or substituted heteroaryl) is substituted, it is substituted with at least one substituent, size-limited substituent, or lower substituent and R 20A and R 20B When the substituted ring formed when the substituents are linked is substituted with multiple groups selected from substituents, size-limiting substituents, and lower-substituted groups, each of the substituents, size-limiting substituents, and / or lower-substituted groups may optionally be different. 20A and R 20B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one substituent. In an embodiment, R 20A and R 20B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one size-limited substituent. In embodiments, R 20A and R 20B If the substituted ring formed when the substituents are linked is substituted, it is substituted with at least one lower substituent.

[0418] In an embodiment, the substitution R 20C(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 20C 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. 20C When R is substituted, it is substituted with at least one substituent. 20C When R is substituted, it is substituted with at least one size-limited substituent. 20C When is substituted, it is substituted with at least one lower substituent.

[0419] In an embodiment, the substitution R 20D (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 20D 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. 20D When R is substituted, it is substituted with at least one substituent. 20D When R is substituted, it is substituted with at least one size-limited substituent. 20D When is substituted, it is substituted with at least one lower substituent.

[0420] In embodiments, R 20 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 20 is a substituted or unsubstituted C 3 ~C 8Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 ~C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 20 is a substitution C 3 ~C 8 In embodiments, R 20 is a substituted 3-8 membered heterocycloalkyl. In embodiments, R 20 is a substitution C 6 ~C 10 In embodiments, R 20 is substituted phenyl. In embodiments, R 20 is a substituted 5-10 membered heteroaryl. In embodiments, R 20 is substituted pyrimidyl. In embodiments, R 20 is substituted tetrahydropyridopyrimidyl. In embodiments, R 20 is a substituted pyridopyrimidyl. In embodiments, R 20 is a substituted quinazolinyl. In embodiments, R 20 is a substituted pyrazolyl. In embodiments, R 20 is a substituted piperazinyl.

[0421] In embodiments, R 1 teeth,

[0422] [ka] In an embodiment, R 1 teeth,

[0423] [ka] In an embodiment, R 1 teeth,

[0424] [ka] In an embodiment, R 1 teeth,

[0425] [ka] In an embodiment, R 1 teeth,

[0426] [ka] In an embodiment, R 1 teeth,

[0427] [ka] In an embodiment, R 1 teeth,

[0428] [ka] In an embodiment, R 1 teeth,

[0429] [ka] In an embodiment, R 1 teeth,

[0430] [ka] In an embodiment, R 1 teeth,

[0431] [ka] In an embodiment, R 1 teeth,

[0432] [ka] In an embodiment, R 1 teeth,

[0433] [ka] In an embodiment, R 1 teeth,

[0434] [ka] In an embodiment, R 1 teeth,

[0435] [ka] It is.

[0436] In embodiments, R 1 teeth,

[0437] [ka] In an embodiment, R 1 teeth,

[0438] [ka] In an embodiment, R 1 teeth,

[0439] [ka] In an embodiment, R 1 teeth,

[0440] [ka] In an embodiment, R 1 teeth,

[0441] [ka] In an embodiment, R 1 teeth,

[0442] [ka] In an embodiment, R 1 teeth,

[0443] [ka] In an embodiment, R 1 teeth,

[0444] [ka] In an embodiment, R 1 teeth,

[0445] [ka] It is.

[0446] R 6 are independently 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, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -OCCl3 , -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0447] R 7 are independently 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, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0448] R 8 are independently 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 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0449] The symbol z6 is an integer from 0 to 7.

[0450] The symbol z7 is an integer from 0 to 7.

[0451] The symbol z8 is an integer from 0 to 5.

[0452] In an embodiment, the substitution R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and / or substituted heteroaryl) are substituted with at least one substituent, size-limited substituent, or lower substituent, and the substituted R 6 When R is substituted with multiple groups selected from substituents, size-limiting substituents, and lower substituents, each substituent, size-limiting substituent, and / or lower substituent may optionally be different. 6 When R is substituted, it is substituted with at least one substituent. 6 When R is substituted, it is substituted with at least one size-limited substituent. 6 When is substituted, it is substituted with at least one lower substituent.

[0453] In embodiments, R 6 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH2 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 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0454] In embodiments, R 6 is independently oxo. In embodiments, R 6 is independently halogen. In an embodiment, R 6 is independently -F. In embodiments, R 6 is independently -Cl. In embodiments, R 6 is independently -Br. In embodiments, R 6 is independently -I. In embodiments, R 6 are independently -CCl 3 In an embodiment, R 6 are independently -CBr 3 In an embodiment, R 6 are independently -CF 3 In an embodiment, R 6 is independently -CI 3 In an embodiment, R 6 are independently -CH 2 In an embodiment, R 6 are independently -CH 2 In an embodiment, R 6 are independently -CH 2 F. In embodiments, R 6 are independently -CH 2 In an embodiment, R 6 are independently -CHCl 2 In an embodiment, R 6 are independently -CHBr 2 In an embodiment, R 6 are independently -CHF 2 In an embodiment, R 6 is independently -CHI 2 In an embodiment, R6 is independently -CN. In embodiments, R 6 is independently -OH. In embodiments, R 6 are independently -NH 2 In an embodiment, R 6 is independently -COOH. In embodiments, R 6 independently, -CONH 2 In an embodiment, R 6 independently, -NO 2 In an embodiment, R 6 is independently -SH. In embodiments, R 6 independently, -SO 3 H. In embodiments, R 6 is independently -OSO 3 H. In embodiments, R 6 independently, -SO 2 NH 2 In an embodiment, R 6 are independently -NHNH 2 In an embodiment, R 6 independently, -ONH 2 In an embodiment, R 6 are independently -NHC(O)NHNH 2 In an embodiment, R 6 are independently -NHC(O)NH 2 In an embodiment, R 6 are independently -NHSO 2 H. In embodiments, R 6 is independently -NHC(O)H. In embodiments, R 6 is independently -NHC(O)OH. In embodiments, R 6 is independently -NHOH. In embodiments, R 6 are independently -OCCl 3 In an embodiment, R 6 are independently -OCBr 3 In an embodiment, R 6 can be used independently, -OCF 3 In an embodiment, R 6 can be used independently.3 In an embodiment, R 6 are independently -OCH 2 In an embodiment, R 6 are independently -OCH 2 In an embodiment, R 6 are independently -OCH 2 F. In embodiments, R 6 are independently -OCH 2 In an embodiment, R 6 are independently -OCHCl 2 In an embodiment, R 6 are independently -OCHBr 2 In an embodiment, R 6 are independently -OCHF 2 In an embodiment, R 6 is, independently, -OCHI 2 In an embodiment, R 6 are independently unsubstituted C 1 ~C 4 In embodiments, R 6 is independently unsubstituted methyl. In embodiments, R 6 is independently unsubstituted ethyl. In embodiments, R 6 is independently unsubstituted propyl. In embodiments, R 6 is independently unsubstituted n-propyl. In embodiments, R 6 is independently unsubstituted isopropyl. In embodiments, R 6 is independently unsubstituted butyl. In embodiments, R 6 is independently unsubstituted n-butyl. In embodiments, R 6 is independently unsubstituted isobutyl. In embodiments, R 6 is independently unsubstituted tert-butyl. In embodiments, R 6 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. 6 is independently a substituted 2-6 membered heteroalkyl. In embodiments, R 6 is independently unsubstituted methoxy. In embodiments, R 6is independently unsubstituted ethoxy. In embodiments, R 6 is independently unsubstituted propoxy. In embodiments, R 6 is independently unsubstituted n-propoxy. In embodiments, R 6 is independently unsubstituted isopropoxy. In embodiments, R 6 is independently unsubstituted butoxy. In embodiments, R 6 is independently unsubstituted n-butoxy. In embodiments, R 6 is independently unsubstituted isobutoxy. In embodiments, R 6 is independently unsubstituted tert-butoxy. In embodiments, R 6 is independently substituted or unsubstituted phenyl. In embodiments, R 6 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 6 is independently -O-alkyl-(substituted or unsubstituted heterocycloalkyl). In embodiments, R 6 are independently -O-CH 2 -(substituted or unsubstituted heterocycloalkyl). In embodiments, R 6 is, independently,

[0455] [ka] In an embodiment, R 6 is, independently,

[0456] [ka] In an embodiment, R 6 is, independently,

[0457] [ka] In an embodiment, R 6 is, independently,

[0458] [ka] In an embodiment, R 6 is, independently,

[0459] [ka] In an embodiment, R 6 is, independently,

[0460] [ka] In an embodiment, R 6 is, independently,

[0461] [ka] In an embodiment, R 6 is, independently,

[0462] [ka] In an embodiment, R 6 is, independently,

[0463] [ka] In an embodiment, R 6 is, independently,

[0464] [ka] It is.

[0465] In embodiments, R 6 are independently halogen, -OH, unsubstituted C 1 ~C 4 alkyl, substituted 2-6 membered heteroalkyl, or substituted 5-6 membered heteroaryl. 6 is independently -F, -Cl, -OH, or unsubstituted methyl.6 is independently a 2-6 membered heteroalkyl substituted with a substituted heterocycloalkyl or an unsubstituted fused heterocycloalkyl. 6 is independently substituted pyridyl.

[0466] In an embodiment, z6 is 0. In an embodiment, z6 is 1. In an embodiment, z6 is 2. In an embodiment, z6 is 3. In an embodiment, z6 is 4. In an embodiment, z6 is 5. In an embodiment, z6 is 6. In an embodiment, z6 is 7.

[0467] In an embodiment, 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. 7 When R is substituted, it is substituted with at least one substituent. 7 When R is substituted, it is substituted with at least one size-limited substituent. 7 When is substituted, it is substituted with at least one lower substituent.

[0468] In embodiments, R 7 are independently 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, -NH2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 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, -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 (e.g., C 1 ~C 8 , C 1 ~C 6 , C 1 ~C 4 , or C 1 ~C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 , C 3 ~C 6 , C 4 ~C 6 , or C 5 ~C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8 membered, 3-6 membered, 4-6 membered, 4-5 membered, or 5-6 membered), substituted or unsubstituted aryl (e.g., C 6 ~C 10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered).

[0469] In embodiments, R 7 is independently oxo. In embodiments, R 7 is independently halogen. In an embodiment, R 7 is independently -F. In embodiments, R 7 is independently -Cl. In embodiments, R 7 is independently -Br. In embodiments, R 7 is independently -I. In embodiments, R 7 are independently -CCl 3 In an embodiment, R 7 are independently -CBr 3 In an embodiment, R 7 are independently -CF 3 In an embodiment, R 7 is independently -CI 3 In an embodiment, R 7 are independently -CH 2 In an embodiment, R 7 are independently -CH 2 In an embodiment, R 7 are independently -CH 2 F. In embodiments, R 7 are independently -CH 2 In an embodiment, R 7 are independently -CHCl 2 In an embodiment, R 7 are independently -CHBr 2 In an embodiment, R 7 are independently -CHF 2 In an embodiment, R 7 is independently -CHI 2 In an embodiment, R 7 is independently -CN. In embodiments, R 7 is independently -OH. In embodiments, R 7 are independently -NH 2 In an embodiment, R 7 is independently -COOH. In embodiments, R 7 independently, -CONH2 In an embodiment, R 7 independently, -NO 2 In an embodiment, R 7 is independently -SH. In embodiments, R 7 independently, -SO 3 H. In embodiments, R 7 is independently -OSO 3 H. In embodiments, R 7 independently, -SO 2 NH 2 In an embodiment, R 7 are independently -NHNH 2 In an embodiment, R 7 independently, -ONH 2 In an embodiment, R 7 are independently -NHC(O)NHNH 2 In an embodiment, R 7 are independently -NHC(O)NH 2 In an embodiment, R 7 are independently -NHSO 2 H. In embodiments, R 7 is independently -NHC(O)H. In embodiments, R 7 is independently -NHC(O)OH. In embodiments, R 7 is independently -NHOH. In embodiments, R 7 are independently -OCCl 3 In an embodiment, R 7 are independently -OCBr 3 In an embodiment, R 7 can be used independently, -OCF 3 In an embodiment, R 7 can be used independently. 3 In an embodiment, R 7 are independently -OCH 2 In an embodiment, R 7 are independently -OCH 2 In an embodiment, R 7 are independently -OCH 2 F. In embodiments, R7 are independently -OCH 2 In an embodiment, R 7 are independently -OCHCl 2 In an embodiment, R 7 are independently -OCHBr 2 In an embodiment, R 7 are independently -OCHF 2 In an embodiment, R 7 is, independently, -OCHI 2 In an embodiment, R 7 are independently unsubstituted C 1 ~C 4 In embodiments, R 7 is independently unsubstituted methyl. In embodiments, R 7 is independently unsubstituted ethyl. In embodiments, R 7 is independently unsubstituted propyl. In embodiments, R 7 is independently unsubstituted n-propyl. In embodiments, R 7 is independently unsubstituted isopropyl. In embodiments, R 7 is independently unsubstituted butyl. In embodiments, R 7 is independently unsubstituted n-butyl. In embodiments, R 7 is independently unsubstituted isobutyl. In embodiments, R 7 is independently unsubstituted tert-butyl. In embodiments, R 7 are independently unsubstituted C 2 ~C 4 In embodiments, R 7 is independently unsubstituted ethynyl. In embodiments, R 7 is independently unsubstituted propynyl. In embodiments, R 7 is independently unsubstituted butynyl. In embodiments, R 7 is independently a substituted or unsubstituted 2-6 membered heteroalkyl. 7 is independently unsubstituted methoxy. In embodiments, R 7 is independently unsubstituted ethoxy. In embodiments, R7 is independently unsubstituted propoxy. In embodiments, R 7 is independently unsubstituted n-propoxy. In embodiments, R 7 is independently unsubstituted isopropoxy. In embodiments, R 7 is independently unsubstituted butoxy. In embodiments, R 7 is independently unsubstituted n-butoxy. In embodiments, R 7 is independently unsubstituted isobutoxy. In embodiments, R 7 is independently unsubstituted tert-butoxy.

[0470] In embodiments, R 7 are independently halogen, -CF 3 , -CN, -OH, -NH 2 , or unsubstituted C 1 ~C 4 In embodiments, R 7 are independently -F, -Cl, -CF 3 , -CN, -OH, -NH 2 or unsubstituted methyl.

[0471] In embodiments, R 7 are independently halogen, -CF 3 , -CN, -OH, -NH 2 , unsubstituted C 1 ~C 4 Alkyl or unsubstituted C 2 ~C 4 In embodiments, R 7 are independently -F, -Cl, -CF 3 , -CN, -OH, -NH 2 , unsubstituted methyl, or unsubstituted ethynyl.

[0472] In an embodiment, z7 is 0. In an embodiment, z7 is 1. In an embodiment, z7 is 2. In an embodiment, z7 is 3. In an embodiment, z7 is 4. In an embodiment, z7 is 5. In an embodiment, z7 is 6. In an embodiment, z7 is 7.

[0473] In an embodiment, 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 R is substituted, it is substituted with at least one substituent. 8 When R is substituted, it is substituted with at least one size-limited substituent. 8 When is substituted, it is substituted with at least one lower substituent.

[0474] In embodiments, R 8 is independently halogen. In an embodiment, R 8 is independently -F. In embodiments, R 8 is independently -Cl. In embodiments, R 8 is independently -Br. In embodiments, R 8 is independently -I. In embodiments, R 8 are independently -CCl 3 In an embodiment, R 8 are independently -CBr 3 In an embodiment, R 8 are independently -CF 3 In an embodiment, R 8 is independently -CI 3 In an embodiment, R 8 are independently -CH 2 In an embodiment, R 8 are independently -CH 2 In an embodiment, R 8 are independently -CH 2 F. In embodiments, R 8 are independently -CH2 In an embodiment, R 8 are independently -CHCl 2 In an embodiment, R 8 are independently -CHBr 2 In an embodiment, R 8 are independently -CHF 2 In an embodiment, R 8 is independently -CHI 2 In an embodiment, R 8 is independently -CN...

Claims

1. 1. A compound, or a pharma- ceutically acceptable salt thereof, having the formula: 【Chemistry 1】 wherein R １ is the Switch II binding pocket binding moiety, L １ is a bond or a bivalent linker, E ２ is an electrophilic moiety capable of forming a covalent bond with a Switch II GTPase protein aspartic acid residue or a Switch II GTPase protein glutamic acid residue, or a pharma- ceutically acceptable salt thereof.

2. E ２ 2. The compound of claim 1, wherein is an electrophilic moiety capable of forming a covalent bond with a Switch II GTPase protein aspartic acid residue.

3. 3. The compound of claim 1 or 2, wherein the Switch II GTPase protein aspartic acid residue is a native Switch II GTPase protein aspartic acid residue.

4. The compound of any one of claims 1 to 3, wherein the Switch II GTPase protein aspartic acid residue is a mutant Switch II GTPase protein aspartic acid residue.

5. 5. The compound of any one of claims 1 to 4, wherein the mutant switch II GTPase protein aspartic acid residue is aspartic acid residue 12 of K-Ras(G12D), H-Ras(G12D), or N-Ras(G12D).

6. 6. The compound of any one of claims 1 to 5, wherein the mutant switch II GTPase protein aspartic acid residue is aspartic acid residue 13 of K-Ras(G13D), H-Ras(G13D), or N-Ras(G13D).

7. E ２ The compound of any one of claims 1 to 6, wherein is an electrophilic moiety capable of forming a covalent bond with a Switch II GTPase protein glutamic acid residue.

8. The compound of any one of claims 1 to 7, wherein the switch II GTPase protein glutamic acid residue is a native switch II GTPase protein glutamic acid residue.

9. 9. The compound of any one of claims 1 to 8, wherein the switch II GTPase protein glutamic acid residue is a mutant switch II GTPase protein glutamic acid residue.

10. E ２ The compound according to any one of claims 1 to 9, wherein comprises a β-lactone.

11. E ２ The compound of any one of claims 1 to 10, wherein comprises a β-lactam.

12. The formula: 【Chemistry 2】 The compound according to any one of claims 1 to 11, having the formula:

13. formula: 【Chemistry 3】 wherein Ring A is cycloalkyl or heterocycloalkyl; L ２ is unsubstituted C １ ~C ４ is alkylene, X is O or S; Y is O, S, or NR ２ and 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ３ are independently oxo, 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, -SO ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; ３ the substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; z3 is an integer from 0 to 10, R ４ 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ５ 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ９ 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 １０ 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

14. The compound of any one of claims 1 to 13, wherein Ring A is a 5-6 membered heterocycloalkyl.

15. The compound according to any one of claims 1 to 14, wherein Ring A is piperidinyl, pyrrolidinyl, or piperazinyl.

16. formula: 【Chemistry 4】 The compound according to any one of claims 1 to 15, having the formula:

17. formula: 【Chemistry 5】 The compound according to any one of claims 1 to 16, having the formula:

18. formula: 【Chemistry 6】 The compound according to any one of claims 1 to 17, having the formula:

19. formula: 【Chemistry 7】 The compound according to any one of claims 1 to 18, having the formula:

20. formula: 【Chemistry 8】 The compound according to any one of claims 1 to 19, having the formula:

21. formula: 【Chemistry 9】 The compound according to any one of claims 1 to 20, having the formula:

22. formula: 【Chemistry 10】 The compound according to any one of claims 1 to 21, having the formula:

23. formula: 【Chemistry 11】 The compound according to any one of claims 1 to 22, having the formula:

24. formula: 【Chemistry 12】 The compound according to any one of claims 1 to 23, having the formula:

25. formula: 【Chemistry 13】 The compound according to any one of claims 1 to 24, having the formula:

26. formula: 【Chemistry 14】 The compound according to any one of claims 1 to 25, having the formula:

27. formula: 【Chemistry 15】 The compound according to any one of claims 1 to 26, having the formula:

28. formula: 【Chemistry 16】 The compound according to any one of claims 1 to 27, having the formula:

29. formula: 【Chemistry 17】 The compound according to any one of claims 1 to 28, having the formula:

30. formula: 【Chemistry 18】 The compound according to any one of claims 1 to 29, having the formula:

31. formula: 【Chemistry 19】 The compound according to any one of claims 1 to 30, having the formula:

32. formula: 【Chemistry 20】 The compound according to any one of claims 1 to 31, having the formula:

33. formula: 【Chemistry 21】 The compound according to any one of claims 1 to 32, having the formula:

34. formula: 【Chemical 22】 The compound according to any one of claims 1 to 33, having the formula:

35. formula: 【Chemistry 23】 The compound according to any one of claims 1 to 34, having the formula:

36. formula: 【Chemistry 24】 The compound according to any one of claims 1 to 35, having the formula:

37. formula: 【Chemistry 25】 The compound according to any one of claims 1 to 36, having the formula:

38. formula: 【Chemistry 26】 The compound according to any one of claims 1 to 37, having the formula:

39. formula: 【Chemical 27】 The compound according to any one of claims 1 to 38, having the formula:

40. R ３ is independently an unsubstituted C １ ~C ４ The compound of any one of claims 1 to 39, which is alkyl.

41. R ３ The compound of any one of claims 1 to 40, wherein is independently unsubstituted methyl.

42. Two R's ３ The compound of any one of claims 1 to 41, wherein the substituents are linked to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl.

43. L １ But, L １０１ -L １０２ -L １０３ - and L １０１ But, E ２ is connected directly to L １０１ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, or —NR １０１ --, --C(O)NR １０１ --, --NR １０１ C(O)-, -NR １０１ C(O)O-, -OC(O)NR １０１ --, --NR １０１ C(O)NR １０１ --, --NR １０１ C(NH)NR １０１ -, -S(O) ２ --, --NR １０１ S (O) ２ -, -S(O) ２ N.R. １０１ -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L １０２ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, or —NR １０２ --, --C(O)NR １０２ --, --NR １０２ C(O)-, -NR １０２ C(O)O-, -OC(O)NR １０２ --, --NR １０２ C(O)NR １０２ --, --NR １０２ C(NH)NR １０２ -, -S(O) ２ --, --NR １０２ S (O) ２ -, -S(O) ２ N.R. １０２ -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L １０３ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, or —NR １０３ --, --C(O)NR １０３ --, --NR １０３ C(O)-, -NR １０３ C(O)O-, -OC(O)NR １０３ --, --NR １０３ C(O)NR １０３ --, --NR １０３ C(NH)NR １０３ -, -S(O) ２ --, --NR １０３ S (O) ２ -, -S(O) ２ N.R. １０３ -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; Each R １０１ , R １０２ , and R １０３ are independently 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

44. L １ The compound according to any one of claims 1 to 43, wherein is a bond.

45. L １ The compound according to any one of claims 1 to 44, wherein is -C(O)-.

46. L １ The compound of any one of claims 1 to 45, wherein is a substituted 2-6 membered heteroalkylene.

47. L １ but, 【Chemistry 28】 The compound according to any one of claims 1 to 46,

48. L １ but, 【Chemical Formula 29】 The compound according to any one of claims 1 to 47,

49. R １ But, -L ２０ -R ２０ and L ２０ is a bond, —C(O)—, —C(O)O—, —OC(O)—, —O—, —S—, or —NR ２００ --, --C(O)NR ２００ --, --NR ２００ C(O)-, -NR ２００ C(O)O-, -OC(O)NR ２００ --, --NR ２００ C(O)NR ２００ --, --NR ２００ C(NH)NR ２００ -, -S(O) ２ --, --NR ２００ S (O) ２ -, -S(O) ２ N.R. ２００ -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R ２００ are independently 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ２０ Hydrogen, halogen, -CX ２０ ３ , -CHX ２０ ２ , -CH ２ X ２０ , -OCX ２０ ３ , -OCH ２ X ２０ , -OCHX ２０ ２ , -CN, -SO ｎ２０ R ２０Ｄ , -SO ｖ２０ N.R. ２０Ａ R ２０Ｂ , -NR ２０Ｃ N.R. ２０Ａ R ２０Ｂ , -ONR ２０Ａ R ２０Ｂ , -NHC(O)NR ２０Ｃ N.R. ２０Ａ R ２０Ｂ , -NHC(O)NR ２０Ａ R ２０Ｂ , -N(O) ｍ２０ , -NR ２０Ａ R ２０Ｂ , -C(O)R ２０Ｃ , -C(O)OR ２０Ｃ , -C(O)NR ２０Ａ R ２０Ｂ , -OR ２０Ｄ , -SR ２０Ｄ , -NR ２０Ａ SO ２ R ２０Ｄ , -NR ２０Ａ C(O)R ２０Ｃ , -NR ２０Ａ C(O)OR ２０Ｃ , -NR ２０Ａ OR ２０Ｃ , -SF ５ , -N ３ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ２０Ａ , R ２０Ｂ , R ２０Ｃ , and R ２０Ｄ are independently hydrogen, -CCl ３ , -CBr ３ , -CF ３ , -CI ３ , -CHCl ２ , -CHBr ２ , -CHF ２ , -CHI ２ , -CH ２ Cl, -CH ２ Br, -CH ２ F, -CH ２ I, -CN, -OH, -NH ２ , -COOH, -CONH ２ , -OCCl ３ , -OCF ３ , -OCBr ３ , -OCI ３ , -OCHCl ２ , -OCHBr ２ , -OCHI ２ , -OCHF ２ , -OCH ２ Cl, -OCH ２ Br, -OCH ２ I, -OCH ２ F, 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 ２０Ａ and R ２０Ｂ the substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; X ２０ is independently -F, -Cl, -Br, or -I; n20 is an integer from 0 to 4; The compound according to any one of claims 1 to 48, wherein m20 and v20 are independently 1 or 2.

50. R １ but, 【Chemistry 30】 and R ６ are independently oxo, 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, -SO ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ７ are independently oxo, 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, -SO ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ８ are independently 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; z6 is an integer from 0 to 7; z7 is an integer from 0 to 7, The compound according to any one of claims 1 to 49, wherein z8 is an integer from 0 to 5.

51. R ６ are independently selected from halogen, —OH, unsubstituted C １ ~C ４ The compound of any one of claims 1 to 50, which is alkyl, substituted 2-6 membered heteroalkyl, or substituted 5-6 membered heteroaryl.

52. R ６ is independently -F, -Cl, -OH, or unsubstituted methyl.

53. R ６ The compound of any one of claims 1 to 52, wherein is independently a 2-6 membered heteroalkyl substituted with a substituted heterocycloalkyl or a substituted or unsubstituted fused heterocycloalkyl.

54. R ６ But independently, 【Chemistry 31】 The compound according to any one of claims 1 to 53,

55. R ６ The compound of any one of claims 1 to 54, wherein is independently substituted pyridyl.

56. The compound of any one of claims 1 to 55, wherein z6 is 1, 2, or 3.

57. R ７ are independently halogen, -CF ３ , -CN, -OH, -NH ２ , unsubstituted C １ ~C ４ Alkyl or unsubstituted C ２ ~C ４ The compound of any one of claims 1 to 56, which is alkynyl.

58. R ７ are independently -F, -Cl, -CF ３ , -CN, -OH, -NH ２ , unsubstituted methyl, or unsubstituted ethynyl.

59. The compound of any one of claims 1 to 58, wherein z7 is 1, 2, or 3.

60. R ８ are independently halogen or unsubstituted C １ ~C ４ 60. The compound of any one of claims 1 to 59, which is alkyl.

61. R ８ The compound of any one of claims 1 to 60, wherein is independently -Cl or unsubstituted methyl.

62. The compound according to any one of claims 1 to 61, wherein z8 is 1.

63. R １ but, 【Chemistry 32】 63. The compound according to any one of claims 1 to 62,

64. formula: 【Chemical 33】 wherein R ４ and R ５ are independently hydrogen or unsubstituted C １ ~C ４ is alkyl, R ６．１ is a halogen, R ６．２ But -O-(C １ ~C ４ alkyl), １ ~C ４ The alkyl is halogen or unsubstituted C １ ~C ３ substituted with 5-8 membered heterocycloalkyl optionally substituted with alkyl; R ７ are independently halogen, —OH, or unsubstituted C ２ is alkynyl, The compound of any one of claims 1 to 63, wherein z7 is 1, 2, or 3.

65. The formula: 【Chemical 34】 65. The compound of any one of claims 1 to 64, having the formula:

66. formula: 【Chemistry 35】 wherein X is O or S; Y is O, S, or NR ２ and 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

67. formula: 【Chemical 36】 67. The compound of any one of claims 1 to 66, having the formula:

68. R １ but, 【Chemical 37】 where: R ６ are independently oxo, 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, -SO ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ７ are independently 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; z6 is an integer from 0 to 3; The compound according to any one of claims 1 to 67, wherein z7 is an integer from 0 to 5.

69. R １ but, 【Chemical Formula 38】 69. The compound according to any one of claims 1 to 68,

70. formula: 【Chemical 39】 70. The compound of any one of claims 1 to 69, having the formula:

71. The formula: 【Chemistry 40】 wherein X is O or S; Y is O, S, or NR ２ and 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ４ 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ５ 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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.

72. formula: 【Chemistry 41】 The compound according to any one of claims 1 to 71, having the formula:

73. R １ but, 【Chemistry 42】 where: R ６ are independently oxo, 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, -SO ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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 ７ are independently 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 ３ H, -OSO ３ H, -SO ２ N.H. ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , -NHC(O)NH ２ , -NHSO ２ H, -NHC(O)H, -NHC(O)OH, -NHOH, -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; z6 is an integer from 0 to 3; The compound according to any one of claims 1 to 72, wherein z7 is an integer from 0 to 5.

74. R １ but, 【Chemistry 43】 The compound according to any one of claims 1 to 73,

75. formula: 【Chemistry 44】 75. The compound of any one of claims 1 to 74, having the formula:

76. 76. A pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

77. 11. A method of treating cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

78. 78. The method of claim 77, wherein the cancer is rectal cancer, colorectal adenocarcinoma, colorectal cancer, non-small cell lung cancer, squamous cell lung cancer, myelodysplastic syndrome, or acute myeloid leukemia.

79. 76. A method of treating a K-Ras(G12D) associated disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

80. 76. A method of treating an H-Ras(G12D) associated disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

81. 76. A method of treating an N-Ras(G12D) associated disease in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

82. 76. A method of regulating the level of activity of K-Ras protein in a cell, comprising contacting said cell with an effective amount of a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

83. 83. The method of claim 82, wherein said modulating said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, K-Ras subcellular localization, K-Ras post-translational processing, or K-Ras post-translational modification.

84. The method of claim 82 or 83, wherein said modulating comprises increasing said activity of said K-Ras protein.

85. The method of claim 82 or 83, wherein said modulating comprises reducing said activity of said K-Ras protein.

86. The method of any one of claims 82 to 85, wherein the K-Ras protein is a human K-Ras protein.

87. 87. The method of claim 86, wherein the human K-Ras protein contains a G12D mutation.

88. 76. A method of regulating the level of activity of H-Ras protein in a cell, comprising contacting said cell with an effective amount of a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

89. 90. The method of claim 88, wherein said modulating said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, H-Ras subcellular localization, H-Ras post-translational processing, or H-Ras post-translational modification.

90. 90. The method of claim 88 or 89, wherein said modulating comprises increasing said activity of said H-Ras protein.

91. 90. The method of claim 88 or 89, wherein said modulating is reducing said activity of said H-Ras protein.

92. The method of any one of claims 88 to 91, wherein the H-Ras protein is a human H-Ras protein.

93. 93. The method of claim 92, wherein the human H-Ras protein contains a G12D mutation.

94. 76. A method of regulating the level of activity of an N-Ras protein in a cell, comprising contacting said cell with an effective amount of a compound according to any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof.

95. 95. The method of claim 94, wherein said modulating said activity comprises modulating GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, N-Ras subcellular localization, N-Ras post-translational processing, or N-Ras post-translational modification.

96. 96. The method of claim 94 or 95, wherein said modulating comprises increasing said activity of said N-Ras protein.

97. 96. The method of claim 94 or 95, wherein said modulating comprises reducing said activity of said N-Ras protein.

98. The method of any one of claims 94 to 97, wherein the N-Ras protein is a human K-Ras protein.

99. 99. The method of claim 98, wherein the human N-Ras protein contains a G12D mutation.

100. 76. A K-Ras protein covalently bound to the compound of any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartic acid residue of said K-Ras protein.

101. 101. The covalently modified K-Ras protein of claim 100, wherein said compound is reversibly covalently attached to an aspartic acid residue of said K-Ras protein.

102. 101. The covalently modified K-Ras protein of claim 100, wherein said compound is irreversibly covalently attached to an aspartic acid residue of said K-Ras protein.

103. 103. The covalently modified K-Ras protein of any one of claims 100 to 102, wherein the covalently modified K-Ras protein has a modulated activity compared to a control, the activity being selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, K-Ras subcellular localization, K-Ras post-translational processing, and K-Ras post-translational modification.

104. 103. The covalently modified K-Ras protein of any one of claims 100 to 102, wherein the K-Ras protein contains a G12D mutation.

105. 105. The covalently modified K-Ras protein of claim 104, wherein the compound is covalently attached to aspartic acid residue 12.

106. 76. An H-Ras protein covalently bound to a compound of any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartic acid residue of said H-Ras protein.

107. 107. The covalently modified H-Ras protein of claim 106, wherein said compound is reversibly covalently bound to an aspartic acid residue of said H-Ras protein.

108. 107. The covalently modified H-Ras protein of claim 106, wherein said compound is irreversibly covalently bound to an aspartic acid residue of said H-Ras protein.

109. 109. The covalently modified H-Ras protein of any one of claims 106 to 108, wherein the covalently modified H-Ras protein has a modulated activity compared to a control, the activity being selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, H-Ras subcellular localization, H-Ras post-translational processing, and H-Ras post-translational modification.

110. 110. The covalently modified H-Ras protein of any one of claims 106 to 109, wherein the H-Ras protein contains a G12D mutation.

111. 111. The covalently modified H-Ras protein of claim 110, wherein said compound is covalently attached to aspartic acid residue 12.

112. 76. An N-Ras protein covalently bound to a compound of any one of claims 1 to 75, or a pharma- ceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartic acid residue of said N-Ras protein.

113. 113. The covalently modified N-Ras protein of claim 112, wherein said compound is reversibly covalently attached to an aspartic acid residue of said N-Ras protein.

114. 113. The covalently modified N-Ras protein of claim 112, wherein said compound is irreversibly covalently attached to an aspartic acid residue of said N-Ras protein.

115. 115. The covalently modified N-Ras protein of any one of claims 112 to 114, wherein the covalently modified H-Ras protein has a modulated activity compared to a control, the activity being selected from GTPase activity, nucleotide exchange, differential GDP or GTP binding, effector protein binding, effector protein activation, guanine exchange factor (GEF) binding, GEF-facilitated nucleotide exchange, phosphate release, nucleotide release, nucleotide binding, N-Ras subcellular localization, N-Ras post-translational processing, and N-Ras post-translational modification.

116. 116. The covalently modified N-Ras protein of any one of claims 112 to 115, wherein the H-Ras protein contains a G12D mutation.

117. 117. The covalently modified N-Ras protein of claim 116, wherein the compound is covalently attached to aspartic acid residue 12.

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