PCNA and EGFR inhibitors for cancer treatment

Abstract

Described herein, inter alia, are methods of treating cancer using EGFR-TK inhibitors and PCNA inhibitors, as well as pharmaceutical compositions comprising EGFR-TK inhibitors and PCNA inhibitors.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 182,408, filed April 30, 2021, the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Lung cancer is the most common cancer worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of lung cancer cases. In Western countries, 10-15% of NSCLC patients express epidermal growth factor receptor (EGFR) mutations in their tumors, with rates as high as 30-40% reported in Asian countries. The main oncogenic EGFR mutations (L858R and exl9del) account for approximately 90% of EGFR NSCLC cases. EGFR exon 20 insertion mutations (Ex20ins) have been described to account for 4-10% of all EGFR mutations in patients. EGFR exon 20 insertion mutations include EGFR20 duplication mutations.

[0003] Patients with EGFR mutations are given EGFR inhibitors as first-line treatment. However, most patients develop acquired resistance. Secondary "gatekeeper" T790M mutations occur in up to 50% of NSCLC patients with primary EGFR mutations treated with first-generation reversible EGFR tyrosine kinase inhibitors (EGFR-TK inhibitors) such as erlotinib, gefitinib, and icotinib (also called first-generation EGFR-TK inhibitors). Second-generation EGFR-TK inhibitors (such as afatinib and dacomitinib) have been developed to overcome this resistance mechanism. These are irreversible agents that covalently bind to cysteine ​​797 at the EGFR ATP site. Second-generation EGFR-TK inhibitors are efficacious against both activating (L858R, exl9del) and acquired T790M mutations in preclinical models. However, their clinical efficacy has proven limited.

[0004] This has led to the development of third-generation EGFR TKIs that retain WT EGFR and also have relatively equal potency for activating EGFR mutations (L858R, exl9del) and acquired T790M. Third-generation EGFR TKIs, such as osimertinib and rociletinib, have been developed. Osimertinib (TAGRISSO®, AstraZeneca) has been approved for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) treatment.

[0005] However, treatment with EGFR-TK inhibitors has not been shown to result in a definitive overall survival benefit. Thus, there is a need for additional treatment options for patients with EGFR cancers. The present disclosure is directed to these and other important ends. Summary of the Invention

[0006] Provided herein are methods of treating cancer by administering to a subject an effective amount of an EGFR-TK inhibitor and an effective amount of a proliferating cell nuclear antigen (PCNA) inhibitor. In embodiments, the PCNA inhibitor has Formula (I):

[0007] [ka] or a pharma- ceutically acceptable salt thereof.

[0008] Provided herein is an effective amount of an EGFR-TK inhibitor and an effective amount of a compound of formula (A):

[0009] [ka] or a pharma- ceutically acceptable salt thereof to a subject.

[0010] Provided herein is a pharmaceutical composition comprising an EGFR-TK inhibitor, a PCNA inhibitor, and a pharma- ceutically acceptable excipient. In an embodiment, the PCNA inhibitor is a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In an embodiment, the PCNA inhibitor is a compound of formula (A) or a pharma- ceutically acceptable salt thereof.

[0011] These and other embodiments of the present disclosure are provided in greater detail herein. [Brief description of the drawings]

[0012] [Figure 1A] Results of AOH1996 tested in combination with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib, afatanib, neratinib, and erlotinib are shown. This combination was most effective at killing the MCF7 cell line, a breast cancer cell line model. At doses .5 / 3.7 in Figure 1B-1C, the top line is AOH1996 and the middle line is afatinib. [Figure 1B] Results of AOH1996 tested in combination with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib, afatanib, neratinib, and erlotinib are shown. This combination was most effective at killing the MCF7 cell line, a breast cancer cell line model. At doses .5 / 3.7 in Figure 1B-1C, the top line is AOH1996 and the middle line is afatinib. [Figure 1C] Results of AOH1996 tested in combination with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib, afatanib, neratinib, and erlotinib are shown. This combination was most effective at killing the MCF7 cell line, a breast cancer cell line model. At doses .5 / 3.7 in Figure 1B-1C, the top line is AOH1996 and the middle line is afatinib. [Figure 1D]Results of AOH1996 tested in combination with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib, afatanib, neratinib, and erlotinib are shown. This combination was most effective at killing the MCF7 cell line, a breast cancer cell line model. At doses .5 / 3.7 in Figure 1B-1C, the top line is AOH1996 and the middle line is afatinib. [Figure 2A] The results of two dose ranges of gefitinib in combination with AOH1996 to test for enhanced efficacy in H358, H3122, and H2228 non-small cell lung cancer (NSCLC) cell lines expressing wild-type EGFR are shown. In Figures 2A-F, squares represent getifinib, circles represent AOH1996, and triangles represent the combination of getifinib and AOH1996. The line containing both circles and squares represents AOH1996, and the squares are circles with standard deviation lines above and below. [Figure 2B] The results of two dose ranges of gefitinib in combination with AOH1996 to test for enhanced efficacy in H358, H3122, and H2228 non-small cell lung cancer (NSCLC) cell lines expressing wild-type EGFR are shown. In Figures 2A-F, squares represent getifinib, circles represent AOH1996, and triangles represent the combination of getifinib and AOH1996. The line containing both circles and squares represents AOH1996, and the squares are circles with standard deviation lines above and below. [Figure 2C] The results of two dose ranges of gefitinib in combination with AOH1996 to test for enhanced efficacy in H358, H3122, and H2228 non-small cell lung cancer (NSCLC) cell lines expressing wild-type EGFR are shown. In Figures 2A-F, squares represent getifinib, circles represent AOH1996, and triangles represent the combination of getifinib and AOH1996. The line containing both circles and squares represents AOH1996, and the squares are circles with standard deviation lines above and below. [Figure 2D]The results of two dose ranges of gefitinib in combination with AOH1996 to test for enhanced efficacy in H358, H3122, and H2228 non-small cell lung cancer (NSCLC) cell lines expressing wild-type EGFR are shown. In Figures 2A-F, squares represent getifinib, circles represent AOH1996, and triangles represent the combination of getifinib and AOH1996. The line containing both circles and squares represents AOH1996, and the squares are circles with standard deviation lines above and below. [Figure 2E] The results of two dose ranges of gefitinib in combination with AOH1996 to test for enhanced efficacy in H358, H3122, and H2228 non-small cell lung cancer (NSCLC) cell lines expressing wild-type EGFR are shown. In Figures 2A-F, squares represent getifinib, circles represent AOH1996, and triangles represent the combination of getifinib and AOH1996. The line containing both circles and squares represents AOH1996, and the squares are circles with standard deviation lines above and below. [Figure 2F] The results of two dose ranges of gefitinib in combination with AOH1996 to test for enhanced efficacy in H358, H3122, and H2228 non-small cell lung cancer (NSCLC) cell lines expressing wild-type EGFR are shown. In Figures 2A-F, squares represent getifinib, circles represent AOH1996, and triangles represent the combination of getifinib and AOH1996. The line containing both circles and squares represents AOH1996, and the squares are circles with standard deviation lines above and below. [Diagram 3] A study of the GI50 values ​​of AOH1996 and gefitinib against a panel of NSCLC cell lines expressing wild-type EGFR. GI50 values ​​for H358, H3122 and H2228 cell lines were derived from dose-response curves performed in our laboratory. GI50 values ​​for the remaining cell lines were obtained through the National Cancer Institute's Developmental Therapeutics Program. [Figure 4A]Dose-response assay comparing AOH1996 alone, osimertinib alone, and the combination of AOH1996 and osimertinib in NSCLC cell lines with wild-type EGFR. [Figure 4B] Dose-response assay comparing AOH1996 alone, osimertinib alone, and the combination of AOH1996 and osimertinib in NSCLC cell lines with wild-type EGFR. [Figure 4C] Dose-response assay comparing AOH1996 alone, osimertinib alone, and the combination of AOH1996 and osimertinib in NSCLC cell lines with wild-type EGFR. [Figure 5A] Dose-response assay of AOH1996 / osimertinib in NSCLC cell lines with mutated EGFR. HCC827 and H1975 cell lines have the EGFR L858R mutation that activates EGFR and makes the cell lines sensitive to EGFR TKIs. The H1975 cell line has an additional T790M mutation that confers resistance to first and second generation EGFR TKIs, but not to third generation TKIs such as osimertinib. HCC827-R and H1975-R cell lines have acquired resistance to osimertinib and were more sensitive to osimertinib in combination with AOH1996 than to either drug alone (Figure 5B, Figure 5D). Figure 5E: Characterization of NSCLCs with acquired resistance to osimertinib revealed many genomic alterations that contribute to resistance. Some of these alterations are present in the NCI60 cell line and are shown in the chart. Each circle represents a cell line with the resistance-conferring genomic alteration listed on the x-axis. BRAF and KRAS mutant cell lines had a significant skew in the distribution for AOH1996 sensitivity. Figure 5F: Two cell lines (14837, 14838) engineered to express oncogenic KRAS in the presence of doxycycline (Dox) were treated with increasing doses of AOH1996 in a dose-response assay. The two cell lines were sensitive to AOH1996 when mutant KRAS was expressed, but not when expression was silenced. [Figure 5B] Dose-response assay of AOH1996 / osimertinib in NSCLC cell lines with mutated EGFR. HCC827 and H1975 cell lines have the EGFR L858R mutation that activates EGFR and makes the cell lines sensitive to EGFR TKIs. The H1975 cell line has an additional T790M mutation that confers resistance to first and second generation EGFR TKIs, but not to third generation TKIs such as osimertinib. HCC827-R and H1975-R cell lines have acquired resistance to osimertinib and were more sensitive to osimertinib in combination with AOH1996 than to either drug alone (Figure 5B, Figure 5D). Figure 5E: Characterization of NSCLCs with acquired resistance to osimertinib revealed many genomic alterations that contribute to resistance. Some of these alterations are present in the NCI60 cell line and are shown in the chart. Each circle represents a cell line with the resistance-conferring genomic alteration listed on the x-axis. BRAF and KRAS mutant cell lines had a significant skew in the distribution for AOH1996 sensitivity. Figure 5F: Two cell lines (14837, 14838) engineered to express oncogenic KRAS in the presence of doxycycline (Dox) were treated with increasing doses of AOH1996 in a dose-response assay. The two cell lines were sensitive to AOH1996 when mutant KRAS was expressed, but not when expression was silenced. [Figure 5C]Dose-response assay of AOH1996 / osimertinib in NSCLC cell lines with mutated EGFR. HCC827 and H1975 cell lines have the EGFR L858R mutation that activates EGFR and makes the cell lines sensitive to EGFR TKIs. The H1975 cell line has an additional T790M mutation that confers resistance to first and second generation EGFR TKIs, but not to third generation TKIs such as osimertinib. HCC827-R and H1975-R cell lines have acquired resistance to osimertinib and were more sensitive to osimertinib in combination with AOH1996 than to either drug alone (Figure 5B, Figure 5D). Figure 5E: Characterization of NSCLCs with acquired resistance to osimertinib revealed many genomic alterations that contribute to resistance. Some of these alterations are present in the NCI60 cell line and are shown in the chart. Each circle represents a cell line with the resistance-conferring genomic alteration listed on the x-axis. BRAF and KRAS mutant cell lines had a significant skew in the distribution for AOH1996 sensitivity. Figure 5F: Two cell lines (14837, 14838) engineered to express oncogenic KRAS in the presence of doxycycline (Dox) were treated with increasing doses of AOH1996 in a dose-response assay. The two cell lines were sensitive to AOH1996 when mutant KRAS was expressed, but not when expression was silenced. [Figure 5D]Dose-response assay of AOH1996 / osimertinib in NSCLC cell lines with mutated EGFR. HCC827 and H1975 cell lines have the EGFR L858R mutation that activates EGFR and makes the cell lines sensitive to EGFR TKIs. The H1975 cell line has an additional T790M mutation that confers resistance to first and second generation EGFR TKIs, but not to third generation TKIs such as osimertinib. HCC827-R and H1975-R cell lines have acquired resistance to osimertinib and were more sensitive to osimertinib in combination with AOH1996 than to either drug alone (Figure 5B, Figure 5D). Figure 5E: Characterization of NSCLCs with acquired resistance to osimertinib revealed many genomic alterations that contribute to resistance. Some of these alterations are present in the NCI60 cell line and are shown in the chart. Each circle represents a cell line with the resistance-conferring genomic alteration listed on the x-axis. BRAF and KRAS mutant cell lines had a significant skew in the distribution for AOH1996 sensitivity. Figure 5F: Two cell lines (14837, 14838) engineered to express oncogenic KRAS in the presence of doxycycline (Dox) were treated with increasing doses of AOH1996 in a dose-response assay. The two cell lines were sensitive to AOH1996 when mutant KRAS was expressed, but not when expression was silenced. [Figure 5E]Dose-response assay of AOH1996 / osimertinib in NSCLC cell lines with mutated EGFR. HCC827 and H1975 cell lines have the EGFR L858R mutation that activates EGFR and makes the cell lines sensitive to EGFR TKIs. The H1975 cell line has an additional T790M mutation that confers resistance to first and second generation EGFR TKIs, but not to third generation TKIs such as osimertinib. HCC827-R and H1975-R cell lines have acquired resistance to osimertinib and were more sensitive to osimertinib in combination with AOH1996 than to either drug alone (Figure 5B, Figure 5D). Figure 5E: Characterization of NSCLCs with acquired resistance to osimertinib revealed many genomic alterations that contribute to resistance. Some of these alterations are present in the NCI60 cell line and are shown in the chart. Each circle represents a cell line with the resistance-conferring genomic alteration listed on the x-axis. BRAF and KRAS mutant cell lines had a significant skew in the distribution for AOH1996 sensitivity. Figure 5F: Two cell lines (14837, 14838) engineered to express oncogenic KRAS in the presence of doxycycline (Dox) were treated with increasing doses of AOH1996 in a dose-response assay. The two cell lines were sensitive to AOH1996 when mutant KRAS was expressed, but not when expression was silenced. [Figure 5F]Dose-response assay of AOH1996 / osimertinib in NSCLC cell lines with mutated EGFR. HCC827 and H1975 cell lines have the EGFR L858R mutation that activates EGFR and makes the cell lines sensitive to EGFR TKIs. The H1975 cell line has an additional T790M mutation that confers resistance to first and second generation EGFR TKIs, but not to third generation TKIs such as osimertinib. HCC827-R and H1975-R cell lines have acquired resistance to osimertinib and were more sensitive to osimertinib in combination with AOH1996 than to either drug alone (Figure 5B, Figure 5D). Figure 5E: Characterization of NSCLCs with acquired resistance to osimertinib revealed many genomic alterations that contribute to resistance. Some of these alterations are present in the NCI60 cell line and are shown in the chart. Each circle represents a cell line with the resistance-conferring genomic alteration listed on the x-axis. BRAF and KRAS mutant cell lines had a significant skew in the distribution for AOH1996 sensitivity. Figure 5F: Two cell lines (14837, 14838) engineered to express oncogenic KRAS in the presence of doxycycline (Dox) were treated with increasing doses of AOH1996 in a dose-response assay. The two cell lines were sensitive to AOH1996 when mutant KRAS was expressed, but not when expression was silenced. [Figure 6A]Figure 6 shows the isolation of chromatin fractions from HCC827 cells treated with AOH1996 or osimertinib alone or in combination. Figure 6A: Growth curves of HCC827 cells treated with 500 nM AOH1996 or 4 nM osimertinib alone or in combination. Chromatin fractionation was performed on parallel sets of cells treated at the 24 hour time point. Figure 6B-C: After fractionation, samples were separated by polyacrylamide gel electrophoresis and immunoblotted to detect PCNA. Ponceau S was used to stain blots for total protein to assess consistency of loading and transfer between samples. The data show that the combination of AOH1996 and osimertinib to treat HCC827 cells resulted in accelerated loss of PCNA from chromatin. [Figure 6B] Figure 6 shows the isolation of chromatin fractions from HCC827 cells treated with AOH1996 or osimertinib alone or in combination. Figure 6A: Growth curves of HCC827 cells treated with 500 nM AOH1996 or 4 nM osimertinib alone or in combination. Chromatin fractionation was performed on parallel sets of cells treated at the 24 hour time point. Figure 6B-C: After fractionation, samples were separated by polyacrylamide gel electrophoresis and immunoblotted to detect PCNA. Ponceau S was used to stain blots for total protein to assess consistency of loading and transfer between samples. The data show that the combination of AOH1996 and osimertinib to treat HCC827 cells resulted in accelerated loss of PCNA from chromatin. [Figure 6C]Figure 6 shows the isolation of chromatin fractions from HCC827 cells treated with AOH1996 or osimertinib alone or in combination. Figure 6A: Growth curves of HCC827 cells treated with 500 nM AOH1996 or 4 nM osimertinib alone or in combination. Chromatin fractionation was performed on parallel sets of cells treated at the 24 hour time point. Figure 6B-C: After fractionation, samples were separated by polyacrylamide gel electrophoresis and immunoblotted to detect PCNA. Ponceau S was used to stain blots for total protein to assess consistency of loading and transfer between samples. The data show that the combination of AOH1996 and osimertinib to treat HCC827 cells resulted in accelerated loss of PCNA from chromatin. [Figure 7A] EGFR-targeted antibodies used to treat colorectal cancer (CRC). CRC cell lines are particularly sensitive to AOH1996. CRC with KRAS and BRAF activating mutations are often difficult to treat, but cell lines with mutant KRAS and BRAF are responsive to AOH1996. Figure 7A: IC50 of CRC cell lines against the remaining NCI60 cell lines. Figure 7B: IC50 of AOH1996 against CRC cell lines categorized by the presence and type of Ras-Raf-Mek-Erk pathway mutations. IC50 for NCI60 cell lines was determined by the NCI Developmental Therapeutics Program. The mutation status of the CRC cell lines was found in the Cellosaurus database. [Figure 7B]EGFR-targeted antibodies used to treat colorectal cancer (CRC). CRC cell lines are particularly sensitive to AOH1996. CRC with KRAS and BRAF activating mutations are often difficult to treat, but cell lines with mutant KRAS and BRAF are responsive to AOH1996. Figure 7A: IC50 of CRC cell lines against the remaining NCI60 cell lines. Figure 7B: IC50 of AOH1996 against CRC cell lines categorized by the presence and type of Ras-Raf-Mek-Erk pathway mutations. IC50 for NCI60 cell lines was determined by the NCI Developmental Therapeutics Program. The mutation status of the CRC cell lines was found in the Cellosaurus database. [Figure 8A] We show that the combination of AOH1996 and osimertinib is more effective at killing NSCLC cell lines harboring wild-type EGFR (H3122, H358) and mutated EGFR (HCC827, H1975) than monotherapy with either agent alone. [Figure 8B] We show that the combination of AOH1996 and osimertinib is more effective at killing NSCLC cell lines harboring wild-type EGFR (H3122, H358) and mutated EGFR (HCC827, H1975) than monotherapy with either agent alone. [Figure 8C] We show that the combination of AOH1996 and osimertinib is more effective at killing NSCLC cell lines harboring wild-type EGFR (H3122, H358) and mutated EGFR (HCC827, H1975) than monotherapy with either agent alone. [Figure 8D] We show that the combination of AOH1996 and osimertinib is more effective at killing NSCLC cell lines harboring wild-type EGFR (H3122, H358) and mutated EGFR (HCC827, H1975) than monotherapy with either agent alone. [Figure 9]MDA-MB-468 cells were serum starved for 24 hours and then treated with AOH1996 and osimertinib for 30 minutes before stimulating the cells by adding EGF for 15 minutes. DMSO control cells show the typical staining pattern for cells in early / metaphase and late S phase. AOH1996-treated cells accumulated EGFR at the plasma membrane, lost punctate staining of PCNA in the nucleus, and increased PCNA localization to the cytoplasm. Cells treated with both drugs had a clearly disorganized localization, reduced EGFR fluorescence, and often segmented PCNA nuclear staining. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. See, for example, Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J.Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any method, apparatus, and material similar or equivalent to those described herein can be used in the practice of this disclosure. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valency known in the chemical arts. The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure.

[0014] The term "proliferating cell nuclear antigen" or "PCNA" refers to a protein of approximately 29 kDa that self-assembles into a protein complex consisting of three subunits of individual PCNA proteins. Together, these linked PCNA molecules form a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. The term "PCNA" may refer to the nucleotide sequence or protein sequence of human PCNA (e.g., Entrez 5111, Uniprot P12004, RefSeq NM_002592, or RefSeq NP_002583). The term "PCNA" includes both the wild-type form of the nucleotide sequence or protein and any variants thereof. In an embodiment, PCNA has a nucleotide sequence corresponding to reference number GI:33239449, corresponding to RefSeq NM_002592.2, corresponding to reference number GI:4505641, or corresponding to RefSeq NP_002583.1.

[0015] The term "AOH1996" refers to a compound of formula (A) having the following structure:

[0016] [ka] This refers to the compound. In an embodiment, the compound of Formula (A) is in the form of a pharma- ceutically acceptable salt.

[0017] The term "EGFR protein" or "EGFR" as provided herein includes any recombinant or naturally occurring form of epidermal growth factor receptor (EGFR), also known as ErbB-1 or HER1 in humans, or a variant or homolog thereof, that maintains EGFR activity (e.g., within the range of at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% activity compared to EGFR). In embodiments, the variant or homolog has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity over the entire sequence or a portion of the sequence (e.g., a 50, 100, 150, or 200 contiguous amino acid portion) compared to a naturally occurring EGFR protein. In embodiments, the EGFR protein is substantially identical to a protein identified by UniProt reference number P00533, or a variant or homolog having substantial identity thereto. The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that binds to EGF family ligands and activates several major pathways, including the RAS-RAF-MEK-ERK pathway, the PI3K-AKT pathway, the PLCγ-PKC pathway, and the STAT pathway. In addition to its role on the cell surface, EGFR is also active in the nucleus, where it plays a role in cell proliferation, DNA repair, and chemotherapy resistance. EGFR signaling is frequently upregulated in cancer.

[0018] The term "EGFR mutation" refers to a mutation in the EGFR protein. Exemplary mutations in the EGFR protein include L858R, ex19del, T790M, and Ex20ins. Ex20ins (or Ex20 insertion mutations) include single insertion mutations and duplication mutations.

[0019] The term "tyrosine kinase" refers to an enzyme that activates proteins through a signaling cascade by the addition of a phosphate group from ATP to a tyrosine residue in the protein, a process called phosphorylation.

[0020] With respect to protein-inhibitor interactions, the terms "inhibit", "inhibit", "inhibiting" and the like refer to adversely affecting (e.g., decreasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to adversely affecting (e.g., decreasing) the protein concentration or level compared to the protein concentration or level in the absence of the inhibitor. In embodiments, inhibition refers to a reduction in a disease or disease symptoms. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes at least partially, partially or completely blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating a signaling or enzyme activity or amount of a protein. In embodiments, inhibition refers to a reduction in the activity of a target protein due to a direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein due to an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing activation of the target protein).

[0021] The terms "inhibitor", "suppressor", or "antagonist", or "down-regulator" refer interchangeably to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the antagonist. In embodiments, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more less than the expression or activity in the absence of the antagonist.

[0022] The term "EGFR-TK inhibitor" or "epidermal growth factor receptor-tyrosine kinase inhibitor" or "EGFR TKI" refers to a tyrosine kinase inhibitor that inhibits or blocks activation of downstream signaling induced by EGFR through binding to the ATP binding site (e.g., a tyrosine kinase inhibitor binds to EGFR and inhibits ATP binding to the tyrosine kinase domain of EGFR). EGFR-TK inhibitors can be used to treat cancers with EGFR mutations and / or aberrant activation of EGFR. Exemplary EGFR-TK inhibitors include osimertinib, gefitinib, afatinib, neratinib, erlotinib, rociletinib, olmutinib, lazertinib, nazartinib, nacotinib, mavereltinib, abivertinib, olafertinib, alflutinib, amivantamb, tarloxitinib, mobocertinib, savolitinib, capmatinib, cetuximab, panitumumab, lapatinib, dacomitinib, necitumumab, vandetanib, icotininib, canertinib, alitinib, varlitinib, tesevatinib, pelitinib, sapitinib, EAI045 (CAS number 1942114-09-1 or 2-(5 -fluoro-2-hydroxyphenyl)-2-(3-oxo-1H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)acetamide), TAK-285 (N-[2-[4-[3-chloro-4-[3-(trifluoromethyl)phenoxy]-anilino]pyrrolo[3,2-d]pyrimidin-5-yl]ethyl]-3-hydroxy-3-methylbutanamide), AG-1478 (Tyrophostin AG1478 or N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinanine), AEE788 (6-{4-[(4-ethyl-1-piperazinyl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-1H-pyrrolo[2,3-d]pyrimidin-4-amine), CUDC-101 (7-[[4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl]oxy]-N-hydroxyheptanamide), WZ8040 (N-[3-[[5-chloro-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]thio]phenyl]-2-propenamide), WZ4002 (N-[3-[[5-chloro-2-[[2-methoxy-4-(4-methyl-1-piperazinyl)phenyl]amino] Examples of EGFR-TK inhibitors include N-[3-[[5-chloro-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]oxy]phenyl]-2-propenamide), WZ3146 (N-[3-[[5-chloro-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-4-pyrimidinyl]oxy]phenyl]-2-propenamide), AG-490 ((2E)-2-cyano-3-(3,4-dihydroxyphenyl)-N-(phenylmethyl)-2-propenamide), and PD153035 (N-(3-bromophenyl)-6,7-dimethoxy-4-quinazolinamine). The EGFR-TK inhibitors described herein may be in the form of a pharma- ceutically acceptable salt.

[0023] 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 the amount of activity that results in disease, and restoring the abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound or using the methods described herein) results in a reduction in the disease or one or more symptoms.

[0024] As used herein, the term "signal transduction pathway" refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit a change in one component to one or more other components, which in turn may transmit the change to additional components, and optionally be propagated to other signal transduction pathway components.

[0025] The term “alkyl,” by itself or as part of another substituent, unless otherwise stated, may be fully saturated, monounsaturated or polyunsaturated, can include divalent and polyvalent groups, and has the specified number of carbon atoms (e.g., C 1 ~C 10 means 1-10 carbons), linear (i.e., unbranched) or branched acyclic carbon chains (or carbons), or combinations thereof. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups are those having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). The alkyl moiety can be an alkenyl moiety. The alkyl moiety can be an alkynyl moiety. The alkyl moiety can be fully saturated.

[0026] 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, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means a divalent radical derived from an alkene, unless otherwise stated.

[0027] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched acyclic chain containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, or S), or a combination thereof, wherein the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. The heteroatom (e.g., O, N, P, S, or Si) can be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, -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 , -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 ) 3Up to two or three heteroatoms may be consecutive, such as: A heteroalkyl moiety may contain one heteroatom A heteroalkyl moiety may contain two, optionally different, heteroatoms A heteroalkyl moiety may contain three, optionally different, heteroatoms A heteroalkyl moiety may contain four, optionally different, heteroatoms

[0028] The term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from 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 It includes groups that are attached to the remainder of the molecule through a heteroatom, such as -R'. When "heteroalkyl" is recited followed by a specific heteroalkyl group, such as -NR'R'', it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited for clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R''.

[0029] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, mean, unless otherwise specified, a non-aromatic cyclic form of "alkyl" and "heteroalkyl", respectively, in which the carbons that make up the ring(s) are not necessarily bonded to hydrogen, since all carbon valencies participate in bonds with non-hydrogen atoms. In addition, 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, 3-hydroxy-cyclobut-3-enyl-1,2,dione, 1H-1,2,4-triazolyl-5(4H)-one, 4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, refer to a divalent radical derived from a cycloalkyl and a heterocycloalkyl, respectively. A heterocycloalkyl moiety can contain one heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moiety can contain two, optionally different, ring heteroatoms. A heterocycloalkyl moiety can contain three, optionally different, ring heteroatoms.

[0030] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, "halo(C 1 -C 4The term "alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl.

[0031] 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.

[0032] The term "aryl", unless otherwise specified, refers to 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 linked together. Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, 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, where at least one of the fused rings is an aromatic heterocycle). 5,6-fused-ring heteroarylene refers to two rings fused together, where one ring has 5 members and the other ring has 6 members, and where at least one ring is 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 remainder of the molecule through a carbon atom or a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, Examples include 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl.Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. "Arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Non-limiting examples of aryl and heteroaryl groups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthalyl, pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl, benzisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, Examples of heteroaryl include pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. The above examples can be substituted or unsubstituted, and the divalent radicals of each of the above heteroaryl examples are non-limiting examples of heteroarylene. The heteroaryl moiety can contain one ring heteroatom. The heteroaryl moiety can contain two optionally different ring heteroatoms. The heteroaryl moiety can contain three optionally different ring heteroatoms. The heteroaryl moiety can contain four optionally different ring heteroatoms. The aryl moiety can have one ring. The aryl moiety may have two, optionally different rings. The aryl moiety may have three, optionally different rings. The aryl moiety may have four, optionally different rings. The heteroaryl moiety may have one ring. The heteroaryl moiety may have two, optionally different rings. The heteroaryl moiety may have three, optionally different rings.

[0033] A fused ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. A fused ring heterocycloalkyl-aryl, a fused ring heterocycloalkyl-heteroaryl, a fused ring heterocycloalkyl-cycloalkyl, or a fused ring heterocycloalkyl-heterocycloalkyl can each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0034] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0035] As used herein, the term “alkylsulfonyl” refers to a group of the formula —S(O 2 )-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' can have a specified number of carbon atoms (e.g., "C 1 -C 4 alkylsulfonyl").

[0036] 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.

[0037] Substituents for alkyl and heteroalkyl groups (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can range in number from zero to (2m'+1), where m' is the total number of carbon atoms in such group, 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', -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, 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 a compound of the invention includes more than one R group, e.g., when more than one of these groups is present, each of the R groups is independently selected as each R', R'', R''', and R'''' group. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will recognize that the term "alkyl" can be used interchangeably with haloalkyl (e.g., -CF3 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 ...

[0038] Similar to the substituents described for the alkyl group, the substituents for the aryl and heteroaryl groups are varied and include, for example, -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO 2 R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O) 2 R', -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, 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 a compound of the invention includes more than one R group, e.g., when more than one of these groups is present, each of the R groups is independently selected as each R', R'', R''', and R'''' group.

[0039] 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 an 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 an 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 an embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0040] 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 may optionally form a ring of the formula -A-(CH 2 ) r A and B may be independently substituted with a substituent of -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2NR'-, or a single bond, where r is an integer from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a group of the formula -(CRR') s -X'- (C''R''R'') d (wherein s and d are independently an integer of 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 - or -S(O) 2 The substituents R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0041] 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.

[0042] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0043] As used herein, a "substituent" is any of the following: (A) oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituted with at least one substituent selected from the following (i) and (ii) ((i) oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (ii)(a): (oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCHF 2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl) and (b): (oxo, halogen, -CF 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF 3 , -OCHF 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl; alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0044] As used herein, "size-limited substituent" or "size-limited substituent" refers to 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 ~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 8each 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.

[0045] As used herein, a "lower substituent" or "lower substituent group" refers to 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 ~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 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0046] In an embodiment, each of the substituents described in the compounds herein is substituted with at least one substituent.In an embodiment, 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 an embodiment, at least one or all of these groups are substituted with at least one size-limiting substituent.In another embodiment, at least one or all of these groups are substituted with at least one lower substituent.

[0047] In embodiments of the compounds herein, 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 In 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.

[0048] In embodiments, each substituted or unsubstituted alkyl is a 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 7each 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 an embodiment, each substituted or unsubstituted alkylene is a substituted or unsubstituted aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-9 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 7 each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-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 9-membered heteroarylene.

[0049] 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 the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as those 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, and methanesulfonic acid. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Other pharmaceutically acceptable carriers known to those skilled in the art are suitable for the present invention. Salts tend to be more soluble in aqueous or other protic solvents than are the corresponding free base forms.

[0050] The compounds described herein may exist as salts with pharma- ceutically acceptable acids and the like. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0051] The neutral forms of the compounds are 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.

[0052] In embodiments, the compounds described herein may exist in unsolvated and solvated forms, such as hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0053] Certain compounds have asymmetric carbon atoms (optical or chiral centers) or double bonds, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)- or (D)- or (L) for amino acids, are encompassed within the scope of the present invention. The compounds do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure includes compounds in racemic and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other geometric centers, it is intended that the compounds include both E and Z geometric isomers, unless otherwise specified. Unless otherwise stated, structures depicted herein are meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center.

[0054] The term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural or configuration of the atoms.

[0055] The term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It will be apparent to one of skill in the art that certain compounds may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the disclosure.

[0056] 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 invention.

[0057] The compounds may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0058] symbol

[0059] [ka] indicates the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0060] 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" group, the term "substituted with a" group means that the particular group can be substituted with one or more of any or all of the specified substituents. 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 The moiety may include alkyl and / or one or more unsubstituted 2-20 membered heteroalkyl. Additionally, when a moiety is substituted with R substituents, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

[0061] "Control" or "control experiment" or "standard control" is used according to its plain and ordinary meaning and refers to an experiment in which the experimental subjects or agents are treated the same as in a parallel experiment except for the omission of the experimental procedure, agent, or variable. In some cases, a control is used as a standard of comparison in evaluating the effect of an experiment. In embodiments, a control is the same experiment or treatment method in the absence of a compound (e.g., as described herein) used in a non-controlled experiment or treatment method that is compared to the control.

[0062] The terms "activation," "activate," "activating," and the like, with respect to protein-activator (e.g., agonist) interactions, refer to favorably affecting (e.g., increasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the activator (e.g., a compound described herein). Thus, activation can include, at least in part, partially or completely increasing stimulation, increasing signaling or enzymatic activity or the amount of a protein that is decreased in a disease, or enabling activation, or activating, sensitizing, or upregulating. Activation can include, at least in part, partially or completely increasing stimulation, increasing signaling or enzymatic activity or the amount of a protein, or enabling activation, or activating, sensitizing, or upregulating.

[0063] 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.

[0064] compound Provided herein are PCNA inhibitors and pharma- ceutically acceptable salts thereof, comprising a compound represented by formula (I):

[0065] [ka] or a pharma- ceutically acceptable salt thereof.

[0066] Ring A is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- to 6-membered heteroaryl. Ring B is a substituted or unsubstituted naphthyl, a substituted or unsubstituted quinolinyl, or a substituted or unsubstituted isoquinolinyl.

[0067] R 1 are independently hydrogen, halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -CN, -SO 2 Cl, -SO n1 R 10 , -SO v1 NR 7 R 8 , -NHNR 7 R 8 , -ONR 7 R 8 , -NHC=(O)NHNR 7 R 8 , -NHC=(O)NR 7 R 8 , -N(O) m1 , -NR 7 R 8 , -C(O)R 9 , -C(O)-OR 9 , -C(O)NR 7 R 8 , -OR 10 , -NR 7 SO 2 R 10 , -NR 7 C=(O)R 9 , -NR 7 C(O)-OR 9 , -NR 7 OR 9 , -OCX 1 3 , -OCHX 1 2 , -OCH 2 X 1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R 1 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. In embodiments, R 1 are independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -CN, -SO n1 R 10 , -SO v1 NR 7 R 8 , -NHNH 2 , -ONR 7 R 8 , -NHC=(O)NHNH 2 , -NHC=(O)NR 7 R 8 , -N(O) m1 , -NR 7 R 8 , -C(O)R 9 , -C(O)-OR 9 , -C(O)NR 7 R 8 , -OR 10 , -NR 7 SO 2 R 10 , -NR 7 C=(O)R 9 , -NR 7 C(O)-OR 9 , -NR 7 OR 9 , -OCX 1 3 , -OCHX 1 2 , -OCH 2 X 1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R 1 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. When z1 is 0, R 1 is understood to be hydrogen.

[0068] R 2 is hydrogen, halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 2 3 , -OCHX 2 2 , -OCH 2 X 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.

[0069] R 3 is hydrogen, halogen, -CX 3 3 , -CHX 32 , -CH 2 X 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 3 3 , -OCHX 3 2 , -OCH 2 X 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.

[0070] R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, -CX A 3 , -CHX A 2 , -CH 2 X A , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCXA 3 , -OCHX A 2 , -OCH 2 X A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 7 Substituents and R 8 The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0071] The symbol z1 is an integer of 0 to 4. The symbols m1 and v1 are independently an integer of 1 or 2. The symbol n1 is an integer of 0 to 4. The symbol X 1 , X 2 , X 3 , and X A is independently -Cl, -Br, -I, or -F.

[0072] In embodiments, the PCNS inhibitor has the formula:

[0073] [ka] is a compound having the formula In the formula, R 1 , R 2 , R 3 , ring A, ring B, and z1 are as described herein and are included in the compounds of formula (I) and are included in the embodiments. In an embodiment, ring A is phenyl (R 4 substituted or unsubstituted) or 5-6 membered heteroaryl (R 4 substituted or unsubstituted) and ring B is naphthyl (R 5 substituted or unsubstituted), quinolinyl (R 5 substituted or unsubstituted), or isoquinolinyl (R 5 (substituted or unsubstituted with).

[0074] R 4are independently halogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -CN, -SO 2 Cl, -SO n4 R 14 , -SO v4 NR 11 R 12 , -NHNR 11 R 12 , -ONR 11 R 12 , -NHC=(O)NHNR 11 R 12 , -NHC=(O)NR 11 R 12 , -N(O) m4 , -NR 11 R 12 , -C(O)R 13 , -C(O)-OR 13 , -C(O)NR 11 R 12 , -OR 14 , -NR 11 SO 2 R 14 , -NR 11 C=(O)R 13 , -NR 11 C(O)-OR 13 , -NR 11 OR 13 , -OCX 4 3 , -OCHX 4 2 , -OCH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R 4 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. In embodiments, R 4 are independently halogen, -CX 43 , -CHX 4 2 , -CH 2 X 4 , -CN, -SO n4 R 14 , -SO v4 NR 11 R 12 , -NHNR 11 R 12 , -ONR 11 R 12 , -NHC=(O)NHNR 11 R 12 , -NHC=(O)NR 11 R 12 , -N(O) m4 , -NR 11 R 12 , -C(O)R 13 , -C(O)-OR 13 , -C(O)NR 11 R 12 , -OR 14 , -NR 11 SO 2 R 14 , -NR 11 C=(O)R 13 , -NR 11 C(O)-OR 13 , -NR 11 OR 13 , -OCX 4 3 , -OCHX 4 2 , -OCH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R 4 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. When z2 is 0, R 4 is understood to be hydrogen.

[0075] R 5are independently halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -CN, -SO 2 Cl, -SO n5 R 18 , -SO v5 NR 15 R 16 , -NHNR 15 R 16 , -ONR 15 R 16 , -NHC=(O)NHNR 15 R 16 , -NHC=(O)NR 15 R 16 , -N(O) m5 , -NR 15 R 16 , -C(O)R 17 , -C(O)-OR 17 , -C(O)NR 15 R 16 , -OR 18 , -NR 15 SO 2 R 18 , -NR 15 C=(O)R 17 , -NR 15 C(O)-OR 17 , -NR 15 OR 17 , -OCX 5 3 , -OCHX 5 2 , -OCH 2 X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R 5 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. In embodiments, R 5 are independently halogen, -CX 53 , -CHX 5 2 , -CH 2 X 5 , -CN, -SO n5 R 18 , -SO v5 NR 15 R 16 , -NHNR 15 R 16 , -ONR 15 R 16 , -NHC=(O)NHNR 15 R 16 , -NHC=(O)NR 15 R 16 , -N(O) m5 , -NR 15 R 16 , -C(O)R 17 , -C(O)-OR 17 , -C(O)NR 15 R 16 , -OR 18 , -NR 15 SO 2 R 18 , -NR 15 C=(O)R 17 , -NR 15 C(O)-OR 17 , -NR 15 OR 17 , -OCX 5 3 , -OCHX 5 2 , -OCH 2 X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R 5 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. When z3 is 0, R 5 is understood to be hydrogen.

[0076] R 11 , R12 , R 13 , and R 14 are independently hydrogen, halogen, -CX B 3 , -CHX B 2 , -CH 2 X B , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX B 3 , -OCHX B 2 , -OCH 2 X B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and bonded to the same nitrogen atom; 11 Substituents and R 12 The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0077] R 15 , R 16 , R 17 , and R 18 are independently hydrogen, halogen, -CX C 3 , -CHX C 2 , -CH 2 X C , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2, -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX C 3 , -OCHX C 2 , -OCH 2 X C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and bonded to the same nitrogen atom; 15 Substituents and R 16 The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0078] The symbol z2 is an integer of 0 to 5. The symbol z3 is an integer of 0 to 7. The symbols m4, m5, v4, and v5 are each independently an integer of 1 or 2. The symbols n4 and n5 are each independently an integer of 0 to 4. The symbol X 4 , X 5 , X B , and X C is independently -Cl, -Br, -I, or -F.

[0079] In an embodiment, ring A is substituted phenyl. In an embodiment, ring A is unsubstituted phenyl. In an embodiment, ring A is phenyl. In an embodiment, ring A is substituted 5-6 membered heteroaryl. In an embodiment, ring A is unsubstituted 5-6 membered heteroaryl. In an embodiment, ring A is 5-6 membered heteroaryl. In an embodiment, ring A is substituted thienyl. In an embodiment, ring A is unsubstituted thienyl. In an embodiment, ring A is thienyl. In an embodiment, ring A is 2-thienyl. In an embodiment, ring A is 3-thienyl. In an embodiment, ring A is substituted pyridyl. In an embodiment, ring A is unsubstituted pyridyl. In an embodiment, ring A is pyridyl. In an embodiment, ring A is 2-pyridyl. In an embodiment, ring A is 3-pyridyl. In an embodiment, ring A is 4-pyridyl. In an embodiment, ring A is substituted thien ... is unsubstituted pyrrolyl. In embodiments, Ring A is substituted pyrrolyl. In embodiments, Ring A is pyrrolyl. In embodiments, Ring A is unsubstituted furanyl. In embodiments, Ring A is substituted furanyl. In embodiments, Ring A In an embodiment, Ring A is furanyl. is unsubstituted pyrazolyl. In embodiments, Ring A is substituted pyrazolyl. In embodiments, Ring A is pyrazolyl. In embodiments, Ring A is unsubstituted imidazolyl. In embodiments, Ring A is substituted imidazolyl. In embodiments, Ring A is imidazolyl. In embodiments, Ring A is unsubstituted oxazolyl. In embodiments, Ring A is substituted oxazolyl. In embodiments, Ring A is oxazolyl. In embodiments, Ring A is unsubstituted isoxazolyl. In embodiments, Ring A is substituted isoxazolyl. In embodiments, Ring A is isoxazolyl. In embodiments, Ring A is unsubstituted thiazolyl. In embodiments, Ring A is substituted thiazolyl. In embodiments, Ring A is thiazolyl. In embodiments, Ring A is unsubstituted triazolyl. In embodiments, Ring A is substituted triazolyl. In embodiments, Ring A is triazolyl. In embodiments, Ring B is substituted naphthyl. In embodiments, Ring B is unsubstituted naphthyl. In embodiments, Ring B is naphthyl. In embodiments, Ring B is 1-naphthyl. In embodiments, Ring B is 2-naphthyl. In embodiments, Ring B is quinolinyl. In embodiments, Ring B is substituted quinolinyl. In embodiments, Ring B is unsubstituted quinolinyl. In embodiments, Ring B is isoquinolinyl. In embodiments, Ring B is substituted isoquinolinyl. In embodiments, Ring B is unsubstituted isoquinolinyl. In embodiments, Ring B is 1-isoquinolinyl. In embodiments, Ring B is 3-isoquinolinyl. In embodiments, Ring B is 4-isoquinolinyl.

[0080] In embodiments, R 1 are independently halogen, -CF 3 , -CHF 2 , -OCF 3 , -OCHF 2 , substituted or unsubstituted C 1 ~C 8 Alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted C 3 ~C 8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 ~C 10aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 1 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 1 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 1 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 1 is independently halogen. In an embodiment, R 1 are independently -CF 3 In an embodiment, R 1 are independently -CHF 2 In an embodiment, R 1 are independently -CH 2 F. In embodiments, R 1 can be used independently, -OCF 3 In an embodiment, R 1 are independently -OCHF 2 In an embodiment, R 1 are independently -OCH 2 F. In embodiments, R 1 are independently substituted or unsubstituted C 1 ~C 8 In embodiments, R 1 is independently a substituted or unsubstituted 2-8 membered heteroalkyl. 1 are independently substituted or unsubstituted C 3 ~C 8 In embodiments, R1 is independently a substituted or unsubstituted 3-8 membered heterocycloalkyl. 1 are independently substituted or unsubstituted C 6 ~C 10 In embodiments, R 1 is independently a substituted or unsubstituted 5-10 membered heteroaryl. 1 is independently -OH. In embodiments, R 1 are independently -NH 2 In an embodiment, R 1 is independently -SH. In embodiments, R 1 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 1 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. 1 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 1 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 1 is independently substituted or unsubstituted phenyl. In embodiments, R 1 is independently a substituted or unsubstituted 5-6 membered heteroaryl.

[0081] In embodiments, R 1 is independently a substitution C 1 ~C 8 In embodiments, R 1 is independently a substituted 2-8 membered heteroalkyl. In embodiments, R 1 is independently a substitution C 3 ~C 8 In embodiments, R 1 is independently a substituted 3-8 membered heterocycloalkyl. 1 is independently a substitution C 6 ~C 10 In embodiments, R 1is independently a substituted 5-10 membered heteroaryl. 1 is independently a substitution C 1 ~C 4 In embodiments, R 1 is independently a substituted 4-membered heteroalkyl. 1 is independently a substitution C 3 ~C 6 In embodiments, R 1 is independently a substituted 3-6 membered heterocycloalkyl. 1 is independently a substituted phenyl. In embodiments, R 1 is independently a substituted 5-6 membered heteroaryl. 1 are independently unsubstituted C 1 ~C 8 In embodiments, R 1 is independently an unsubstituted 2-8 membered heteroalkyl. In embodiments, R 1 are independently unsubstituted C 3 ~C 8 In embodiments, R 1 is independently an unsubstituted 3-8 membered heterocycloalkyl. 1 are independently unsubstituted C 6 ~C 10 In embodiments, R 1 is independently an unsubstituted 5-10 membered heteroaryl. 1 are independently unsubstituted C 1 ~C 4 In embodiments, R 1 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1 are independently unsubstituted C 3 ~C 6 In embodiments, R 1 is independently an unsubstituted 3-6 membered heterocycloalkyl. 1 is independently unsubstituted phenyl. In embodiments, R 1is independently an unsubstituted 5-6 membered heteroaryl. 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently unsubstituted methoxy. In embodiments, R 1 is independently unsubstituted ethoxy. In embodiments, R 1 is independently -F. In embodiments, R 1 is independently -Cl. In embodiments, R 1 is independently -Br. In embodiments, R 1 is independently -I. In embodiments, R 1 is independently hydrogen. In embodiments, R 1 are independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl.

[0082] In an embodiment, z1 is 1. In an embodiment, z1 is 0. In an embodiment, z1 is 2. In an embodiment, z1 is 3. In an embodiment, z1 is 4.

[0083] In embodiments, R 2 is hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH 2 , substituted or unsubstituted C 1 ~C6 Alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. 2 is hydrogen. In embodiments, R 2 is unsubstituted methyl. In embodiments, R 2 is unsubstituted ethyl. In embodiments, R 2 is unsubstituted isopropyl. In embodiments, R 2 is unsubstituted tert-butyl.

[0084] In embodiments, R 2 is hydrogen, halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0085] In embodiments, R 3 is hydrogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH 2 , substituted or unsubstituted C 1 ~C 6 Alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 3 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl. 3 is hydrogen. In embodiments, R 3 is unsubstituted methyl. In embodiments, R 3 is unsubstituted ethyl. In embodiments, R 3 is unsubstituted isopropyl. In embodiments, R 3 is unsubstituted tert-butyl. In embodiments, R 3 is hydrogen, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0086] In embodiments, R 4 are independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 ~C 8 Alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted C 3 ~C 8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 ~C 10aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 4 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 4 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 4 is independently halogen. In an embodiment, R 4 is independently -OH. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted methoxy. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently -F. In embodiments, R 4 is independently -Cl. In embodiments, R 4 is independently -Br. In embodiments, R 4 is independently -I. In embodiments, R 4 are independently -CF 3 In an embodiment, R 4 are independently -NH 2 In an embodiment, R 4 is independently -SH. In embodiments, R 4 is independently unsubstituted isopropyl. In embodiments, R 4is independently unsubstituted tert-butyl. In embodiments, R 4 is independently unsubstituted ethoxy. In embodiments, R 4 is independently unsubstituted propoxy.

[0087] In embodiments, R 4 is independently halogen. In an embodiment, R 4 is independent of -CX 4 3 In an embodiment, R 4 are independently -CHX 4 2 In an embodiment, R 4 are independently -CH 2 X 4 In an embodiment, R 4 is independently -CN. In embodiments, R 4 independently, -SO n4 R 14 In an embodiment, R 4 is independently -SR 14 In an embodiment, R 4 independently, -SO v4 NR 11 R 12 In an embodiment, R 4 are independently -NHNR 11 R 12 In an embodiment, R 4 is independently -ONR 11 R 12 In an embodiment, R 4 are independently -NHC=(O)NHNR 11 R 12 In an embodiment, R 4 are independently -NHC=(O)NR 11 R 12 In an embodiment, R 4 are independently -N(O) m4 In an embodiment, R 4 are independently -NR 11 R 12 In an embodiment, R 4 are independently -C(O)R13 In an embodiment, R 4 are independently -C(O)-OR 13 In an embodiment, R 4 are independently -C(O)NR 11 R 12 In an embodiment, R 4 are independently -OR 14 In an embodiment, R 4 are independently -NR 11 SO 2 R 14 In an embodiment, R 4 are independently -NR 11 C=(O)R 13 In an embodiment, R 4 are independently -NR 11 C(O)-OR 13 In an embodiment, R 4 are independently -NR 11 OR 13 In an embodiment, R 4 -OCX 4 3 In an embodiment, R 4 can be used independently, -OCHX 4 2 In an embodiment, R 4 are independently -OCH 2 X 4 In an embodiment, R 4 are independently -CF 3 In an embodiment, R 4 are independently -CHF 2 In an embodiment, R 4 are independently -CH 2 F. In embodiments, R 4 independently, -SO 2 CH 3 In an embodiment, R 4 independently, -SO 2 NH 2 In an embodiment, R 4 is independently -SH. In embodiments, R 4 are independently -N(O) 2In an embodiment, R 4 are independently -NH 2 In an embodiment, R 4 are independently -C(O)CH 3 In an embodiment, R 4 is independently -C(O)OH. In embodiments, R 4 are independently -C(O)NH 2 In an embodiment, R 4 is independently -OH. In embodiments, R 4 can be used independently, -OCF 3 In an embodiment, R 4 are independently -OCHF 2 In an embodiment, R 4 are independently -OCH 2 It's F.

[0088] In embodiments, R 4 are independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 ~C 8 Alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted C 3 ~C 8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 ~C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 4 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4 are independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl.

[0089] In embodiments, R 4 is independently substituted or unsubstituted alkyl. In embodiments, R 4 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 4 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 4 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 4 is independently substituted or unsubstituted aryl. In embodiments, R 4 is independently substituted or unsubstituted heteroaryl. In an embodiment, two adjacent R 4 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl. In embodiments, two adjacent R 4 The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl. In embodiments, two adjacent R 4 The substituents may be optionally linked to form a substituted or unsubstituted aryl. In embodiments, two adjacent R 4 The substituents may be optionally linked to form a substituted or unsubstituted heteroaryl.

[0090] In embodiments, R 4 are independently substituted or unsubstituted alkyl (e.g., C 1 ~C 8Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 4 are independently substituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), substituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted aryl (e.g., C 6 ~C 10 Aryl or C 6aryl), or substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 4 are independently unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0091] In embodiments, R 14 are independently hydrogen, -CX B 3 , -CHX B 2 , -CH 2 X B , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 14 is independently hydrogen. In embodiments, R 14 is independent of -CX B3 In an embodiment, R 14 are independently -CHX B 2 In an embodiment, R 14 are independently -CH 2 X B In an embodiment, R 14 is independently -CN. In embodiments, R 14 is independently -COOH. In embodiments, R 14 independently, -CONH 2 In an embodiment, R 14 is independently substituted or unsubstituted alkyl. In embodiments, R 14 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 14 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 14 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 14 is independently substituted or unsubstituted aryl. In embodiments, R 14 is independently substituted or unsubstituted heteroaryl. In embodiments, R 14 is independently substituted alkyl. In embodiments, R 14 is independently substituted heteroalkyl. In embodiments, R 14 is independently substituted cycloalkyl. In embodiments, R 14 is independently a substituted heterocycloalkyl. In embodiments, R 14 is independently substituted aryl. In embodiments, R 14 is independently substituted heteroaryl. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 is independently unsubstituted heteroalkyl. In embodiments, R 14 is independently unsubstituted cycloalkyl. In embodiments, R 14 is independently unsubstituted heterocycloalkyl. In embodiments, R 14is independently unsubstituted aryl. In embodiments, R 14 is independently unsubstituted heteroaryl. In embodiments, R 14 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 14 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. 14 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 14 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 14 is independently substituted or unsubstituted phenyl. In embodiments, R 14 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 14 is independently a substitution C 1 ~C 4 In embodiments, R 14 is independently a substituted 2-4 membered heteroalkyl. In embodiments, R 14 is independently a substitution C 3 ~C 6 In embodiments, R 14 is independently a substituted 3-6 membered heterocycloalkyl. 14 is independently a substituted phenyl. In embodiments, R 14 is independently a substituted 5-6 membered heteroaryl. 14 are independently unsubstituted C 1 ~C 4 In embodiments, R 14 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 14 are independently unsubstituted C 3 ~C 6 In embodiments, R 14 is independently an unsubstituted 3-6 membered heterocycloalkyl. 14is independently unsubstituted phenyl. In embodiments, R 14 is independently an unsubstituted 5-6 membered heteroaryl. 14 is hydrogen or unsubstituted methyl.

[0092] In embodiments, R 14 is substituted or unsubstituted pyrazolyl. In embodiments, R 14 is substituted or unsubstituted pyridyl. In embodiments, R 14 is a substituted or unsubstituted imidazolyl. In embodiments, R 14 is a substituted or unsubstituted oxazolyl. In embodiments, R 14 is a substituted or unsubstituted isoxazolyl. In embodiments, R 14 is substituted or unsubstituted thiazolyl. In embodiments, R 14 is substituted or unsubstituted furanyl. In embodiments, R 14 is substituted or unsubstituted pyrrolyl. In embodiments, R 14 is substituted or unsubstituted thienyl. In embodiments, R 14 is a substituted pyrazolyl. In embodiments, R 14 is a substituted pyridyl. In embodiments, R 14 is a substituted imidazolyl. In embodiments, R 14 is a substituted oxazolyl. In embodiments, R 14 is a substituted isoxazolyl. In embodiments, R 14 is a substituted thiazolyl. In embodiments, R 14 is substituted furanyl. In embodiments, R 14 is a substituted pyrrolyl. In embodiments, R 14 is substituted thienyl. In embodiments, R 14 is unsubstituted pyrazolyl. In embodiments, R 14 is unsubstituted pyridyl. In embodiments, R 14 is unsubstituted imidazolyl. In embodiments, R 14 is unsubstituted oxazolyl. In embodiments, R 14is unsubstituted isoxazolyl. In embodiments, R 14 is unsubstituted thiazolyl. In embodiments, R 14 is unsubstituted furanyl. In embodiments, R 14 is unsubstituted pyrrolyl. In embodiments, R 14 is unsubstituted thienyl.

[0093] In embodiments, R 14 is independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 3 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 14 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C4 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 14 is independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 are independently unsubstituted C 1 ~C 6 In embodiments, R 14 are independently unsubstituted C 1 ~C 5 In embodiments, R 14 are independently unsubstituted C 1 ~C 4 In embodiments, R 14 are independently unsubstituted C 1 ~C 3 In embodiments, R 14 are independently unsubstituted C 1 ~C 2 In embodiments, R 14 are independently unsubstituted C 2 ~C 6 In embodiments, R 14 are independently unsubstituted C 2 ~C 5 In embodiments, R 14 are independently unsubstituted C 2 ~C 4 In embodiments, R 14 are independently unsubstituted C 2 ~C 3 In embodiments, R 14 are independently unsubstituted C 3 ~C 6 In embodiments, R 14 are independently unsubstituted C 4 ~C 6 In embodiments, R 14 are independently unsubstituted C 5 ~C 6In embodiments, R 14 are independently -CF 3 In an embodiment, R 14 are independently -CHF 2 In an embodiment, R 14 are independently -CH 2 F. In embodiments, R 14 are independently -CCl 3 In an embodiment, R 14 are independently -CHCl 2 In an embodiment, R 14 are independently -CH 2 In an embodiment, R 14 are independently -CBr 3 In an embodiment, R 14 are independently -CHBr 2 In an embodiment, R 14 are independently -CH 2 In an embodiment, R 14 is independently -CI 3 In an embodiment, R 14 is independently -CHI 2 In an embodiment, R 14 are independently -CH 2 In an embodiment, R 14 are independently unsubstituted C 1 ~C 4 In embodiments, R 14 are independently unsubstituted C 1 ~C 3 In embodiments, R 14 are independently unsubstituted C 1 ~C 2 In embodiments, R 14 are independently unsubstituted C 2 ~C 6 In embodiments, R 14 are independently unsubstituted C 2 ~C 5 In embodiments, R 14 are independently unsubstituted C 2 ~C4 In embodiments, R 14 are independently unsubstituted C 2 ~C 3 In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14 is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R 14 is independently unsubstituted butyl. In embodiments, R 14 is independently unsubstituted isobutyl. In embodiments, R 14 is independently unsubstituted tert-butyl.

[0094] In embodiments, z2 is 1. In embodiments, z2 is 0. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5.

[0095] In embodiments, R 5 are independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 ~C 8 Alkyl, substituted or unsubstituted 2-8 membered heteroalkyl, substituted or unsubstituted C 3 ~C 8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C 6 ~C 10 aryl, or substituted or unsubstituted 5-10 membered heteroaryl. 5 are independently halogen, -CF3 , -CHF 2 , -CH 2 F, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -OCF 3 , -OCHF 2 , -OCH 2 F, substituted or unsubstituted C 1 ~C 8 alkyl, or substituted or unsubstituted 2-8 membered heteroalkyl.

[0096] In embodiments, R 5 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 5 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 5 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 5 is independently halogen. In an embodiment, R 5 is independently -OH. In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted methoxy. In embodiments, R 5 is independently unsubstituted ethyl. In embodiments, R 5 is independently -F. In embodiments, R 5 is independently -Cl. In embodiments, R 5is independently -Br. In embodiments, R 5 is independently -I. In embodiments, R 5 are independently -CF 3 In an embodiment, R 5 are independently -NH 2 In an embodiment, R 5 is independently -SH. In embodiments, R 5 is independently unsubstituted isopropyl. In embodiments, R 5 is independently unsubstituted tert-butyl. In embodiments, R 5 is independently unsubstituted ethoxy. In embodiments, R 5 is independently unsubstituted propoxy.

[0097] In embodiments, R 5 are independently substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 5are independently substituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), substituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), substituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), substituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), substituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or substituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 5 are independently unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 5 are independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl. 5 is unsubstituted C 1 ~C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl. 5 is unsubstituted C 1 ~C 4 In embodiments, R 5 is an unsubstituted 2-4 membered heteroalkyl.

[0098] In embodiments, R 5 is independently unsubstituted alkyl. In embodiments, R 5 are independently unsubstituted C 1 ~C 6 In embodiments, R 5 are independently unsubstituted C 1 ~C 5 In embodiments, R 5 are independently unsubstituted C 1 ~C 4 In embodiments, R 5 are independently unsubstituted C 1 ~C 3 In embodiments, R 5 are independently unsubstituted C 1 ~C 2 In embodiments, R 5 are independently unsubstituted C 2 ~C 6 In embodiments, R 5are independently unsubstituted C 2 ~C 5 In embodiments, R 5 are independently unsubstituted C 2 ~C 4 In embodiments, R 5 are independently unsubstituted C 2 ~C 3 In embodiments, R 5 are independently unsubstituted C 3 ~C 6 In embodiments, R 5 are independently unsubstituted C 4 ~C 6 In embodiments, R 5 are independently unsubstituted C 5 ~C 6 It is an alkyl.

[0099] In an embodiment, z3 is 1. In an embodiment, z3 is 0. In an embodiment, z3 is 2. In an embodiment, z3 is 3. In an embodiment, z3 is 4. In an embodiment, z3 is 5. In an embodiment, z3 is 6. In an embodiment, z3 is 7.

[0100] In embodiments, R 11 , R 12 , R 13 , or R 14 are independently hydrogen, -CX B 3 , -CHX B 2 , -CH 2 X B , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 11 , R 12 , R 13 , or R 14 is independently hydrogen. In embodiments, R 11, R 12 , R 13 , or R 14 is independent of -CX B 3 In an embodiment, R 11 , R 12 , R 13 , or R 14 are independently -CHX B 2 In an embodiment, R 11 , R 12 , R 13 , or R 14 are independently -CH 2 X B In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently -CN. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently -COOH. In embodiments, R 11 , R 12 , R 13 , or R 14 independently, -CONH 2 In an embodiment, R 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 11 , R 12 , R 13, or R 14 is independently substituted or unsubstituted aryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted heteroaryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted heterocycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted aryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently substituted heteroaryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted alkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted cycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14is independently unsubstituted heterocycloalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted aryl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently unsubstituted heteroaryl. In embodiments, R 11 , R 12 , R 13 , or R 14 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. 11 , R 12 , R 13 , or R 14 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 11 , R 12 , R 13 , or R 14 is independently substituted or unsubstituted phenyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 11 , R 12 , R 13 , or R 14 is independently a substitution C 1 ~C 4 In embodiments, R 11 , R 12 , R 13, or R 14 is independently a substituted 2-4 membered heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substitution C 3 ~C 6 In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted 3-6 membered heterocycloalkyl. 11 , R 12 , R 13 , or R 14 is independently a substituted phenyl. In embodiments, R 11 , R 12 , R 13 , or R 14 is independently a substituted 5-6 membered heteroaryl. 11 , R 12 , R 13 , or R 14 are independently unsubstituted C 1 ~C 4 In embodiments, R 11 , R 12 , R 13 , or R 14 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 11 , R 12 , R 13 , or R 14 are independently unsubstituted C 3 ~C 6 In embodiments, R 11 , R 12 , R 13 , or R 14 is independently an unsubstituted 3-6 membered heterocycloalkyl. 11 , R 12 , R 13 , or R 14 is independently unsubstituted phenyl. In embodiments, R 11 , R 12 , R 13 , or R14 is independently unsubstituted 5-6 membered heteroaryl.

[0101] In an embodiment, R 11 and R 12 The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form a substituted or unsubstituted heteroaryl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form a substituted heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form a substituted heteroaryl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form an unsubstituted heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form an unsubstituted heteroaryl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form a substituted or unsubstituted 3-6 membered heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form a substituted or unsubstituted 5-6 membered heteroaryl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form a substituted 3-6 membered heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form a substituted 5-6 membered heteroaryl. In embodiments, R 11 and R 12The substituents may be optionally linked to form an unsubstituted 3-6 membered heterocycloalkyl. In embodiments, R 11 and R 12 The substituents may be optionally linked to form an unsubstituted 5- to 6-membered heteroaryl.

[0102] In embodiments, R 15 , R 16 , R 17 , or R 18 are independently hydrogen, -CX C 3 , -CHX C 2 , -CH 2 X C , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 15 , R 16 , R 17 , or R 18 is independently hydrogen. In embodiments, R 15 , R 16 , R 17 , or R 18 is independent of -CX C 3 In an embodiment, R 15 , R 16 , R 17 , or R 18 are independently -CHX C 2 In an embodiment, R 15 , R 16 , R 17 , or R 18 are independently -CH 2 X C In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently -CN. In embodiments, R 15 , R 16 , R17 , or R 18 is independently -COOH. In embodiments, R 15 , R 16 , R 17 , or R 18 independently, -CONH 2 In an embodiment, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted aryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted heteroaryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted cycloalkyl. In embodiments, R 15 , R16 , R 17 , or R 18 is independently a substituted heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted aryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently substituted heteroaryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted alkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted cycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted heterocycloalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted aryl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted heteroaryl. In embodiments, R 15 , R 16 , R 17 , or R 18 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted 2-4 membered heteroalkyl.15 , R 16 , R 17 , or R 18 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 15 , R 16 , R 17 , or R 18 is independently substituted or unsubstituted phenyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 15 , R 16 , R 17 , or R 18 is independently a substitution C 1 ~C 4 In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted 2-4 membered heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substitution C 3 ~C 6 In embodiments, R 15 , R 16 , R 17 , or R 18 is independently a substituted 3-6 membered heterocycloalkyl. 15 , R 16 , R 17 , or R 18 is independently a substituted phenyl. In embodiments, R 15 , R 16 , R 17 , or R 18is independently a substituted 5-6 membered heteroaryl. 15 , R 16 , R 17 , or R 18 are independently unsubstituted C 1 ~C 4 In embodiments, R 15 , R 16 , R 17 , or R 18 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 15 , R 16 , R 17 , or R 18 are independently unsubstituted C 3 ~C 6 In embodiments, R 15 , R 16 , R 17 , or R 18 is independently an unsubstituted 3-6 membered heterocycloalkyl. 15 , R 16 , R 17 , or R 18 is independently unsubstituted phenyl. In embodiments, R 15 , R 16 , R 17 , or R 18 is independently unsubstituted 5-6 membered heteroaryl.

[0103] In an embodiment, R 15 and R 16 The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form a substituted or unsubstituted heteroaryl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form a substituted heterocycloalkyl. In embodiments, R 15 and R 16The substituents may be optionally linked to form a substituted heteroaryl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form an unsubstituted heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form an unsubstituted heteroaryl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form a substituted or unsubstituted 3-6 membered heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form a substituted or unsubstituted 5-6 membered heteroaryl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form a substituted 3-6 membered heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form a substituted 5-6 membered heteroaryl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form an unsubstituted 3-6 membered heterocycloalkyl. In embodiments, R 15 and R 16 The substituents may be optionally linked to form an unsubstituted 5- to 6-membered heteroaryl.

[0104] In an embodiment, m1 is 1. In an embodiment, m1 is 2. In an embodiment, v1 is 1. In an embodiment, v1 is 2. In an embodiment, m4 is 1. In an embodiment, m4 is 2. In an embodiment, m5 is 1. In an embodiment, m5 is 2. In an embodiment, v4 is 1. In an embodiment, v4 is 2. In an embodiment, v5 is 1. In an embodiment, v5 is 2. In an embodiment, n1 is 0. In an embodiment, n1 is 1. In an embodiment, n1 is 2. In an embodiment, n1 is 3. In an embodiment, n1 is 4. In an embodiment, n4 is 0. In an embodiment, n4 is 1. In an embodiment, n4 is 2. In an embodiment, n4 is 3. In an embodiment, n4 is 4. In an embodiment, n5 is 0. In an embodiment, n5 is 1. In an embodiment, n5 is 2. In an embodiment, n5 is 3. In an embodiment, n5 is 4.

[0105] In an embodiment, X 1 is independently -Cl. In an embodiment, X 1 is independently -Br. In an embodiment, X 1 is independently -I. In an embodiment, X 1 is independently -F. In an embodiment, X 2 is independently -Cl. In an embodiment, X 2 is independently -Br. In an embodiment, X 2 is independently -I. In an embodiment, X 2 is independently -F. In an embodiment, X 3 is independently -Cl. In an embodiment, X 3 is independently -Br. In an embodiment, X 3 is independently -I. In an embodiment, X 3 is independently -F. In an embodiment, X 4 is independently -Cl. In an embodiment, X 4 is independently -Br. In an embodiment, X 4 is independently -I. In an embodiment, X4 is independently -F. In an embodiment, X 5 is independently -Cl. In an embodiment, X 5 is independently -Br. In an embodiment, X 5 is independently -I. In an embodiment, X 5 is independently -F. In an embodiment, X A is independently -Cl. In an embodiment, X A is independently -Br. In an embodiment, X A is independently -I. In an embodiment, X A is independently -F. In an embodiment, X B is independently -Cl. In an embodiment, X B is independently -Br. In an embodiment, X B is independently -I. In an embodiment, X B is independently -F. In an embodiment, X C is independently -Cl. In an embodiment, X C is independently -Br. In an embodiment, X C is independently -I. In an embodiment, X C are independently -F.

[0106] In embodiments, the PCNS inhibitor has the formula:

[0107] [ka] is a compound having the formula In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , Ring A, Ring B, z1, z2, and z3 are as described herein and are included in the compounds of formula (I) and (II). In an embodiment, z1 is 0. In an embodiment, z2 is 0. In an embodiment, z3 is 0. In an embodiment, R 2 is hydrogen. In embodiments, R 3 is hydrogen.

[0108] In embodiments, the PCNS inhibitor has the formula:

[0109] [ka] is a compound having the formula In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , Ring A, Ring B, z1, z2, and z3 are as described herein and are included in the compounds of formula (I) and (II).

[0110] In embodiments, the PCNS inhibitor has the formula:

[0111] [ka] is a compound having the formula In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , Ring A, Ring B, z1, z2, and z3 are as described herein and are included in the compounds of formula (I) and (II).

[0112] In embodiments, the PCNS inhibitor has the formula:

[0113] [ka] is a compound having the formula In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , z1, z2, and z3 are as described herein and are included in the compounds of formulae (I)-(V).

[0114] In embodiments, the PCNS inhibitor has the formula:

[0115] [ka] is a compound having the formula In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and z2 are as described herein and are included in the compounds of formulae (I)-(V).

[0116] In embodiments, the PCNS inhibitor has the formula:

[0117] [ka] is a compound having the formula In the formula, R 2 , R 3 , R 4 , R 7 , R 8 , R 15 , R 16 and z2 are as described herein and are included in the compounds of formulae (I)-(V).

[0118] In embodiments, the PCNS inhibitor has the formula:

[0119] [ka] is a compound having the formula In the formula, R 1 , R 2 , R 3 , R 4 , z1, and z2 are as described herein and are included in the compounds of formulae (I)-(V).

[0120] In embodiments, the PCNS inhibitor has the formula:

[0121] [ka] is a compound having the formula In the formula, R2 , R 3 , R 4 and z2 are as described herein and are included in the compounds of formulae (I)-(V).

[0122] In embodiments, the PCNS inhibitor has the formula:

[0123] [ka] is a compound having the formula In the formula, R 2 , R 3 , and R 4 is as described herein and is included in the compounds of formulae (I) to (V).

[0124] In embodiments, the PCNS inhibitor has the formula:

[0125] [ka] is a compound having the formula In the formula, R 4 is as described herein and is included in the compounds of formulae (I)-(V). In embodiments, R 4 are independently -OR 14 In an embodiment, R 4 is independently -SR 14 In an embodiment, R 14 is independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 3In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 14 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 4 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 14 is independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 are independently unsubstituted C 1 ~C 6 In embodiments, R 14 are independently unsubstituted C 1 ~C 5 In embodiments, R 14 are independently unsubstituted C 1 ~C 4 In embodiments, R 14 are independently unsubstituted C 1 ~C 3 In embodiments, R 14 are independently unsubstituted C 1 ~C 2In embodiments, R 14 are independently unsubstituted C 2 ~C 6 In embodiments, R 14 are independently unsubstituted C 2 ~C 5 In embodiments, R 14 are independently unsubstituted C 2 ~C 4 In embodiments, R 14 are independently unsubstituted C 2 ~C 3 In embodiments, R 14 are independently unsubstituted C 3 ~C 6 In embodiments, R 14 are independently unsubstituted C 4 ~C 6 In embodiments, R 14 are independently unsubstituted C 5 ~C 6 In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14 is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R 14 is independently unsubstituted tert-butyl.

[0126] In embodiments, the PCNS inhibitor has the formula:

[0127] [ka] is a compound having the formula In the formula, R 4 is as described herein and is included in the compounds of formulae (I)-(V). In embodiments, R 4 are independently -OR 14 In an embodiment, R 4 is independently -SR14 In an embodiment, R 14 is independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 3 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 14 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 4 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 14 is independently hydrogen. In embodiments, R 14is independently unsubstituted alkyl. In embodiments, R 14 are independently unsubstituted C 1 ~C 6 In embodiments, R 14 are independently unsubstituted C 1 ~C 5 In embodiments, R 14 are independently unsubstituted C 1 ~C 4 In embodiments, R 14 are independently unsubstituted C 1 ~C 3 In embodiments, R 14 are independently unsubstituted C 1 ~C 2 In embodiments, R 14 are independently unsubstituted C 2 ~C 6 In embodiments, R 14 are independently unsubstituted C 2 ~C 5 In embodiments, R 14 are independently unsubstituted C 2 ~C 4 In embodiments, R 14 are independently unsubstituted C 2 ~C 3 In embodiments, R 14 are independently unsubstituted C 3 ~C 6 In embodiments, R 14 are independently unsubstituted C 4 ~C 6 In embodiments, R 14 are independently unsubstituted C 5 ~C 6 In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14 is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R14 is independently unsubstituted tert-butyl.

[0128] In embodiments, the PCNS inhibitor has the formula:

[0129] [ka] is a compound having the formula In the formula, R 4 is as described herein and is included in the compounds of formulae (I)-(V). In embodiments, R 4 are independently -OR 14 In an embodiment, R 4 is independently -SR 14 In an embodiment, R 14 is independently hydrogen or unsubstituted alkyl. In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 3 In embodiments, R 14 are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 14 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 14are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 14 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 4 ~C 6 In embodiments, R 14 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 14 is independently hydrogen. In embodiments, R 14 is independently unsubstituted alkyl. In embodiments, R 14 are independently unsubstituted C 1 ~C 6 In embodiments, R 14 are independently unsubstituted C 1 ~C 5 In embodiments, R 14 are independently unsubstituted C 1 ~C 4 In embodiments, R 14 are independently unsubstituted C 1 ~C 3 In embodiments, R 14 are independently unsubstituted C 1 ~C 2 In embodiments, R 14 are independently unsubstituted C 2 ~C 6 In embodiments, R 14 are independently unsubstituted C 2 ~C 5 In embodiments, R 14 are independently unsubstituted C 2 ~C 4 In embodiments, R 14 are independently unsubstituted C 2 ~C 3 In embodiments, R 14 are independently unsubstituted C 3 ~C6 In embodiments, R 14 are independently unsubstituted C 4 ~C 6 In embodiments, R 14 are independently unsubstituted C 5 ~C 6 In embodiments, R 14 is independently unsubstituted methyl. In embodiments, R 14 is independently unsubstituted ethyl. In embodiments, R 14 is independently unsubstituted propyl. In embodiments, R 14 is independently unsubstituted isopropyl. In embodiments, R 14 is independently unsubstituted tert-butyl.

[0130] In embodiments, the PCNS inhibitor has the formula:

[0131] [ka] It is a compound having the formula:

[0132] In embodiments, the PCNS inhibitor has the formula:

[0133] [ka] It is a compound having the formula:

[0134] In embodiments, the PCNS inhibitor has the formula:

[0135] [ka] It is a compound having the formula:

[0136] In embodiments, the PCNS inhibitor has the formula:

[0137] [ka] It is a compound having the formula:

[0138] In embodiments, the PCNS inhibitor has the formula:

[0139] [ka] It is a compound having the formula:

[0140] In embodiments, the PCNS inhibitor has the formula:

[0141] [ka] It is a compound having the formula:

[0142] In embodiments, the PCNS inhibitor has the formula:

[0143] [ka] It is a compound having the formula:

[0144] In embodiments, R 1 are independently hydrogen, oxo, halogen, -CX 1 3 , -CHX 1 2 , -OCH 2 X 1 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 1 3 , -OCHX 12 , -OCH 2 X 1 , R 30 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 30 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 30 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 30 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 30 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 30 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 1 is halogen. In an embodiment, X 1 is F. In an embodiment, R 1 are independently halogen, -CX 1 3 , -CHX 1 2 , -OCH 2 X 1 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 1 3 , -OCHX 1 2 , -OCH 2 X 1 , R 30 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 30 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 30 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 30 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 30 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 30 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0145] R 30 are independently oxo, halogen, -CX 30 3 , -CHX30 2 , -CH 2 X 30 , -OCH 2 X 30 , -OCHX 30 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 30 3 , R 31 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 31 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 31 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 31 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 31 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R31 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 30 is halogen. In an embodiment, X 30 is F.

[0146] R 31 are independently oxo, halogen, -CX 31 3 , -CHX 31 2 , -CH 2 X 31 , -OCH 2 X 31 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 31 3 , -OCHX 31 2 , R 32 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 32 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 32 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 32 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 32 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 32 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 31 is halogen. In an embodiment, X 31 is F.

[0147] In embodiments, R 2 is hydrogen, oxo, halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCH 2 X 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 2 3 , -OCHX 2 2 , R 33 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C1 ~C 4 alkyl), R 33 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 33 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 33 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 33 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 33 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 2 is halogen. In an embodiment, X 2 is F.

[0148] In embodiments, R 2 is halogen, -CX 2 3 , -CHX 2 2 , -OCH 2 X 2 , -CH 2 X 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 2 3 , -OCHX 2 2 , R 33 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 33 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 33 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 33 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 33 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 33 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 2 is hydrogen.

[0149] R 33 are independently oxo, halogen, -CX 33 3 , -CHX 33 2 , -CHX 33 2 , -OCH 2 X 33 , -OCHX33 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 33 3 , -OCHX 33 2 , R 34 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 34 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 34 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 34 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 34 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 34-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 33 is halogen. In an embodiment, X 33 is F.

[0150] R 34 are independently oxo, halogen, -CX 34 3 , -CHX 34 2 , -CH 2 X 34 2 , -OCH 2 X 34 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 34 3 , -OCHX 34 2 , R 35 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 35 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 35 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 35 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 35 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 35 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 34 is halogen. In an embodiment, X 34 is F.

[0151] In embodiments, R 3 is hydrogen, oxo, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCH 2 X 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 3 3 , -OCHX 3 2 , R 36 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C1 ~C 4 alkyl), R 36 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 36 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 36 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 36 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 36 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 3 is halogen. In an embodiment, X 3 is F. In an embodiment, R 3 is halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCH 2 X 3 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 3 3 , -OCHX 3 2 , R 36 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 36 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 36 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 36 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 36 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 36 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 3 is hydrogen.

[0152] R 36 are independently oxo, halogen, -CX 36 3 , -CHX 36 2 , -CH 2 X 36 , -OCH 2 X 36 , -CN, -OH, -NH 2 , -COOH, -CONH2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 36 3 , -OCHX 36 2 , R 37 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 37 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 37 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 37 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 37 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 37 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 36 is halogen. In an embodiment, X 36 is F.

[0153] R 37 are independently oxo, halogen, -CX 37 3 , -CHX 37 2 , -CH 2 X 37 , -OCH 2 X 37 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 37 3 , -OCHX 37 2 , R 38 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 38 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 38 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 38-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 38 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 38 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 37 is halogen. In an embodiment, X 37 is F.

[0154] In embodiments, R 4 are independently hydrogen, oxo, halogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -OCH 2 X 4 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 4 3 , -OCHX 4 2 , R 39 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 39-substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 39 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 39 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 39 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 39 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 4 is halogen. In an embodiment, X 4 is F. In an embodiment, R 4 are independently halogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -OCH 2 X 4 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 43 , -OCHX 4 2 , R 39 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 39 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 39 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 39 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 39 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 39 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0155] R 39 are independently oxo, halogen, -CX 39 3 , -CHX 39 2 , -CH 2 X 39 , -OCH 2 X 39 , -OCHX 39 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 39 3 , -OCHX 39 2 , R 40 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 40 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 40 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 40 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 40 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 40 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 39 is halogen. In an embodiment, X 39 is F.

[0156] R 40 are independently oxo, halogen, -CX 40 3 , -CHX 40 2 , -CH 2 X 40 , -OCH 2 X 40 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 40 3 , -OCHX 40 2 , R 41 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 41 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 41 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 41 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 41-substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 41 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 40 is halogen. In an embodiment, X 40 is F.

[0157] In embodiments, R 5 are independently hydrogen, oxo, halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCH 2 X 5 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 5 3 , -OCHX 5 2 , R 42 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 42 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 42-substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 42 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 42 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 42 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 5 is halogen. In an embodiment, X 5 is F. In an embodiment, R 5 are independently halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCH 2 X 5 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 5 3 , -OCHX 5 2 , R 42 -substituted or unsubstituted alkyl (e.g., C 1 ~C8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 42 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 42 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 42 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 42 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 42 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0158] R 42 are independently oxo, halogen, -CX 42 3 , -CHX 42 2 , -CH 2 X 42 , -OCH 2 X 42 , -OCHX 42 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2, -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 42 3 , -OCHX 42 2 , R 43 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 43 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 43 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 43 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 43 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 43 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 42 is halogen. In an embodiment, X 42 is F.

[0159] R 43 are independently oxo, halogen, -CX 43 3 , -CHX 43 2 , -CH2 X 43 , -OCH 2 X 43 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 43 3 , -OCHX 43 2 , R 44 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 44 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 44 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 44 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 44 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 44-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 43 is halogen. In an embodiment, X 43 is F.

[0160] In embodiments, R 7 are independently hydrogen, oxo, halogen, -CX 7 3 , -CHX 7 2 , -CH 2 X 7 , -OCH 2 X 7 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 7 3 , -OCHX 7 2 , R 48 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 48 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 48 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 48 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 48 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 48 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 7 is halogen. In an embodiment, X 7 is F. In an embodiment, R 7 and R 8 The substituents are optionally linked to form R 48 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), or R 48 - may form a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0161] In embodiments, R 7 is independently hydrogen or unsubstituted alkyl. In embodiments, R 7 are independently hydrogen or unsubstituted C 1 ~C 6 In embodiments, R 7 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 7 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 7 are independently hydrogen or unsubstituted C 1 ~C 3 In embodiments, R 7are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 7 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 7 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 7 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 7 are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 7 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 7 are independently hydrogen or unsubstituted C 4 ~C 6 In embodiments, R 7 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 7 is independently hydrogen. In embodiments, R 7 is independently unsubstituted alkyl. In embodiments, R 7 are independently unsubstituted C 1 ~C 6 In embodiments, R 7 are independently unsubstituted C 1 ~C 5 In embodiments, R 7 are independently unsubstituted C 1 ~C 4 In embodiments, R 7 are independently unsubstituted C 1 ~C 3 In embodiments, R 7 are independently unsubstituted C 1 ~C 2 In embodiments, R 7 are independently unsubstituted C2 ~C 6 In embodiments, R 7 are independently unsubstituted C 2 ~C 5 In embodiments, R 7 are independently unsubstituted C 2 ~C 4 In embodiments, R 7 are independently unsubstituted C 2 ~C 3 In embodiments, R 7 are independently unsubstituted C 3 ~C 6 In embodiments, R 7 are independently unsubstituted C 4 ~C 6 In embodiments, R 7 are independently unsubstituted C 5 ~C 6 In embodiments, R 7 is hydrogen. In embodiments, R 7 are independently hydrogen, halogen, -CX 7 3 , -CHX 7 2 , -CH 2 X 7 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and bonded to the same nitrogen atom; 7 and R 8 The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

[0162] R 48 are independently oxo, halogen, -CX 48 3 , -CHX 48 2 , -CH 2 X 48 , -OCH2 X 48 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 48 3 , -OCHX 48 2 , R 49 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 49 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 49 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 49 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 49 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 49-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 48 is halogen. In an embodiment, X 48 is F.

[0163] R 49 are independently oxo, halogen, -CX 49 3 , -CHX 49 2 , -CH 2 X 49 , -OCH 2 X 49 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 49 3 , -OCHX 49 2 , R 50 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 50 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 50 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C5 ~C 6 Cycloalkyl), R 50 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 50 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 50 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 49 is halogen. In an embodiment, X 49 is F.

[0164] In embodiments, R 8 are independently hydrogen, oxo, halogen, -CX 8 3 , -CHX 8 2 , -CH 2 X 8 , -OCH 2 X 8 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 8 3 , -OCHX 8 2 , R 51 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C1 ~C 4 alkyl), R 51 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 51 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 51 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 51 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 51 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 8 is halogen. In an embodiment, X 8 is F. In an embodiment, X 7 is F. In an embodiment, R 7 and R 8 The substituents are optionally linked to form R 51 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 51 - may form a substituted or unsubstituted heteroaryl (for example, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, or a 5- to 6-membered heteroaryl).

[0165] In embodiments, R 8 is independently hydrogen or unsubstituted alkyl. In embodiments, R 8 are independently hydrogen or unsubstituted C 1 ~C6 In embodiments, R 8 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 8 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 8 are independently hydrogen or unsubstituted C 1 ~C 3 In embodiments, R 8 are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 8 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 8 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 8 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 8 are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 8 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 8 are independently hydrogen or unsubstituted C 4 ~C 6 In embodiments, R 8 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 8 is independently hydrogen. In embodiments, R 8 is independently unsubstituted alkyl. In embodiments, R 8 are independently unsubstituted C 1 ~C 6 In embodiments, R 8 are independently unsubstituted C 1 ~C5 In embodiments, R 8 are independently unsubstituted C 1 ~C 4 In embodiments, R 8 are independently unsubstituted C 1 ~C 3 In embodiments, R 8 are independently unsubstituted C 1 ~C 2 In embodiments, R 8 are independently unsubstituted C 2 ~C 6 In embodiments, R 8 are independently unsubstituted C 2 ~C 5 In embodiments, R 8 are independently unsubstituted C 2 ~C 4 In embodiments, R 8 are independently unsubstituted C 2 ~C 3 In embodiments, R 8 are independently unsubstituted C 3 ~C 6 In embodiments, R 8 are independently unsubstituted C 4 ~C 6 In embodiments, R 8 are independently unsubstituted C 5 ~C 6 In embodiments, R 8 is hydrogen. In embodiments, R 8 are independently hydrogen, halogen, -CX 8 3 , -CHX 8 2 , -CH 2 X 8 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0166] R 51 are independently oxo, halogen, -CX 51 3 , -CHX 51 2 , -CH 2 X 51 , -OCH 2 X 51 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 51 3 , -OCHX 51 2 , R 52 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 52 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 52 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 52 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R52 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 52 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 51 is halogen. In an embodiment, X 51 is F.

[0167] R 52 are independently oxo, halogen, -CX 52 3 , -CHX 52 2 , -CH 2 X 52 , -OCH 2 X 52 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 52 3 , -OCHX 52 2 , R 53 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 53 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R53 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 53 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 53 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 53 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 52 is halogen. In an embodiment, X 52 is F.

[0168] In embodiments, R 9 are independently hydrogen, oxo, halogen, -CX 9 3 , -CHX 9 2 , -CH 2 X 9 , -OCH 2 X 9 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 9 3 , -OCHX 9 2 , R54 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 54 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 54 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 54 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 54 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 54 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 9 is halogen. In an embodiment, X 9 is F. In an embodiment, R 9 is hydrogen. In embodiments, R 9 are independently hydrogen, halogen, -CX 9 3 , -CHX 9 2 , -CH 2 X 9 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0169] R 54 are independently oxo, halogen, -CX 54 3 , -CHX 54 2 , -CH 2 X 54 , -OCH 2 X 54 , -OCHX 54 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 54 3 , -OCHX 54 2 , R 55 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 55 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 55 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 55-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 55 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 55 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 54 is halogen. In an embodiment, X 54 is F.

[0170] R 55 are independently oxo, halogen, -CX 55 3 , -CHX 55 2 , -CH 2 X 55 , -OCH 2 X 55 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 55 3 , -OCHX 55 2 , R 56 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 56-substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 56 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 56 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 56 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 56 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 55 is halogen. In an embodiment, X 55 is F.

[0171] In embodiments, R 10 are independently hydrogen, oxo, halogen, -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -OCH 2 X 10 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 10 3 , -OCHX 10 2 , R 57 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 57 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 57 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 57 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 57 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 57 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 10 is halogen. In an embodiment, X 10 is F. In an embodiment, R 10 is hydrogen. In embodiments, R 10 , are independently hydrogen, halogen, -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -CN, -COOH, -CONH 2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0172] R 57 are independently oxo, halogen, -CX 57 3 , -CHX 57 2 , -CH 2 X 57 , -OCH 2 X 57 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 57 3 , -OCHX 57 2 , R 58 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 58 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 58 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5~C 6 Cycloalkyl), R 58 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 58 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 58 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 57 is halogen. In an embodiment, X 57 is F.

[0173] R 58 are independently oxo, halogen, -CX 58 3 , -CHX 58 2 , -CH 2 X 58 , -OCH 2 X 58 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 58 3 , -OCHX 58 2 , R 59 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4alkyl), R 59 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 59 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 59 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 59 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 59 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 58 is halogen. In an embodiment, X 58 is F.

[0174] In embodiments, R 11 are independently hydrogen, oxo, halogen, -CX 11 3 , -CHX 11 2 , -CH 2 X 11 , -OCH 2 X 11 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2, -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 11 3 , -OCHX 11 2 , R 60 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 60 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 60 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 60 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 60 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 60 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 11 is halogen. In an embodiment, X 11 is F. In an embodiment, R 11 and R 12 The substituents are optionally linked to form R 60 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 60-substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 11 is hydrogen. In embodiments, R 11 are independently hydrogen, halogen, -CX 11 3 , -CHX 11 2 , -CH 2 X 11 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0175] R 60 are independently oxo, halogen, -CX 60 3 , -CHX 60 2 , -CH 2 X 60 , -OCH 2 X 60 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 60 3 , -OCHX 60 2 , R 61 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C1 ~C 4 alkyl), R 61 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 61 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 61 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 61 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 61 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 60 is halogen. In an embodiment, X 60 is F.

[0176] R 61 are independently oxo, halogen, -CX 61 3 , -CHX 61 2 , -CH 2 X 61 , -OCH 2 X 61 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 61 3 , -OCHX 61 2 , R 62 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 62 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 62 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 62 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 62 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 62 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 61 is halogen. In an embodiment, X 61 is F.

[0177] In embodiments, R 12 are independently hydrogen, oxo, halogen, -CX 12 3 , -CHX 12 2 , -CH 2 X 12 , -OCH2 X 12 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 12 3 , -OCHX 12 2 , R 63 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 63 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 63 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 63 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 63 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 63-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 12 is halogen. In an embodiment, X 12 is F. In an embodiment, R 11 and R 12 The substituents are optionally linked to form R 63 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 63 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 12 is hydrogen. In embodiments, R 12 are independently hydrogen, halogen, -CX 12 3 , -CHX 12 2 , -CH 2 X 12 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0178] R 63 are independently oxo, halogen, -CX 63 3 , -CHX 63 2 , -CH 2 X 63 , -OCH 2 X 63 , -CN, |-OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 63 3 , -OCHX 63 2 , R 64 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 64 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 64 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 64 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 64 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 64 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 63 is halogen. In an embodiment, X 63 is F.

[0179] R 64 are independently oxo, halogen, -CX 64 3 , -CHX 642 , -CH 2 X 64 , -OCH 2 X 64 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 64 3 , -OCHX 64 2 , R 65 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 65 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 65 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 65 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 65 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 65-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 64 is halogen. In an embodiment, X 64 is F.

[0180] In embodiments, R 13 are independently hydrogen, oxo, halogen, -CX 13 3 , -CHX 13 2 , -CH 2 X 13 , -OCH 2 X 13 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 13 3 , -OCHX 13 2 , R 66 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 66 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 66 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 66 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 66 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 66 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 13 is halogen. In an embodiment, X 13 is F. In an embodiment, R 13 is hydrogen. In embodiments, R 13 are independently hydrogen, halogen, -CX 13 3 , -CHX 13 2 , -CH 2 X 13 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0181] R 66 are independently oxo, halogen, -CX 66 3 , -CHX 66 2 , -CH 2 X 66 , -OCH 2 X 66 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2, -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 66 3 , -OCHX 66 2 , R 67 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 67 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 67 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 67 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 67 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 67 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 66 is halogen. In an embodiment, X 66 is F.

[0182] R 67 are independently oxo, halogen, -CX 67 3 , -CHX 672 , -CH 2 X 67 , -OCH 2 X 67 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 67 3 , -OCHX 67 2 , R 68 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 68 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 68 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 68 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 68 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 68-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 67 is halogen. In an embodiment, X 67 is F.

[0183] In embodiments, R 14 are independently hydrogen, oxo, halogen, -CX 14 3 , -CHX 14 2 , -CH 2 X 14 , -OCH 2 X 14 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 14 3 , -OCHX 14 2 , R 69 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 69 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 69 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 69 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 69 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 69 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 14 is halogen. In an embodiment, X 14 is F. In an embodiment, R 14 is hydrogen. In embodiments, R 14 are independently hydrogen, halogen, -CX 14 3 , -CHX 14 2 , -CH 2 X 14 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0184] R 69 are independently oxo, halogen, -CX 69 3 , -CHX 69 2 , -CH 2 X 69 , -OCH 2 X 69 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2, -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 69 3 , -OCHX 69 2 , R 70 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 70 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 70 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 70 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 70 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 70 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 69 is halogen. In an embodiment, X 69 is F.

[0185] R 70 are independently oxo, halogen, -CX 70 3 , -CHX 702 , -CH 2 X 70 , -OCH 2 X 70 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 70 3 , -OCHX 70 2 , R 71 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 71 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 71 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 71 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 71 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 71-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 70 is halogen. In an embodiment, X 70 is F.

[0186] In embodiments, R 15 are independently hydrogen, oxo, halogen, -CX 15 3 , -CHX 15 2 , -CH 2 X 15 , -OCH 2 X 15 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 15 3 , -OCHX 15 2 , R 72 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 72 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 72 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 72 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 72 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 72 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 15 is halogen. In an embodiment, X 15 is F. In an embodiment, R 15 and R 16 The substituents are optionally linked to form R 72 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 72 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 15 is hydrogen. In embodiments, R 15 are independently hydrogen, halogen, -CX 15 3 , -CHX 15 2 , -CH 2 X 15 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0187] In embodiments, R 15 is independently hydrogen or unsubstituted alkyl. In embodiments, R 15are independently hydrogen or unsubstituted C 1 ~C 6 In embodiments, R 15 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 15 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 15 are independently hydrogen or unsubstituted C 1 ~C 3 In embodiments, R 15 are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 15 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 15 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 15 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 15 are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 15 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 15 are independently hydrogen or unsubstituted C 4 ~C 6 In embodiments, R 15 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 15 is independently hydrogen. In embodiments, R 15 is independently unsubstituted alkyl. In embodiments, R 15 are independently unsubstituted C 1 ~C 6 In embodiments, R15 are independently unsubstituted C 1 ~C 5 In embodiments, R 15 are independently unsubstituted C 1 ~C 4 In embodiments, R 15 are independently unsubstituted C 1 ~C 3 In embodiments, R 15 are independently unsubstituted C 1 ~C 2 In embodiments, R 15 are independently unsubstituted C 2 ~C 6 In embodiments, R 15 are independently unsubstituted C 2 ~C 5 In embodiments, R 15 are independently unsubstituted C 2 ~C 4 In embodiments, R 15 are independently unsubstituted C 2 ~C 3 In embodiments, R 15 are independently unsubstituted C 3 ~C 6 In embodiments, R 15 are independently unsubstituted C 4 ~C 6 In embodiments, R 15 are independently unsubstituted C 5 ~C 6 It is an alkyl.

[0188] R 72 are independently oxo, halogen, -CX 72 3 , -CHX 72 2 , -CH 2 X 72 , -OCH 2 X 72 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2, -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 72 3 , -OCHX 72 2 , R 73 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 73 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 73 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 73 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 73 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 73 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 72 is halogen. In an embodiment, X 72 is F.

[0189] R 73 are independently oxo, halogen, -CX 73 3 , -CHX 73 2 , -CH 2 X 73 , -OCH 2 X 73 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 73 3 , -OCHX 73 2 , R 74 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 74 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 74 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 74 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 74-substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 74 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 73 is halogen. In an embodiment, X 73 is F.

[0190] In embodiments, R 16 are independently hydrogen, oxo, halogen, -CX 16 3 , -CHX 16 2 , -CH 2 X 16 , -OCH 2 X 16 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 16 3 , -OCHX 16 2 , R 75 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 75 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 75-substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 75 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 75 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 75 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 16 is halogen. In an embodiment, X 16 is F. In an embodiment, R 15 and R 16 The substituents are optionally linked to form R 75 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl) or R 75 -substituted or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl). In some embodiments, R 16 is hydrogen. In embodiments, R 16 are independently hydrogen, halogen, -CX 16 3 , -CHX 16 2 , -CH 2 X 16 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0191] In embodiments, R 16 is independently hydrogen or unsubstituted alkyl. In embodiments, R 16 are independently hydrogen or unsubstituted C 1 ~C 6 In embodiments, R 16 are independently hydrogen or unsubstituted C 1 ~C 5 In embodiments, R 16 are independently hydrogen or unsubstituted C 1 ~C 4 In embodiments, R 16 are independently hydrogen or unsubstituted C 1 ~C 3 In embodiments, R 16 are independently hydrogen or unsubstituted C 1 ~C 2 In embodiments, R 16 are independently hydrogen or unsubstituted C 2 ~C 6 In embodiments, R 16 are independently hydrogen or unsubstituted C 2 ~C 5 In embodiments, R 16 are independently hydrogen or unsubstituted C 2 ~C 4 In embodiments, R 16 are independently hydrogen or unsubstituted C 2 ~C 3 In embodiments, R 16 are independently hydrogen or unsubstituted C 3 ~C 6 In embodiments, R 16 are independently hydrogen or unsubstituted C 4 ~C 6 In embodiments, R 16 are independently hydrogen or unsubstituted C 5 ~C 6 In embodiments, R 16 is independently hydrogen. In embodiments, R 16is independently unsubstituted alkyl. In embodiments, R 16 are independently unsubstituted C 1 ~C 6 In embodiments, R 16 are independently unsubstituted C 1 ~C 5 In embodiments, R 16 are independently unsubstituted C 1 ~C 4 In embodiments, R 16 are independently unsubstituted C 1 ~C 3 In embodiments, R 16 are independently unsubstituted C 1 ~C 2 In embodiments, R 16 are independently unsubstituted C 2 ~C 6 In embodiments, R 16 are independently unsubstituted C 2 ~C 5 In embodiments, R 16 are independently unsubstituted C 2 ~C 4 In embodiments, R 16 are independently unsubstituted C 2 ~C 3 In embodiments, R 16 are independently unsubstituted C 3 ~C 6 In embodiments, R 16 are independently unsubstituted C 4 ~C 6 In embodiments, R 16 are independently unsubstituted C 5 ~C 6 It is an alkyl.

[0192] R 75 are independently oxo, halogen, -CX 75 3 , -CHX 75 2 , -CH 2 X 75 , -OCH2 X 75 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 75 3 , -OCHX 75 2 , R 76 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 76 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 76 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 76 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 76 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 76-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 75 is halogen. In an embodiment, X 75 is F.

[0193] R 76 are independently oxo, halogen, -CX 76 3 , -CHX 76 2 , -CH 2 X 76 , -OCH 2 X 76 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 76 3 , -OCHX 76 2 , R 77 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 77 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 77 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C5 ~C 6 Cycloalkyl), R 77 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 77 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 77 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 76 is halogen. In an embodiment, X 76 is F.

[0194] In embodiments, R 17 are independently hydrogen, oxo, halogen, -CX 17 3 , -CHX 17 2 , -CH 2 X 17 , -OCH 2 X 17 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 17 3 , -OCHX 17 2 , R 78 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C1 ~C 4 alkyl), R 78 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 78 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 78 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 78 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 78 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 17 is halogen. In an embodiment, X 17 is F. In an embodiment, R 17 is hydrogen. In embodiments, R 17 are independently hydrogen, halogen, -CX 17 3 , -CHX 17 2 , -CH 2 X 17 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0195] R 78 are independently oxo, halogen, -CX 78 3 , -CHX 782 , -CH 2 X 78 , -OCH 2 X 78 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 78 3 , -OCHX 78 2 , R 79 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 79 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 79 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 79 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 79 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 79-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 78 is halogen. In an embodiment, X 78 is F.

[0196] R 79 are independently oxo, halogen, -CX 79 3 , -CHX 79 2 , -CH 2 X 79 , -OCH 2 X 79 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 79 3 , -OCHX 79 2 , R 80 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 80 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 80 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C5 ~C 6 Cycloalkyl), R 80 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 80 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 80 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 79 is halogen. In an embodiment, X 79 is F.

[0197] In embodiments, R 18 are independently hydrogen, oxo, halogen, -CX 18 3 , -CHX 18 2 , -CH 2 X 18 , -OCH 2 X 18 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 18 3 , -OCHX 18 2 , R 81 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C1 ~C 4 alkyl), R 81 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 81 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 81 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 81 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 81 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 18 is halogen. In an embodiment, X 18 is F. In an embodiment, R 18 is hydrogen. In embodiments, R 18 are independently hydrogen, halogen, -CX 18 3 , -CHX 18 2 , -CH 2 X 18 , -CN, -COOH, -CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0198] R 81 are independently oxo, halogen, -CX 81 3 , -CHX 812 , -CH 2 X 81 , -OCH 2 X 81 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 81 3 , -OCHX 81 2 , R 82 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 82 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 82 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 Cycloalkyl), R 82 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 82 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 82-Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 81 is halogen. In an embodiment, X 81 is F.

[0199] R 82 are independently oxo, halogen, -CX 82 3 , -CHX 82 2 , -CH 2 X 82 , -OCH 2 X 82 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCX 82 3 , -OCHX 82 2 , R 83 -substituted or unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), R 83 -substituted or unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), R 83 -substituted or unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C5 ~C 6 Cycloalkyl), R 83 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), R 83 -substituted or unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or R 83 -Substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 82 is halogen. In an embodiment, X 82 is F.

[0200] R 32 , R 35 , R 38 , R 41 , R 44 , R 50 , R 53 , R 56 , R 59 , R 62 , R 65 , R 68 , R 71 , R 74 , R 77 , R 80 , and R 83 are independently hydrogen, oxo, halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCF 3 , -OCHF 2 , -CCl 3 , -CHCl 2 , -CH 2 Cl, -OCH 2 Cl, -OCCl 3 , -OCHCl 2 , -CBr 3 , -CHBr 2 , -CH 2 Br, -OCH 2 Br, -OCBr 3 , -OCHBr 2, -CI 3 , -CHI 2 , -CH 2 I, -OCH 2 I, -OCI 3 , -OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). 32 , R 35 , R 38 , R 41 , R 44 , R50 , R 53 , R 56 , R 59 , R 62 , R 65 , R 68 , R 71 , R 74 , R 77 , R 80 , and R 83 are independently oxo, halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCH 2 F, -OCF 3 , -OCHF 2 , -CCl 3 , -CHCl 2 , -CH 2 Cl, -OCH 2 Cl, -OCCl 3 , -OCHCl 2 , -CBr 3 , -CHBr 2 , -CH 2 Br, -OCH 2 Br, -OCBr 3 , -OCHBr 2 , -CI 3 , -CHI 2 , -CH 2 I, -OCH 2 I, -OCI 3 , -OCHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHC=(O)NHNH 2 , -NHC=(O)NH 2 , -NHSO 2 H, -NHC=(O)H, -NHC(O)-OH, -NHOH, unsubstituted alkyl (e.g., C 1 ~C 8 Alkyl, C 1 ~C 6 Alkyl or C1 ~C 4 alkyl), unsubstituted heteroalkyl (e.g., 2-10 membered heteroalkyl, 2-8 membered heteroalkyl, 4-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 ~C 8 Cycloalkyl, C 4 ~C 8 Cycloalkyl or C 5 ~C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 ~C 10 Aryl or C 6 aryl), or unsubstituted heteroaryl (for example, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0201] In embodiments, the compounds described herein include R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 In such embodiments, each variable may optionally be different and appropriately labeled to more clearly distinguish each group. For example, each R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R15 , R 16 , R 17 , R 18 and / or R 19 are different, for example, R 1.1 , R 1.2 , R 1.3 , R 1.4 , R 1.5 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 , R 5.6 , R 5.7 , R 7.1 , R 7.2 , R 7.3 , R 7.4 , R 7.5 , R 7.6 , R 7.7 , R 7.8 , R 7.9 , R 7.10 , R 7.11 , R 7.12 , R 7.13 , R 7.14 , R 7.15 , R 7.16 , R 7.17 , R 7.18 , R 7.19 , R 7.20 , R 7.21 , R 7.22 , R 7.23 , R 7.24 , R 7.25 , R 7.26 , R 7.27 , R 7.28 , R 7.29 , R 7.30 , R 7.31 , R 7.32 , R 7.33 , R 7.34 , R 7.35 , R 7.36 , R 7.37 , R 7.38 , R 7.39 , R 7.40 , R 7.41 , R 7.42 , R 8.1 , R8.2 、R 8.3 、R 8.4 、R 8.5 、R 8.6 、R 8.7 、R 8.8 、R 8.9 、R 8.10 、R 8.11 、R 8.12 、R 8.13 、R 8.14 、R 8.15 、R 8.16 、R 8.17 、R 8.18 、R 8.19 、R 8.20 、R 8.21 、R 8.22 、R 8.23 、R 8.24 、R 8.25 、R 8.26 、R 8.27 、R 8.28 、R 8.29 、R 8.30 、R 8.31 、R 8.32 、R 8.33 、R 8.34 、R 8.35 、R 8.36 、R 8.37 、R 8.38 、R 8.39 、R 8.40 、R 8.41 、R 8.42 、R 9.1 、R 9.2 、R 9.3 、R 9.4 、R 9.5 、R 9.6 、R 9.7 、R 9.8 、R 9.9 、R 9.10 、R 9.11 、R 9.12 、R 9.13 、R 9.14 、R 9.15 、R 9.16 、R 9.17 、R 9.18 、R 9.19 、R 9.20 、R 9.21 、R 9.22 、R 9.23 、R 9.24 、R 9.25 、R 9.26、R 9.27 、R 9.28 、R 9.29 、R 9.30 、R 9.31 、R 9.32 、R 9.33 、R 9.34 、R 9.35 、R 9.36 、R 9.37 、R 9.38 、R 9.39 、R 9.40 、R 9.41 、R 9.42 、R 10.1 、R 10.2 、R 10.3 、R 10.4 、R 10.5 、R 10.6 、R 10.7 、R 10.8 、R 10.9 、R 10.10 、R 10.11 、R 10.12 、R 10.13 、R 10.14 、R 10.15 、R 10.16 、R 10.17 、R 10.18 、R 10.19 、R 10.20 、R 10.21 、R 10.22 、R 10.23 、R 10.24 、R 10.25 、R 10.26 、R 10.27 、R 10.28 、R 10.29 、R 10.30 、R 10.31 、R 10.32 、R 10.33 、R 10.34 、R 10.35 、R 10.36 、R 10.37 、R 10.38 、R 10.39 、R 10.40 、R 10.41 、R 10.42 、R 11.1 、R 11.2 、R 11.3 、R 11.4 、R 11.5 、R 11.6 、R 11.7 、R 11.8 、R11.9 、R 11.10 、R 11.11 、R 11.12 、R 11.13 、R 11.14 、R 11.15 、R 11.16 、R 11.17 、R 11.18 、R 11.19 、R 11.20 、R 11.21 、R 11.22 、R 11.23 、R 11.24 、R 11.25 、R 11.26 、R 11.27 、R 11.28 、R 11.29 、R 11.30 、R 11.31 、R 11.32 、R 11.33 、R 11.34 、R 11.35 、R 11.36 、R 11.37 、R 11.38 、R 11.39 、R 11.40 、R 11.41 、R 11.42 、R 12.1 、R 12.2 、R 12.3 、R 12.4 、R 12.5 、R 12.6 、R 12.7 、R 12.8 、R 12.9 、R 12.10 、R 12.11 、R 12.12 、R 12.13 、R 12.14 、R 12.15 、R 12.16 、R 12.17 、R 12.18 、R 12.19 、R 12.20 、R 12.21 、R 12.22 、R 12.23 、R 12.24 、R 12.25 、R 12.26 、R 12.27 、R 12.28 、R 12.29 、R 12.30 、R 12.31 、R 12.32 、R 12.33、R 12.34 、R 12.35 、R 12.36 、R 12.37 、R 12.38 、R 12.39 、R 12.40 、R 12.41 、R 12.42 、R 13.1 、R 13.2 、R 13.3 、R 13.4 、R 13.5 、R 13.6 、R 13.7 、R 13.8 、R 13.9 、R 13.10 、R 13.11 、R 13.12 、R 13.13 、R 13.14 、R 13.15 、R 13.16 、R 13.17 、R 13.18 、R 13.19 、R 13.20 、R 13.21 、R 13.22 、R 13.23 、R 13.24 、R 13.25 、R 13.26 、R 13.27 、R 13.28 、R 13.29 、R 13.30 、R 13.31 、R 13.32 、R 13.33 、R 13.34 、R 13.35 、R 13.36 、R 13.37 、R 13.38 、R 13.39 、R 13.40 、R 13.41 、R 13.42 、R 14.1 、R 14.2 、R 14.3 、R 14.4 、R 14.5 、R 14.6 、R 14.7 、R 14.8 、R 14.9 、R 14.10 、R 14.11 、R 14.12 、R 14.13 、R 14.14 、R 14.15 、R14.16 、R 14.17 、R 14.18 、R 14.19 、R 14.20 、R 14.21 、R 14.22 、R 14.23 、R 14.24 、R 14.25 、R 14.26 、R 14.27 、R 14.28 、R 14.29 、R 14.30 、R 14.31 、R 14.32 、R 14.33 、R 14.34 、R 14.35 、R 14.36 、R 14.37 、R 14.38 、R 14.39 、R 14.40 、R 14.41 、R 14.42 、R 15.1 、R 15.2 、R 15.3 、R 15.4 、R 15.5 、R 15.6 、R 15.7 、R 15.8 、R 15.9 、R 15.10 、R 15.11 、R 15.12 、R 15.13 、R 15.14 、R 15.15 、R 15.16 、R 15.17 、R 15.18 、R 15.19 、R 15.20 、R 15.21 、R 15.22 、R 15.23 、R 15.24 、R 15.25 、R 15.26 、R 15.27 、R 15.28 、R 15.29 、R 15.30 、R 15.31 、R 15.32 、R 15.33 、R 15.34 、R 15.35 、R 15.36 、R 15.37 、R 15.38 、R 15.39 、R 15.40、R 15.41 、R 15.42 、R 16 .1 、R 16.2 、R 16.3 、R 16.4 、R 16.5 、R 16.6 、R 16.7 、R 16.8 、R 16.9 、R 16.10 、R 16.11 、R 16.12 、R 16.13 、R 16.14 、R 16.15 、R 16.16 、R 16.17 、R 16.18 、R 16.19 、R 16.20 、R 16.21 、R 16.22 、R 16.23 、R 16.24 、R 16.25 、R 16.26 、R 16.27 、R 16.28 、R 16.29 、R 16.30 、R 16.31 、R 16.32 、R 16.33 、R 16.34 、R 16.35 、R 16.36 、R 16.37 、R 16.38 、R 16.39 、R 16.40 、R 16.41 、R 16.42 、R 17.1 、R 17.2 、R 17.3 、R 17.4 、R 17.5 、R 17.6 、R 17.7 、R 17.8 、R 17.9 、R 17.10 、R 17.11 、R 17.12 、R 17.13 、R 17.14 、R 17.15 、R 17.16 、R 17.17 、R 17.18 、R 17.19 、R 17.20 、R 17.21, R 17.22 , R 17.23 , R 17.24 , R 17.25 , R 17.26 , R 17.27 , R 17.28 , R 17.29 , R 17.30 , R 17.31 , R 17.32 , R 17.33 , R 17.34 , R 17.35 , R 17.36 , R 17.37 , R 17.38 , R 17.39 , R 17.40 , R 17.41 , R 17.42 , R 18.1 , R 18.2 , R 18.3 , R 18.4 , R 18.5 , R 18.6 , R 18.7 , R 18.8 , R 18.9 , R 18.10 , R 18.11 , R 18.12 , R 18.13 , R 18.14 , R 18.15 , R 18.16 , R 18.17 , R 18.18 , R 18.19 , R 18.20 , R 18.21 , R 18.22 , R 18.23 , R 18.24 , R 18.25 , R 18.26 , R 18.27 , R 18.28 , R 18.29 , R 18.30 , R 18.31 , R 18.32 , R 18.33 , R 18.34 , R 18.35 , R 18.36 , R 18.37 , R 18.38 , R 18.39 , R 18.40 , R 18.41 , R 18.42 In this case, the definition is R 1 is R 1.1 , R1.2 , R 1.3 , R 1.4 , R 1.5 Considering that, R 4 is R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 Considering that, R 5 is R 5.1 , R 5.2 , R 5.3 , R 5.4 , R 5.5 , R 5.6 , R 5.7 Considering that, R 7 is R 7.1 , R 7.2 , R 7.3 , R 7.4 , R 7.5 , R 7.6 , R 7.7 , R 7.8 , R 7.9 , R 7.10 , R 7.11 , R 7.12 , R 7.13 , R 7.14 , R 7.15 , R 7.16 , R 7.17 , R 7.18 , R 7.19 , R 7.20 , R 7.21 , R 7.22 , R 7.23 , R 7.24 , R 7.25 , R 7.26 , R 7.27 , R 7.28 , R 7.29 , R 7.30 , R 7.31 , R 7.32 , R 7.33 , R 7.34 , R 7.35 , R 7.36 , R 7.37 , R 7.38 , R 7.39 , R 7.40 , R 7.41 , R 7.42 Considering that, R 8 is R 8.1 , R 8.2 , R 8.3 , R8.4 、R 8.5 、R 8.6 、R 8.7 、R 8.8 、R 8.9 、R 8.10 、R 8.11 、R 8.12 、R 8.13 、R 8.14 、R 8.15 、R 8.16 、R 8.17 、R 8.18 、R 8.19 、R 8.20 、R 8.21 、R 8.22 、R 8.23 、R 8.24 、R 8.25 、R 8.26 、R 8.27 、R 8.28 、R 8.29 、R 8.30 、R 8.31 、R 8.32 、R 8.33 、R 8.34 、R 8.35 、R 8.36 、R 8.37 、R 8.38 、R 8.39 、R 8.40 、R 8.41 、R 8.42 とみなし、R 9 は、R 9.1 、R 9.2 、R 9.3 、R 9.4 、R 9.5 、R 9.6 、R 9.7 、R 9.8 、R 9.9 、R 9.10 、R 9.11 、R 9.12 、R 9.13 、R 9.14 、R 9.15 、R 9.16 、R 9.17 、R 9.18 、R 9.19 、R 9.20 、R 9.21 、R 9.22 、R 9.23 、R 9.24 、R 9.25 、R 9.26 、R9.27 、R 9.28 、R 9.29 、R 9.30 、R 9.31 、R 9.32 、R 9.33 、R 9.34 、R 9.35 、R 9.36 、R 9.37 、R 9.38 、R 9.39 、R 9.40 、R 9.41 、R 9.42 とみなし、R 10 は、R 10.1 、R 10.2 、R 10.3 、R 10.4 、R 10.5 、R 10.6 、R 10.7 、R 10.8 、R 10.9 、R 10.10 、R 10.11 、R 10.12 、R 10.13 、R 10.14 、R 10.15 、R 10.16 、R 10.17 、R 10.18 、R 10.19 、R 10.20 、R 10.21 、R 10.22 、R 10.23 、R 10.24 、R 10.25 、R 10.26 、R 10.27 、R 10.28 、R 10.29 、R 10.30 、R 10.31 、R 10.32 、R 10.33 、R 10.34 、R 10.35 、R 10.36 、R 10.37 、R 10.38 、R 10.39 、R 10.40 、R 10.41 、R 10.42 とみなし、R 11 は、R 11.1 、R 11.2 、R 11.3 、R 11.4 、R 11.5 、R 11.6 、R11.7 、R 11.8 、R 11.9 、R 11.10 、R 11.11 、R 11.12 、R 11.13 、R 11.14 、R 11.15 、R 11.16 、R 11.17 、R 11.18 、R 11.19 、R 11.20 、R 11.21 、R 11.22 、R 11.23 、R 11.24 、R 11.25 、R 11.26 、R 11.27 、R 11.28 、R 11.29 、R 11.30 、R 11.31 、R 11.32 、R 11.33 、R 11.34 、R 11.35 、R 11.36 、R 11.37 、R 11.38 、R 11.39 、R 11.40 、R 11.41 、R 11.42 とみなし、R 12 は、R 12.1 、R 12.2 、R 12.3 、R 12.4 、R 12.5 、R 12.6 、R 12.7 、R 12.8 、R 12.9 、R 12.10 、R 12.11 、R 12.12 、R 12.13 、R 12.14 、R 12.15 、R 12.16 、R 12.17 、R 12.18 、R 12.19 、R 12.20 、R 12.21 、R 12.22 、R 12.23 、R 12.24 、R 12.25 、R 12.26 、R 12.27 、R 12.28 、R 12.29 、R12.30 、R 12.31 、R 12.32 、R 12.33 、R 12.34 、R 12.35 、R 12.36 、R 12.37 、R 12.38 、R 12.39 、R 12.40 、R 12.41 、R 12.42 とみなし、R 13 は、R 13.1 、R 13.2 、R 13.3 、R 13.4 、R 13.5 、R 13.6 、R 13.7 、R 13.8 、R 13.9 、R 13.10 、R 13.11 、R 13.12 、R 13.13 、R 13.14 、R 13.15 、R 13.16 、R 13.17 、R 13.18 、R 13.19 、R 13.20 、R 13.21 、R 13.22 、R 13.23 、R 13.24 、R 13.25 、R 13.26 、R 13.27 、R 13.28 、R 13.29 、R 13.30 、R 13.31 、R 13.32 、R 13.33 、R 13.34 、R 13.35 、R 13.36 、R 13.37 、R 13.38 、R 13.39 、R 13.40 、R 13.41 、R 13.42 とみなし、R 14 は、R 14.1 、R 14.2 、R 14.3 、R 14.4 、R 14.5 、R 14.6 、R 14.7 、R 14.8 、R14.9 、R 14.10 、R 14.11 、R 14.12 、R 14.13 、R 14.14 、R 14.15 、R 14.16 、R 14.17 、R 14.18 、R 14.19 、R 14.20 、R 14.21 、R 14.22 、R 14.23 、R 14.24 、R 14.25 、R 14.26 、R 14.27 、R 14.28 、R 14.29 、R 14.30 、R 14.31 、R 14.32 、R 14.33 、R 14.34 、R 14.35 、R 14.36 、R 14.37 、R 14.38 、R 14.39 、R 14.40 、R 14.41 、R 14.42 とみなし、R 15 は、R 15.1 、R 15.2 、R 15.3 、R 15.4 、R 15.5 、R 15.6 、R 15.7 、R 15.8 、R 15.9 、R 15.10 、R 15.11 、R 15.12 、R 15.13 、R 15.14 、R 15.15 、R 15.16 、R 15.17 、R 15.18 、R 15.19 、R 15.20 、R 15.21 、R 15.22 、R 15.23 、R 15.24 、R 15.25 、R 15.26 、R 15.27 、R 15.28 、R 15.29 、R 15.30 、R 15.31 、R15.32 、R 15.33 、R 15.34 、R 15.35 、R 15.36 、R 15.37 、R 15.38 、R 15.39 、R 15.40 、R 15.41 、R 15.42 とみなし、R 16 は、R 16.1 、R 16.2 、R 16.3 、R 16.4 、R 16.5 、R 16.6 、R 16.7 、R 16.8 、R 16.9 、R 16.10 、R 16.11 、R 16.12 、R 16.13 、R 16.14 、R 16.15 、R 16.16 、R 16.17 、R 16.18 、R 16.19 、R 16.20 、R 16.21 、R 16.22 、R 16.23 、R 16.24 、R 16.25 、R 16.26 、R 16.27 、R 16.28 、R 16.29 、R 16.30 、R 16.31 、R 16.32 、R 16.33 、R 16.34 、R 16.35 、R 16.36 、R 16.37 、R 16.38 、R 16.39 、R 16.40 、R 16.41 、R 16.42 とみなし、R 17 は、R 17.1 、R 17.2 、R 17.3 、R 17.4 、R 17.5 、R 17.6 、R 17.7 、R 17.8 、R 17.9 、R 17.10 、R 17.11 、R17.12 and R 17.13 and R 17.14 and R 17.15 and R 17.16 and R 17.17 and R 17.18 and R 17.19 and R 17.20 and R 17.21 and R 17.22 and R 17.23 and R 17.24 and R 17.25 and R 17.26 and R 17.27 and R 17.28 and R 17.29 and R 17.30 and R 17.31 and R 17.32 and R 17.33 and R 17.34 and R 17.35 and R 17.36 and R 17.37 and R 17.38 and R 17.39 and R 17.40 and R 17.41 and R 17.42 regarded as, and / or, R 18 is R 18.1 and R 18.2 and R 18.3 and R 18.4 and R 18.5 and R 18.6 and R 18.7 and R 18.8 and R 18.9 and R 18.10 and R 18.11 and R 18.12 and R 18.13 and R 18.14 and R 18.15 and R 18.16 and R 18.17 and R 18.18 and R 18.19 and R 18.20 and R 18.21 and R 18.22 and R 18.23 and R 18.24 and R 18.25 and R 18.26 and R 18.27 and R 18.28 and R 18.29 and R 18.30 and R 18.31 and R 18.32 and R 18.33 and R 18.34 and R18.35 , R 18.36 , R 18.37 , R 18.38 , R 18.39 , R 18.40 , R 18.41 , R 18.42 R 1 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 Variants used within the definitions of, and / or other variations that appear in multiple instances and are different, may likewise be appropriately labeled to more clearly distinguish each group.

[0202] In embodiments, the PCNS inhibitor has the formula:

[0203] [ka] is a compound having the formula In the formula, R 2 , R 3 , R 5 and z3 are as described herein and are included in the compounds of formulae (I) to (V). 1.1 , R 1.2 , and R 1.3 Each independently represents any of the R 1 This is the part. R 4.1 , R 4.2 , and R 4.3 Each independently represents any of the R 4 In an embodiment, z3 is 0. In an embodiment, R 1.1 , R 1.2 , R 1.3 , R 4.1 , R 4.2 , R 4.3 , R2 and / or R 3 In one embodiment, one or more of R 1.1 , R 1.2 and / or R 1.3 is hydrogen. In embodiments, R 4.1 , R 4.2 and / or R 4.3 is hydrogen. In embodiments, R 2 is hydrogen. In embodiments, R 3 is hydrogen. In embodiments, R 4.1 is hydrogen and R 4.2 is -OH, and R 4.3 is hydrogen. In embodiments, R 4.1 is hydrogen and R 4.2 is hydrogen and R 4.3 is -OH. In embodiments, R 4.1 is hydrogen and R 4.2 is unsubstituted methoxy, R 4.3 is hydrogen. In embodiments, R 4.1 is hydrogen and R 4.2 is hydrogen and R 4.3 is unsubstituted methoxy. 5 It will be understood that is a floating substituent and may be located on either or both of the rings.

[0204] In embodiments, the PCNS inhibitor has the formula:

[0205] [ka] is a compound having the formula In the formula, R 2 , R 3 , R 5 and z3 are as described herein and are included in the compounds of formulae (I) to (V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 , R 1.2 , and R 1.3 Each independently represents any of the R 1 This is the part. R 4.1and R 4.3 Each independently represents any of the R 4 This is the part.

[0206] W 1 is N or C(R 4.2 ) W 2 is N or C(R 5.1 ) W 3 is N or C(R 5.2 ) R 5.1 and R 5.2 Each independently represents any of the R 5 This is the part. R 4.2 is independently any of the R 4 In an embodiment, W 1 is N. In embodiments, W 2 is N. In embodiments, W 3 is N. In embodiments, W 1 is C(R 4.2 In an embodiment, W 2 is C(R 5.1 In an embodiment, W 3 is C(R 5.2 In an embodiment, W 1 is CH. In embodiments, W 2 is CH. In embodiments, W 3 is CH.

[0207] In embodiments, the PCNS inhibitor has the formula:

[0208] [ka] is a compound having the formula In the formula, R 2 , R 3 , R 5 and z3 are as described herein and are included in the compounds of formulae (I) to (V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 and R 1.3Each independently represents any of the R 1 This is the part. R 4.1 and R 4.3 Each independently represents any of the R 4 This is the part.

[0209] In embodiments, the PCNS inhibitor has the formula:

[0210] [ka] is a compound having the formula In the formula, R 2 , R 3 , R 5 and z3 are as described herein and are included in the compounds of formulae (I) to (V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 and R 1.3 Each independently represents any of the R 1 This is the part. R 4.1 , R 4.2 , and R 4.3 Each independently represents any of the R 4 This is the part.

[0211] In embodiments, the PCNS inhibitor has the formula:

[0212] [ka] is a compound having the formula In the formula, R 2 , R 3 , R 5 and z3 are as described herein and are included in the compounds of formulae (I) to (V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 and R 1.3 Each independently represents any of the R 1 This is the part. R 4.1and R 4.3 Each independently represents any of the R 4 This is the part.

[0213] W 1 is N or C(R 4.2 ) W 2 is N or C(R 5.1 ) W 3 is N or C(R 5.2 ) R 5.1 and R 5.2 Each independently represents any of the R 5 This is the part. R 4.2 is independently any of the R 4 In an embodiment, W 1 is N. In embodiments, W 2 is N. In embodiments, W 3 is N. In embodiments, W 1 is C(R 4.2 In an embodiment, W 2 is C(R 5.1 In an embodiment, W 3 is C(R 5.2 In an embodiment, W 1 is CH. In embodiments, W 2 is CH. In embodiments, W 3 is CH.

[0214] In an embodiment of the compounds of formulae (VI)-(X), R 2 is hydrogen. In an embodiment of the compounds of formulae (VI)-(X), R 3 is hydrogen. In an embodiment of the compounds of formulae (VI)-(X), R 2 and R 3 is hydrogen.

[0215] In embodiments, R 1.1 is independently halogen. In an embodiment, R 1.1 are independently -CF 3 In an embodiment, R 1.1 are independently -CHF2 In an embodiment, R 1.1 are independently -CH 2 F. In embodiments, R 1.1 can be used independently, -OCF 3 In an embodiment, R 1.1 are independently -OCHF 2 In an embodiment, R 1.1 are independently -OCH 2 F. In embodiments, R 1.1 is independently -OH. In embodiments, R 1.1 are independently -NH 2 In an embodiment, R 1.1 is independently -SH. In embodiments, R 1.1 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 1.1 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. 1.1 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 1.1 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 1.1 is independently substituted or unsubstituted phenyl. In embodiments, R 1.1 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 1.1 is independently a substitution C 1 ~C 4 In embodiments, R 1.1 is independently a substituted 4-membered heteroalkyl. In embodiments, R 1.1 is independently a substitution C 3 ~C 6 In embodiments, R 1.1 is independently a substituted 3-6 membered heterocycloalkyl. 1.1 is independently a substituted phenyl. In embodiments, R 1.1is independently a substituted 5-6 membered heteroaryl. 1.1 are independently unsubstituted C 1 ~C 4 In embodiments, R 1.1 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.1 are independently unsubstituted C 3 ~C 6 In embodiments, R 1.1 is independently an unsubstituted 3-6 membered heterocycloalkyl. 1.1 is independently unsubstituted phenyl. In embodiments, R 1.1 is independently an unsubstituted 5-6 membered heteroaryl. 1.1 is independently unsubstituted methyl. In embodiments, R 1.1 is independently unsubstituted ethyl. In embodiments, R 1.1 is independently unsubstituted isopropyl. In embodiments, R 1.1 is independently unsubstituted tert-butyl. In embodiments, R 1.1 is independently unsubstituted methoxy. In embodiments, R 1.1 is independently unsubstituted ethoxy. In embodiments, R 1.1 is independently -F. In embodiments, R 1.1 is independently -Cl. In embodiments, R 1.1 is independently -Br. In embodiments, R 1.1 is independently -I. In embodiments, R 1.1 are independently hydrogen.

[0216] In embodiments, R 1.2 is independently halogen. In an embodiment, R 1.2 are independently -CF 3 In an embodiment, R 1.2 are independently -CHF 2 In an embodiment, R 1.2 are independently -CH 2 F. In embodiments, R 1.2can be used independently, -OCF 3 In an embodiment, R 1.2 are independently -OCHF 2 In an embodiment, R 1.2 are independently -OCH 2 F. In embodiments, R 1.2 is independently -OH. In embodiments, R 1.2 are independently -NH 2 In an embodiment, R 1.2 is independently -SH. In embodiments, R 1.2 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 1.2 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. 1.2 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 1.2 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 1.2 is independently substituted or unsubstituted phenyl. In embodiments, R 1.2 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 1.2 is independently a substitution C 1 ~C 4 In embodiments, R 1.2 is independently a substituted 4-membered heteroalkyl. 1.2 is independently a substitution C 3 ~C 6 In embodiments, R 1.2 is independently a substituted 3-6 membered heterocycloalkyl. 1.2 is independently a substituted phenyl. In embodiments, R 1.2 is independently a substituted 5-6 membered heteroaryl. 1.2 are independently unsubstituted C 1 ~C 4 In embodiments, R 1.2is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.2 are independently unsubstituted C 3 ~C 6 In embodiments, R 1.2 is independently an unsubstituted 3-6 membered heterocycloalkyl. 1.2 is independently unsubstituted phenyl. In embodiments, R 1.2 is independently an unsubstituted 5-6 membered heteroaryl. 1.2 is independently unsubstituted methyl. In embodiments, R 1.2 is independently unsubstituted ethyl. In embodiments, R 1.2 is independently unsubstituted isopropyl. In embodiments, R 1.2 is independently unsubstituted tert-butyl. In embodiments, R 1.2 is independently unsubstituted methoxy. In embodiments, R 1.2 is independently unsubstituted ethoxy. In embodiments, R 1.2 is independently -F. In embodiments, R 1.2 is independently -Cl. In embodiments, R 1.2 is independently -Br. In embodiments, R 1.2 is independently -I. In embodiments, R 1.2 are independently hydrogen.

[0217] In embodiments, R 1.3 is independently halogen. In an embodiment, R 1.3 are independently -CF 3 In an embodiment, R 1.3 are independently -CHF 2 In an embodiment, R 1.3 are independently -CH 2 F. In embodiments, R 1.3 can be used independently, -OCF 3 In an embodiment, R 1.3 are independently -OCHF 2 In an embodiment, R 1.3 are independently -OCH2 F. In embodiments, R 1.3 is independently -OH. In embodiments, R 1.3 are independently -NH 2 In an embodiment, R 1.3 is independently -SH. In embodiments, R 1.3 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 1.3 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. 1.3 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 1.3 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 1.3 is independently substituted or unsubstituted phenyl. In embodiments, R 1.3 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 1.3 is independently a substitution C 1 ~C 4 In embodiments, R 1.3 is independently a substituted 4-membered heteroalkyl. In embodiments, R 1.3 is independently a substitution C 3 ~C 6 In embodiments, R 1.3 is independently a substituted 3-6 membered heterocycloalkyl. 1.3 is independently a substituted phenyl. In embodiments, R 1.3 is independently a substituted 5-6 membered heteroaryl. 1.3 are independently unsubstituted C 1 ~C 4 In embodiments, R 1.3 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.3 are independently unsubstituted C 3 ~C 6 In embodiments, R1.3 is independently an unsubstituted 3-6 membered heterocycloalkyl. 1.3 is independently unsubstituted phenyl. In embodiments, R 1.3 is independently an unsubstituted 5-6 membered heteroaryl. 1.3 is independently unsubstituted methyl. In embodiments, R 1.3 is independently unsubstituted ethyl. In embodiments, R 1.3 is independently unsubstituted isopropyl. In embodiments, R 1.3 is independently unsubstituted tert-butyl. In embodiments, R 1.3 is independently unsubstituted methoxy. In embodiments, R 1.3 is independently unsubstituted ethoxy. In embodiments, R 1.3 is independently -F. In embodiments, R 1.3 is independently -Cl. In embodiments, R 1.3 is independently -Br. In embodiments, R 1.3 is independently -I. In embodiments, R 1.3 are independently hydrogen.

[0218] In embodiments, R 1.4 is independently halogen. In an embodiment, R 1.4 are independently -CF 3 In an embodiment, R 1.4 are independently -CHF 2 In an embodiment, R 1.4 are independently -CH 2 F. In embodiments, R 1.4 can be used independently, -OCF 3 In an embodiment, R 1.4 are independently -OCHF 2 In an embodiment, R 1.4 are independently -OCH 2 F. In embodiments, R 1.4 is independently -OH. In embodiments, R 1.4 are independently -NH 2 In an embodiment, R1.4 is independently -SH. In embodiments, R 1.4 are independently substituted or unsubstituted C 1 ~C 4 In embodiments, R 1.4 is independently a substituted or unsubstituted 2-4 membered heteroalkyl. 1.4 are independently substituted or unsubstituted C 3 ~C 6 In embodiments, R 1.4 is independently a substituted or unsubstituted 3-6 membered heterocycloalkyl. 1.4 is independently substituted or unsubstituted phenyl. In embodiments, R 1.4 is independently a substituted or unsubstituted 5-6 membered heteroaryl. 1.4 is independently a substitution C 1 ~C 4 In embodiments, R 1.4 is independently a substituted 4-membered heteroalkyl. In embodiments, R 1.4 is independently a substitution C 3 ~C 6 In embodiments, R 1.4 is independently a substituted 3-6 membered heterocycloalkyl. 1.4 is independently a substituted phenyl. In embodiments, R 1.4 is independently a substituted 5-6 membered heteroaryl. 1.4 are independently unsubstituted C 1 ~C 4 In embodiments, R 1.4 is independently an unsubstituted 2-4 membered heteroalkyl. In embodiments, R 1.4 are independently unsubstituted C 3 ~C 6 In embodiments, R 1.4 is independently an unsubstituted 3-6 membered heterocycloalkyl. 1.4 is independently unsubstituted phenyl. In embodiments, R 1.4is independently an unsubstituted 5-6 membered heteroaryl. 1.4 is independently unsubstituted methyl. In embodiments, R 1.4 is independently unsubstituted ethyl. In embodiments, R 1.4 is independently unsubstituted isopropyl. In embodiments, R 1.4 is independently unsubstituted tert-butyl. In embodiments, R 1.4 is independently unsubstituted methoxy. In embodiments, R 1.4 is independently unsubstituted ethoxy. In embodiments, R 1.4 is independently -F. In embodiments, R 1.4 is independently -Cl. In embodiments, R 1.4 is independently -Br. In embodiments, R 1.4 is independently -I. In embodiments, R 1.4 are independently hydrogen.

[0219] In embodiments, R 4.1 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.1 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 4.1 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 4.1 is independently halogen. In an embodiment, R 4.1 is independently -OH. In embodiments, R 4.1is independently unsubstituted methyl. In embodiments, R 4.1 is independently unsubstituted methoxy. In embodiments, R 4.1 is independently unsubstituted ethyl. In embodiments, R 4.1 is independently -F. In embodiments, R 4.1 is independently -Cl. In embodiments, R 4.1 is independently -Br. In embodiments, R 4.1 is independently -I. In embodiments, R 4.1 are independently -CF 3 In an embodiment, R 4.1 are independently -NH 2 In an embodiment, R 4.1 is independently -SH. In embodiments, R 4.1 is independently hydrogen. In embodiments, R 4.1 is independently unsubstituted isopropyl. In embodiments, R 4.1 is independently unsubstituted ethoxy. In embodiments, R 4.1 is independently unsubstituted tert-butyl. In embodiments, R 4.1 is independently unsubstituted propoxy.

[0220] In embodiments, R 4.2 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.2 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 4.2is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 4.2 is independently halogen. In an embodiment, R 4.2 is independently -OH. In embodiments, R 4.2 is independently unsubstituted methyl. In embodiments, R 4.2 is independently unsubstituted methoxy. In embodiments, R 4.2 is independently unsubstituted ethoxy. In embodiments, R 4.2 is independently unsubstituted ethyl. In embodiments, R 4.2 is independently -F. In embodiments, R 4.2 is independently -Cl. In embodiments, R 4.2 is independently -Br. In embodiments, R 4.2 is independently -I. In embodiments, R 4.2 are independently -CF 3 In an embodiment, R 4.2 are independently -NH 2 In an embodiment, R 4.2 is independently -SH. In embodiments, R 4.2 is independently hydrogen. In embodiments, R 4.2 is independently unsubstituted isopropyl. In embodiments, R 4.2 is independently unsubstituted ethoxy. In embodiments, R 4.2 is independently unsubstituted tert-butyl. In embodiments, R 4.2 is independently unsubstituted propoxy.

[0221] In embodiments, R 4.3 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.3 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 4.3 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 4.3 is independently halogen. In an embodiment, R 4.3 is independently -OH. In embodiments, R 4.3 is independently unsubstituted methyl. In embodiments, R 4.3 is independently unsubstituted methoxy. In embodiments, R 4.3 is independently unsubstituted ethyl. In embodiments, R 4.3 is independently -F. In embodiments, R 4.3 is independently -Cl. In embodiments, R 4.3 is independently -Br. In embodiments, R 4.3 is independently -I. In embodiments, R 4.3 are independently -CF 3 In an embodiment, R 4.3 are independently -NH 2 In an embodiment, R 4.3 is independently -SH. In embodiments, R 4.3 is independently hydrogen. In embodiments, R 4.3 is independently unsubstituted isopropyl. In embodiments, R 4.3 is independently unsubstituted ethoxy. In embodiments, R 4.3 is independently unsubstituted tert-butyl. In embodiments, R 4.3 is independently unsubstituted propoxy.

[0222] In embodiments, R 4.4 are independently halogen, -CF 3 , -OH, -NH2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.4 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 4.4 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 4.4 is independently halogen. In an embodiment, R 4.4 is independently -OH. In embodiments, R 4.4 is independently unsubstituted methyl. In embodiments, R 4.4 is independently unsubstituted methoxy. In embodiments, R 4.4 is independently unsubstituted ethyl. In embodiments, R 4.4 is independently -F. In embodiments, R 4.4 is independently -Cl. In embodiments, R 4.4 is independently -Br. In embodiments, R 4.4 is independently -I. In embodiments, R 4.4 are independently -CF 3 In an embodiment, R 4.4 are independently -NH 2 In an embodiment, R 4.4 is independently -SH. In embodiments, R 4.4 is independently hydrogen. In embodiments, R 4.4 is independently unsubstituted isopropyl. In embodiments, R 4.4 is independently unsubstituted ethoxy. In embodiments, R 4.4 is independently unsubstituted tert-butyl. In embodiments, R 4.4is independently unsubstituted propoxy.

[0223] In embodiments, R 4.5 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 4.5 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 4.5 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 4.5 is independently halogen. In an embodiment, R 4.5 is independently -OH. In embodiments, R 4.5 is independently unsubstituted methyl. In embodiments, R 4.5 is independently unsubstituted methoxy. In embodiments, R 4.5 is independently unsubstituted ethyl. In embodiments, R 4.5 is independently -F. In embodiments, R 4.5 is independently -Cl. In embodiments, R 4.5 is independently -Br. In embodiments, R 4.5 is independently -I. In embodiments, R 4.5 are independently -CF 3 In an embodiment, R 4.5 are independently -NH 2 In an embodiment, R 4.5 is independently -SH. In embodiments, R 4.5 is independently hydrogen. In embodiments, R 4.5is independently unsubstituted isopropyl. In embodiments, R 4.5 is independently unsubstituted ethoxy. In embodiments, R 4.5 is independently unsubstituted tert-butyl. In embodiments, R 4.5 is independently unsubstituted propoxy.

[0224] In embodiments, R 5.1 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 5.1 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 5.1 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 5.1 is independently halogen. In an embodiment, R 5.1 is independently -OH. In embodiments, R 5.1 is independently unsubstituted methyl. In embodiments, R 5.1 is independently unsubstituted methoxy. In embodiments, R 5.1 is independently unsubstituted ethyl. In embodiments, R 5.1 is independently -F. In embodiments, R 5.1 is independently -Cl. In embodiments, R 5.1 is independently -Br. In embodiments, R 5.1 is independently -I. In embodiments, R 5.1 are independently -CF 3 In an embodiment, R 5.1are independently -NH 2 In an embodiment, R 5.1 is independently -SH. In embodiments, R 5.1 is independently hydrogen. In embodiments, R 5.1 is independently unsubstituted isopropyl. In embodiments, R 5.1 is independently unsubstituted ethoxy. In embodiments, R 5.1 is independently unsubstituted tert-butyl. In embodiments, R 5.1 is independently unsubstituted propoxy.

[0225] In embodiments, R 5.2 are independently halogen, -CF 3 , -OH, -NH 2 , -SH, substituted or unsubstituted C 1 ~C 4 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C 3 ~C 6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl. 5.2 are independently halogen, -OH, -NH 2 , -SH, unsubstituted C 1 ~C 4 In an embodiment, R is an alkyl, an unsubstituted 2-4 membered heteroalkyl, or an unsubstituted 2-4 membered heteroalkyl. 5.2 is independently halogen, -OH, unsubstituted methyl, or unsubstituted methoxy. 5.2 is independently halogen. In an embodiment, R 5.2 is independently -OH. In embodiments, R 5.2 is independently unsubstituted methyl. In embodiments, R 5.2 is independently unsubstituted methoxy. In embodiments, R 5.2 is independently unsubstituted ethyl. In embodiments, R 5.2 is independently -F. In embodiments, R 5.2 is independently -Cl. In embodiments, R 5.2is independently -Br. In embodiments, R 5.2 is independently -I. In embodiments, R 5.2 are independently -CF 3 In an embodiment, R 5.2 are independently -NH 2 In an embodiment, R 5.2 is independently -SH. In embodiments, R 5.2 is independently hydrogen. In embodiments, R 5.2 is independently unsubstituted isopropyl. In embodiments, R 5.2 is independently unsubstituted ethoxy. In embodiments, R 5.2 is independently unsubstituted tert-butyl. In embodiments, R 5.2 is independently unsubstituted propoxy.

[0226] In the embodiment, W 1 is N. In embodiments, W 1 is C(R 4.2 In an embodiment, W 2 is N. In embodiments, W 2 is C(R 5.1 In an embodiment, W 3 is N. In embodiments, W 3 is C(R 5.2 In an embodiment, W 1 is C(H). In an embodiment, W 2 is C(H). In an embodiment, W 3 is C(H).

[0227] In embodiments, R 1.1 and R 1.3 In an embodiment, R 1.1 and R 1.3 is -F. In embodiments, R 1.1 and R 1.3 In an embodiment, R 1.1 and R 1.3 is -Cl. In embodiments, R 1.1 and R 1.3is unsubstituted methyl. In embodiments, R 1.1 and R 1.3 -CF 3 In an embodiment, R 1.1 and R 1.3 is -NH 2 In an embodiment, R 1.1 and R 1.3 is -OH. In embodiments, R 1.1 and R 1.3 is unsubstituted methoxy. In embodiments, R 1.1 and R 1.3 is halogen. In embodiments, R 1.1 and R 1.3 is unsubstituted C 1 ~C 4 In embodiments, R 1.1 and R 1.3 is a substitution C 1 ~C 4 In embodiments, R 1.1 and R 1.3 is halogen-substituted C 1 ~C 4 In embodiments, R 1.1 and R 1.3 is unsubstituted C 1 ~C 2 In embodiments, R 1.1 and R 1.3 is a substitution C 1 ~C 2 In embodiments, R 1.1 and R 1.3 is halogen-substituted C 1 ~C 2 It is an alkyl.

[0228] In embodiments, R 4.1 and R 4.3 In an embodiment, R 4.1 and R 4.3 is -F. In embodiments, R 4.1 and R 4.3 In an embodiment, R 4.1 and R 4.3 In embodiments, R 4.1 and R4.3 is unsubstituted methyl. In embodiments, R 4.1 and R 4.3 -CF 3 In an embodiment, R 4.1 and R 4.3 is -NH 2 In an embodiment, R 4.1 and R 4.3 is -OH. In embodiments, R 4.1 and R 4.3 is unsubstituted methoxy. In embodiments, R 4.1 and R 4.3 is halogen. In embodiments, R 4.1 and R 4.3 is unsubstituted C 1 ~C 4 In embodiments, R 4.1 and R 4.3 is a substitution C 1 ~C 4 In embodiments, R 4.1 and R 4.3 is halogen-substituted C 1 ~C 4 In embodiments, R 4.1 and R 4.3 is unsubstituted C 1 ~C 2 In embodiments, R 4.1 and R 4.3 is a substitution C 1 ~C 2 In embodiments, R 4.1 and R 4.3 is halogen-substituted C 1 ~C 2 It is an alkyl.

[0229] In embodiments, the PCNS inhibitor has the formula:

[0230] [ka] is a compound having the formula In the formula, R 2 , R 3 , R 5and z3 are as described herein and are included in the compounds of formulae (I) to (V). 1.1 , R 1.2 , R 1.3 , and R 1.4 Each independently represents any of the R 1 In an embodiment, R 1.1 , R 1.2 , R 1.3 and / or R 1.4 is hydrogen. In embodiments, R 4.1 , R 4.2 , R 4.3 , R 4.4 and / or R 4.5 is hydrogen. In embodiments, R 2 is hydrogen. In embodiments, R 3 is hydrogen. In embodiments, R 1.1 is halogen. In embodiments, R 1.2 is halogen. In embodiments, R 1.3 is halogen. In embodiments, R 1.4 is halogen. In embodiments, R 1.1 In embodiments, R 1.2 In embodiments, R 1.3 In embodiments, R 1.4 In embodiments, R 1.1 is -F. In embodiments, R 1.2 is -F. In embodiments, R 1.3 is -F. In embodiments, R 1.4 is -F. In embodiments, R 1.2 , R 1.3 , and R 1.4 is hydrogen and R 1.1 is halogen. In embodiments, R 1.1 , R 1.3 , and R 1.4 is hydrogen and R 1.2 is halogen. In embodiments, R 1.2 , R 1.1 , and R 1.4 is hydrogen and R 1.3is halogen. In embodiments, R 1.2 , R 1.3 , and R 1.1 is hydrogen and R 1.4 is halogen. In embodiments, R 1.2 , R 1.3 , and R 1.4 is hydrogen and R 1.1 In embodiments, R 1.1 , R 1.3 , and R 1.4 is hydrogen and R 1.2 In embodiments, R 1.2 , R 1.1 , and R 1.4 is hydrogen and R 1.3 In embodiments, R 1.2 , R 1.3 , and R 1.1 is hydrogen and R 1.4 In embodiments, R 1.2 , R 1.3 , and R 1.4 is hydrogen and R 1.1 is -F. In embodiments, R 1.1 , R 1.3 , and R 1.4 is hydrogen and R 1.2 is -F. In embodiments, R 1.2 , R 1.1 , and R 1.4 is hydrogen and R 1.3 is -F. In embodiments, R 1.2 , R 1.3 , and R 1.1 is hydrogen and R 1.4 is -F. W 1 is N or C(R 4.2 ) W 2 is N or C(R 5.1 ) W 3 is N or C(R 5.2 In an embodiment, W 1 is N. In embodiments, W 2 is N. In embodiments, W 3 is N. In embodiments, W 1 is C(R4.2 In an embodiment, W 2 is C(R 5.1 In an embodiment, W 3 is C(R 5.2 In an embodiment, W 1 is CH. In embodiments, W 2 is CH. In embodiments, W 3 is CH. 5.1 and R 5.2 Each independently represents any of the R 5 In an embodiment, z3 is 0. 4.1 , R 4.2 , R 4.3 , R 4.4 , and R 4.5 Each independently represents any of the R 4 In an embodiment, R 4.1 is unsubstituted methoxy. In embodiments, R 4.2 is unsubstituted methoxy. In embodiments, R 4.3 is unsubstituted methoxy. In embodiments, R 4.4 is unsubstituted methoxy. In embodiments, R 4.5 is unsubstituted methoxy. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is unsubstituted methoxy. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is unsubstituted methoxy. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is unsubstituted methoxy. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is unsubstituted methoxy. In embodiments, R4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is unsubstituted methoxy. In embodiments, R 4.1 is unsubstituted ethoxy. In embodiments, R 4.2 is unsubstituted ethoxy. In embodiments, R 4.3 is unsubstituted ethoxy. In embodiments, R 4.4 is unsubstituted ethoxy. In embodiments, R 4.5 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is unsubstituted ethoxy. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is unsubstituted ethoxy. In embodiments, R 4.1 is -OH. In embodiments, R 4.2 is -OH. In embodiments, R 4.3 is -OH. In embodiments, R 4.4 is -OH. In embodiments, R 4.5 is -OH. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5is hydrogen and R 4.1 is -OH. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is -OH. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is -OH. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is -OH. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is -OH. In embodiments, R 4.1 is halogen. In embodiments, R 4.2 is halogen. In embodiments, R 4.3 is halogen. In embodiments, R 4.4 is halogen. In embodiments, R 4.5 is halogen. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is halogen. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is halogen. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is halogen. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is halogen. In embodiments, R 4.2, R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is halogen. In embodiments, R 4.1 is unsubstituted methyl. In embodiments, R 4.2 is unsubstituted methyl. In embodiments, R 4.3 is unsubstituted methyl. In embodiments, R 4.4 is unsubstituted methyl. In embodiments, R 4.5 is unsubstituted methyl. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is unsubstituted methyl. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is unsubstituted methyl. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is unsubstituted methyl. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is unsubstituted methyl. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is unsubstituted methyl. In embodiments, R 1.1 , R 1.2 , R 1.3 , R 1.4 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 2 and / or R 3 At least one of R is hydrogen. 5 It will be understood that is a floating substituent and may be located on either or both of the rings.

[0231] In embodiments, the PCNS inhibitor has the formula:

[0232] [ka] is a compound having the formula In the formula, R 1.1 , R 1.3 , R 1.4 , R 2 , R 3 , R 4.1 , R 4.3 , R 4.4 , R 4.5 , R 5 , W 1 , W 2 , W 3 and z3 are as described herein and are included in the compounds of formulae (I) to (V). 5 It will be understood that R is a floating substituent and may be located on either or both of the rings. 1.1 , R 1.3 , and R 1.4 Each independently represents any of the R 1 This is the part. R 4.1 , R 4.3 , R 4.4 , and R 4.5 Each independently represents any of the R 4 In an embodiment, R 1.1 , R 1.3 and / or R 1.4 is hydrogen. In embodiments, R 4.1 , R 4.2 , R 4.3 , R 4.4 and / or R 4.5 is hydrogen. In embodiments, R 2 is hydrogen. In embodiments, R 3 is hydrogen. In embodiments, R 1.1 is halogen. In embodiments, R 1.3 is halogen. In embodiments, R 1.4 is halogen. In embodiments, R 1.1In embodiments, R 1.3 In embodiments, R 1.4 In embodiments, R 1.1 is -F. In embodiments, R 1.3 is -F. In embodiments, R 1.4 is -F. In embodiments, R 1.3 and R 1.4 is hydrogen and R 1.1 is halogen. In embodiments, R 1.1 and R 1.4 is hydrogen and R 1.3 is halogen. In embodiments, R 1.3 and R 1.1 is hydrogen and R 1.4 is halogen. In embodiments, R 1.3 and R 1.4 is hydrogen and R 1.1 In embodiments, R 1.1 and R 1.4 is hydrogen and R 1.3 In embodiments, R 1.3 and R 1.1 is hydrogen and R 1.4 In embodiments, R 1.3 and R 1.4 is hydrogen and R 1.1 is -F. In embodiments, R 1.1 and R 1.4 is hydrogen and R 1.3 is -F. In embodiments, R 1.3 and R 1.1 is hydrogen and R 1.4 is -F. W 1 is N or C(R 4.2 ) W 2 is N or C(R 5.1 ) W 3 is N or C(R 5.2 In an embodiment, W 1 is N. In embodiments, W 2 is N. In embodiments, W 3 is N. In embodiments, W 1 is C(R4.2 In an embodiment, W 2 is C(R 5.1 In an embodiment, W 3 is C(R 5.2 In an embodiment, W 1 is CH. In embodiments, W 2 is CH. In embodiments, W 3 is CH. 5.1 and R 5.2 Each independently represents any of the R 5 In an embodiment, z3 is 0. 4.1 , R 4.2 , R 4.3 , R 4.4 , and R 4.5 Each independently represents any of the R 4 In an embodiment, R 4.1 is unsubstituted methoxy. In embodiments, R 4.2 is unsubstituted methoxy. In embodiments, R 4.3 is unsubstituted methoxy. In embodiments, R 4.4 is unsubstituted methoxy. In embodiments, R 4.5 is unsubstituted methoxy. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is unsubstituted methoxy. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is unsubstituted methoxy. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is unsubstituted methoxy. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is unsubstituted methoxy. In embodiments, R4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is unsubstituted methoxy. In embodiments, R 4.1 is unsubstituted ethoxy. In embodiments, R 4.2 is unsubstituted ethoxy. In embodiments, R 4.3 is unsubstituted ethoxy. In embodiments, R 4.4 is unsubstituted ethoxy. In embodiments, R 4.5 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is unsubstituted ethoxy. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is unsubstituted ethoxy. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is unsubstituted ethoxy. In embodiments, R 4.1 is -OH. In embodiments, R 4.2 is -OH. In embodiments, R 4.3 is -OH. In embodiments, R 4.4 is -OH. In embodiments, R 4.5 is -OH. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5is hydrogen and R 4.1 is -OH. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is -OH. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is -OH. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is -OH. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is -OH. In embodiments, R 4.1 is halogen. In embodiments, R 4.2 is halogen. In embodiments, R 4.3 is halogen. In embodiments, R 4.4 is halogen. In embodiments, R 4.5 is halogen. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is halogen. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is halogen. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is halogen. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is halogen. In embodiments, R 4.2, R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is halogen. In embodiments, R 4.1 is unsubstituted methyl. In embodiments, R 4.2 is unsubstituted methyl. In embodiments, R 4.3 is unsubstituted methyl. In embodiments, R 4.4 is unsubstituted methyl. In embodiments, R 4.5 is unsubstituted methyl. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.1 is unsubstituted methyl. In embodiments, R 4.1 , R 4.3 , R 4.4 , and R 4.5 is hydrogen and R 4.2 is unsubstituted methyl. In embodiments, R 4.2 , R 4.1 , R 4.4 , and R 4.5 is hydrogen and R 4.3 is unsubstituted methyl. In embodiments, R 4.2 , R 4.3 , R 4.1 , and R 4.5 is hydrogen and R 4.4 is unsubstituted methyl. In embodiments, R 4.2 , R 4.3 , R 4.4 , and R 4.1 is hydrogen and R 4.5 is unsubstituted methyl. In embodiments, R 1.1 , R 1.3 , R 1.4 , R 4.1 , R 4.2 , R 4.3 , R 4.4 , R 4.5 , R 2 and / or R 3 At least one of R is hydrogen. 5 It will be understood that is a floating substituent and may be located on either or both of the rings.

[0233] In embodiments, the PCNS inhibitor has the formula:

[0234] [ka] It is a compound having the formula:

[0235] In embodiments, the PCNS inhibitor has the formula:

[0236] [ka] It is a compound having the formula:

[0237] In embodiments, the PCNS inhibitor has the formula:

[0238] [ka] It is a compound having the formula:

[0239] In embodiments, the PCNS inhibitor has the formula:

[0240] [ka] It is a compound having the formula:

[0241] In embodiments, the PCNS inhibitor has the formula:

[0242] [ka]

[0243] [ka] It is a compound having the formula:

[0244] Pharmaceutical Compositions Provided herein is a pharmaceutical composition comprising a PCNA inhibitor as described herein or a pharma- ceutically acceptable salt thereof (including embodiments thereof), a pharma- ceutically acceptable excipient, and a compound. Provided herein is a pharmaceutical composition comprising an EGFR-TK inhibitor as described herein or a pharma- ceutically acceptable salt thereof (including embodiments thereof), a pharma- ceutically acceptable excipient, and a compound. "Active ingredient" refers to a PCNA inhibitor and / or an EGFR-TK inhibitor. In the methods described herein, the active ingredients can be administered to a patient separately (e.g., a first pharmaceutical composition comprising a PCNA inhibitor and a second pharmaceutical composition comprising an EGFR-TK inhibitor, where the first and second pharmaceutical compositions are different), or the active ingredients can be administered to a patient as a single composition (e.g., a single pharmaceutical composition comprising a PCNA inhibitor and an EGFR-TK inhibitor).

[0245] Pharmaceutical compositions include compositions that contain an active ingredient in a therapeutically effective amount, i.e., an amount effective to achieve the intended purpose. The actual amount effective for a particular application will vary, inter alia, depending on the condition being treated. When administered in a method for treating disease (cancer), such compositions contain an effective amount of active ingredient to achieve the desired result, e.g., treating cancer, inhibiting cell proliferation. Determining a therapeutically effective amount of a compound is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0246] For preparing pharmaceutical compositions from the compounds described herein, pharma-ceutically acceptable carriers can be either solid or liquid.Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances that can also act as diluents, flavorings, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

[0247] In powders, the carrier is a finely divided solid in admixture with the finely divided active ingredient (e.g., a compound provided herein). In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted into the desired shape and size. Powders and tablets preferably contain from 1% to 99% of the active compound.

[0248] Suitable solid excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, pectin, dextrin, starch, tragacanth, low melting wax, cocoa butter, carbohydrates, sugars including but not limited to lactose, sucrose, mannitol, or sorbitol, starches from corn, wheat, rice, potato, or other plants, celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose, gums such as gum arabic, gum tragacanth, and proteins including but not limited to gelatin and collagen. If necessary, disintegrating or solubilizing agents such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof such as sodium alginate, can be added.

[0249] Dragee cores are provided with suitable coatings such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions that may also contain suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention can also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.

[0250] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0251] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0252] When parenteral application is necessary or desired, the particularly suitable mixtures for the compounds of the present invention are injection solutions, sterile solutions, preferably oily or water-soluble solutions, as well as suspensions, emulsions, or implants, including suppositories. Particularly, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, and the like. Ampoules are convenient unit doses. The compounds of the present invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the present invention are well known to those skilled in the art and are described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub., Easton, PA) and WO 96 / 05309.

[0253] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers and thickeners as desired.Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water containing a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, or a dispersing or wetting agent such as naturally occurring phosphatides (e.g., lecithin), condensation products of fatty acids and alkylene oxides (e.g., polyoxyethylene stearate), condensation products of long-chain aliphatic alcohols and ethylene oxide (e.g., heptadecaethyleneoxycetanol), condensation products of partial esters derived from fatty acids and hexitols and ethylene oxide (e.g., polyoxyethylene sorbitol monooleate), or condensation products of partial esters derived from fatty acids and hexitol anhydrides and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame, or saccharin. The preparation may be adjusted for osmolality.

[0254] Also included are solid form preparations that are intended to be converted immediately prior to use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0255] Oily suspensions may contain thickening agents such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners may be added to provide palatable oral preparations, such as glycerol, sorbitol, or sucrose. These preparations may be preserved by the addition of an antioxidant, such as ascorbic acid. Pharmaceutical preparations may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as those mentioned above, or a mineral oil, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents, as in the preparation of syrups and elixirs. Such preparations may also contain a demulcent, a preservative, or a coloring agent.

[0256] The compounds described herein can be administered to a patient alone or co-administered. Co-administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (two or more compounds). Thus, the preparation can also be combined with other active substances if desired.

[0257] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0258] The amount of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1,000 mg, and most typically from 10 mg to 500 mg, depending on the particular application and the potency of the active ingredient. The amount of active compound may also be defined as mg / kg, ranging from about 0.1 mg / kg to 500 mg / kg. The composition may also contain other compatible therapeutic agents, if desired.

[0259] The ratio of toxicity to therapeutic effect of a particular compound is its therapeutic index, or LD 50 (the amount of compound that is lethal to 50% of the population) and ED 50 Therapeutic indices can be expressed as a ratio of the ED (the amount of a compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds is preferably within the ED range with little or no toxicity. 50 The plasma concentration range includes: 0.5 to 1.0 mg / kg / day, 1.0 to 1.5 mg / kg / day, 1 ...

[0260] Treatment method The present disclosure provides a method of treating cancer in a patient in need of such treatment by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of an EGFR-TK inhibitor or a pharma- ceutically acceptable salt thereof. In an embodiment, the present disclosure provides a method of treating cancer in a patient in need of such treatment by administering an effective amount of a first pharmaceutical composition comprising AOH1996 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, and an effective amount of a second pharmaceutical composition comprising an EGFR-TK inhibitor and a pharma- ceutically acceptable excipient. In an embodiment, the present disclosure provides a method of treating cancer in a patient in need of such treatment by administering an effective amount of a pharmaceutical composition comprising AOH1996 or a pharma- ceutically acceptable salt thereof, an EGFR-TK inhibitor and a pharma- ceutically acceptable excipient. In an embodiment, the cancer is lung cancer, colorectal cancer, colon cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In embodiments, the cancer is non-small cell lung cancer, colorectal cancer, colon cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In embodiments, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is non-small cell lung cancer. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is colon cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is squamous cell carcinoma. In embodiments, the cancer is squamous cell carcinoma. In embodiments, the cancer is thyroid cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer has an EGFR mutation, a KRAS mutation, a BRAF mutation, or a combination of two or more thereof. In embodiments, the cancer has an EGFR mutation. In embodiments, the EGFR mutation comprises L858R, ex19del, Ex10ins, T790M, or a combination of two or more thereof. In embodiments, the EGFR mutation comprises L858R and ex19del. In embodiments, the EGFR mutation comprises L858R. In embodiments, the EGFR mutation comprises ex19del. In embodiments, the EGFR mutation comprises Ex10ins.In an embodiment, the EGFR mutation comprises L858R, ex19del, and T790M. In an embodiment, the EGFR mutation comprises L858R and T790M. In an embodiment, the EGFR mutation comprises T790M. In an embodiment, the cancer has a KRAS mutation. In an embodiment, the KRAS mutation is G12, G13, or Q61. In an embodiment, the KRAS mutation is G12C, G12S, G12V, G12D, G12A, G13D, G13C, Q61H, or Q61R. In an embodiment, the KRAS mutation is a G12 mutation. In an embodiment, the KRAS mutation is a G12C mutation. In an embodiment, the KRAS mutation is a G12S mutation. In an embodiment, the KRAS mutation is a G12V mutation. In an embodiment, the KRAS mutation is a G12D mutation. In embodiments, the KRAS mutation is a G12A mutation. In embodiments, the KRAS mutation is a G13 mutation. In embodiments, the KRAS mutation is a G13D mutation. In embodiments, the KRAS mutation is a G13C mutation. In embodiments, the KRAS mutation is a Q61 mutation. In embodiments, the KRAS mutation is a Q61H mutation. In embodiments, the KRAS mutation is a Q61R mutation. In embodiments, the cancer has a BRAF mutation. In embodiments, the BRAF mutation is a V600E mutation. In embodiments, the cancer is an EGFR-TK resistant cancer. In embodiments, the method of treating cancer further comprises administering to the patient an effective amount of one or more anti-cancer agents.

[0261] The present disclosure relates to a combination of an effective amount of AOH1996 or a pharma- ceutical acceptable salt thereof and an effective amount of osimertinib, gefitinib, afatinib, neratinib, erlotinib, rociletinib, olmutinib, lazertinib, nazartinib, nacotinib, mavelertinib, abivertinib, olafertinib, alflutinib, amivantamb, tarloxitinib, mobocertinib, savolitinib, capmatinib, cetuximab, panitumumab, lapatinib, or combination thereof. In one embodiment, the cancer is lung cancer, colorectal cancer, colon cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In another embodiment, the cancer is non-small cell lung cancer, colorectal cancer, colon cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In an embodiment, the cancer is lung cancer. In an embodiment, the cancer is non-small cell lung cancer. In an embodiment, the cancer is colorectal cancer. In an embodiment, the cancer is colon cancer. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is breast cancer. In an embodiment, the cancer is squamous cell carcinoma. In an embodiment, the cancer is thyroid cancer. In an embodiment, the cancer is head and neck cancer. In an embodiment, the cancer has an EGFR mutation, a KRAS mutation, a BRAF mutation, or a combination of two or more thereof. In an embodiment, the cancer has an EGFR mutation. In an embodiment, the EGFR mutation comprises L858R, ex19del, Ex10ins, T790M, or a combination of two or more thereof. In an embodiment, the EGFR mutation comprises L858R and ex19del. In an embodiment, the EGFR mutation comprises L858R. In an embodiment, the EGFR mutation comprises ex19del. In an embodiment, the EGFR mutation comprises Ex10ins.In an embodiment, the EGFR mutation comprises L858R, ex19del, and T790M. In an embodiment, the EGFR mutation comprises L858R and T790M. In an embodiment, the EGFR mutation comprises T790M. In an embodiment, the cancer has a KRAS mutation. In an embodiment, the KRAS mutation is G12, G13, or Q61. In an embodiment, the KRAS mutation is G12C, G12S, G12V, G12D, G12A, G13D, G13C, Q61H, or Q61R. In an embodiment, the KRAS mutation is a G12 mutation. In an embodiment, the KRAS mutation is a G12C mutation. In an embodiment, the KRAS mutation is a G12S mutation. In an embodiment, the KRAS mutation is a G12V mutation. In an embodiment, the KRAS mutation is a G12D mutation. In an embodiment, the KRAS mutation is a G12A mutation. In an embodiment, the KRAS mutation is a G13 mutation. In an embodiment, the KRAS mutation is a G13D mutation. In an embodiment, the KRAS mutation is a G13C mutation. In an embodiment, the KRAS mutation is a Q61 mutation. In an embodiment, the KRAS mutation is a Q61H mutation. In an embodiment, the KRAS mutation is a Q61R mutation. In an embodiment, the cancer has a BRAF mutation. In an embodiment, the BRAF mutation is a V600E mutation. In an embodiment, the cancer is an EGFR-TK resistant cancer. In an embodiment, the EGFR-TK inhibitor and the compound that is AOH1996 or a pharma- ceutically acceptable salt thereof are administered separately to the patient. In an embodiment, the method of treating cancer comprises administering to a patient a first pharmaceutical composition comprising an EGFR-TK inhibitor and a pharma- ceutically acceptable excipient, and a second pharmaceutical composition (i.e., the first and second pharmaceutical compositions are different) comprising AOH1996 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In an embodiment, the method comprises administering to a patient a pharmaceutical composition comprising an EGFR-TK inhibitor, AOH1996 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In an embodiment, the method of treating cancer further comprises administering to the patient an effective amount of one or more anti-cancer agents.

[0262] In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of osimertinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of osimertinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of gefitinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of afatinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of erlotinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of rociletinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of olmutinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of lazertinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of nazartinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of nacotinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of mavereltinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of avivertinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996, or a pharma- ceutically acceptable salt thereof, and an effective amount of olafertinib.In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of alflutinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of amivantamb. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of tarloxitinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of mobocertinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of EAI045. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of savolitinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of capmatinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of cetuximab. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of panitumumab. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of lapatinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of dacomitinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of necitumumab. In an embodiment, the method includes treating cancer by administering an effective amount of AOH1996, or a pharma- ceutically acceptable salt thereof, and an effective amount of vandetanib.In an embodiment, the method includes treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of icotininib. In an embodiment, the method includes treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of canertinib. In an embodiment, the method includes treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of alitinib. In an embodiment, the method includes treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of varlitinib. In an embodiment, the method includes treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of tesevatinib. In an embodiment, the method includes treating cancer by administering an effective amount of AOH1996 or a pharmaceutically acceptable salt thereof and an effective amount of pelitinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of sapitinib. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of TAK-285. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of AG-1478. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of AEE788. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of CUDC-101. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of WZ8040. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996, or a pharma- ceutically acceptable salt thereof, and an effective amount of WZ4002.In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of WZ3146. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of AG-490. In an embodiment, the method comprises treating cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of PD153035. In an embodiment, the EGFR-TK inhibitor described herein is in the form of a pharma- ceutically acceptable salt. In an embodiment, the cancer is lung cancer, colorectal cancer, colon cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In an embodiment, the cancer is non-small cell lung cancer, colorectal cancer, colon cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In embodiments, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, thyroid cancer, or head and neck cancer. In embodiments, the cancer is lung cancer. In embodiments, the cancer is non-small cell lung cancer. In embodiments, the cancer is colorectal cancer. In embodiments, the cancer is colon cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is breast cancer. In embodiments, the cancer is squamous cell carcinoma. In embodiments, the cancer is squamous cell carcinoma. In embodiments, the cancer is thyroid cancer. In embodiments, the cancer is head and neck cancer. In embodiments, the cancer has an EGFR mutation, a KRAS mutation, a BRAF mutation, or a combination of two or more thereof. In embodiments, the cancer has an EGFR mutation. In embodiments, the EGFR mutation comprises L858R, ex19del, Ex10ins, T790M, or a combination of two or more thereof. In an embodiment, the EGFR mutation comprises L858R and ex19del. In an embodiment, the EGFR mutation comprises L858R. In an embodiment, the EGFR mutation comprises ex19del. In an embodiment, the EGFR mutation comprises Ex10ins. In an embodiment, the EGFR mutation comprises L858R, ex19del, and T790M. In an embodiment, the EGFR mutation comprises L858R and T790M. In an embodiment, the EGFR mutation comprises T790M.In an embodiment, the cancer has a KRAS mutation. In an embodiment, the KRAS mutation is G12, G13, or Q61. In an embodiment, the KRAS mutation is G12C, G12S, G12V, G12D, G12A, G13D, G13C, Q61H, or Q61R. In an embodiment, the KRAS mutation is a G12 mutation. In an embodiment, the KRAS mutation is a G12C mutation. In an embodiment, the KRAS mutation is a G12S mutation. In an embodiment, the KRAS mutation is a G12V mutation. In an embodiment, the KRAS mutation is a G12D mutation. In an embodiment, the KRAS mutation is a G12A mutation. In an embodiment, the KRAS mutation is a G13 mutation. In an embodiment, the KRAS mutation is a G13D mutation. In an embodiment, the KRAS mutation is a G13C mutation. In an embodiment, the KRAS mutation is a Q61 mutation. In an embodiment, the KRAS mutation is a Q61H mutation. In an embodiment, the KRAS mutation is a Q61R mutation. In an embodiment, the cancer has a BRAF mutation. In an embodiment, the BRAF mutation is a V600E mutation. In an embodiment, the cancer is an EGFR-TK resistant cancer. In an embodiment, the EGFR-TK inhibitor and a compound that is AOH1996 or a pharma- ceutically acceptable salt thereof are administered separately to a patient. In an embodiment, a method of treating cancer comprises administering to a patient a first pharmaceutical composition comprising an EGFR-TK inhibitor and a pharma- ceutically acceptable excipient, and a second pharmaceutical composition (i.e., the first pharmaceutical composition and the second pharmaceutical composition are different) comprising AOH1996 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. In embodiments, the method comprises administering to the patient a pharmaceutical composition comprising an EGFR-TK inhibitor, AOH1996 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. In embodiments, the method of treating cancer further comprises administering to the patient an effective amount of one or more anti-cancer agents.

[0263] The present disclosure provides a method for treating non-small cell lung cancer in a patient in need thereof by administering an effective amount of AOH1996 or a pharma- ceutical acceptable salt thereof and an effective amount of an EGFR-TK inhibitor. In an embodiment, the method comprises administering an effective amount of AOH1996 or a pharma- ceutical acceptable salt thereof and an effective amount of osimertinib, gefitinib, afatinib, neratinib, erlotinib, rociletinib, olmutinib, lazertinib, nazartinib, nacotinib, mavelertinib, abivertinib, olafertinib, alflutinib, amivantamb, tarloxitinib, mobocertinib, savolitinib, capmatinib, sempervirgin ... In an embodiment, the method comprises administering an effective amount of AOH1996 or a pharmacologic acceptable salt thereof and an effective amount of osimertinib to treat non-small cell lung cancer. In an embodiment, the method comprises treating non-small cell lung cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of osimertinib. In an embodiment, the method comprises treating non-small cell lung cancer by administering an effective amount of AOH1996 or a pharma- ceutically acceptable salt thereof and an effective amount of gefitinib. In an embod...

Claims

1. 1. A medicament for use in a method for treating cancer in a subject in need of such treatment, said medicament comprising an EGFR-TK inhibitor and / or a proliferating cell nuclear antigen inhibitor, said method comprising administering to said subject an effective amount of an EGFR-TK inhibitor and an effective amount of a proliferating cell nuclear antigen inhibitor.

2. The proliferating cell nuclear antigen inhibitor is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compound of formula (I) has the following formula: 【Chemistry 1】 and During the ceremony, Ring A is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5- to 6-membered heteroaryl; Ring B is substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl; R １ are independently halogen, -CX １ ３ , -CHX １ ２ , -CH ２ X １ , -CN, -SO ｎ１ R １０ , -SO ｖ１ N.R. ７ R ８ , -NHNH ２ , -ONR ７ R ８ , -NHC=(O)NHNH ２ , -NHC=(O)NR ７ R ８ , -N(O) ｍ１ , -NR ７ R ８ , -C(O)R ９ , —C(O)—OR ９ , -C(O)NR ７ R ８ , -OR １０ , -NR ７ SO ２ R １０ , -NR ７ C=(O)R ９ , -NR ７ C(O)-OR ９ , -NR ７ OR ９ , -OCX １ ３ , -OCHX １ ２ , -OCH ２ X １ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R １ 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; R ２ are independently hydrogen, halogen, -CX ２ ３ , -CHX ２ ２ , -CH ２ X ２ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ３ are independently hydrogen, halogen, -CX ３ ３ , -CHX ３ ２ , -CH ２ X ３ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ７ , R ８ , R ９ , and R １０ are independently hydrogen, halogen, -CX Ａ ３ , -CHX Ａ ２ , -CH ２ X Ａ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R are attached to the same nitrogen atom. ７ and R ８ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z1 is independently an integer from 0 to 4; m1 and v1 are independently 1 or 2; n1 is independently an integer from 0 to 4; X １ , X ２ , X ３ , and X Ａ The agent of claim 1, wherein:

3. The compound of formula (I) is a compound of formula (II) or a pharma- ceutically acceptable salt thereof, and the compound of formula (II) is represented by the following formula: 【Chemistry 2】 and During the ceremony, R ４ are independently halogen, -CX ４ ３ , -CHX ４ ２ , -CH ２ X ４ , -CN, -SO ｎ４ R １４ , -SO ｖ４ N.R. １１ R １２ , -NHNH ２ , -ONR １１ R １２ , -NHC=(O)NHNH ２ , -NHC=(O)NR １１ R １２ , -N(O) ｍ４ , -NR １１ R １２ , -C(O)R １３ , —C(O)—OR １３ , -C(O)NR １１ R １２ , -OR １４ , -NR １１ SO ２ R １４ , -NR １１ C=(O)R １３ , -NR １１ C(O)-OR １３ , -NR １１ OR １３ , -OCX ４ ３ , -OCHX ４ ２ , -OCH ２ X ４ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R ４ 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; R ５ are independently halogen, -CX ５ ３ , -CHX ５ ２ , -CH ２ X ５ , -CN, -SO ｎ５ R １８ , -SO ｖ５ N.R. １５ R １６ , -NHNH ２ , -ONR １５ R １６ , -NHC=(O)NHNH ２ , -NHC=(O)NR １５ R １６ , -N(O) ｍ５ , -NR １５ R １６ , -C(O)R １７ , —C(O)—OR １７ , -C(O)NR １５ R １６ , -OR １８ , -NR １５ SO ２ R １８ , -NR １５ C=(O)R １７ , -NR １５ C(O)-OR １７ , -NR １５ OR １７ , -OCX ５ ３ , -OCHX ５ ２ , -OCH ２ X ５ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and two adjacent R ５ 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; R １１ , R １２ , R １３ , and R １４ are independently hydrogen, halogen, -CX Ｂ ３ , -CHX Ｂ ２ , -CH ２ X Ｂ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R are attached to the same nitrogen atom. １１ and R １２ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R １５ , R １６ , R １７ , and R １８ are independently hydrogen, halogen, -CX Ｃ ３ , -CHX Ｃ ２ , -CH ２ X Ｃ , -CN, -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R are attached to the same nitrogen atom. １５ and R １６ The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; z2 is independently an integer from 0 to 5; z3 is independently an integer from 0 to 7; m4, m5, v4, and v5 are independently 1 or 2; n4 and n5 are independently an integer from 0 to 4; X ４ , X ５ , X Ｂ , and X Ｃ The agent according to claim 2, wherein:

4. The compound of formula (I) is a compound of formula (III) or a pharma- ceutically acceptable salt thereof, a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, or a compound of formula (V) or a pharma- ceutically acceptable salt thereof, The compound of formula (III) has the following formula: 【Chemistry 3】 and The compound of formula (IV) is of the formula: 【Chemistry 4】 The compound of formula (V) is represented by the following formula: 【Chemistry 5】 The drug according to claim 2,

5. R １ are independently halogen, -CF ３ , -CHF ２ , -CH ２ F, -OCF ３ , -OCHF ２ , -OCH ２ F, -OH, -NH ２ , -SH, unsubstituted C １ ~C ４ alkyl, or unsubstituted 2-4 membered heteroalkyl; R 2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl; R 3 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl; R 4 is independently -OR 14 , halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl; R 14 is hydrogen or unsubstituted C 1 -C 5 alkyl; R 5 is independently halogen, -CF 3 , -CHF 2 , -CH 2 F, -OCF 3 , -OCHF 2 , -OCH 2 F, -OH, -NH 2 , -SH, unsubstituted C 1 -C 4 alkyl, or unsubstituted 2-4 membered heteroalkyl; Ring A is phenyl, thienyl, or pyridyl, and ring B is naphthyl, quinolinyl, or isoquinolinyl; The drug according to claim 4.

6. The compound of formula (I) has the following formula: 【Chemistry 6】 The drug of claim 2 , having the formula:

7. The compound of formula (I) has the following formula: 【Chemistry 7】 The drug of claim 2 , having the formula:

8. The EGFR-TK inhibitor is osimertinib, gefitinib, afatinib, neratinib, erlotinib, rociletinib, olmutinib, lazertinib, nazartinib, nacotinib, mavereltinib, abivertinib, olafertinib, alflutinib, amivantamb, tarloxitinib, mobocertinib, savolitinib, capmatinib, cetuximab, panitinib, The agent of claim 1 or 2, which is tumumab, lapatinib, dacomitinib, necitumumab, vandetanib, icotininib, canertinib, alitinib, varlitinib, tesevatinib, pelitinib, sapitinib, EAI045, TAK-285, AG-1478, AEE788, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, or PD153035.

9. The drug according to claim 1 or 2, wherein the EGFR-TK inhibitor is osimertinib, gefitinib, afatinib, neratinib, or erlotinib.

10. 3. The method of claim 1 or 2, wherein the cancer is colorectal cancer, pancreatic cancer, breast cancer, thyroid cancer, head and neck cancer, leukemia, lung cancer, brain cancer, neuroblastoma, melanoma, ovarian cancer, renal cancer, or prostate cancer.

11. The drug described in claim 1 or 2, wherein the cancer is non-small cell lung cancer or breast cancer.

12. The cancer is non-small cell lung cancer or breast cancer, the EGFR-TK inhibitor is osimertinib, gefitinib, afatinib, neratinib, or erlotinib, and the compound of formula (I) is represented by the following formula: 【Chemistry 8】 The drug of claim 2 , having the formula:

13. The drug described in claim 1 or 2, wherein the cancer has an EGFR mutation.

14. The drug described in claim 13, wherein the EGFR mutation includes L858R, ex19del, Ex10ins, T790M, or a combination of two or more thereof.

15. The drug described in claim 1 or 2, wherein the cancer has a KRAS mutation or a BRAF mutation.

16. The method of claim 1, comprising: (i) a first pharmaceutical composition comprising an EGFR-TK inhibitor and a pharma- ceutically acceptable excipient; and (ii) a second pharmaceutical composition comprising a proliferating cell nuclear antigen inhibitor and a pharma- ceutically acceptable excipient.

17. The agent of claim 1 or 2, comprising a pharmaceutical composition comprising an EGFR-TK inhibitor, a proliferating cell nuclear antigen inhibitor, and a pharma- ceutically acceptable excipient.

18. A pharmaceutical composition comprising an EGFR-TK inhibitor, a compound of formula (A) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient, wherein the compound of formula (A) has the following formula: 【Chemistry 9】 13. A pharmaceutical composition comprising:

19. The EGFR-TK inhibitor is osimertinib, gefitinib, afatinib, neratinib, erlotinib, rociletinib, olmutinib, lazertinib, nazartinib, nacotinib, mavereltinib, abivertinib, olafertinib, alflutinib, amivantamb, tarloxitinib, mobocertinib, savolitinib, capmatinib, cetuximab, panitinib, or the like. The pharmaceutical composition of claim 18, which is selected from the group consisting of tumumab, lapatinib, dacomitinib, necitumumab, vandetanib, icotininib, canertinib, alitinib, varlitinib, tesevatinib, pelitinib, sapitinib, EAI045, TAK-285, AG-1478, AEE788, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, and PD153035.

20. The pharmaceutical composition of claim 18, wherein the EGFR-TK inhibitor is osimertinib, gefitinib, afatinib, erlotinib, or neratinib.

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