Small-molecule inhibitors of ADAR1

Abstract

The present disclosure provides compounds represented by Formula (IX): and the pharmaceutically acceptable salts and / or solvates thereof, wherein R1, R2, R3, R4, R5, and X are as defined in the specification. Compounds having Formula (I) are adenosine deaminase acting on RNA 1 (ADAR1) inhibitors useful for the treatment of cancer and other diseases. Compounds having Formula (I) can be administered to a subject as a single agent or in combination with immune checkpoint inhibitors.

Description

SMALL-MOLECULE INHIBITORS OF AD ARISTATEMENT REGARDING SEQUENCE LISTING

[0001] This application contains, as a separate part of the disclosure, a Sequence Listing in computer readable form (Filename: 2024194_SeqListing; Size: 127,902 bytes; Created January 8, 2025), which is incorporated by reference in its entirety.BACKGROUNDField

[0002] The present disclosure provides adenosine deaminase acting on RNA 1 (AD ARI) inhibitors. ADAR1 inhibitors are useful for treating cancer when administered to a subject as a single agent or in combination with one or more immune checkpoint inhibitors.Background

[0003] Adenosine deaminase acting on RNA 1 (AD ARI) is an RNA editing enzyme that catalyzes the deamination of adenosine to inosine (A-to-I) in double-stranded RNAs (dsRNAs). There are two protein isoforms of AD ARI, the full-length AD ARI pl50 (150 kDa) and the shorter AD ARI pl 10 (110 kDa). AD ARI pl 10 is constitutively expressed in the nucleus, while ADAR1 pl50 is localized in the cytoplasm. Nishikura, Nat Rev Mol Cell Biol 17, 83-96 (2016). ADAR 1 -mediated A-to-I editing disrupts dsRNA structures and protects dsRNAs from dsRNA-sensing molecules, such as MDA5, thereby inhibiting the type-I and type-III-IFN-mediated response and innate immunity. Liddicoat et al., Science 349, 1115-1120 (2015). ADAR1 plays pivotal roles in viral infection (Pfaller et al., Annu Rev Virol 8, 239-264 (2021)), autoimmune disease (Chung, H. et al., Cell 172, 811-824 e814 (2018)), and cancer immunity. Ishizuka et al., Nature 565, 43-48 (2019); Gannon et al., Nat Commun 9, 5450 (2018); Liu et al., Nat Med 25, 95-102 (2019); Quin et al., Biochem Sci 46, 758-771 (2021). IFNy (type-II IFN) transcriptionally stimulates ADAR1 expression. Patterson et al., Mol Cell Biol 15, 5376-5388 (1995). However, the posttranslational modification (PTM), endogenous regulation, and pharmacological manipulation of AD ARI remain largely unknown.

[0004] Active cancer metabolic reprogramming supplies energy and nutrient materials for tumor cell growth and fosters immunosuppression. Zou et al., Cell Metab 35, 1101-1113 (2023); O'Sullivan et al., Nat Rev Immunol 19, 324-335 (2019); Lim et al., Elife 9 (2020); Tsai et al., Cell Metab 35, 118-133 el 17 (2023); Arner et al., Cancer Cell 41, 421-433 (2023). Targeting cancer metabolism can potentiate immunotherapy response in tumor bearing animal models. Bader et al., Mol Cell 78, 1019-1033 (2020); Stine et al., Nat Rev Drug Discov 21, 141-162 (2022). It is posited and tested that metabolic restriction induces tumor regression and improves cancer outcome. Meynet et al., Trends Mol Med 20, 419-427 (2014); Vidoni et al., J Cancer Prev 26, 224-236 (2021). However, the underlying cellular and molecular mechanisms and the potential connection between tumor metabolic reprogramming and RNA-editing activity in the tumor microenvironment (TME) are largely unexplored. There exists a need in the art for safe and efficacious small molecule therapeutics that target cancer metabolism.BRIEF SUMMARY

[0005] In one aspect, the present disclosure provides compounds represented by any one of Formulae (I)-(VII) or (IX)-(XVII), and the pharmaceutically acceptable salts and solvates thereof, and compounds of Table 1A and Table 2A, and the pharmaceutically acceptable salts and solvates thereof. These compounds, and the pharmaceutically acceptable salts and solvates thereof, are collectively referred to herein as "Compounds of the Disclosure" or individually as a "Compound of the Disclosure." Compounds of the Disclosure are adenosine deaminase acting on RNA 1 (ADAR1) inhibitors and are thus useful in treating diseases or conditions, e.g., cancer, wherein inhibition of ADAR1 provides a therapeutic benefit to a subject.

[0006] In another aspect, the present disclosure provides pharmaceutical compositions comprising a Compound of the Disclosure and a pharmaceutically acceptable excipient.

[0007] In another aspect, the present disclosure provides methods of treating cancer in a subject by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need thereof.

[0008] In another aspect, the present disclosure provides a Compound of the Disclosure for use in treating cancer in a subject in need thereof.

[0009] In another aspect, the present disclosure provides the use of a Compound of the Disclosure in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0010] In another aspect, the present disclosure provides methods of treating cancer in a subject by administering a therapeutically effective amount of a Compound of the Disclosure in combination with one or more immune checkpoint inhibitors to a subject in need thereof. Immune checkpoint inhibitors include, but are not limited to, anti-PD-1 antibodies, anti-PD-Ll antibodies, anti-CTLA-4 antibodies, anti-LAG3 antibodies, anti- TIM3 antibodies, anti-VISTA antibodies, anti-TIGIT antibodies, and anti-cd47 antibodies.

[0011] In another aspect, the present disclosure provides a Compound of the Disclosure for use in treating cancer in combination with one or more immune checkpoint inhibitors.

[0012] In another aspect, the present disclosure provides the use of a Compound of the Disclosure in the manufacture of a medicament for treating cancer in combination with one or more immune checkpoint inhibitors.

[0013] In another aspect, the present disclosure provides methods of inhibiting ADAR1 in a subject in need thereof by administering a therapeutically effective amount of a Compound of the Disclosure to the subject.

[0014] In another aspect, the present disclosure provides methods of sensitizing tumor response to immune checkpoint blockade (ICB) by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need thereof.

[0015] In another aspect, present disclosure provides kits for carrying out the methods of the present disclosure.

[0016] In another aspect, the present disclosure provides compounds represented by Formula (VIII), and the pharmaceutically acceptable salts and solvates thereof, and compounds of Table 1C, and the pharmaceutically acceptable salts and solvates thereof. These compounds are synthetic intermediates that can be used, for example, to prepare Compounds of the Disclosure.

[0017] In another aspect, the present disclosure provides compounds represented by any one of Formulae (XVIII)-(XXV), and the pharmaceutically acceptable salts and solvates thereof, and the compounds of Table 8, and the pharmaceutically acceptable salts and solvates thereof. These compounds are synthetic intermediates that can be used, for example, to prepare Compounds of the Disclosure.BRIEF DESCRIPTION OF DRAWINGS

[0018] FIGS, la-e are box plots showing the calculated by Z score in the indicated metabolic pathways (FIGS, la-d) and IFN signaling pathway (FIG. le) in each group (based on the immunotherapy responses, cancer patients receiving immune checkpoint blockade (ICB) were divided into CR (complete response), PR / SD (partial response / stable disease) and PD (progressive disease) groups). Nutrient metabolism (FIG. Id) was calculated by the sum of glucose (FIG. la), glutamine (FIG. lb), and fatty acids (FIG. 1c) metabolism, n = 50 patients, P values were determined by one-way ANOVA.

[0019] FIG. If is a diagram showing the IFN cycling and magnified IFN response during metabolic restriction.

[0020] FIGS. Ig-h are heat maps showing CHL1 (FIG. 1g) or B16 (FIG. Ih) cells treated with BPTES in the presence or absence of IFNy for 24 hours. Transcripts of the indicated IFN signaling genes were determined by qPCR. n = 3 biological independent samples.

[0021] FIG. li are four bar graphs showing B16 cells treated with the indicated conditions for 36 hours. Transcripts of the indicated IFN signaling genes were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by 2-sided t-test.

[0022] FIG. Ij is a bar graph showing B16 cells carrying the indicated shRNAs treated with IFNy for 48 hours. IFN|3 levels in the culture medium were determined by ELISA. Data are mean ± SD. n = 3 biological independent samples.

[0023] FIG. Ik is a Venn diagram showing B16 cells treated with BPTES in the presence or absence of IFNy for 36 hours. RNA-seq was performed in these B16 cells. The overlapping of differentially expressed genes (DEGs) between groups is shown. The indicated IFN signaling genes were enriched upon BPTES plus IFNy treatment.

[0024] Fig 11 is a graph showing an ontology analysis performed with the differentially expressed genes between BPTES plus IFNy and IFNy treatments. Arrows indicate immune-related biological processes enriched in BPTES plus IFNy group compared with IFNy alone group.

[0025] Extended Data ("ED") FIG. la is a bar graph showing CHL1 cells treated with the indicated inhibitors in the presence or absence of IFNy for 48 hours. Cell surface expression of HLA-ABC was determined by FACS. Data are mean ± SD. n = 3 biological independent samples.

[0026] ED FIG. lb is a bar graph showing CHL1 cells treated with the indicated concentrations of BPTES in the presence or absence of IFNy for 48 hours. Cell surface expression of HLA-ABC was determined by FACS. Data are mean ± SD. n = 3 biological independent samples. P values by one-way ANOVA.

[0027] ED FIG. 1c is six bar graphs showing human cancer cells (A2058, SW480, and CAOV3) or mouse cancer cells (B16, CT26, and ID8) treated with BPTES in the presence or absence of IFNy for 48 hours. Surface staining of MHC-I was determined by FACS. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0028] ED FIG. Id is a bar graph showing B16 cells carrying the indicated shRNAs were treated with IFNy for 48 hours. Surface expression of MHC-I (H2-Kb) was determined by FACS. Data are mean ± SD. n = 3 biological independent samples.

[0029] ED FIG. le is four bar graphs showing CHE1 cells treated with BPTES and / or IFNy for 36 hours. The MHC-I-related gene transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0030] ED FIGS. If-g is a Western blot image and graph, respectively, showing B16 control cells (shFluc) or metabolically restricted cells (shGdh, shPkm) treated with IFNy for the indicated hours. The indicated proteins were determined by Western blot (only 1 of 2 blots is shown). Surface expression of H2-Kbwas determined by FACS, n = 3 biological independent samples.

[0031] ED FIG. Ih is two bar graphs showing B16 cells or mouse embryonic fibroblasts (MEF) treated with the indicated conditions for 24 hours. Ifiibl transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples.

[0032] ED FIG. li is four bar graphs showing wild type (WT), type-I IFN receptor knock out (Ifnarl KO), or type-III IFN receptor knockout (Ifnlrl KO) B16 cells were treated with the indicated conditions for 36 hours. The indicated IFN signaling gene transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0033] ED FIG. Ij is seven bar graphs showing RNA-seq performed in B16 cells treated with BPTES in the presence or absence of IFNy for 40 hours. Transcripts per million (TPM) of the indicated IFN signaling genes are shown, n = 2 biological independent samples.

[0034] ED FIGS. Ik-1 is volcano map or scatter plot, respectively, showing the differentially expressed genes between BPTES plus IFNy group and IFNy group.

[0035] ED FIG. Im is a graph showing the gene ontology analysis of the differentially expressed genes between BPTES plus IFNy group and BPTES group. Arrows indicate the enriched immune-related processes.

[0036] FIG. 2a is a schematic diagram showing the common signaling pathways that trigger IFN production.

[0037] FIG. 2b is a graph showing WT or the indicated KO B16 cells treated with BPTES and / or IFNy for 24 hours. Ifnbl transcripts were determined by qPCR. n = 3 biological independent samples.

[0038] FIG. 2c is a graph showing Ifihl KO B16 cells carrying indicated shRNAs treated with IFNy for 48 hours. IFN|3 in the culture medium was determined by EEISA, n = 3 biological independent samples.

[0039] FIG. 2d is a schematic diagram showing the purification of cytosolic RNA samples and transfection into untreated cells.

[0040] FIGS. 2e-f is a dot plot and bar graph, respectively, showing B16 cells treated with BPTES and / or IFNy for 24 hours. Cytosolic RNA samples were incubated with / without RNase III and dot-plotted on membrane. DsRNA was determined by anti- dsRNA antibody (FIG. 2e). Cytosolic RNA samples were transfected into B16 cells for 12 hours. Ifnbl transcripts were determined by qPCR (FIG. 2f). Data are mean ± SD. n = 3 biological independent samples.

[0041] FIGS. 2g-h is a line graph and Kaplan-Meier curve, respectively, showing tumor growth curves and mouse overall survival. WT B16 cells carrying shFluc or shGdh inoculated into C57BE / 6 mice. The mice were treated with IgG or anti-PD-El antibody, n = 5 mice per group. P values by two-sided t test.

[0042] FIGS. 2i-j is a line graph and Kaplan-Meier curve, respectively, showing tumor growth curves and mouse overall survival. Ifihl KO B16 cells carrying shFluc or shGdh were inoculated into C57BE / 6 mice. The mice were treated with IgG or anti-PD-El antibody, n = 5 mice per group. P values by two-sided t test.

[0043] ED FIG. 2a is a Western blot showing WT or Ifihl KO B16 cells treated withIFNy for 24 hours. Protein levels of the indicated genes were determined by Western blot.1 of 2 blots is shown.

[0044] ED FIG. 2b is a Western blot showing WT or Ifihl KO B16 cells were treated with the indicated concentrations of BPTES in the presence or absence of IFNy for 24 hours. Protein levels of the indicated genes were determined by Western blot. 1 of 2 blots is shown.

[0045] FIG. 3a is a schematic diagram showing the RNA editing of endogenous retrovirus (ERV) regulates MDA5 activation and IFN production.

[0046] FIG. 3b is a schematic diagram showing the construction of the RNA editing reporter (RE-Euc).

[0047] FIG. 3c is a bar graph showing B16 cells transfected with RE-Euc and treated with BPTES and / or IFNy for 36 hours. Relative luminescence was determined by dual luciferase reporter assay. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0048] FIG. 3d is a Western blot showing WT or Adar 1 KO B16 cells treated with IFNy for 24 hours. Protein levels of the indicated genes were determined by Western blot. Adarl pl50 and pl 10 were detected. 1 of 3 blots is shown.

[0049] FIGS. 3e-g are bar graphs showing WT or Adarl KO B16 cells carrying RE-Euc were treated with BPTES and / or IFNy. Relative luminescence (FIG. 3e) or Ifnbl transcripts (FIG. 3f) were determined at 24 hours. Surface expression of H2-Kb(FIG. 3g) was determined at 48 hours. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0050] FIG. 3h is a Western blot showing Adarl -overexpressing B16 cells (Adarl-OE) incubated with BPTES for 24 hours. Palmitoylated Adarl was determined by pulldown assay following Click-IT reaction. 1 of 2 blots is shown.

[0051] FIG. 3i is a Western blot showing B16 cell forced expression of Adarl incubated with BPTES and / or 2-BP for 24 hours. Palmitoylated Adarl was determined by pulldown assay following Click-IT reaction. 1 of 2 blots is shown.

[0052] FIG. 3j is a schematic diagram showing ADAR1 domains and putative palmitoylation sites. The amino acid sequence around Cysio8i / io82 on ADAR1 is conserved across multiple species.

[0053] FIG. 3k Adarl KO B16 cells stably transfected with wild type Adarl (WT) or Cysio8i / io82 mutant Adarl (C2A) and treated with BPTES for 24 hours. Palmitoylation of Adarl were detected by Click-IT assay. 1 of 2 blots is shown.

[0054] FIG. 31 is a Western blot showing WT or C2A B16 cells transfected with RE-Luc and treated with increasing concentrations of BPTES for 24 hours. Relative luminescence was determined by dual luciferase reporter assay.

[0055] FIGS. 3m-n are bar graphs showing WT or C2A B16 cells were treated with BPTES in the presence or absence of IFNy. Ifnbl transcripts were determined at 24 hours (FIG. 3m). Surface expression of H2-Kbwas determined at 48 hours (FIG. 3n). Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0056] FIG. 3o is a schematic diagram showing the purification of the Zinc binding proteins with Zn-NTA agarose.

[0057] FIGS. 3p-q is a Western blot and line graph, respectively, showing WT or C2A B16 cells treated with increasing concentrations of BPTES (0, 1, 2, 5, 10 pM) for 24 hours. The Zinc binding proteins were enriched by Zn-NTA beads via the pulldown assay. Adarl protein was detected in the pulldown products and input. 1 of 2 blots is shown (FIG. 3p). Relative Zinc affinity was calculated by the enrichment of Adarl protein upon Zn-NTA pulldown assay (FIG. 3q).

[0058] FIG. 3r is a schematic diagram showing S-palmitoylation regulates ADAR1 RNA editing activity.

[0059] ED FIG. 3a is a schematic diagram showing domains of the two ADAR1 isoforms.

[0060] ED FIG. 3b is a Western blot showing B16 cells treated with IFNy for indicated hours. Adarl protein was determined by Western blot. 1 of 3 blots is shown.

[0061] ED FIG. 3c is two bar graphs showing B16 cells transfected with RE-Luc and / or Adarl -OE for 48 hours (left). WT or Adarl KO B16 cells were transfected with RE-Luc for 48 hours. Relative luminescence was determined by dual luciferase reporter assay. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0062] ED FIG. 3d is a Western blot showing B16 cells were treated with the indicated concentrations of BPTES in the presence or absence of IFNy for 24 hours. Adarl protein was determined by Western blot. 1 of 2 blots is shown.

[0063] ED FIG. 3e is an image of B16 cells carrying Adarl -OE treated with BPTES for 24 hours. Adarl protein was enriched by Co-IP with Flag antibody. Post-translational modifications were detected in the IP products.

[0064] ED FIG. 3f is two bar graphs showing B16 cells treated with BPTES and / or IFNy in the presence or absence of 2-BP. Ifnbl transcripts were determined at 24 hours. Surface expression of H2-Kbwas determined at 48 hours.

[0065] ED FIG. 3g is a table showing predicted palmitoylation sites on AD ARI by CSS- Palm.

[0066] ED FIG. 3h is a Western blot showing B16 cells carrying Adarl treated with the increasing concentrations of BPTES (0, 1, 2, 5, 10 pM) in the presence or absence of 25pM 2-BP for 24 hours. Adarl protein was determined by pulldown assay with Zn- NTA.

[0067] FIG. 4a is a graph showing B16 cells treated with BPTES for 12 hours. The indicated gene transcripts were determined by qPCR. n = 3 biological independent samples.

[0068] FIG. 4b is bar graph showing B16 cells transfected with RE-Luc, PRL-SV40, and the indicated Zdhhc plasmids overnight and treated with IFNy for 24 hours. Relative luminescence was determined. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0069] FIG. 4c-d are bar graphs showing B16 cells ectopically expressed with the indicated Zdhhc genes overnight and treated with IFNy. Ifnbl transcripts were determined at 24 hours (FIG. 4c). Surface expression of H2-Kbwas determined at 48 hours (FIG. 4d).

[0070] FIG. 4e is five bar graphs showing Zdhhc2-overexpressed B16 cells treated with IFNy for 36 hours. The indicated IFN signaling gene transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0071] FIG. 4f is a Western blot showing B16 cells treated with BPTES for the indicated hours. Zdhhc2 protein was determined by Western blot. 1 of 2 blots is shown.

[0072] FIG. 4g is a Western blot showing WT or Zdhhc2 KO B16 cells treated with BPTES at the indicated concentrations for 24 hours. Zdhhc2 protein was determined by Western blot. 1 of 2 blots is shown.

[0073] FIG. 4h is three bar graphs showing Zdhhc2 KO B16 cells treated with BPTES and / or IFNy for 36 hours. The indicated gene transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0074] FIG. 4i is a Western blot showing Adar 1 -overexpressing B16 cells forced to express Zdhhc2 at different levels for 48 hours. Palmitoylation of Adarl was determined by Click-IT assay.

[0075] FIG. 4j-k are Western blots showing B16 cells forced to express Adarl (Flag- tagged) and / or Zdhhc2 (HA-tagged) for 48 hours. Co-Immunoprecipitation (Co-IP) was performed with antibody against HA (Fig, 4j) or Flag (FIG. 4k). The indicated proteins were determined in the IP products or input samples. 1 of 2 blots is shown.

[0076] FIG. 41 is an image showing B16 cells forced to express Adarl (Flag-tagged) and / or Zdhhc2 (HA-tagged) for 48 hours. Immunofluorescence staining was performed with antibody against HA (Alexa Fluor 488) or Flag (Alexa Fluor 647). 1 of 4 captures is shown.

[0077] FIG. 4m is a Western blot showing the indicated proteins determined in WT or Srebpl KO B16 cells.

[0078] FIG. 4n is three bar graphs showing WT or Srepbl KO B16 cells were treated with IFNy for 36 hours. The indicated gene transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0079] FIG. 4o is a schematic diagram showing metabolic restriction enables IFN signaling amplification through the SREBP1-ZDHHC2-ADAR1 axis.

[0080] ED FIG. 4a is a bar graph showing CHL1 cells transfected with the indicated shRNAs for 24 hours. ZDHHC2 transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples.

[0081] ED FIG. 4b is an image showing ChlP-seq in GM78 cells with antibody against SREPB1 or SREPB2 shows the enrichment of SREBP1 but not SREBP2 in the ZDHHC2 promoter. The binding motif of SREBP1 in the human and mouse ZDHHC2 promoter is shown.

[0082] ED FIG. 4c is two bar graphs showing CHL1 cells treated with SREBP1 inhibitor (Fatostatin) or SREPB2 inhibitor (Betulin) at the indicated concentrations for 24 hours. ZDHHC2 transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0083] ED FIG. 4d is a Western blot showing Adarl expressing B16 cells treated with Fatostatin at the indicated concentrations for 24 hours. Palmitoylation of Adarl was determined by Click-IT assay. 1 of 2 blots is shown.

[0084] ED FIG. 4e-g are bar graphs showing CHL1 cells were treated with the indicated concentrations of Fatostatin in the presence or absence of IFNy. RNA editing efficacy (ED FIG. 4e) and IFNB1 transcripts (ED FIG. 4f) were determined at 24 hours. Surface expression of HEA-ABC (ED FIG. 4g) was determined at 48 hours. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0085] ED FIG. 4h is a bar graph showing ZDHHC2 transcripts were determined by qPCR in WT or Srebpl KO B16 cells. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0086] ED FIG. 4i and 4j are bar graphs showing WT or Srebpl KO B16 cells treated with BPTES and / or IFNy. Ifnbl transcripts (ED FIG. 4i) were determined at 24 hours. Surface expression of H2-Db (ED FIG. 4j) were determined at 48 hours.

[0087] ED FIG. 4k is a schematic diagram showing the working model of SREBP1 and small activating RNAs (saRNAs) targeting the ZDHHC2 promoter.

[0088] ED FIG. 41 and 4m are three bar graphs and a Western blot, respectively, showing B16 cells transfected with Zdhhc2 saRNAs for 24 hours. Expression of the indicated genes was determined by qPCR (ED FIG. 41) or Western blot (ED FIG. 4m). Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test. 1 of 2 blots is shown.

[0089] ED FIG. 4n-o are bar graphs showing B16 cells transfected with Zdhhc2 saRNAs and treated with IFNy. Expression of the indicated genes was determined at 24 hours (ED FIG. 4n) or 48 hours (ED FIG. 4o). Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test. 1 of 2 blots is shown.

[0090] ED FIG. 4p-q are bar graphs showing Zdhhc2 KO B16 cells transfected with Zdhhc2 saRNAs and treated with IFNy. Expression of the indicated genes was determined at 24 hours (ED FIG. 4p) or 48 hours (ED FIG. 4q). Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test. 1 of 2 blots is shown.

[0091] FIG. 5a is a schematic diagram showing the screening of the cysteine-targeting covalent inhibitors for their potential modification in ADAR 1 -RNA editing activity.

[0092] FIG. 5b-d are bar graphs showing B16 cells pretreated with IFNy overnight and subsequently treated with the indicated inhibitors at I pM. RNA editing efficacy (FIG. 5b) and Ifnbl transcripts (FIG. 5c) were determined at 24 hours. Surface expression ofH2-Kb(FIG. 5d) was determined at 48 hours. Data are mean ± SD. n = 3 biological independent samples.

[0093] FIG. 5e is the structure of Neratinib. Rectangle indicates the active cysteine- targeting group.

[0094] FIG. 5f-g are line graphs showing IFNy-pretreated B16 cells treated with 1 pM Neratinib at the indicated times (FIG. 5f) or with different concentrations of Neratinib at 8 hours (FIG. 5g). Ifnbl transcripts were determined by qPCR.

[0095] FIG. 5h-i are bar graphs showing WT, Adarl KO (h), or Adar 1 C2A mutant B16 cells treated with IFNy overnight and subsequently incubated with Neratinib at IpM for 8 hours. Ifnbl transcripts were determined by qPCR. Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0096] FIG. 5j is the structure of Neratinib-inactive. Rectangle indicates the inactive cysteine-targeting group.

[0097] FIG. 5k-n are bar graphs showing IFNy-pretreated B16 cells treated with Neratinib or Neratinib-inactive at I pM. Expression of the indicated genes were determined at 24 (FIG. 5k), 36 (FIG. 51, FIG. 5m), and 48 hours (FIG. 5n). Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0098] FIG. 5o is a Western blot showing B16-Adarl KO cells forced to express Adarl for 48 hours. Protein samples were incubated with biotin-Neratinib or Neratinib overnight, followed by pulldown assay with Streptavidin. Adarl and Gapdh proteins were detected in the Pulldown products or input samples. 1 of 2 blots is shown.

[0099] FIG. 5p is a Western blot showing B16-Adarl KO cells transfected with WT Adarl or C2A mutant plasmids for 48 hours. Protein samples were incubated with Biotin-Neratinib overnight, followed by pulldown assay with Streptavidin. Adarl and Gapdh proteins were detected in the Pulldown products or input samples. 1 of 2 blots is shown.

[0100] FIG. 5q is a schematic working model showing Neratinib regulates ADAR1 activity at Cysiosi / 1082.

[0100] FIG. 5r-s is four line graphs and a Kaplan-Meier curve, respectively, showing C57BL / 6 mice carrying B16 tumors treated with Neratinib and / or anti-PD-Ll antibody. Tumor growth curves (FIG. 5r) or mouse overall survival (FIG. 5s) were plotted. Data are mean ± SD. n = 12-14 mice. P values by two-sided t test.

[0101] ED FIG. 5a is a table showing information on the FDA-approved Cysteine- targeting covalent inhibitors.

[0102] ED FIG. 5b-c are each three line graphs showing human cancer cells (CHE1, SW480, and CAOV3) treated with Neratinib and / or IFNy. Expression of the indicated gene transcripts was determined at 24 (ED FIG. 5b) or 48 hours (ED FIG. 5c). Data are mean ± SD. n = 3 biological independent samples. P values by two-sided t test.

[0103] ED FIG. 5d is a Western blot showing Adar 1 -overexpressing B16 cells (IFNy pretreated) treated with different concentrations of Neratinib (0, 0.1, 0.2, 0.5, 1, 2, 5, and 10 pM) for 24 hours. Adarl protein was determined in the Zn-NTA pulldown products or input samples. 1 of 2 blots is shown.

[0104] ED FIG. 5e is the structure of biotin-Neratinib.

[0105] ED FIG. 5f is a Western blot showing expression levels of the indicated proteins in SKBR3 or B16F0 cells determined by Western blot. 1 of 2 blots is shown.

[0106] ED FIG. 5g is two Western blots showing SKBR3 or B16F0 cells treated with the indicated concentrations of Neratinib for 4 hours. Phosphorylated AKT levels were determined by Western blot. 1 of 2 blots is shown.

[0107] ED FIG. 5h is a line graph showing B16 tumor-bearing mice treated with anti- PD-E1 antibody and / or Neratinib. Tumor growth curves were plotted. Data are shown as mean ± SD. n =12 -14 mice per group.

[0108] ED FIG. 5i-j are representative dot plots (ED FIG. 5i) and the percentages (ED FIG. 5j) of intra-tumoral IFNy+, TNFD+, and Granzyme B+ CD8+ T cells in mice bearing B16 tumors treated with the indicated drugs, n = 6, P value by t-test.

[0109] ED FIG. 5k is a schematic working model suggesting that during metabolic restriction or therapeutic targeting, the Zinc cofactor binding site of ADAR1 can be occupied by the ZDHHC2-mediated palmitoylation or the Neratinib-mediated covalent modification, respectively, thereby diminishing ADAR1-RNA editing activity and eliciting type-I / III IFN production.DETAILED DESCRIPTIONI. Compounds of the Disclosure

[0110] In one embodiment, the present disclosure provides a compound havingFormula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0111] R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;

[0112] Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9,;

[0113] Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;

[0114] R8and R9are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, and (C1-C6alkoxy)C1-C6alkyl; or

[0115] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;

[0116] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0117] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4- to 7-membered heterocyclo)C1-C6alkyl;

[0118] R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl;

[0119] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0120] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl.

[0121] In another embodiment, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -CH=CHRla.

[0122] In another embodiment, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is -C=CRlb.

[0123] In another embodiment, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, with the following provisos:

[0124] (i) if R4is cyano and R1is -CH2NR8R9, then R8and R9are each independently selected from the group consisting of hydrogen, C2-C6 alkyl, C3-C6cycloalkyl, and (C1-C6alkoxy )C1-C6alkyl; or R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo; or

[0125] (ii) if R1is -CH2NR8R9and R8and R9are each methyl, then R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0126] (iii) if R1is -CH2NR8R9, R8and R9are each methyl, and R4is cyano, then R3is C1-C6alkyl or C3-C6cycloalkyl.

[0127] In another embodiment, the present disclosure provides a compound having Formula (II):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0128] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0129] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0130] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C6alkoxy, C3-C6cycloalkyl, (optionally substituted heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-; and

[0131] Rla, R2, R3, and R4are as defined in connection with Formula (I).

[0132] In another embodiment, the present disclosure provides a compound having Formula (III):(III), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0133] R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl; and

[0134] Rla, R2, R3, R4, R6a, and R6bare as defined in connection with Formula (II).

[0135] In another embodiment, the present disclosure provides a compound having Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted 5-membered heteroaryl.

[0136] In another embodiment, the present disclosure provides a compound havin Formula (IV):(IV), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0137] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo; and

[0138] Rla, R2, R3, R4, and R6aare as defined in connection with Formula (III).

[0139] In another embodiment, the present disclosure provides a compound having Formula (V):(V),or a pharmaceutically acceptable salt or solvate thereof, wherein Rla, R2, R3, R4, R5b, and R6aare as defined in connection with Formula (IV).

[0140] In another embodiment, the present disclosure provides a compound having Formula (VI):or a pharmaceutically acceptable salt or solvate thereof, wherein Rla, R2, R3, R4, R5b, and R6aare as defined in connection with Formula (IV).

[0141] In another embodiment, the present disclosure provides a compound having Formula (VII):or a pharmaceutically acceptable salt or solvate thereof, wherein Rla, R2, R3, R4, R5b, and R6aare as defined in connection with Formula (IV).

[0142] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein Rlais hydrogen.

[0143] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein Rlais C1-C4 alkyl.

[0144] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein Rlais optionally substituted 4- to 7-membered heterocyclo.

[0145] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof,wherein Rlais -CH2NR8R9. In another embodiment, R8and R9are C1-C6alkyl. In another embodiment, R8and R9are methyl. In another embodiment, R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo. In another embodiment, R8and R9taken together with the nitrogen atom to which they are attached form:

[0146] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein R2is -OR7. In another embodiment, R7is methyl, ethyl, or propyl. In another embodiment, R7is ethyl. In another embodiment, R7is C3-C6cycloalkyl. In another embodiment, R7is (C3-C6cycloalkyl)C1-C6-alkyl. In another embodiment, R7is (C1-C6- alkoxy)C1-C6alkyl. In another embodiment, R7is optionally substituted 4- to 7-membered heterocyclo. In another embodiment, R7is(optionally substituted 4- to 7-membered heterocyclo)C1-C6alkyl.

[0147] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein R3is hydrogen or C1-C6alkyl. In another embodiment, R3is hydrogen. In another embodiment, R3is methyl. In another embodiment, R3is ethyl.

[0148] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein R3is C3-C6cycloalkyl. In another embodiment, R4is cyclopropyl.

[0149] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein R4is hydrogen or cyano. In another embodiment, R4is hydrogen. In another embodiment, R4is cyano.

[0150] In another embodiment, the present disclosure provides a compound having any one of Formulae (I)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein R6ais hydrogen or halogen. In another embodiment, R6ais hydrogen. In another embodiment, R6ais chloro.

[0151] In another embodiment, the present disclosure provides a compound having any one of Formulae (IV)-(VII), or pharmaceutically acceptable salts or solvates thereof, wherein R5bis hydrogen or C1-C6alkyl.

[0152] In another embodiment, Compounds of the Disclosure are compounds having Formula (IX):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0153] X is selected from the group consisting of -O- and -NRa-;

[0154] Rais selected from the group consisting to hydrogen and C1-C4 alkyl;

[0155] R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;

[0156] Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9;

[0157] Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;

[0158] R8is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4-to 7-membered heterocyclo, C2-C12 alkynyl, and (C1-C6alkoxy)C1-C6alkyl;

[0159] R9is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0160] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;

[0161] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0162] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;

[0163] R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;

[0164] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0165] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10- membered heteroaryl.

[0166] In another embodiment, Compounds of the Disclosure are compounds having Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of:

[0167] In another embodiment, Compounds of the Disclosure are compounds having Formula (X):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0168] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0169] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0170] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C4 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, (optionally substituted 4- to 7-membered heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-; and

[0171] Rla, R2, R3, R4, and X are as defined in connection with Formula (IX).

[0172] In another embodiment, Compounds of the Disclosure are compounds havingFormula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0173] R6bis hydrogen; and

[0174] R6Cis selected from the group consisting of:

[0175] In another embodiment, Compounds of the Disclosure are compounds having Formula (XI):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0176] R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl;

[0177] Rla, R2, R3, R4, and X are as defined in connection with Formula (IX); and

[0178] R6aand R6bare as defined in connection with Formula (X).

[0179] In another embodiment, Compounds of the Disclosure are compounds havingFormula (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted 5-membered heteroaryl, e.g., imidazole.

[0180] In another embodiment, Compounds of the Disclosure are compounds having Formula (XII):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0181] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0182] Rla, R2, R3, R4, and X are as defined in connection with Formula (IX); and

[0183] R6ais as defined in connection with Formula (X).

[0184] In another embodiment, Compounds of the Disclosure are compounds having Formula (XIII):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0185] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0186] Rla, R2, R3, R4, and X are as defined in connection with Formula (IX); and

[0187] R6ais as defined in connection with Formula (X).

[0188] In another embodiment, Compounds of the Disclosure are compounds having Formula (XIV):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0189] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0190] Rla, R2, R3, R4, and X are as defined in connection with Formula (IX); and

[0191] R6ais as defined in connection with Formula (X).

[0192] In another embodiment, Compounds of the Disclosure are compounds having Formula (XV):(XV), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0193] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0194] Rla, R2, R3, R4, and X are as defined in connection with Formula (IX); and

[0195] R6ais as defined in connection with Formula (X).

[0196] In another embodiment, Compounds of the Disclosure are compounds having Formula (XVI):(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0197] R5is selected from the group consisting of optionally substituted 5- to 7-membered heterocylo and optionally substituted 5- to 10-membered heteroaryl; and

[0198] Rla, R2, R3, R4, and X are as defined in connection with Formula (IX).

[0199] In another embodiment, Compounds of the Disclosure are compounds havingFormula (XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 7-membered heterocylo. In another embodiment, R5is selected from the group consisting of:

[0200] In another embodiment, Compounds of the Disclosure are compounds havingFormula (XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein R5isoptionally substituted 5- to 10-membered heteroaryl. In another embodiment, R5is selected from the group consisting of:

[0201] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais hydrogen.

[0202] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais C1-C4 alkyl.

[0203] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais -CFhNR8R9; and R8and R9are C1-C6alkyl. In another embodiment, R8and R9are methyl. In another embodiment, R8is optionally substituted 4-to 7-membered heterocyclo. In another embodiment, R8is selected from the group consisting of:In another embodiment, R8is C2-C10 alkynyl. In another embodiment, R8is selected from the group consisting of:

[0204] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais -CFhNR8R9; and R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo. In another embodiment, R8and R9taken together with the nitrogen atom to which they are attached form:

[0205] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais selected from the group consisting of:

[0206] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -OR7. In another embodiment, R7is selected from the group consisting of methyl, ethyl, and propyl. In another embodiment, R7is ethyl.

[0207] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from the group consisting of hydrogen and C1-C6alkyl. In anotherembodiment, R3is hydrogen. In another embodiment, R3is methyl. In another embodiment, R3is ethyl.

[0208] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from the group consisting of hydrogen and cyano. In another embodiment, R4is hydrogen. In another embodiment, R4is cyano.

[0209] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (X)-(XV), or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais selected from the group consisting of hydrogen and halogen. In another embodiment, R6ais hydrogen. In another embodiment, R6ais chloro.

[0210] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), wherein X is -O-.

[0211] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVI), wherein X is -NH-.

[0212] In another embodiment, Compounds of the Disclosure are compounds having Formula (XVII):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0213] R3is selected from the group consisting of methyl, ethyl, propyl, isopropyl, and cyclopropyl;

[0214] R5is selected from the group consisting of optionally substituted 4- to 7-membered heterocyclo, optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10-membered heteroaryl;

[0215] R8is selected from the group consisting of C1-C6alkyl, optionally substituted 4-to 7-membered heterocyclo, and C2-C12 alkynyl; and

[0216] R9is C1-C6alkyl; or

[0217] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo.

[0218] In another embodiment, Compounds of the Disclosure are compounds having any one of Formulae (IX)-(XVII), or a pharmaceutically acceptable salt or solvate thereof, with the following provisos:

[0219] (i) if R4is cyano and R1is -CH2NR8R9, then R8is selected from the group consisting of hydrogen, C2-C6 alkyl, C3-C6cycloalkyl, optionally substituted 4-to 7-membered heterocyclo, C2-C12 alkynyl, and (C1-C6alkoxy )C1-C6alkyl; R9is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; or R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo; or

[0220] (ii) if R1is -CH2NR8R9and R8and R9are each methyl, then R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0221] (iii) if R1is -CH2NR8R9, R8and R9are each methyl, and R4is cyano, then R3is C1-C6alkyl or C3-C6cycloalkyl.

[0222] In another embodiment, the present disclosure provides any one or more of the compounds of Table 1A, or pharmaceutically acceptable salts or solvates thereof.Table 1A

[0223] In another embodiment, the present disclosure provides any one or more of the compounds of Table 2A, or pharmaceutically acceptable salts or solvates thereof.Table 2 A

[0224] In another embodiment, the present disclosure provides any one or more of the compounds of Table 1 A and 2A, or pharmaceutically acceptable salts or solvates thereof.

[0225] In another embodiment, the present disclosure provides any one or more of the following compounds:

[0226] In another embodiment, the present disclosure provides any one or more of the following compounds:

[0227] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable excipient.

[0228] In another embodiment, the present disclosure provides any one or more of the compounds of Table IB, or pharmaceutically acceptable salts or solvates thereof.Table IBII. Synthetic Intermediates

[0229] In another embodiment, the present disclosure provides compounds having Formula (VIII):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0230] R10is selected from the group consisting of chloro and -N(H)R5;

[0231] R11is selected from the group consisting of hydrogen and -C(=O)CH3; and

[0232] R2, R3, R4, and R5are as defined in connection with Formula (I) or Formula (IX).

[0233] In another embodiment, the present disclosure provides a compound having Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R10is chloro.

[0234] In another embodiment, the present disclosure provides a compound having Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0235] R10is -N(H)R5;

[0236]

[0237] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0238] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0239] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C6alkoxy, C3-C6cycloalkyl, (optionally substituted heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-.

[0240] In another embodiment, the present disclosure provides a compound having Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0241] R10is -N(H)R5;

[0242]

[0243] R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl;

[0244] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0245] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl.

[0246] In another embodiment, the present disclosure provides a compound having Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of optionally substituted 5- to 7-membered heterocylo and optionally substituted 5- to 10-membered heteroaryl.

[0247] In another embodiment, Compounds of the Disclosure are compounds having Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 7-membered heterocylo. In another embodiment, R5is selected from the group consisting of:

[0248] In another embodiment, Compounds of the Disclosure are compounds having Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 10-membered heteroaryl. In another embodiment, R5is selected from the group consisting of:

[0249] In another embodiment, the present disclosure provides a compound having Formula (VIII), or pharmaceutically acceptable salts or solvates thereof, wherein R2is -OR7. In another embodiment, R7is methyl, ethyl, or propyl. In another embodiment, R7is ethyl. In another embodiment, R7is C3-C6cycloalkyl. In another embodiment, R7is (C3-C6cycloalkyl)C1-C6-alkyl. In another embodiment, R7is (C1-C6- alkoxy)C1-C6alkyl. In another embodiment, R7is optionally substituted 4- to 7-membered heterocyclo. In another embodiment, R7is(optionally substituted 4- to 7-membered heterocyclo)C1-C6alkyl.

[0250] In another embodiment, the present disclosure provides a compound having Formula (VIII), or pharmaceutically acceptable salts or solvates thereof, wherein R3ishydrogen or C1-C6alkyl. In another embodiment, R3is hydrogen. In another embodiment, R3is methyl. In another embodiment, R3is ethyl.

[0251] In another embodiment, the present disclosure provides a compound having Formula (VIII), or pharmaceutically acceptable salts or solvates thereof, wherein R3is C3-C6cycloalkyl. In another embodiment, R4is cyclopropyl.

[0252] In another embodiment, the present disclosure provides a compound having Formula (VIII), or pharmaceutically acceptable salts or solvates thereof, wherein R4is hydrogen or cyano. In another embodiment, R4is hydrogen. In another embodiment, R4is cyano.

[0253] In another embodiment, the present disclosure provides a compound having Formula (VIII), or pharmaceutically acceptable salts or solvates thereof, wherein R6ais hydrogen or halogen. In another embodiment, R6ais hydrogen. In another embodiment, R6ais chloro.

[0254] In another embodiment, the present disclosure provides a compound having Formula (VIII), or pharmaceutically acceptable salts or solvates thereof, wherein R11is hydrogen.

[0255] In another embodiment, the present disclosure provides a compound having Formula (VIII), or pharmaceutically acceptable salts or solvates thereof, wherein R11is -C(=O)CH3.

[0256] In another embodiment, the present disclosure provides any one or more of the compounds of Table 1C, or pharmaceutically acceptable salts or solvates thereof. Compounds having Formula (VIII) and the compounds of Table 1C are synthetic intermediates that can be used, for example, to prepare certain Compounds of the Disclosure.Table 1C

[0257] In another embodiment, the present disclosure provides compounds havingFormula (XVIII):(XVIII), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0258] X is selected from the group consisting of -O- and -NRa-;

[0259] Rais selected from the group consisting to hydrogen and C1-C4 alkyl;

[0260] LG is a leaving group;

[0261] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0262] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;

[0263] R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;

[0264] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0265] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo,optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10- membered heteroaryl.

[0266] In another embodiment, the present disclosure provides compounds having Formula (XVIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of:

[0267] In another embodiment, the present disclosure provides compounds having Formula (XIX):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0268] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0269] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0270] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C4 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, (optionally substituted 4- to 7-membered heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-; and

[0271] LG, R2, R3, R4, and X are as defined in connection with Formula (VXIII).

[0272] In another embodiment, the present disclosure provides compounds having Formula (XIX), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0273] R6bis hydrogen; and

[0274] R6Cis selected from the group consisting of:

[0275] In another embodiment, the present disclosure provides compounds having Formula (XX):(XX), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0276] R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl;

[0277] LG, R2, R3, R4, and X are as defined in connection with Formula (XVIII); and

[0278] R6aand R6bare as defined in connection with Formula (XIX).

[0279] In another embodiment, Compounds of the Disclosure are compounds having Formula (XX), or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted 5-membered heteroaryl, e.g., imidazole.

[0280] In another embodiment, the present disclosure provides compounds having Formula (XXI):(XXI), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0281] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0282] LG, R2, R3, R4, and X are as defined in connection with Formula (XVIII); and

[0283] R6ais as defined in connection with Formula (XIX).

[0284] In another embodiment, Compounds of the Disclosure are compounds having Formula (XXII):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0285] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0286] LG, R2, R3, R4, and X are as defined in connection with Formula (XVIII); and

[0287] R6ais as defined in connection with Formula (XIX).

[0288] In another embodiment, the present disclosure provides compounds having Formula (XXIII):(XXIII), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0289] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0290] LG, R2, R3, R4, and X are as defined in connection with Formula (XVIII); and

[0291] R6ais as defined in connection with Formula (XIX).

[0292] In another embodiment, the present disclosure provides compounds having Formula (XXIV):(XXIV), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0293] R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo;

[0294] LG, R2, R3, R4, and X are as defined in connection with Formula (XVIII); and

[0295] R6ais as defined in connection with Formula (XIX).

[0296] In another embodiment, the present disclosure provides compounds having Formula (XXV):(XXV), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0297] R5is selected from the group consisting of optionally substituted 5- to 7-membered heterocylo and optionally substituted 5- to 10-membered heteroaryl; and

[0298] LG, R2, R3, R4, and X are as defined in connection with Formula (XVIII).

[0299] In another embodiment, the present disclosure provides compounds havingFormula (XXV), or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 7-membered heterocylo. In another embodiment, R5is selected from the group consisting of:

[0300] In another embodiment, the present disclosure provides compounds havingFormula (XXV), or a pharmaceutically acceptable salt or solvate thereof, wherein R5isoptionally substituted 5- to 10-membered heteroaryl. In another embodiment, R5is selected from the group consisting of:

[0301] In another embodiment, the present disclosure provides compounds having any one of Formulae (XVIII)-(XXV), or a pharmaceutically acceptable salt or solvate thereof, wherein LG is chloro.

[0302] In another embodiment, the present disclosure provides any one or more of the compounds of Table 8, see EXAMPLE 59, or pharmaceutically acceptable salts or solvates thereof. Compounds having Formulae (XVIII)-(XXV), and the compounds of Table 8 are synthetic intermediates that can be used, for example, to prepare certain Compounds of the Disclosure.III. Therapeutic Methods and Uses

[0303] Compounds of the Disclosure inhibit adenosine deaminase acting on RNA 1 enzymes (ADAR1) and are thus useful in the treatment of a variety of diseases and conditions. In particular, Compounds of the Disclosure are useful in methods of treating a disease or condition wherein ADAR1 inhibition provides a benefit, for example, cancers and proliferative diseases, viral infections, and autoimmune diseases. The therapeutic methods of the present disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to a subject, e.g., a cancer patient, in need thereof. The present methods also encompass administering a second therapeutic agent, e.g., an immune checkpoint inhibitor (ICI), to the subject in combination with the Compound of the Disclosure.

[0304] The present disclosure provides Compounds of the Disclosure as ADAR1 inhibitors for the treatment of a variety of diseases and conditions wherein inhibition of ADAR1 has a beneficial effect. Compounds of the Disclosure typically have IC50 (the drug concentration that results in 50% ADAR1 inhibition) values of less than 100 pM, e.g., less than 50 pM, less than 25 pM, and less than 5 pM, less than about 1 pM, lessthan about 0.5 pM, or less than about 0.1 pM. In some embodiments, Compounds of the Disclosure typically have IC50 values of less than about 0.01 pM. In some embodiments, Compounds of the Disclosure typically have IC50 values of less than about 0.001 pM. In one embodiment, the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein ADAR1 provides a benefit comprising administering a therapeutically effective amount of a Compound of the Disclosure and optionally one or more ICIs to an individual in need thereof

[0305] Since Compounds of the Disclosure are AD ARI inhibitors, a number of diseases and conditions mediated by ADAR1 can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a condition or disorder responsive to ADAR1 in an animal, e.g., a human, suffering from, or at risk of suffering from, the condition or disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.

[0306] The present disclosure is further directed to a method of inhibiting ADAR1 in a subject in need thereof, said method comprising administering to the subject an effective amount of a Compound of the Disclosure.

[0307] The present disclosure is further directed to a method of sensitizing tumor response to immunotherapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Compound or the Disclosure and one or more ICIs. Is some aspects, the tumor is resistant to immune checkpoint blockade.

[0308] In another aspect, the present disclosure provides a method of treating cancer in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure and optionally one or more ICIs. In another aspect, the present disclosure provides a method of treating cancer in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure. In another aspect, the present disclosure provides a method of treating cancer in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure in combination with a therapeutically effective amount of one or more ICIs. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure treat cancer by inhibiting ADAR1 and / or sensitizing cancer cells administration of ICIs. Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table 2.Table 2

[0309] In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 3. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.Table 3

[0310] In another embodiment, the cancer is a leukemia, for example, a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment, the cancer is NUT-midline carcinoma. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment, the cancer isa neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

[0311] In another embodiment, the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non- small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0312] In another embodiment, a Compound of the Disclosure are administered to a subject in need thereof to treat breast cancer, ovarian cancer, or prostate cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is metastatic castration-resistant prostate cancer.

[0313] The methods of the present disclosure can be accomplished by administering a Compound of the Disclosure as the neat compound or as a pharmaceutical composition. Administration of a pharmaceutical composition, or neat Compound of the Disclosure, can be performed during or after the onset of the disease or condition of interest. Typically, the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.

[0314] In one embodiment, a Compound of the Disclosure is administered as a single agent to treat a disease or condition wherein inhibition of ADAR1 provides a benefit, e.g., cancer. In another embodiment, a Compound of the Disclosure is administered in combination with a second therapeutic agent, e.g., one or more ICIs, useful in the treatment of a disease or condition wherein inhibition of ADAR1 provides a benefit. A Compound of the Disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the Compound of the Disclosure and second therapeutic agent can be administered as a single pharmaceutical composition or two separate pharmaceutical compositions. In someembodiments, the second therapeutic agent is one or more ICIs, e.g., one or more anti-PD-1 antibodies, one or more anti-PD-Ll antibodies, one or more anti-CTLA-4 antibodies, one or more anti-LAG3 antibodies, one or more anti-TIM3 antibodies, one or more anti- VISTA antibodies, one or more anti-TIGIT antibodies, or one or more anti- cd47 antibodies, or a combination thereof, e.g., nivolumab, pembrolizumab, dostarlimab, retifanlimab, cemiplimab, avelumab, atezolizumab, or durvalumab, or a combination thereof.

[0315] The second therapeutic agent is administered in an amount to provide its desired therapeutic effect. The effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is, for example, administered to an individual in need thereof within such established ranges. In some embodiments, administration of a Compound of the Disclosure sensitizs the cancer cells to ICB and thus the effective dosage of one or more ICIs co-administered with the Compound of the Disclosure is less, e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% less, than the established ranges for the one or more ICIs known in the art.

[0316] A Compound of the Disclosure and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the Compound of the Disclosure is administered before the second therapeutic agent or vice versa. One or more doses of the Compound of the Disclosure and / or one or more doses of the second therapeutic agent can be administered. The Compound of the Disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.

[0317] In some methods of the present disclosure, a therapeutically effective amount of a Compound of the Disclosure, typically formulated in accordance with pharmaceutical practice, is administered to a subject, e.g., a human cancer patient, in need thereof. In some methods of the present disclosure, a therapeutically effective amount of a Compound of the Disclosure, typically formulated in accordance with pharmaceutical practice, is administered to a subject in need thereof in combination with a therapeutically effective amount of an ICI. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and / or malfunctions that are present, the risks of developing particular signs, symptoms and / or malfunctions, and other factors.

[0318] A Compound of the Disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracistemal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation at a particular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.

[0319] Pharmaceutical compositions include those wherein a Compound of the Disclosure is administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a Compound of the Disclosure that is sufficient to maintain therapeutic effects.

[0320] Toxicity and therapeutic efficacy of the Compounds of the Disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals. The dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0321] A therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the ADAR1 inhibitor that are sufficient to maintain the desired therapeutic effects. The desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required. For example, a Compound of the Disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4);four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two days rest, and another five daily doses (5 / 2 / 5); or, any dose regimen determined to be appropriate for the circumstance.

[0322] A Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of, for example, about 0.005 to about 5000 milligrams per dose, about 10 to about 1000 milligrams per dose, about 10 to about 500 milligrams per dose, or about 10 to about 100 milligrams per dose. For example, a Compound of the Disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, or about 1000 milligrams, including all doses between 0.005 and 5000 milligrams.

[0323] The dosage of a composition containing a Compound of the Disclosure, or a composition containing the same, can be from about 1 ng / kg to about 200 mg / kg, about 1 pg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 pg / kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 pg / kg, about 10 pg / kg, about 25 pg / kg, about 50 pg / kg, about 75 pg / kg, about 100 pg / kg, about 125 pg / kg, about 150 pg / kg, about 175 pg / kg, about 200 pg / kg, about225 pg / kg, about 250 pg / kg, about 275 pg / kg, about 300 pg / kg, about 325 pg / kg, about350 pg / kg, about 375 pg / kg, about 400 pg / kg, about 425 pg / kg, about 450 pg / kg, about475 pg / kg, about 500 pg / kg, about 525 pg / kg, about 550 pg / kg, about 575 pg / kg, about600 pg / kg, about 625 pg / kg, about 650 pg / kg, about 675 pg / kg, about 700 pg / kg, about725 pg / kg, about 750 pg / kg, about 775 pg / kg, about 800 pg / kg, about 825 pg / kg, about850 pg / kg, about 875 pg / kg, about 900 pg / kg, about 925 pg / kg, about 950 pg / kg, about975 pg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, or more. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines the actual dosingregimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject.

[0324] Compounds of the Disclosure typically are administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of Compound of the Disclosure.

[0325] These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of the Compound of the Disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a Compound of the Disclosure. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a Compound of the Disclosure.

[0326] When a therapeutically effective amount of a Compound of the Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.

[0327] Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.

[0328] Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Buffers and pH modifiers can also be added to stabilize the pharmaceutical composition.

[0329] Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0330] Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0331] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a- I l l -Compound of the Disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0332] Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the Compound of the Disclosure also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the Compound of the Disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.

[0333] In particular, the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.IV. Immune Checkpoint Inhibitors

[0334] Immune checkpoint inhibitors (ICIs) are therapies that blockade immune system inhibitor checkpoints. Immune checkpoints can be stimulatory or inhibitory. Blockade of inhibitory immune checkpoint activates immune system function and can be used for cancer immunotherapy. Pardoll, Nature Reviews. Cancer 12:252-64 (2012). Tumor cells turn off activated T cells when they attach to specific T-cell receptors. ICIs prevent tumor cells from attaching to T cells, which results in T cells remaining activated. Ineffect, the coordinated action by cellular and soluble components combats pathogens and injuries by cancers. The modulation of immune system pathways may involve changing the expression or the functional activity of at least one component of the pathway to then modulate the response by the immune system. U.S. 2015 / 0250853. Examples of ICIs include, but are not limited to, TIGIT inhibitors, PD-1 inhibitors, PD-L1 (B7-H1) inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, and cd47 inhibitors. The effective dosage range for ICIs is generally known in the art, and the immune checkpoint inhibitor(s) is(are) administered to a subject in need thereof within, for example, such established ranges.

[0335] In one embodiment, methods and uses of the present disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to a subject in combination with a therapeutically effective amount of one or more ICIs to treat cancer.

[0336] In another embodiment, methods of the present disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to a subject in combination with one or more PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, TIGIT inhibitors, or cd47 inhibitors, or a combination thereof.

[0337] In another embodiment, the one or more ICIs comprise a programmed cell death (PD-1) inhibitor. PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-L1, a ligand of PD-1, enhances immune function and mediates antitumor activity. Examples of PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies of anti-PD- 1 antibodies, see U.S. 2013 / 0309250, U.S. 6,808,710, U.S. 7,595,048, U.S. 8,008,449, U.S. 8,728,474, U.S. 8,779,105, U.S. 8,952,136, U.S. 8,900,587, U.S. 9,073,994, U.S. 9,084,776, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0338] In another embodiment, the one or more ICIs comprise a PD-L1 (also known as B7-H1 or CD274) inhibitor. Examples of PD-L1 inhibitors include antibodies that specifically bind to PD-L1. Particular anti-PD-Ll antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, KN035, and BMS-936559. For a generaldiscussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. 8,217,149, U.S. 2014 / 0341917, U.S. 2013 / 0071403, WO 2015036499, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0339] In another embodiment, the one or more ICIs comprise a CTLA-4 inhibitor. CTLA-4, also known as cytotoxic T-lymphocyte antigen 4, is a protein receptor that downregulates the immune system. CTLA-4 is characterized as a "brake" that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. Lor a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. 6,984,720, U.S. 6,207,156, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0340] In another embodiment, the one or more ICIs comprise a LAG3 inhibitor. LAG3, Lymphocyte Activation Gene 3, is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation. In addition, LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation. U.S. 2014 / 0286935. Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Particular anti- LAG3 antibodies include, but are not limited to, GSK2831781. Lor a general discussion of the availability, methods of production, mechanism of action, and studies, see, U.S. 2011 / 0150892, U.S. 2014 / 0093511, U.S. 2015 / 0259420, and Huang et al., Immunity 21:503-13 (2004).

[0341] In another embodiment, the one or more ICIs comprise a TIM3 inhibitor. TIM3, T-cell immunoglobulin and mucin domain 3, is an immune checkpoint receptor that functions to limit the duration and magnitude of TH1 and TCI T-cell responses. The TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8+ T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology Research 2:393-98 (2014). Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3. Lor a general discussion of the availability, methods of production, mechanism of action, and studies of TIM3 inhibitors, see U.S. 20150225457,U.S. 20130022623, U.S. 8,522,156, Ngiow et al., Cancer Res 71: 6567-71 (2011), Ngiow, et al., Cancer Res 71:3540-51 (2011), and Anderson, Cancer Immunology Res 2:393-98 (2014).

[0342] In another embodiment, the one or more ICIs comprise a cd47 inhibitor. See Unanue, E.R., PNAS 110:10886-87 (2013).

[0343] In another embodiment, the one or more ICIs comprise a TIGIT inhibitor.

[0344] T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is an inhibitory receptor expressed on several immune cell types, including CD8+ T cells, natural killer, or NK, cells, T regulatory cells, or Tregs, and follicular T helper cells. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumor cells to down-regulate T cell and natural killer (NK) cell functions. See, e.g., Harjunpaa, Clinical Experimental Immunology 200(2): 108- 19 (2020). TIGIT has been shown to be a mediator of resistance to existing checkpoint inhibitors, including anti-PD-1. TIGIT also directly suppresses the antitumor effector function on CD8 T cells. TIGIT inhibitors may include antibodies and small molecules. Non-limiting exemplary TIGIT inhibitor antibodies include vibostolimab (MK-7684), tiragolumab (RG6058), EOS_448, BMS- 986207, BGB-A1217, MTIG7192A, AB 154, ASP8374, and MK-7684.

[0345] The term "antibody" is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity. In another embodiment, "antibody" is meant to include soluble receptors that do not possess the Fc portion of the antibody. In one embodiment, the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.

[0346] Another class of ICIs include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction. Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. 8,114,845.

[0347] Another class of ICIs include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. 8,907,053 and have the structure:or a pharmaceutically acceptable salt thereof, wherein the compound comprises at least 5 amino acids useful as therapeutic agents capable of inhibiting the PD-1 signaling pathway.

[0348] Another class of ICIs include inhibitors of certain metabolic enzymes, such as indoleamine 2,3 dioxygenase (IDO), which is expressed by infiltrating myeloid cells and tumor cells. The IDO enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions. Pardoll, Nature Reviews. Cancer 12:252-64 (2012); Lob, Cancer Immunol Immunother 58:153-57 (2009). Particular IDO blocking agents include, but are not limited to, levo-1- methyl typtophan (L-1MT) and 1-methyl-tryptophan (1MT). Qian et al., Cancer Res 69:5498-504 (2009); and Lob et al., Cancer Immunol Immunother 58:153-7 (2009).

[0349] In one embodiment, the one or more ICIs comprise nivolumab, pembrolizumab, pidilizumab, STLA1110, avelumab, atezolizumab, durvalumab, STI A1014, ipilimumab, tremelimumab, cemiplimab, tislelizumab, toripalimab, camrelizumab, GSK2831781, BMS-936559 or MED 14736, or a combination thereof.

[0350] Therapeutically effective amounts of a Compound of the Disclosure and, optionally, the one or more ICIs formulated in accordance with standard pharmaceutical practices, are administered to a human patient in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and / or malfunctions that are present, the risks of developing particular signs, symptoms and / or malfunctions, and other factors.

[0351] A Compound of the Disclosure and, optionally, the one or more ICIs can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation at aparticular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique. In one embodiment, a Compound of the Disclosure is administered orally to the subject. In one embodiment, a Compound of the Disclosure is administered intraveneously to the subject.

[0352] Pharmaceutical compositions include those wherein a Compound of the Disclosure and, optionally, the one or more ICIs are administered in an effective amount to achieve their intended purpose. The exact formulation, route of administration, and dosage of each combination partner is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a Compound of the Disclosure, and, optionally, the one or more ICIs that is sufficient to maintain therapeutic effects.

[0353] Toxicity and therapeutic efficacy of a Compound of the Disclosure and / or the one or more ICIs can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no unacceptable toxicity in a patient. The dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0354] A therapeutically effective amount of a Compound of the Disclosure, and, optionally, the one or more ICIs required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and ultimately is determined by the attendant physician. For example, dosage amounts and intervals can be adjusted individually to provide plasma levels of a Compound of the Disclosure and / or the one or more ICIs that are sufficient to maintain the desired therapeutic effects. The desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses of the therapeutic agent(s) may be desired or required. For example, a Compound of the Disclosure and / or the one or more ICIs can be administered at a frequency of: one dose per day; four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose deliveredper day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two days rest, and another five daily doses (5 / 2 / 5); or, any dose regimen determined to be appropriate for the circumstance.

[0355] The one or more ICIs are administered to the subject in therapeutically effective amounts. These amounts are guided by standard clinical practice, e.g., according to the prescribing information associated with the ICIs. For example, when the immune checkpoint inhibitor is a monoclonal antibody, about 1 to about 2000 mg can be administered to the subject as an intravenous infusion every 2-4 weeks. For example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg of the antibody can be administered.

[0356] For example, when the one or more ICIs is nivolumab, 240 mg may be administered to the subject by intravenous infusion every two weeks, or 480 mg may be administered by intravenous infusion every for weeks.

[0357] For example, when the one or more ICIs is pembrolizumab, 200 mg may be administered to the subject by intravenous infusion every three weeks, or 400 mg may be administered to the subject by intravenous infusion every six weeks.

[0358] For example, when the one or more ICIs is avelumab, 800 mg may be administered to the subject by intravenous infusion every two weeks.

[0359] For example, when the one or more ICIs is atezolizumab, 840 mg may be administered by intravenous infusion every two weeks, or 1200 mg may be administered by intravenous infusion every three weeks, or 1680 mg may be administered by intravenous infusion every four weeks.

[0360] For example, when the one or more ICIs is ipilumumab, 3 mg / kg may be administered to the subject by intravenous infusion every three weeks.

[0361] For example, when the one or more ICIs is tremelimumab, 3 to 20 mg / kg may be administered to the subject by intravenous infusion every four weeks.

[0362] For example, when the one or more ICIs is GSK2831781, 1.5 to 5 mg / kg may be administered to the subject by intravenous infusion every 2-4 weeks.

[0363] Representative dosing regimens for certain ICIs to treat certain cancers are provided in Table 4.Table 4

[0364] In one embodiment, the one or more ICIs is an antibody, and 1-20 mg / kg is administered to the subject by intravenous infusion every 2-4 weeks. In another embodiment, 20-2000 mg of the antibody is administered to the subject by intravenous infusion every 2-4 weeks. In another embodiment, a Compound of the Disclosure is administered prior to administration of the antibody. In another embodiment, a Compound of the Disclosure is administered to the subject 1, 2, 3, 4, 5, 6, or 7 days prior to the day of administration of the antibody. In another embodiment, a Compound of the Disclosure is administered to the subject the day the antibody is administered. In another embodiment, a Compound of the Disclosure is administered to the subject 1, 2, 3, 4, 5, 6, or 7 days after the day of administration of the antibody.

[0365] For example, the subject receives pembrolizumab administered by intravenous infusion every three weeks and a Compound of the Disclosure is administered orally, wherein the first dose of a Compound of the Disclosure is administered prior to the first dose of pembrolizumab, the first dose of a Compound of the Disclosure is administered on the same day as the first dose of pembrolizumab, or the first dose of a Compound of the Disclosure is administered after to the first dose of pembrolizumab, e.g., until disease progression or until there is no therapeutic benefit.

[0366] For example, the subject receives nivolumab administered by intravenous infusion every two weeks and a Compound of the Disclosure orally administered 3 to 7 times a week, wherein the first dose of a Compound of the Disclosure is administered prior to the first dose of nivolumab, the first dose of a Compound of the Disclosure is administered on the same day as the first dose of nivolumab, or the first dose of a Compound of the Disclosure is administered after to the first dose of nivolumab, e.g., until disease progression or until there is no therapeutic benefit.

[0367] In another embodiment, the treatment of the cancer patient with a Compound of the Disclosure and one or more ICIs induces anti-proliferative response faster than when the immune checkpoint inhibitor is administered alone, e.g., the Compound of the Disclosure sensitizes the cancer cells to treatment is the immune checkpoint inhibitor.IV. Kits

[0368] In another embodiment, the present disclosure provides kits for carrying out the methods and uses described herein, the kit comprising: (i) a Compound of the Disclosure; and (ii) a label with instructions for how to use the kit.

[0369] In another embodiment, the present disclosure provides a kit for carrying out the methods and uses described herein, the kit comprising: (i) one or more immune checkpoint inhibitors; and (ii) a label with instructions for how to use the kit.

[0370] In another embodiment, the present disclosure provides a kit for carrying out the methods and uses described herein, the kit comprising: (i) a Compound of the Disclosure; (ii) one or more immune checkpoint inhibitors; and (iii) a label with instructions for how to use the kit.

[0371] In another embodiment, the label is approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health Labor and Welfare (MHLW).V. Particular Embodiments

[0372] The disclosure provides the following particular embodiments relating to Compounds of the Disclosure having any one of Formula (I)-(VII).

[0373] Embodiment 1. A compound having Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0374] R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;

[0375] Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9;

[0376] Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;

[0377] R8and R9are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, and (C1-C6alkoxy)C1-C6alkyl; or

[0378] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;

[0379] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0380] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl,(C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;

[0381] R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;

[0382] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0383] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl.

[0384] Embodiment 2. The compound any Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, with the following provisos:

[0385] (i) if R4is cyano and R1is -CH2NR8R9, then R8and R9are each independently selected from the group consisting of hydrogen, C2-C6 alkyl, C3-C6cycloalkyl, and (Ci- C<> alkoxy)C1-C6alkyl; or R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo; or

[0386] (ii) if R1is -CH2NR8R9and R8and R9are each methyl, then R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0387] (iii) if R1is -CH2NR8R9, R8and R9are each methyl, and R4is cyano, then R3is C1-C6alkyl or C3-C6cycloalkyl.

[0388] Embodiment 3. The compound of Embodiments 1 or 2 having Formula (II):(II), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0389] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0390] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0391] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C6alkoxy, C3-C6cycloalkyl, (optionally substituted heterocyclo)-O-,(aryl)alkyl-O-, and (heteroaryl)alkyl-O-.

[0392] Embodiment 4. The compound of Embodiment 3 having Formula (III):or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

[0393] Embodiment 5. The compound of Embodiment 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted 5-membered heteroaryl.

[0394] Embodiment 6. The compound of Embodiment 4, or a pharmaceutically acceptable salt or solvate thereof, having Formula (IV):wherein R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo.

[0395] Embodiment 7. The compound of Embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, having Formula (V):

[0396] Embodiment 8. The compound of Embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, having Formula (VI):

[0397] Embodiment 9. The compound of Embodiment 6, or a pharmaceutically acceptable salt or solvate thereof, having Formula (VII):(VII).

[0398] Embodiment 10. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais hydrogen.

[0399] Embodiment 11. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais C1-C4 alkyl.

[0400] Embodiment 12. The compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais -CH2NR8R9.

[0401] Embodiment 13. The compound of Embodiment 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9are C1-C6alkyl.

[0402] Embodiment 14. The compound of Embodiment 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9are methyl.

[0403] Embodiment 15. The compound of Embodiment 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo.

[0404] Embodiment 16. The compound of Embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9taken together with the nitrogen atom to which they are attached form:

[0405] Embodiment 17. The compound of any one of Embodiments 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -OR7.

[0406] Embodiment 18. The compound of Embodiment 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is methyl, ethyl, or propyl.

[0407] Embodiment 19. The compound of Embodiment 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is ethyl.

[0408] Embodiment 20. The compound of any one of Embodiments 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen or C1-C6alkyl.

[0409] Embodiment 21. The compound of Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

[0410] Embodiment 22. The compound of Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is methyl.

[0411] Embodiment 23. The compound of Embodiment 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is ethyl.

[0412] Embodiment 24. The compound of any one of Embodiments 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen or cyano.

[0413] Embodiment 25. The compound of Embodiment 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

[0414] Embodiment 26. The compound of Embodiment 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is cyano.

[0415] Embodiment 27. The compound of any one of Embodiments 3-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais hydrogen or halogen.

[0416] Embodiment 28. The compound of Embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais hydrogen.

[0417] Embodiment 29. The compound of Embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais chloro.

[0418] Embodiment 30. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, selected from any one or more of the compounds of Table 1A.

[0419] Embodiment 31. The compound of Embodiment 30, or a pharmaceutically acceptable salt or solvate thereof, selected from any one or more of:

[0420] Embodiment 32. A pharmaceutical composition comprising the compound of any one of Embodiments 1-31 and a pharmaceutically acceptable excipient.

[0421] Embodiment 33. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-31 or the pharmaceutical composition of Embodiment 32.

[0422] Embodiment 34. The method of Embodiment 34 further comprising administering a therapeutically effective amount one or more immune checkpoint inhibitors to the subject.

[0423] Embodiment 35. The method of Embodiment 34, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies, one or more anti-PD-Ll antibodies, one or more anti-CTLA-4 antibodies, one or more anti-LAG3 antibodies, one or more anti-TIM3 antibodies, one or more anti- VISTA antibodies, one ormore anti-TIGIT antibodies, or one or more anti-cd47 antibodies, or a combination thereof.

[0424] Embodiment 36. The method of Embodiment 35 wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies.

[0425] Embodiment 37. The method of Embodiment 36, wherein the one or more anti-PD-1 antibodies comprise nivolumab, pembrolizumab, dostarlimab, retifanlimab, cemiplimab, vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680) and / or Acrixolimab (YBL-006).

[0426] Embodiment 38. The method any one of Embodiments 35-37, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-Ll antibodies.

[0427] Embodiment 39. The method of Embodiment 38, wherein the one or more anti-PD-Ll antibodies comprise avelumab, atezolizumab, durvalumab, KN035, and / or cosibelimab (CK-301).

[0428] Embodiment 40. The method of any one of Embodiments 35-39, wherein the one or more immune checkpoint inhibitors comprise one or more anti-CTLA-4 antibodies.

[0429] Embodiment 41. The method of Embodiment 40, wherein the one or more anti-CTLA-4 antibodies comprise ipilimumab and / or tremelimumab.

[0430] Embodiment 42. The method of any one of Embodiments 35-41, wherein the one or more immune checkpoint inhibitors comprise one or more anti-LAG3 antibodies.

[0431] Embodiment 43. The method of Embodiment 42, wherein the one or more anti-LAG3 antibodies comprise relatlimab.

[0432] Embodiment 44. The method of any one of Embodiments 35-43 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIM3 antibodies.

[0433] Embodiment 45. The method of any one of Embodiments 35-44 wherein the one or more immune checkpoint inhibitors comprise one or more anti- VISTA antibodies.

[0434] Embodiment 46. The method of any one of Embodiments 35-45 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIGIT antibodies.

[0435] Embodiment 47. The method of any one of Embodiments 35-46 wherein the one or more immune checkpoint inhibitors comprise one or more anti-cd47 antibodies.

[0436] Embodiment 48. The method of Embodiment 34 comprising administering a therapeutically effective amount of nivolumab, pembrolizumab, dostarlimab, retifanlimab, or cemiplimab to the subject.

[0437] Embodiment 49. The method of Embodiments 34 or 48 comprising administering a therapeutically effective amount of avelumab, atezolizumab, or durvalumab to the subject.

[0438] Embodiment 50. The method of any one of Embodiments 33-49, wherein the cancer is any one or more of the cancers of Table 2 and / or Table 3.

[0439] Embodiment 51. A method of inhibiting adenosine deaminase acting on RNA 1 (ADAR1) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Embodiment 32.

[0440] Embodiment 52. A method of providing immuno-oncology therapy to a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Embodiment 32.

[0441] Embodiment 53. A method of sensitizing tumor response to immunotherapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-31, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Embodiment 42.

[0442] Embodiment 54. The method of Embodiment 53, wherein the tumor is resistant to immune checkpoint blockade.

[0443] Embodiment 55. The method of any one of Embodiments 51-54 comprising administering to the subject a therapeutically effective amount of Neratinib:

[0444] Embodiment 56. A kit for carrying out the method of any one of Embodiments 33-55, the kit comprising: (i) a compound having Formula (I), or a pharmaceutically acceptable salt or solvate thereof; and (ii) a label with instructions for how to use the kit.

[0445] Embodiment 57. A kit for carrying out the method of any one of Embodiments 33-55, the kit comprising: (i) one or more immune checkpoint inhibitors; and (ii) a label with instructions for how to use the kit.

[0446] Embodiment 58. A kit for carrying out the method of any one of Embodiments 33-55, the kit comprising: (i) a compound having Formula (I), or a pharmaceutically acceptable salt or solvate thereof; (ii) one or more immune checkpoint inhibitors; and (iii) a label with instructions for how to use the kit.

[0447] Embodiment 59. The kit of any one of Embodiments 56-58, wherein the label is approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health Labor and Welfare (MHLW).

[0448] The present disclosure also provides the following particular embodiments relating to compounds having Formula (VIII) and Compounds of the Disclosure having any one of Formula (IX)-(XVI).

[0449] Embodiment 1. A compound having Formula (IX):(IX), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0450] X is selected from the group consisting of -O- and -NRa-;

[0451] Rais selected from the group consisting to hydrogen and C1-C4 alkyl;

[0452] R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;

[0453] Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9;

[0454] Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;

[0455] R8is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4-to 7-membered heterocyclo, C2-C12 alkynyl, and (C1-C6alkoxy)C1-C6alkyl;

[0456] R9is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0457] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;

[0458] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0459] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;

[0460] R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;

[0461] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0462] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10- membered heteroaryl.

[0463] Embodiment 2. The compound Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, with the following provisos:

[0464] (i) if R4is cyano and R1is -CH2NR8R9, then R8is hydrogen, C2-C6 alkyl, C3-C6cycloalkyl, optionally substituted 4-to 7-membered heterocyclo, C2-C12 alkynyl, and (Ci- Ce alkoxy)C1-C6alkyl; R9is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; or R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo; or

[0465] (ii) if R1is -CH2NR8R9and R8and R9are each methyl, then R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, and C3-C6cycloalkyl; or

[0466] (iii) if R1is -CH2NR8R9, R8and R9are each methyl, and R4is cyano, then R3is C1-C6alkyl or C3-C6cycloalkyl.

[0467] Embodiment 3. The compound of Embodiments 1 or 2 having Formula(X):(X), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0468] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0469] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0470] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C4 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, (optionally substituted 4- to 7-membered heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-.

[0471] Embodiment 4. The compound of Embodiment 3, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0472] R6bis hydrogen; and

[0473] R6Cis selected from the group consisting of:or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

[0474] Embodiment 6. The compound of Embodiment 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted 5-membered heteroaryl.

[0475] Embodiment 7. The compound of Embodiment 5, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XII):(XII), wherein R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo.

[0476] Embodiment 8. The compound of Embodiment 7, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XIII):(XIII).

[0477] Embodiment 9. The compound of Embodiment 7, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XIV):(XIV).

[0478] Embodiment 10. The compound of Embodiment 7, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XV):(XV).

[0479] Embodiment 11. The compound of Embodiments 1 or 2 having Formula (XVI):or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of optionally substituted 5- to 7-membered heterocylo and optionally substituted 5- to 10-membered heteroaryl.

[0480] Embodiment 12. The compound of Embodiment 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 7-membered heterocylo.

[0481] Embodiment 13. The compound of Embodiment 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of:

[0482] Embodiment 14. The compound of Embodiment 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 10-membered heteroaryl.

[0483] Embodiment 15. The compound of Embodiment 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of:

[0484] Embodiment 16. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais hydrogen.

[0485] Embodiment 17. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais C1-C4 alkyl.

[0486] Embodiment 18. The compound of any one of Embodiments 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais -CH2NR8R9.

[0487] Embodiment 19. The compound of Embodiment 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9are C1-C6alkyl.

[0488] Embodiment 20. The compound of Embodiment 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9are methyl.

[0489] Embodiment 21. The compound of Embodiment 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is optionally substituted 4-to 7-membered heterocyclo.

[0490] Embodiment 22. The compound of Embodiment 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is selected from the group consisting of:

[0491] Embodiment 23. The compound of Embodiment 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C2-C10 alkynyl.

[0492] Embodiment 24. The compound of Embodiment 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo.

[0493] Embodiment 25. The compound of Embodiment 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9taken together with the nitrogen atom to which they are attached form:

[0494] Embodiment 26. The compound of any one of Embodiments 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -OR7.

[0495] Embodiment 27. The compound of Embodiment 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is selected from the group consisting of methyl, ethyl, and propyl.

[0496] Embodiment 28. The compound of Embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is ethyl.

[0497] Embodiment 29. The compound of any one of Embodiments 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from the group consisting of hydrogen and C1-C6alkyl.

[0498] Embodiment 30. The compound of Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

[0499] Embodiment 31. The compound of Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is methyl.

[0500] Embodiment 32. The compound of Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is ethyl.

[0501] Embodiment 33. The compound of any one of Embodiments 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from the group consisting of hydrogen and cyano.

[0502] Embodiment 34. The compound of Embodiment 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

[0503] Embodiment 35. The compound of Embodiment 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is cyano.

[0504] Embodiment 36. The compound of any one of Embodiments 3-10 or 15-35, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais selected from the group consisting of hydrogen and halogen.

[0505] Embodiment 37. The compound of Embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais hydrogen.

[0506] Embodiment 38. The compound of Embodiment 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais chloro.

[0507] Embodiment 39. The compound of any one of Embodiments 1-38, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

[0508] Embodiment 40. The compound of any one of Embodiments 1-38, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.

[0509] Embodiment 41 The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, selected from any one or more of the compounds of Table 1A and / or Table 2 A.

[0510] Embodiment 42. The compound of Embodiment 41, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of:

[0511] Embodiment 43. A pharmaceutical composition comprising the compound of any one of Embodiments 1-42 and a pharmaceutically acceptable excipient.

[0512] Embodiment 44. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-42 or the pharmaceutical composition of Embodiment 32.

[0513] Embodiment 45. The method of Embodiment 44 further comprising administering a therapeutically effective amount one or more immune checkpoint inhibitors to the subject.

[0514] Embodiment 46. The method of Embodiment 44, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies, one or more anti-PD-Ll antibodies, one or more anti-CTLA-4 antibodies, one or more anti-LAG3 antibodies, one or more anti-TIM3 antibodies, one or more anti- VISTA antibodies, one or more anti-TIGIT antibodies, or one or more anti-cd47 antibodies, or a combination thereof.

[0515] Embodiment 47. The method of Embodiment 46 wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies.

[0516] Embodiment 48. The method of Embodiment 47, wherein the one or more anti-PD-1 antibodies comprise nivolumab, pembrolizumab, dostarlimab, retifanlimab, cemiplimab, vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680) and / or Acrixolimab (YBL-006).

[0517] Embodiment 49. The method any one of Embodiments 46-48, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-Ll antibodies.

[0518] Embodiment 50. The method of Embodiment 49, wherein the one or more anti-PD-Ll antibodies comprise avelumab, atezolizumab, durvalumab, KN035, and / or cosibelimab (CK-301).

[0519] Embodiment 51. The method of any one of Embodiments 46-50, wherein the one or more immune checkpoint inhibitors comprise one or more anti-CTLA-4 antibodies.

[0520] Embodiment 52. The method of Embodiment 51, wherein the one or more anti-CTLA-4 antibodies comprise ipilimumab and / or tremelimumab.

[0521] Embodiment 53. The method of any one of Embodiments 46-52, wherein the one or more immune checkpoint inhibitors comprise one or more anti-LAG3 antibodies.

[0522] Embodiment 54. The method of Embodiment 53, wherein the one or more anti-LAG3 antibodies comprise relatlimab.

[0523] Embodiment 55. The method of any one of Embodiments 46-54 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIM3 antibodies.

[0524] Embodiment 56. The method of any one of Embodiments 46-55 wherein the one or more immune checkpoint inhibitors comprise one or more anti- VISTA antibodies.

[0525] Embodiment 57. The method of any one of Embodiments 46-56 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIGIT antibodies.

[0526] Embodiment 58. The method of any one of Embodiments 46-57 wherein the one or more immune checkpoint inhibitors comprise one or more anti-cd47 antibodies.

[0527] Embodiment 59. The method of Embodiment 45 comprising administering a therapeutically effective amount of nivolumab, pembrolizumab, dostarlimab, retifanlimab, or cemiplimab to the subject.

[0528] Embodiment 60. The method of Embodiments 45 or 59 comprising administering a therapeutically effective amount of avelumab, atezolizumab, or durvalumab to the subject.

[0529] Embodiment 61. The method of any one of Embodiments 44-60, wherein the cancer is any one or more of the cancers of Table 2 and / or Table 3.

[0530] Embodiment 62. A method of inhibiting adenosine deaminase acting onRNA 1 (ADAR1) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-42, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Embodiment 43.

[0531] Embodiment 63. A method of providing immuno-oncology therapy to a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-42, or apharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Embodiment 43.

[0532] Embodiment 64. A method of sensitizing tumor response to immunotherapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of Embodiments 1-42, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of Embodiment 43.

[0533] Embodiment 65. The method of Embodiment 64, wherein the tumor is resistant to immune checkpoint blockade.

[0534] Embodiment 66. The method of any one of Embodiments 62-65 comprising administering to the subject a therapeutically effective amount of Neratinib:Embodiment 67. A kit for carrying out the method of any one of Embodiments 44-66, the kit comprising: (i) a compound having Formula (IX), or a pharmaceutically acceptable salt or solvate thereof; and (ii) a label with instructions for how to use the kit.Embodiment 68. A kit for carrying out the method of any one of Embodiments 44-66, the kit comprising: (i) one or more immune checkpoint inhibitors; and (ii) a label with instructions for how to use the kit.Embodiment 69. A kit for carrying out the method of any one of Embodiments 44-66, the kit comprising: (i) a compound having Formula (IX), or a pharmaceutically acceptable salt or solvate thereof; (ii) one or more immune checkpoint inhibitors; and (iii) a label with instructions for how to use the kit.Embodiment 70. The kit of any one of Embodiments 67-69, wherein the label is approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health Labor and Welfare (MHLW).Embodiment 71. A compound having Formula (VIII):or a pharmaceutically acceptable salt or solvate thereof, wherein:R10is selected from the group consisting of chloro and -N(H)R5;R11is selected from the group consisting of hydrogen and -C(=0)CH3;R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0535] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10- membered heteroaryl.

[0536] The present disclosure also provides the following particular embodiments relating to therapeutic methods of treatment, purpose-limited products, and purposelimited processes.A. Therapeutic Method of Treatment Embodiments

[0537] Embodiment 1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject:

[0538] (a) compound having Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0539] R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;

[0540] Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9,;

[0541] Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;

[0542] R8and R9are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, and (C1-C6alkoxy) C1-C6alkyl; or

[0543] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;

[0544] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0545] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C<> cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6-alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4- to 7-membered heterocyclo)C1-C6alkyl;

[0546] R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl;

[0547] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0548] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl; and

[0549] (b) a therapeutically effective amount one or more immune checkpoint inhibitors.

[0550] Embodiment !. The method of Embodiment 1, wherein the compound having Formula (I) is a compound having Formula (II):

[0551] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0552] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0553] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0554] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C6alkoxy, C3-C6cycloalkyl, (optionally substituted heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-.

[0555] Embodiment 3. The method of Embodiment 2, wherein the compound having Formula (I) is a compound having Formula (III):or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

[0556] Embodiment 4. The method of Embodiment 3, wherein R5ais optionally substituted 5-membered heteroaryl.

[0557] Embodiment 5. The method of Embodiment 3, wherein the compound having Formula (III) is a compound having Formula (IV):wherein R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo.

[0558] Embodiment 6. The method of Embodiment 5, wherein the compound having Formula (IV) is a compound having Formula (V):

[0559] Embodiment 7. The method of Embodiment 5, wherein the compound having Formula (IV) is a compound having Formula (VI):

[0560] Embodiment 8. The method of Embodiment 5, wherein the compound having Formula (IV) is a compound having Formula (VII):(VII).

[0561] Embodiment 9. The method of any one of Embodiments 1-8, wherein Rlais hydrogen.

[0562] Embodiment 10. The method of any one of Embodiments 1-8, wherein RlaisCi-C4alkyl.

[0563] Embodiment 11. The method of any one of Embodiments 1-8, wherein Rlais -CH2NR8R9.

[0564] Embodiment 12. The method of Embodiment 11, wherein R8and R9are C1-C6alkyl.

[0565] Embodiment 13. The method of Embodiment 12, wherein R8and R9are methyl.

[0566] Embodiment 14. The method of Embodiment 11, wherein R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo.

[0567] Embodiment 15. The method of Embodiment 14, wherein R8and R9taken together with the nitrogen atom to which they are attached form:

[0568] Embodiment 16. The method of any one of Embodiments 1-15, wherein R2is -OR7.

[0569] Embodiment 17. The method of Embodiment 16, wherein R7is methyl, ethyl, or propyl.

[0570] Embodiment 18. The method of Embodiment 17, wherein R7is ethyl.

[0571] Embodiment 19. The method of any one of Embodiments 1-18, wherein R3is hydrogen or C1-C6alkyl.

[0572] Embodiment 20. The method of Embodiment 19, wherein R3is hydrogen.

[0573] Embodiment 21. The method of Embodiment 19, wherein R3is methyl.

[0574] Embodiment 22. The method of Embodiment 19, wherein R3is ethyl.

[0575] Embodiment 23. The method of any one of Embodiments 1-22, wherein R4is hydrogen or cyano.

[0576] Embodiment 24. The method of Embodiment 23, wherein R4is hydrogen.

[0577] Embodiment 25. The method of Embodiment 23, wherein R4is cyano.

[0578] Embodiment 26. The method of any one of Embodiments 2-25, wherein R6ais hydrogen or halogen.

[0579] Embodiment 27. The method of Embodiment 26, wherein R6ais hydrogen.

[0580] Embodiment 28. The method of Embodiment 26, wherein R6ais chloro.

[0581] Embodiment 29. The method of Embodiment 1, selected from any one or more of the compounds of Table 1 A.

[0582] Embodiment 30. The method of Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, selected from any one or more of:

[0583] Embodiment 31. The method of any one of Embodiments 1-30, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies, one or more anti-PD-Ll antibodies, one or more anti-CTLA-4 antibodies, one or more anti-LAG3 antibodies, one or more anti-TIM3 antibodies, one or more anti- VISTA antibodies, one or more anti-TIGIT antibodies, or one or more anti-cd47 antibodies, or a combination thereof.

[0584] Embodiment 32. The method of Embodiment 31 wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies.

[0585] Embodiment 33. The method of Embodiment 32, wherein the one or more anti-PD-1 antibodies comprise nivolumab, pembrolizumab, dostarlimab, retifanlimab, cemiplimab, vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680) and / or Acrixolimab (YBL-006).

[0586] Embodiment 34. The method any one of Embodiments 31-33, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-Ll antibodies.

[0587] Embodiment 35. The method of Embodiment 34, wherein the one or more anti-PD-Ll antibodies comprise avelumab, atezolizumab, durvalumab, KN035, and / or cosibelimab (CK-301).

[0588] Embodiment 36. The method of any one of Embodiments 31-35, wherein the one or more immune checkpoint inhibitors comprise one or more anti-CTLA-4 antibodies.

[0589] Embodiment 37. The method of Embodiment 36, wherein the one or more anti-CTLA-4 antibodies comprise ipilimumab and / or tremelimumab.

[0590] Embodiment 38. The method of any one of Embodiments 31-37, wherein the one or more immune checkpoint inhibitors comprise one or more anti-LAG3 antibodies.

[0591] Embodiment 39. The method of Embodiment 38, wherein the one or more anti-LAG3 antibodies comprise relatlimab.

[0592] Embodiment 40. The method of any one of Embodiments 31-39 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIM3 antibodies.

[0593] Embodiment 41. The method of any one of Embodiments 31-40 wherein the one or more immune checkpoint inhibitors comprise one or more anti- VISTA antibodies.

[0594] Embodiment 42. The method of any one of Embodiments 31-41 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIGIT antibodies.

[0595] Embodiment 43. The method of any one of Embodiments 31-42 wherein the one or more immune checkpoint inhibitors comprise one or more anti-cd47 antibodies.

[0596] Embodiment 44. The method of Embodiment 31 comprising administering a therapeutically effective amount of nivolumab, pembrolizumab, dostarlimab, retifanlimab, or cemiplimab to the subject.

[0597] Embodiment 45. The method of Embodiments 31 or 44 comprising administering a therapeutically effective amount of avelumab, atezolizumab, or durvalumab to the subject.

[0598] Embodiment 46. The method of any one of Embodiments 1-45, wherein the cancer is any one or more of the cancers of Table 2 and / or Table 3.

[0599] Embodiment 47. A kit for carrying out the method of any one ofEmbodiments 1-46, the kit comprising: (i) the compound pharmaceutically acceptable salt or solvate thereof; and (ii) a label with instructions for how to use the kit.

[0600] Embodiment 48. A kit for carrying out the method of any one of Embodiments 1-46, the kit comprising: (i) one or more immune checkpoint inhibitors; and (ii) a label with instructions for how to use the kit.

[0601] Embodiment 49. A kit for carrying out the method of any one of Embodiments 1-46, the kit comprising: (i) the compound, or a pharmaceutically acceptable salt or solvate thereof; (ii) one or more immune checkpoint inhibitors; and (iii) a label with instructions for how to use the kit.

[0602] Embodiment 50. The kit of any one of Embodiments 47-9, wherein the label is approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health Labor and Welfare (MHLW).B. Purpose-Limited Product Embodiments

[0603] Embodiment 1. A compound having Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0604] R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;

[0605] Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9,;

[0606] Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;

[0607] R8and R9are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, and (C1-C6alkoxy)C1-C6alkyl; or

[0608] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;

[0609] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0610] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C<> cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6-alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4- to 7-membered heterocyclo)C1-C6alkyl;

[0611] R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl;

[0612] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0613] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl,

[0614] for use in treating cancer in a subject in need thereof, wherein the compound having Formula (I) is to be administered in combination with one or more immune checkpoint inhibitors.Embodiment 2. The compound for use of Embodiment 1, wherein the compound having Formula (I) is a compound having Formula (II):(II), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0615] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0616] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0617] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C6alkoxy, C3-C6cycloalkyl, (optionally substituted heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-.Embodiment 3. The compound for use of Embodiment 2, wherein the compound having Formula (I) is a compound having Formula (III):(III),or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

[0618] Embodiment 4. The compound for use of Embodiment 3, wherein R5ais optionally substituted 5-membered heteroaryl.

[0619] Embodiment 5. The compound for use of Embodiment 3, wherein the compound having Formula (III) is a compound having Formula (IV):wherein R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6-membered heterocyclo.

[0620] Embodiment 6. The compound for use of Embodiment 5, wherein the compound having Formula (IV) is a compound having Formula (V):

[0621] Embodiment 7. The compound for use of Embodiment 5, wherein the compound having Formula (IV) is a compound having Formula (VI):

[0622] Embodiment 8. The compound for use of Embodiment 5, wherein the compound having Formula (IV) is a compound having Formula (VII):(VII).

[0623] Embodiment 9. The compound for use of any one of Embodiments 1-8, wherein Rlais hydrogen.

[0624] Embodiment 10. The compound for use of any one of Embodiments 1-8, wherein Rlais C1-C4 alkyl.

[0625] Embodiment 11. The compound for use of any one of Embodiments 1-8, wherein Rlais -CH2NR8R9.

[0626] Embodiment 12. The compound for use of Embodiment 11, wherein R8andR9are C1-C6alkyl.

[0627] Embodiment 13. The compound for use of Embodiment 12, wherein R8andR9are methyl.

[0628] Embodiment 14. The compound for use of Embodiment 11, wherein R8andR9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo.

[0629] Embodiment 15. The compound for use of Embodiment 14, wherein R8and R9taken together with the nitrogen atom to which they are attached form:

[0630] Embodiment 16. The compound for use of any one of Embodiments 1-15, wherein R2is -OR7.

[0631] Embodiment 17. The compound for use of Embodiment 16, wherein R7is methyl, ethyl, or propyl.

[0632] Embodiment 18. The compound for use of Embodiment 17, wherein R7is ethyl.

[0633] Embodiment 19. The compound for use of any one of Embodiments 1-18, wherein R3is hydrogen or C1-C6alkyl.

[0634] Embodiment 20. The compound for use of Embodiment 19, wherein R3is hydrogen.

[0635] Embodiment 21. The compound for use of Embodiment 19, wherein R3is methyl.

[0636] Embodiment 22. The compound for use of Embodiment 19, wherein R3is ethyl.

[0637] Embodiment 23. The compound for use of any one of Embodiments 1-22, wherein R4is hydrogen or cyano.

[0638] Embodiment 24. The compound for use of Embodiment 23, wherein R4is hydrogen.

[0639] Embodiment 25. The compound for use of Embodiment 23, wherein R4is cyano.

[0640] Embodiment 26. The compound for use of any one of Embodiments 2-25, wherein R6ais hydrogen or halogen.

[0641] Embodiment 27. The compound for use of Embodiment 26, wherein R6ais hydrogen.

[0642] Embodiment 28. The compound for use of Embodiment 26, wherein R6ais chloro.

[0643] Embodiment 29. The compound for use of Embodiment 1, selected from any one or more of the compounds of Table 1 A.

[0644] Embodiment 30. The compound for use of Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, selected from any one or more of:

[0645] Embodiment 31. The compound for use of any one of Embodiments 1-30, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies, one or more anti-PD-Ll antibodies, one or more anti-CTLA-4 antibodies, one or more anti-LAG3 antibodies, one or more anti-TIM3 antibodies, one or more anti- VISTA antibodies, one or more anti-TIGIT antibodies, or one or more anti-cd47 antibodies, or a combination thereof.

[0646] Embodiment 32. The compound for use of Embodiment 31 wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies.

[0647] Embodiment 33. The compound for use of Embodiment 32, wherein the one or more anti-PD-1 antibodies comprise nivolumab, pembrolizumab, dostarlimab, retifanlimab, cemiplimab, vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IB 1308), tislelizumab (BGB-A317), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680) and / or Acrixolimab (YBL-006).

[0648] Embodiment 34. The compound for use any one of Embodiments 31-33, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-Ll antibodies.

[0649] Embodiment 35. The compound for use of Embodiment 34, wherein the one or more anti-PD-Ll antibodies comprise avelumab, atezolizumab, durvalumab, KN035, and / or cosibelimab (CK-301).

[0650] Embodiment 36. The compound for use of any one of Embodiments 31-35, wherein the one or more immune checkpoint inhibitors comprise one or more anti- CTLA-4 antibodies.

[0651] Embodiment 37. The compound for use of Embodiment 36, wherein the one or more anti-CTLA-4 antibodies comprise ipilimumab and / or tremelimumab.

[0652] Embodiment 38. The compound for use of any one of Embodiments 31-37, wherein the one or more immune checkpoint inhibitors comprise one or more anti-LAG3 antibodies.

[0653] Embodiment 39. The compound for use of Embodiment 38, wherein the one or more anti-LAG3 antibodies comprise relatlimab.

[0654] Embodiment 40. The compound for use of any one of Embodiments 31-39 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIM3 antibodies.

[0655] Embodiment 41. The compound for use of any one of Embodiments 31-40 wherein the one or more immune checkpoint inhibitors comprise one or more anti- VISTA antibodies.

[0656] Embodiment 42. The compound for use of any one of Embodiments 31-41 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIGIT antibodies.

[0657] Embodiment 43. The compound for use of any one of Embodiments 31-42 wherein the one or more immune checkpoint inhibitors comprise one or more anti-cd47 antibodies.

[0658] Embodiment 44. The compound for use of Embodiment 31 comprising administering a therapeutically effective amount of nivolumab, pembrolizumab, dostarlimab, retifanlimab, or cemiplimab to the subject.

[0659] Embodiment 45. The compound for use of Embodiments 31 or 44 comprising administering a therapeutically effective amount of avelumab, atezolizumab, or durvalumab to the subject.

[0660] Embodiment 46. The compound for use of any one of Embodiments 1-45, wherein the cancer is any one or more of the cancers of Table 2 and / or Table 3.C. Purpose-limited Process Embodiments

[0661] Embodiment 1. Use of a compound having Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0662] R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;

[0663] Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9,;

[0664] Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;

[0665] R8and R9are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, and (C1-C6alkoxy)C1-C6alkyl; or

[0666] R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;

[0667] R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;

[0668] R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C<> cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6-alkoxyjC1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4- to 7-membered heterocyclo)C1-C6alkyl;

[0669] R3is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl;

[0670] R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; and

[0671] R5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, and optionally substituted heteroaryl,

[0672] in the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the compound having Formula (I) is to be administered in combination with one or more immune checkpoint inhibitors.

[0673] Embodiment !. The use of Embodiment 1, wherein the compound having Formula (I) is a compound having Formula (II):(ID, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0674] R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;

[0675] R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; and

[0676] R6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C6alkoxy, C3-C6cycloalkyl, (optionally substituted heterocyclo)-O-, (aryl)alkyl-O-, and (heteroaryl)alkyl-O-.

[0677] Embodiment 3. The use of Embodiment 2, wherein the compound having Formula (I) is a compound having Formula (III):or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

[0678] Embodiment 4. The use of Embodiment 3, wherein R5ais optionally substituted 5-membered heteroaryl.

[0679] Embodiment 5. The use of Embodiment 3, wherein the compound havingFormula (III) is a compound having Formula (IV):wherein R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo.

[0680] Embodiment 6. The use of Embodiment 5, wherein the compound having Formula (IV) is a compound having Formula (V):

[0681] Embodiment 7. The use of Embodiment 5, wherein the compound havingFormula (IV) is a compound having Formula (VI):(VI).

[0682] Embodiment 8. The use of Embodiment 5, wherein the compound havingFormula (IV) is a compound having Formula (VII):(VII).

[0683] Embodiment 9. The use of any one of Embodiments 1-8, wherein Rlais hydrogen.

[0684] Embodiment 10. The use of any one of Embodiments 1-8, wherein Rlais Ci-C4alkyl.

[0685] Embodiment 11. The use of any one of Embodiments 1-8, wherein Rlais -CH2NR8R9.

[0686] Embodiment 12. The use of Embodiment 11, wherein R8and R9are C1-C6alkyl.

[0687] Embodiment 13. The use of Embodiment 12, wherein R8and R9are methyl.

[0688] Embodiment 14. The use of Embodiment 11, wherein R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo.

[0689] Embodiment 15. The use of Embodiment 14, wherein R8and R9taken together with the nitrogen atom to which they are attached form:

[0690] Embodiment 16. The use of any one of Embodiments 1-15, wherein R2is -OR7.

[0691] Embodiment 17. The use of Embodiment 16, wherein R7is methyl, ethyl, or propyl.

[0692] Embodiment 18. The use of Embodiment 17, wherein R7is ethyl.

[0693] Embodiment 19. The use of any one of Embodiments 1-18, wherein R3is hydrogen or C1-C6alkyl.

[0694] Embodiment 20. The use of Embodiment 19, wherein R3is hydrogen.

[0695] Embodiment 21. The use of Embodiment 19, wherein R3is methyl.

[0696] Embodiment 22. The use of Embodiment 19, wherein R3is ethyl.

[0697] Embodiment 23. The use of any one of Embodiments 1-22, wherein R4is hydrogen or cyano.

[0698] Embodiment 24. The use of Embodiment 23, wherein R4is hydrogen.

[0699] Embodiment 25. The use of Embodiment 23, wherein R4is cyano.

[0700] Embodiment 26. The use of any one of Embodiments 2-25, wherein R6ais hydrogen or halogen.

[0701] Embodiment 27. The use of Embodiment 26, wherein R6ais hydrogen.

[0702] Embodiment 28. The use of Embodiment 26, wherein R6ais chloro.

[0703] Embodiment 29. The use of Embodiment 1, selected from any one or more of the compounds of Table 1A.

[0704] Embodiment 30. The use of Embodiment 29, or a pharmaceutically acceptable salt or solvate thereof, selected from any one or more of:

[0705] Embodiment 31. The use of any one of Embodiments 1-30, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies, one or more anti-PD-Ll antibodies, one or more anti-CTLA-4 antibodies, one or more anti- LAG3 antibodies, one or more anti-TIM3 antibodies, one or more anti-VISTA antibodies, one or more anti-TIGIT antibodies, or one or more anti-cd47 antibodies, or a combination thereof.

[0706] Embodiment 32. The use of Embodiment 31 wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies.

[0707] Embodiment 33. The use of Embodiment 32, wherein the one or more anti-PD-1 antibodies comprise nivolumab, pembrolizumab, dostarlimab, retifanlimab, cemiplimab, vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), INCMGA00012 (MGA012), AMP-224, AMP-514 (MEDI0680) and / or Acrixolimab (YBL-006).

[0708] Embodiment 34. The use any one of Embodiments 31-33, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-Ll antibodies.

[0709] Embodiment 35. The use of Embodiment 34, wherein the one or more anti- PD-L1 antibodies comprise avelumab, atezolizumab, durvalumab, KN035, and / or cosibelimab (CK-301).

[0710] Embodiment 36. The use of any one of Embodiments 31-35, wherein the one or more immune checkpoint inhibitors comprise one or more anti-CTLA-4 antibodies.

[0711] Embodiment 37. The use of Embodiment 36, wherein the one or more anti-CTLA-4 antibodies comprise ipilimumab and / or tremelimumab.

[0712] Embodiment 38. The use of any one of Embodiments 31-37, wherein the one or more immune checkpoint inhibitors comprise one or more anti-LAG3 antibodies.

[0713] Embodiment 39. The use of Embodiment 38, wherein the one or more anti-LAG3 antibodies comprise relatlimab.

[0714] Embodiment 40. The use of any one of Embodiments 31-39 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIM3 antibodies.

[0715] Embodiment 41. The use of any one of Embodiments 31-40 wherein the one or more immune checkpoint inhibitors comprise one or more anti- VISTA antibodies.

[0716] Embodiment 42. The use of any one of Embodiments 31-41 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIGIT antibodies.

[0717] Embodiment 43. The use of any one of Embodiments 31-42 wherein the one or more immune checkpoint inhibitors comprise one or more anti-cd47 antibodies.

[0718] Embodiment 44. The use of Embodiment 31 comprising administering a therapeutically effective amount of nivolumab, pembrolizumab, dostarlimab, retifanlimab, or cemiplimab to the subject.

[0719] Embodiment 45. The use of Embodiments 31 or 44 comprising administering a therapeutically effective amount of avelumab, atezolizumab, or durvalumab to the subject.

[0720] Embodiment 46. The use of any one of Embodiments 1-45, wherein the cancer is any one or more of the cancers of Table 2 and / or Table 3.VII. Definitions

[0721] The term "halo" or "halogen" as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I.

[0722] The term "nitro" as used herein by itself or as part of another group refers to -NO2.

[0723] The term "cyano" as used herein by itself or as part of another group refers to -CN.

[0724] The term "hydroxy" as herein used by itself or as part of another group refers to -OH.

[0725] The term "alkyl" as used herein by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C1-C12 alkyl, or the number of carbon atoms designated, e.g., a Ci alkyl such as methyl, a C2 alkyl such as ethyl, etc. In one embodiment, the alkyl is a C1-C10 alkyl. In another embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C12 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, zso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0726] The term "alkenyl" as used herein by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C2-C6 alkenyl group. In another embodiment, the alkenyl group is a C2-C4 alkenyl group. In another embodiment, the alkenyl group has one carbon-to-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0727] The term "alkynyl" as used herein by itself or as part of another group refers to an alkyl group containing one or two carbon-to-carbon triple bonds. In one embodiment, the alkynyl is a C2-C6 alkynyl. In another embodiment, the alkynyl is a C2-C4 alkynyl. In another embodiment, the alkynyl has one carbon-to-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0728] The term "haloalkyl" as used herein by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl is substituted by one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted by one, two, or three fluorine atoms. In another embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl group is a Ci or C2 alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0729] The terms "hydroxy alkyl" or "(hydroxy)alkyl" as used herein by themselves or as part of another group refer to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a Ci or C2 alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxy alkyl group is a dihydroxy alkyl group, i.e., substituted with two hydroxy groups. Non-limiting exemplary (hydroxyl) alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1 -hydroxy ethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-l- methylpropyl, and l,3-dihydroxyprop-2-yl.

[0730] The term "alkoxy" as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C1-C6alkyl and resulting alkoxy is thus referred to as a "C1-C6alkoxy." In another embodiment, the alkyl is a C1-C4 alkyl group and resulting alkoxy is thus referred to as a "C1-C4 alkoxy." Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy. The term "haloalkoxy" as used herein by itself or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C6haloalkyl. In another embodiment, the haloalkyl group is a C1-C4 haloalkyl group. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0731] The terms "alkoxyalkyl" or "(alkoxy)alkyl" as used herein by themselves or as part of another group refers to an alkyl group substituted with one alkoxy group. In one embodiment, the alkoxy is a C1-C6alkoxy. In another embodiment, the alkoxy is a C1-C4 alkoxy. In another embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. Thus, in some embodiments, the "(alkoxy)alkyl" is a (C1-C6alkoxy)C1-C6alkyl; Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, secbutoxymethyl, and pentyloxy methyl.

[0732] The term "cycloalkyl" as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-12 cycloalkyl, or the number of carbons designated, e.g., a C3 cycloalkyl such a cyclopropyl, a C4 cycloalkyl such as cyclobutyl, etc. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl is a C3-8 cycloalkyl. In another embodiment, the cycloalkyl is a C3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C5 cycloalkyl, i.e., cyclopentyl or cyclopentenyl. In another embodiment, the cycloalkyl is a Ce cycloalkyl, i.e., cyclohexyl or cyclohexenyl. Non-limiting exemplary C3-12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

[0733] The term "optionally substituted cycloalkyl" as used herein by itself or as part of another group refers to a cycloalkyl group that is either unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, or alkoxyalkyl. The term optionally substituted cycloalkyl also includes cycloalkyl groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as:

[0734] The term "(cycloalkyl)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one optionally substituted cycloalkyl group. In one embodiment, the (cycloalkyl)alkyl group is a C1-C6alkyl substituted with one optionally substituted C3-C6cycloalkyl group, i.e., an "(optionally substituted C3-C6cycloalkyl)Ci- C<> alkyl." In another embodiment, the (cycloalkyl)alkyl group is a C1-C4 alkyl substituted with one optionally substituted optionally substituted C3-C6cycloalkyl, i.e., an "(optionally substituted C3-C6cycloalkyl)Ci-C4 alkyl." In another embodiment, the (cycloalkyl)alkyl group is a C1-C2 alkyl substituted with one optionally substituted C3-C6cycloalkyl group, i.e., an "(optionally substituted C3-C6cycloalkyl heteroaryl)Ci-C2alkyl." In another embodiment, the (cycloalkyl)alkyl group is a C1-C2 alkyl substituted with one cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0735] The term "heterocyclo" as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, e.g., spirocyclic, or tricyclic groups containing three to eighteen ring members, i.e., a 3- to 18-membered heterocyclo, comprising one, two, three, or four heteroatoms, or the number of ring atoms designated. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide, i.e., S(=O), or sulfone, i.e., S(=O)2. The term heterocyclo includes groups wherein one or more -CH2- groups is replaced with one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2- one. The term heterocyclo also includes groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as indoline, indolin-2-one, 2,3-dihydro- lH-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-lH-benzo[d]azepine, or 1,3,4,5-tetrahydro- 2H-benzo [d] azepin-2-one .

[0736] In one embodiment, the heterocyclo group is a 4- to 8-membered cyclic group containing one ring and one or two oxygen atoms, e.g., tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, e.g., pyrrolidine, piperidine, or piperazine, or one oxygen and one nitrogen atom, e.g., morpholine, and, optionally, one -CH2- group is replaced with one -C(=O)- group, e.g., pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclo group is a 5- to 8-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH2- group is replaced with one -C(=O)- group. In another embodiment, the heterocyclo group is a 4- to 7-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH2- group is replaced with one -C(=O)- group. In another embodiment, the heterocyclo group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH2- group is replaced with one -C(=O)- group. In another embodiment, the heterocyclo group is a 8- to 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be linked to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include:

[0737] The term "optionally substituted heterocyclo" as used herein by itself or part of another group refers to a heterocyclo group that is either unsubstituted or substituted with one to four substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, or alkoxyalkyl. Substitution may occur on any available carbon or nitrogen atom of the heterocyclo group.

[0738] The term "(heterocyclo)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one optionally substituted heterocyclo group. In one embodiment, the (heterocyclo)alkyl group is a C1-C6alkyl substituted with one optionally substituted 4- to 7-membered heterocyclo group, i.e., an "(optionally substituted 4- to 7-membered heterocyclo)C1-C6alkyl." In another embodiment, the (heterocyclo)alkyl group is a C1-C4 alkyl substituted with one optionally substituted optionally substituted heterocyclo group, i.e., an "(optionally substituted heterocyclo group)Ci-C4 alkyl." In another embodiment, the (heterocyclo group)alkyl group is a C1-C2 alkyl substituted with one optionally substituted heterocyclo group group, i.e., an "(optionally substituted heterocyclo group heteroaryl)Ci-C2 alkyl."

[0739] The term "aryl" as used herein by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., Ce-Cu aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0740] The term "optionally substituted aryl" as used herein by itself or as part of another group refers to aryl that is either unsubstituted or substituted with one to five substituents, wherein the substituents are each independently halo, nitro, cyano, hydroxy, amino haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, aryloxy, aralkyloxy, hetero aryloxy,(heterocyclo)alkyloxy, heterocyclooxy, (aryl)alkyl, (heteroaryl)alkyl, or (hetero aryl) alkyloxy .

[0741] In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Non-limiting exemplary optionally substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclo groups. Non-limiting examples include: 2,3-dihydro- IH-inden-l-yl, 1,2,3,4-tetrahydronaphthalen-l-yl, l,3,4,5-tetrahydro-2H-benzo[c]azepin- 2-yl, 1,2,3,4-tetrahydroisoquinolin-l-yl, and 2-oxo-2,3,4,5-tetrahydro-lH- benzo [d] azepin- 1 -y 1.

[0742] The term "heteroaryl" as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to 14 fourteen ring members, i.e., a 5- to 14-membered heteroaryl, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo [b] thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 377-indolyl, indolyl, indazolyl,purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4a77-carbazolyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., lH-pyrrol-2-yl and lH-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H- imidazol-4-yl), pyrazolyl (e.g., lH-pyrazol-3-yl, lH-pyrazol-4-yl, and lH-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2- yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3- yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A nonlimiting exemplary N-oxide is pyridyl N-oxide.

[0743] The term "optionally substituted heteroaryl" as used herein by itself or as part of another group refers to a heteroaryl that is either unsubstituted or substituted with one to four substituents, wherein the substituents are independently halo, nitro, cyano, hydroxy, amino haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, aryloxy, aralkyloxy, heteroaryloxy, (heterocyclo)alkyloxy, heterocyclooxy, (aryl)alkyl, (heteroaryl)alkyl, or (hetero aryl) alkyloxy .

[0744] In one embodiment, the optionally substituted heteroaryl has two substituents. In another embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.

[0745] The term "(heteroaryl)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one optionally substituted heteroaryl group. In one embodiment, the alkyl group is a C1-C6alkyl substituted with one optionally substituted 5- to 14-membered heteroaryl group, i.e., an "(optionally substituted 5- to 14-membered heteroaryl)C1-C6alkyl." In another embodiment, the alkyl group is a C1-C6alkyl substituted with one optionally substituted 5- to 9-membered heteroaryl group, i.e., an "(optionally substituted 5- to 9-membered heteroaryl)C1-C6alkyl." In another embodiment, the alkyl group is a C1-C6alkyl substituted with one optionally substituted 5- or 6-membered heteroaryl group, i.e., an "(optionally substituted 5- or 6-memberedheteroaryl)C1-C6alkyl." In another embodiment, the alkyl group is a C1-C4 alkyl substituted with one optionally substituted 5- to 9-membered heteroaryl group, i.e., an "(optionally substituted 5- to 9-membered heteroaryl)Ci-C4 alkyl." In another embodiment, the alkyl group is a C1-C4 alkyl substituted with one optionally substituted 5- or 6-membered heteroaryl group, i.e., an "(optionally substituted 5- or 6-membered heteroaryl)Ci-C4 alkyl." In another embodiment, the alkyl group is a C1-C2 alkyl substituted with one optionally substituted 5- or 6-membered heteroaryl group, i.e., an "(optionally substituted 5- or 6-membered heteroaryl)Ci-C2 alkyl." In another embodiment, the alkyl group is a C1-C2 alkyl substituted with one optionally substituted pyridyl group, i.e., an "(optionally substituted pyridyl)Ci-C2 alkyl." Non-limiting examples include:

[0746] The terms "aralkyl" or "(aryl)alkyl" as used herein by themselves or as part of another group refers to an alkyl substituted with one optionally substituted aryl group. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C1-C6alkyl, i.e., an "(optionally substituted aryl)C1-C6alkyl." In another embodiment, the alkyl is a C1-C4 alkyl, i.e., an "(optionally substituted aryl)Ci-C4 alkyl." In another embodiment, the alkyl is a Ci or C2 alkyl, i.e., an "(optionally substituted aryl)Ci-C2 alkyl." In another embodiment, the alkyl is a Ci or C2 alkyl and the optionally substituted aryl is an optionally substituted phenyl i.e., an "(optionally substituted phenyl)Ci-C2 alkyl." Non-limiting exemplary (aryl)alkyl groups include benzyl and phenethyl.

[0747] The term "aryloxy" as used herein by itself or as part of another group refers to an optionally substituted aryl group attached to a terminal oxygen atom. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. A non-limiting exemplary aryloxy group is PhO-.

[0748] The term "heteroaryloxy" as used herein by itself or as part of another group refers to an optionally substituted heteroaryl group attached to a terminal oxygen atom. A non-limiting exemplary hetereo aryloxy group is:

[0749] The term "heterocyclooxy" as used herein by itself or as part of another group refers to an optionally substituted heterocyclo group attached to a terminal oxygen atom. In one embodiment, the optionally substituted heterocyclo group is an optionally substituted 4- to 7-membered heterocyclo group and resulting heterocyclooxy is thus referred to as a "4- to 7-membered heterocyclooxy." Non-limiting exemplary heterocyclooxy groups include:

[0750] The term "aralkyloxy" as used herein by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCfTO-.

[0751] The term "(heteroaryl)alkyloxy" as used herein by itself or as part of another group refers to an (heteroaryl)alkyl group attached to a terminal oxygen atom. Non-limiting exemplary (hetero aryl) alkyloxy groups include:

[0752] The term "(heterocyclo)alkyloxy" as used herein by itself or as part of another group refers to an (heterocyclo)alkyl group attached to a terminal oxygen atom. Non-limiting exemplary (hetero aryl) alkyloxy groups include:

[0753] The term "amino" as used by itself or as part of another group refers to a radical of the formula -NRaaRbb, wherein Raaand Rbbare independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl.

[0754] In one embodiment, the amino is -NH2.

[0755] In another embodiment, the amino is an "alkylamino," i.e., an amino group wherein Raais C1-6 alkyl and Rbbis hydrogen. In one embodiment, Raais C1-C4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0756] In another embodiment, the amino is a "dialkylamino," i.e., an amino group wherein Raaand Rbbare each independently C1-6 alkyl. In one embodiment, R55aand R55bare each independently C1-C4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2and -N(CH3)CH2CH(CH3)2.

[0757] The term "a disease or condition wherein ADAR1 inhibition provides a benefit" and the like pertains to a disease or condition in which AD ARI is important or necessary, e.g., for the onset, progress, expression of that disease or condition, or a disease or a condition which is known to be treated by an ADAR1 inhibitor. Examples of such conditions include, but are not limited to, a cancer. One of ordinary skill in the art is readily able to determine whether a compound treats a disease or condition mediated by an ADAR1 inhibitor for any particular cell type, for example, by assays which conveniently can be used to assess the activity of particular compounds.

[0758] The term "disease" or "condition" denotes disturbances and / or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and / or malfunctions. Compounds of the Disclosure are ADAR1 inhibitors and can be used in treating or preventing diseases and conditions wherein ADAR1 inhibition provides a benefit.

[0759] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, e.g., cancer, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure and optionally an immune checkpoint inhibitor to a subject need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

[0760] As used herein, the terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease or condition and / or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms "prevent," "preventing" and "prevention" may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously- controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.

[0761] The term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the present disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to a subject in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent or stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent or stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and / or kills existing cancer cells, it may be cytostatic and / or cytotoxic.

[0762] The term "container" means any receptacle and closure therefore suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0763] The term "insert" means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product.

[0764] Concurrent administration," "administered in combination," "simultaneous administration," and similar phrases mean that two or more agents are administered concurrently to the subject being treated. By "concurrently," it is meant that each agent is administered either simultaneously or sequentially in any order at different points in time. However, if not administered simultaneously, it is meant that they are administered to a subject in a sequence and sufficiently close in time so as to provide the desiredtherapeutic effect and can act in concert. For example, a Compound of the Disclosure can be administered at the same time or sequentially in any order at different points in time as a second therapeutic agent. A Compound of the Disclosure and the second therapeutic agent can be administered separately, in any appropriate form and by any suitable route. When a Compound of the Disclosure and the second therapeutic agent are not administered concurrently, it is understood that they can be administered in any order to a subject in need thereof. For example, a Compound of the Disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent treatment modality, e.g., an ICI, to a subject in need thereof. In various embodiments, a Compound of the Disclosure and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In one embodiment, the components of the combination therapies are administered at about 1 minute to about 24 hours apart.

[0765] The present disclosure encompasses any Compound of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H (or deuterium (D)),3H, nC,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively, e.g.,3H,nC, and14C. In one embodiment, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a positionwith an atom having a different atomic mass or mass number." Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.

[0766] Compounds of the Disclosure may contain one or more asymmetric carbon atoms and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure. All conformational isomers, i.e., stereoisomers produced by rotation about a c bond, are also encompassed by the present disclosure.

[0767] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0768] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0769] The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

[0770] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one embodiment, Compounds of the Disclosure are racemic.

[0771] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0772] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 65:2193 (1996), unless otherwise indicated.

[0773] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and 5 enantiomers, the percent enantiomeric excess is defined as | R - 5 | *100, where R and 5 are the respectivemole or weight fractions of enantiomers in a mixture such that R + 5 = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([cx]obs / [cx]max)*100, where [cc]obs is the optical rotation of the mixture of enantiomers and [cx]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

[0774] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11.

[0775] As used herein, the term "and / or" is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or B; A or C; B or C; A and B; A and C; B and C; A (alone); B (alone); and C (alone).

[0776] The term "leaving group" as used herein refers to an atom or group of atoms that becomes detached from an atom or group of atoms in what is considered to be the residual or main part of the molecule in a specified reaction. Non-limiting exemplary leaving groups include -Cl, -I, -Br, -OTf, -OMs, and -OTs.

[0777] The word "comprising" is used in a manner consistent with its open-ended meaning, that is, to mean that a given product, composition, or process can optionally also have additional features or elements beyond those expressly described. It is understood that wherever embodiments are described with the language "comprising," otherwise analogous embodiments described in terms of "consisting of" and / or "consisting essentially of" are also contemplated and within the scope of this disclosure.

[0778] Pharmaceutically acceptable salts and solvates, e.g., hydrates, of the Compounds of the Disclosure can also be used in the methods disclosed herein.

[0779] The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure. Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation. Salts of Compounds of the Disclosure can be acid addition salts formed with acceptable acids. Examples of acids which can be employed to form salts include inorganic acids such as nitric, boric, hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Non-limiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the disclosure can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference to Compounds of the Disclosure appearing herein is intended to include Compounds of the Disclosure as well as salts, hydrates, or solvates thereof.

[0780] The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. The term "solvate" as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule such as, e.g., a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.

[0781] One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):6Q1-611 (2004), whichdescribes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by van Tender el al., AAPS Pharm. Sci. Tech., 5( 7): Article 12 (2004), and A.L. Bingham el al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.

[0782] The term "Neratinib" refers to (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide.In some embodiments in connection with the methods and / or uses of the present disclosure, Neratinib or Neratinib maleate is administered to a subject in a daily dose of 240 mg or less, e.g., 200 mg or less, 160 mg or less, or 120 mg or less. In some embodiments, Neratinib or Neratinib maleate is administered to a subject in a daily dose of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, or 110 mg.EXAMPLESGeneral Procedures:

[0783] Unless otherwise specified, all commercial reagents were used as supplied without further purification, and all reactions were performed under a nitrogen atmosphere in a dry solvent under anhydrous conditions. NMR spectra were obtained on a Bruker 400 Ascend spectrometer at afrequency of 400 MHz. Chemical shifts (5) are reported in parts per million (ppm) relative to an internal standard. The final products were purified on a preparative high-performance liquid chromatography (HPLC) column (Waters 2545, Quaternary Gradient Module) with a SunFire Prep C18 OBD 5 pm 50 x 100 mm reversed-phase column. The mobile phase was a gradient of solvent A (H2O with 0.1% TFA) and solvent B (CH3CN with 0.1% of TFA) at a flow rate of 60 mL / min and 1% / min increase of solvent B. All final compounds have purity >95% as determined by Waters ACQUITY ultraperformance liquid chromatograph (UPLC) using reversed- phase column (SunFire, C18, 5 pm, 4.6 x 150 mm) and a solvent gradient of A (H2O with 0.1% of TFA) and solvent B (CH3CN with 0.1% of TFA). Electrospray ionization (ESI)mass spectral (MS) analysis was performed on a Thermo Scientific LCQ Fleet mass spectrometer.EXAMPLE 1General Procedure A - Preparation of compounds having Formula IIIScheme 1NaH, DMF, rt (n = 1)(or)ep . IV

[0784] Condition 1A of Step A.l. Sodium hydride (60%, 5.69 mmol) in dry DMF (3 mL) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added a compound having Formula I (2.85 mmol) in anhydrous DMF (2 mL). 2-Chloro-l-fluoro-4-nitrobenzene (compound II) (2.85 mmol) was added to the above solution and the resulting solution was stirred at rt for 6 h. Cold water was added slowly to the reaction mixture, and a yellow precipitate resulted. The yellow solid is isolated by vacuum filtration, washed with cold water, and air dried to give the title compound as yellow solids.

[0785] Condition IB of Step A.l. To a solution of compound having Formula I (2.85 mmol) and CS2CO3 (5.7 mmol) in dry acetonitrile (10 mL) under a nitrogen atmosphere was added 2-chloro-l-fluoro-4-nitrobenzene (compound II) (2.85 mmol) and the resulting solution was stirred at 60 °C for 12 h. The reaction solution was cool to rt, filtered and washed with ethyl acetate. The filtrate was evaporated to give the compounds as yellow solids.

[0786] The following compounds having Formula III were prepared using this general procedure:EXAMPLE 2General Procedure BPreparation of compounds having Formula IV

[0787] Condition IB of Step A.2. A mixture of Formula III (2.51 mmol), iron (12.56 mmol) and NH4CI (25.11 mmol) in 70% ethanol in water was heated at 70 °C for 1 h. The reaction mixture was allowed to cool to rt, and then filtered over celite®. The filtrate was evaporated under vacuum giving an orange solid which was stirred with EtOAc, and then the resulting mixture was filtered. The filtrate was dried over anhydrous Na2SO4 and evaporated under vacuum to afford the desired compound IV as brown solid. The crude compound was used for the next step without further purification.

[0788] Condition 2B of Step A.2. A mixture of Formula III (2.51 mmol), and iron (12.56 mmol) in acetic acid (10 mF) was stirred at rt for 3 h. The reaction mixture was then filtered over celite® and washed with ethyl acetate. The filtrate was evaporated under vacuum giving an orange solid which was stirred with EtOAc and saturated NaHCOa. The ethyl acetate was separated, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous Na2SO4 and evaporated under vacuum to afford the desired compound having Formula IV

[0789] The following compounds were prepared using this general procedure:EXAMPLE 3General Procedure C - Preparation of Compounds having Formula VIScheme 2Cpd Nos 2 and 29

[0790] Methansulfonic acid (3 eq.) was added at room temperature to a suspension of amide compound having a Formula V (1 eq.) and the appropriate amine having Formula IV (1.2 eq.) in anhydrous ethyl alcohol. The mixture was then refluxed for 3 ~ 6 h. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to yield the desired compounds having Formula VI as a light-yellow solid.

[0791] The following compounds of Formula VI were prepared using this general procedure:EXAMPLE 4General Procedure D - Preparation of Cpd. Nos. 1, 3, 4, 6, 12-23, 25, 26, 28, and 31-32

[0792] ('E)-4-(Dimethylamino)but-2-enoyl chloride hydrochloride (1.1 eq.) was added at 0 °C to a suspension of a compound having Formula VI (1 eq.) in N-methylpyrrolidine (4 vol.). See Scheme 2. The mixture was then allowed to ambient temperature and stirred for 2 h. The compound was purified by preparative HPLC to yield Cpd. Nos. 1, 3, 4, 6, 12-23, 25-26, 28, 31 and 32.

[0793] Cpd. No. 1: (E)-N-(4-((3-chloro-4-methoxyphenyl)amino)-3-cyano-7- ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4- methoxyphenyl)amino)-7 -ethoxy quinoline-3-carbonitrile and (E)-4-(dimethylamino)but- 2-enoyl chloride hydrochloride. Yield 58%; LC-MS calculated for C25H26CIN5O3 [M + H]+= 480.18, found 480.12;1H NMR (400 MHz, CDCI3) 8 9.20 (s, 1H), 8.46 (s, 1H), 8.07 (s, 1H), 7.74 (br. s„ 1H), 7.23 (s, 1H), 7.16 (d, J = 2.57 Hz, 1H), 6.94 - 7.09 (m, 2H), 6.81 (d, J = 8.68 Hz, 1H), 6.21 (d, J = 15.28 Hz, 1H), 4.28 (q, J = 6.97 Hz, 2H), 3.92 (s, 3H), 3.10 - 3.18 (m, 2H), 2.30 (s, 6H), 1.59 (t, J= 6.97 Hz, 3H).

[0794] Cpd. No. 3: (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano- 7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-(pyridin- 2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile and (E)-4- (dimethylamino)but-2-enoyl chloride hydrochloride. Yield 68%; LC-MS calculated for C30H29CIN6O3 [M + H]+= 557.21, found 557.06;1H NMR (400 MHz, DMSO-d6) 8 9.62 (s, 1H), 9.49 (s, 1H), 8.98 (s, 1H), 8.57 - 8.63 (m, 1H), 8.48 (s, 1H), 7.88 (dt, J = 1.71, 7.70 Hz, 1H), 7.59 (d, J = 7.82 Hz, 1H), 7.33 - 7.45 (m, 3H), 7.26 (d, J = 8.93 Hz, 1H), 7.21 (dd, J = 2.45, 8.80 Hz, 1H), 6.79 (td, J = 5.96, 15.34 Hz, 1H), 6.60 (d, J = 15.41 Hz, 1H), 5.29 (s, 2H), 4.31 (q, J = 6.97 Hz, 2H), 3.08 (dd, J = 1.04, 5.93 Hz, 2H), 1.48 (t, J = 6.97 Hz, 3H).

[0795] Cpd. No. 4: (E)-N-(4-((3-chlorophenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4- (dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7- ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 62%; LC-MS calculated for C30H29CIN6O3 [M + H]+= 557.21, found 557.06;1H NMR (400 MHz, DMSO-d6) 8 9.62 (s, 1H), 9.49 (s, 1H), 8.98 (s, 1H),8.57 - 8.63 (m, 1H), 8.48 (s, 1H), 7.88 (dt, J = 1.71, 7.70 Hz, 1H), 7.59 (d, J = 7.82 Hz, 1H), 7.33 - 7.45 (m, 3H), 7.26 (d, J = 8.93 Hz, 1H), 7.21 (dd, J = 2.45, 8.80 Hz, 1H), 6.79 (td, J = 5.96, 15.34 Hz, 1H), 6.60 (d, J = 15.41 Hz, 1H), 5.29 (s, 2H), 4.31 (q, J = 6.97 Hz, 2H), 3.08 (dd, J= 1.04, 5.93 Hz, 2H), 1.48 (t, J = 6.97 Hz, 3H).

[0796] Cpd. No. 6: (E)-N-(3-cyano-7-ethoxy-4-((4-methoxyphenyl)amino)quinolin-6-yl)- 4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-7-ethoxy-4-((4- methoxyphenyl)amino)quinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 56%; LC-MS calculated for C25H27N5O3 [M + H]+= 446.22, found 446.27;1H NMR (400 MHz, CDCI3) 8 9.08 (s, 1H), 8.57 (s, 1H), 7.79 (br. s„ 1H), 7.27 - 7.29 (m, 2H), 7.01 (m, 3H), 6.72 (d, J = 15.16 Hz, 1H), 4.39 (q, J = 6.52 Hz, 2H), 3.87 (s, 3H), 2.89 (s, 6H), 1.57 (t, J = 6.79 Hz, 3H).

[0797] Cpd. No. 12: (E)-N-(4-((3-chloro-4-((6-methylpyridin-2- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-((6-methylpyridin-2-yl)methoxy)phenyl)amino)-7- ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 55%; LC-MS calculated for C31H31CIN6O3 [M + H]+= 571.22, found 571.12;1H NMR (400 MHz, CD3OD) 8 9.24 (s, 1H), 8.81 (s, 1H), 8.20 (t, J = 7.89 Hz, 1H), 7.83 (d, J = 7.82 Hz, 1H), 7.62 - 7.67 (m, 2H), 7.43 - 7.49 (m, 2H), 7.35 (d, J = 8.80 Hz, 1H), 6.96 - 7.06 (m, 1H), 6.82 - 6.89 (m, 1H), 5.47 (s, 2H), 4.45 (q, J = 6.97 Hz, 2H), 4.04 (d, J = 6.60 Hz, 2H), 2.96 (s, 6H), 2.74 (s, 3H), 1.61 (t, J = 6.97 Hz, 3H).

[0798] Cpd. No. 13: (E)-N-(4-((3-chloro-4-(pyridin-4-yloxy)phenyl)amino)-3-cyano-7- ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-(pyridin- 4-yloxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but- 2-enoyl chloride hydrochloride. Yield 65%; LC-MS calculated for C29H27CIN6O3 [M + H]+= 543.19, found 543.15;1H NMR (400 MHz, CD3OD) 8 9.22 (s, 1H), 8.94 (s, 1H), 8.36 - 8.44 (m, 2H), 7.80 - 7.88 (m, 2H), 7.65 (dd, J = 2.32, 8.56 Hz, 1H), 7.54 (s, 1H), 7.11 - 7.18 (m, 2H), 6.98 (td, J = 7.05, 15.25 Hz, 1H), 6.87 (d, J = 15.16 Hz, 1H), 4.46 (q, J = 6.97 Hz, 2H), 4.05 (dd, J = 0.73, 6.97 Hz, 2H), 2.97 (s, 6H), 1.61 (t, J = 6.97 Hz, 3H).

[0799] Cpd. No. 14: (E)-N-(4-((3-chloro-4-((5-isopropylpyridin-2- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-((5-isopropylpyridin-2-yl)methoxy)phenyl)amino)-7- ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 72%; LC-MS calculated for C33H35CIN5O3 [M + H]+= 599.26, found 599.27;1H NMR (400 MHz, CD3OD) 8 9.24 (s, 1H), 8.81 (s, 1H), 8.72 (d, J = 2.08 Hz, 1H), 8.38 (dd, J = 2.08, 8.31 Hz, 1H), 8.03 (d, J = 8.19 Hz, 1H), 7.65 (d, J = 2.57 Hz, 1H), 7.44 - 7.52 (m, 2H), 7.36 (d, J = 8.93 Hz, 1H), 6.96 - 7.08 (m, 1H), 6.82 - 6.90 (m, 1H), 5.55 (s, 2H), 4.44 (q, J = 6.97 Hz, 2H), 4.05 (dd, J = 0.92, 7.15 Hz, 2H), 3.20 (td, J= 6.92, 13.91 Hz, 1H), 2.96 (s, 6H), 1.57 - 1.63 (m, 3H), 1.39 (d, J= 6.97 Hz, 6H).

[0800] Cpd. No.15: (E)-N-(4-((3-chloro-4-((6-ethylpyridin-2-yl)methoxy)phenyl)amino)-3-cyano-7 -ethoxy quinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4- ((6-ethylpyridin-2-yl)methoxy)phenyl)amino)-7 -ethoxy quinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 74%; LC-MS calculated for C32H33CIN6O3 [M + H]+= 585.24, found 585.21;1H NMR (400 MHz, CD3OD) 8 9.25 (s, 1H), 8.82 (s, 1H), 8.36 (t, J = 7.95 Hz, 1H), 7.93 (d, J = 7.70 Hz, 1H), 7.79 (d, J = 7.82 Hz, 1H), 7.65 (d, J = 2.45 Hz, 1H), 7.43 - 7.52 (m, 2H), 7.37 (d, J = 8.80 Hz, 1H), 6.94 - 7.06 (m, 1H), 6.82 - 6.91 (m, 1H), 5.54 (s, 2H), 4.44 (q, J = 6.85 Hz, 2H), 4.04 (d, J = 6.97 Hz, 2H), 3.08 (q, J = 7.50 Hz, 2H), 2.96 (s, 6H), 1.60 (t, J = 6.91 Hz, 3H), 1.43 (t, J = 7.58 Hz, 3H).

[0801] Cpd. No.16: (E)-N-(4-((3-chloro-4-((2-methylpyridin-4-yl)oxy)phenyl)amino)-3- cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4- ((2-methylpyridin-4-yl)oxy)phenyl)amino)-7 -ethoxyquinoline-3-carbonitrile and (E)-4- (dimethylamino)but-2-enoyl chloride hydrochloride. Yield 62%; LC-MS calculated for C30H29CIN6O3 [M + H]+= 557.21, found 557.03;1H NMR (400 MHz, CD3OD) 8 9.31 (s, 1H), 8.88 (s, 1H), 8.65 (d, J = 6.85 Hz, 1H), 7.91 (d, J = 2.32 Hz, 1H), 7.70 (dd, J = 2.38, 8.62 Hz, 1H), 7.62 (d, J = 8.68 Hz, 1H), 7.55 (s, 1H), 7.48 (dd, J = 2.57, 6.85 Hz, 1H), 7.39 (d, J = 2.45 Hz, 1H), 6.98 - 7.07 (m, 1H), 6.84 - 6.93 (m, 1H), 4.45 (q, J = 6.97 Hz, 2H), 4.06 (d, J = 6.97 Hz, 2H), 2.97 (s, 6H), 2.71 (s, 3H), 1.61 (t, J = 6.97 Hz, 3H).

[0802] Cpd. No. 17: (E)-N-(4-((3-chloro-4-((6-isopropylpyridin-3- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-((6-isopropylpyridin-3-yl)methoxy)phenyl)amino)-7- ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 44%; LC-MS calculated for C33H35CIN6O3 [M + H]+= 599.26, found 598.99;1H NMR (400 MHz, CD3OD) 8 9.25 (s, 1H), 8.79 - 8.85 (m, 2H), 8.65 (dd, J = 2.02, 8.38 Hz, 1H), 8.04 (d, J = 8.44 Hz, 1H), 7.64 (d, J = 2.45 Hz, 1H), 7.44 - 7.50 (m, 2H), 7.36 - 7.41 (m, 1H), 6.96 - 7.05 (m, 1H), 6.83 - 6.90 (m, 1H), 5.51 (s, 2H), 4.45 (q, J = 6.97 Hz, 2H), 4.05 (dd, J = 0.86, 7.09 Hz, 2H), 3.41 (td, J = 6.92, 13.91 Hz, 1H), 2.96 (s, 6H), 1.61 (t, J = 6.97 Hz, 3H), 1.48 (d, J = 6.97 Hz, 6H).

[0803] Cpd. No. 18: (E)-N-(4-((3-chloro-4-((2-isopropylpyridin-4-yl)oxy)phenyl)amino)-3-cyano-7 -ethoxy quinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4- ((2-isopropylpyridin-4-yl)oxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 61%; LC-MS calculated for C32H33CIN6O3 [M + H]+= 585.24, found 585.02;1H NMR (400 MHz, CD3OD) 8 9.30 (s, 1H), 8.86 (s, 1H), 8.66 (d, J = 6.85 Hz, 1H), 7.90 (d, J = 2.32 Hz, 1H), 7.69 (dd, J = 2.38, 8.62 Hz, 1H), 7.63 (d, J = 8.56 Hz, 1H), 7.47 - 7.54 (m, 2H), 7.41 (d, J = 2.69 Hz, 1H), 7.02 (td, J = 7.08, 15.19 Hz, 1H), 6.88 (d, J = 15.28 Hz, 1H), 4.46 (q, J = 7.05 Hz, 2H), 4.05 (dd, J = 0.98, 7.09 Hz, 2H), 3.23 - 3.31 (m, 1H), 2.97 (s, 6H), 1.62 (t, J = 6.97 Hz, 3H), 1.40 (d, J = 6.97 Hz, 6H).

[0804] Cpd. No. 19: (E)-N-(4-((3-chloro-4-((6-(prop-l-en-2-yl)pyridin-2- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-((6-(prop- l-en-2-yl)pyridin-2- yl)methoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 53%; LC-MS calculated for C33H33CIN6O3 [M + H]+= 597.24, found 597.26;1H NMR (400 MHz, CD3OD) 8 9.23 (s, 1H), 8.81 (s, 1H), 7.88 (t, J = 7.89 Hz, 1H), 7.55 - 7.65 (m, 3H), 7.45 (s, 1H), 7.41 (dd, J = 2.57, 8.80 Hz, 1H), 7.31 (d, J = 8.93 Hz, 1H), 6.95 - 7.05 (m, 1H), 6.82 - 6.89 (m, 1H), 5.87 - 5.93 (m, 1H), 5.34 - 5.42 (m, 3H), 4.44 (q, J = 6.97 Hz, 2H), 4.04 (dd, J = 1.04, 7.15 Hz, 2H), 2.96 (s, 6H), 2.20 - 2.28 (m, 3H), 1.61 (t, J = 6.97 Hz, 3H).

[0805] Cpd. No. 20: (E)-N-(4-((3-chloro-4-((6-isopropylpyridin-2- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-((6-isopropylpyridin-2-yl)methoxy)phenyl)amino)-7- ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 67%; LC-MS calculated for C33H35CIN6O3 [M + H]+= 599.26, found 599.23;1H NMR (400 MHz, CD3OD) 8 9.25 (s, 1H), 8.82 (s, 1H), 8.32 (t, J = 7.95 Hz, 1H), 7.89 (d, J = 7.09 Hz, 1H), 7.74 - 7.79 (m, 1H), 7.65 (d, J = 2.57 Hz, 1H), 7.45 - 7.50 (m, 2H), 7.37 (d, J = 8.93 Hz, 1H), 7.01 (td, J = 7.12, 15.22 Hz, 1H), 6.83 - 6.89 (m, 1H), 5.53 (s, 2H), 4.45 (q, J = 6.97 Hz, 2H), 4.04 (dd, J = 0.98, 7.09 Hz, 2H), 3.29-3.36 (m, 1H), 2.96 (s, 6H), 1.61 (t, J = 6.97 Hz, 3H), 1.45 (d, J= 6.97 Hz, 6H).

[0806] Cpd. No. 21: (E)-N-(4-((4-((6-(tert-butyl)pyridin-3-yl)methoxy)-3- chlorophenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between 6- amino-4-((4-((6-(tert-butyl)pyridin-3-yl)methoxy)-3-chlorophenyl)amino)-7- ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 42%; LC-MS calculated for C34H37CIN6O3 [M + H]+= 613.27, found 613.25;1H NMR (400 MHz, CD3OD) 8 9.24 (s, 1H), 8.73 - 8.88 (m, 2H), 8.56 (dd, J = 1.71, 8.44 Hz, 1H), 8.07 (d, J = 8.44 Hz, 1H), 7.63 (d, J = 2.45 Hz, 1H), 7.43 - 7.52 (m, 2H), 7.34 - 7.43 (m, 1H), 6.95 - 7.07 (m, 1H), 6.86 (d, J = 15.16 Hz, 1H), 5.50 (s, 2H), 4.44 (q, J = 6.89 Hz, 2H), 4.04 (d, J = 6.97 Hz, 2H), 2.96 (s, 6H), 1.60 (t, J = 6.85 Hz, 3H), 1.54 (s, 9H).

[0807] Cpd. No. 22: (E)-N-(4-((3-chloro-4-((6-isobutylpyridin-3- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-((6-isobutylpyridin-3-yl)methoxy)phenyl)amino)-7- ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 61%; LC-MS calculated for C34H37CIN6O3 [M + H]+= 613.27, found 613.16;1H NMR (400 MHz, CD3OD) 8 9.25 (s, 1H), 8.82 - 8.88 (m, 1H), 8.80 (s, 1H), 8.61 (dd, J = 1.90, 8.25 Hz, 1H), 7.97 (d, J = 8.31 Hz, 1H), 7.64 (d, J = 2.57 Hz, 1H), 7.48 (td, J = 2.69, 5.87 Hz, 2H), 7.36 - 7.41 (m, 1H), 6.96 - 7.06 (m, 1H), 6.81 - 6.91 (m, 1H), 5.51 (s, 2H), 4.45 (q, J = 7.01 Hz, 2H), 4.04 (d, J = 6.85 Hz, 2H), 2.89 -3.01 (m, 8H), 2.17 (quind, J= 6.86, 13.63 Hz, 1H), 1.61 (t, J= 6.97 Hz, 3H), 1.03 (d, J = 6.72 Hz, 6H).

[0808] Cpd. No. 23: (E)-N-(4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between 6-amino-4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 66%; LC-MS calculated for C35H37CIN6O4 [M + H]+= 641.27, found 641.15;1H NMR (400 MHz, CD3OD) 8 9.25 (s, 1H), 8.79 - 8.86 (m, 2H), 8.56 (dd, J = 1.90, 8.38 Hz, 1H), 7.96 (d, J= 8.44 Hz, 1H), 7.64 (d, J = 2.57 Hz, 1H), 7.43 - 7.50 (m, 2H), 7.36 - 7.41 (m, 1H), 6.96 - 7.05 (m, 1H), 6.86 (d, J = 15.16 Hz, 1H), 5.49 (s, 2H), 4.45 (q, J = 6.97 Hz, 2H), 4.12 (td, J = 3.01, 11.34 Hz, 2H), 4.04 (d, J = 6.60 Hz, 2H), 3.27-3.35 (m, 1H), 3.56 - 3.69 (m, 2H), 3.23 - 3.31 (m, 1H), 1.91 - 2.02 (m, 4H), 1.61 (t, J = 6.97 Hz, 3H)

[0809] Cpd. No. 25: (E)-N-(4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-7-ethoxy-2-methylquinolin-6-yl)-4-(dimethylamino)but-2- enamide was prepared in a manner according to general procedure D by coupling between N4-(3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)methoxy)phenyl)-7- ethoxy-2-methylquinoline-4,6-diamine and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 60%; LC-MS calculated for C35H40CIN5O4 [M + H]+= 630.29, found 630.56;1H NMR (400 MHz, CD3OD) 8 9.10 (s, 1H), 8.74 (d, J = 1.56, 1H), 8.26 (dd, J = 1.83, 8.19 Hz, 1H), 7.71 (d, J = 8.19 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 1.22 Hz, 2H), 7.30 (s, 1H), 6.94 - 7.05 (m, 1H), 6.79 - 6.88 (m, 1H), 6.58 (s, 1H), 5.39 (s, 2H), 4.41 (q, J = 6.97 Hz, 2H), 4.11 (dd, J = 2.75, 10.33 Hz, 2H), 4.05 (d, J = 7.09 Hz, 2H), 3.62 (dt, J = 3.30, 11.25 Hz, 2H), 3.08 - 3.26 (m, 1H), 2.97 (s, 6H), 2.60 (s, 3H), 1.91 - 2.00 (m, 4H), 1.61 (t, J = 6.97 Hz, 3H)

[0810] Cpd. No. 26: (E)-N-(4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between N4-(3- chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)methoxy)phenyl)-7- ethoxyquinoline-4,6-diamine and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 55%; LC-MS calculated for C34H38CIN5O4 [M + H]+= 616.27, found 616.52;1H NMR (400 MHz, CD3OD) 8 9.17 (s, 1H), 8.79 (s, 1H), 8.33 (m, 1H),8.26 (d, J= 8.19 Hz, 1H), 7.76 (d, J = 8.19 Hz, 1H), 7.56 (s, 1H), 7.43 (m, 2H), 7.41 (s, 1H), 6.94 - 7.05 (m, 1H), 6.79 - 6.88 (m, 1H), 6.75 (d, J = 4.0 Hz, 1H), 5.41 (s, 2H), 4.41 (q, J = 6.97 Hz, 2H), 4.11 (dd, J = 2.75, 10.33 Hz, 2H), 4.05 (d, J = 7.09 Hz, 2H), 3.62 (dt, J= 3.30, 11.25 Hz, 2H), 3.18 - 3.26 (m, 1H), 2.97 (s, 6H), 1.87 - 2.03 (m, 4H), 1.61 (t, 7= 6.97 Hz, 3H).

[0811] Cpd. No. 28: (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7- ethoxy-2-ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between N4-(3-chloro-4-(pyridin-2- ylmethoxy)phenyl)-7-ethoxy-2-ethylquinoline-4,6-diamine and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride. Yield 72%; LC-MS calculated for C31H34CIN5O3 [M + H]+= 560.25, found 560.45;1H NMR (400 MHz, CD3OD) 8 9.10 (s, 1H), 8.59 - 8.67 (m, 1H), 7.99 - 8.06 (m, 1H), 7.76 - 7.83 (m, 1H), 7.57 (d, J = 2.32 Hz, 1H), 7.46 - 7.53 (m, 1H), 7.28 - 7.45 (m, 3H), 6.95 - 7.04 (m, 1H), 6.81 - 6.89 (m, 1H), 6.60 (s, 1H), 5.38 (s, 2H), 4.41 (q, J = 6.89 Hz, 2H), 4.05 (dd, J = 0.92, 7.15 Hz, 2H), 2.97 (s, 6H), 2.84 - 2.90 (m, 2H), 1.61 (t, J= 6.97 Hz, 3H), 1.34 (t, 7= 7.58 Hz, 3H).

[0812] Cpd. No. 31: (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7- ethoxy-2-methylquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between N4-(3-chloro-4-(pyridin- 2-ylmethoxy )phenyl)-7 -ethoxy-2-methylquinoline-4,6-diamine and 4-(dimethylamino)butanoyl chloride hydrochloride. Yield 73%; LC-MS calculated for C30H32CIN5O3 [M + H]+= 546.23, found 546.44;1H NMR (400 MHz, CD3OD) 8 9.09 (s, 1H), 8.59 - 8.67 (m, 1H), 8.01 (dt, 7 = 1.77, 7.73 Hz, 1H), 7.56 (d, 7 = 2.20 Hz, 1H), 7.49 (dd, 7 = 5.14, 6.48 Hz, 1H), 7.33 - 7.41 (m, 2H), 7.29 (s, 1H), 6.95 - 7.04 (m, 1H), 6.85 (d, 7 = 15.16 Hz, 1H), 6.58 (s, 1H), 5.38 (s, 2H), 4.41 (q, 7 = 6.97 Hz, 2H), 4.05 (dd, 7 = 0.98, 7.09 Hz, 2H), 2.97 (s, 6H), 2.60 (s, 3H), 1.61 (t, 7 = 6.97 Hz, 3H).

[0813] Cpd. No. 32: (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7- ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide was prepared in a manner according to general procedure D by coupling between N4-(3-chloro-4-(pyridin-2- ylmethoxy)phenyl)-7 -ethoxy quinoline-4,6-diamine and 4-(dimethylamino)butanoyl chloride hydrochloride. Yield 56%; LC-MS calculated for C29H30CIN5O3 [M + H]+= 532.21, found 532.43;1H NMR (400 MHz, CD3OD) 8 9.17 (s, 1H), 8.73 - 8.77 (m, 1H),8.27 - 8.28 (m, 2H), 7.99 (d, 7 = 8.0 Hz, 1H), 7.71- 7.74 (m, 1H), 7.58 - 7.62 (m, 1H),7.33 - 7.41 (m, 3H), 6.95 - 7.04 (m, 1H), 6.85 (d, J= 15.16 Hz, 1H), 6.77 (d, J= 4.0 Hz, 1H), 5.49 (s, 2H), 4.42 (q, J = 6.97 Hz, 2H), 4.05 (dd, J = 0.98, 7.09 Hz, 2H), 2.97 (s, 6H), 1.61 (t, 7 = 6.97 Hz, 3H).EXAMPLE 5General procedure F - Preparation of Cpds Nos. 5, 7, and 8Scheme 3

[0814] To a solution of (E)-4-bromobut-2-cnoic acid (0.204 mmol) in CH2Q2 (1 mL) was added 2.0 M solution of oxalyl chloride in CH2Q2 (0.204 mmol) followed by 1 drop of DMF. The solution was stirred for 2 h during which time gas evolution ceased. The solvent was evaporated giving the carboxylic acid chloride. A solution of 6-amino-4-((3- chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile (0.157 mmol) in NMP was stirred under nitrogen in an ice bath as a solution of the acid chloride prepared above in NMP (0.2 mL) was added. The mixture was then allowed to ambient temperature and stirred for 2 h. Then, appropriate amine (0.204 mmol) was added, and the resulting mixture was stirred at rt for 12 h. The compounds were purified by preparative HPLC to yield the desired compound as a light-yellow solid. In addition to this one pot method, intermediate Compound VII (-Br and -Cl mixture) was isolated and treated with appropriate amine in the presence of CS2CO3 in acetonitrile at 60 °C for 2 hto afford desired compounds such as Cpd. No. 5 (Step C.2), Cpd. No. 7 (Step C.3), and Cpd. No. 8 (Step C.4) in higher yields.

[0815] (E)-4-bromo-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7- ethoxyquinolin-6-yl)but-2-enamide VII. LCMS calculated for C28H23BrClNsO3 [M + H]+= 592.08, found 592.25 and 593.72.

[0816] (E)-4-chloro-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7- ethoxyquinolin-6-yl)but-2-enamide VII. LCMS calculated for C28H23CI2N5O3 [M + H]+= 548.13, found 547.81

[0817] Cpd No. 5: (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano- 7-ethoxyquinolin-6-yl)-4-morpholinobut-2-enamide was prepared in a manner according to general procedure F by SN2 reaction of Compound VII with morpholine in NMP (or) CS2CO3 in acetonitrile. Yield 78%; LC-MS calculated for C32H31CIN6O4 [M + H]+= 599.22, found 599.46;1H NMR (400 MHz, CDCI3) 8 9.06 (s, 1H), 8.62 (br. s„ 2H), 7.86 - 7.93 (m, 1H), 7.83 (br. s„ 1H), 7.75 (d, J = 7.70 Hz, 1H), 7.45 (d, J = 2.20 Hz, 1H), 7.34 - 7.41 (m, 1H), 7.21 - 7.27 (m, 1H), 7.12 (d, J = 8.56 Hz, 1H), 6.94 - 7.04 (m, 1H), 6.68 (d, J = 15.28 Hz, 1H), 5.38 (s, 2H), 4.40 (d, J = 6.60 Hz, 2H), 3.99 (br. s„ 4H), 3.87 (d, J= 5.99 Hz, 2H), 3.25 (br. s„ 4H), 1.57 (t, J= 6.24 Hz, 3H).

[0818] Cpd. No. 7: (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano- 7-ethoxyquinolin-6-yl)-4-(piperidin-l-yl)but-2-enamide was prepared in a manner according to general procedure F by SN2 reaction of Compound VII with piperidine in NMP (or) CS2CO3 in acetonitrile. Yield 72%; LC-MS calculated for C33H33CIN6O3 [M + H]+= 597.24, found 597.40;1H NMR (400 MHz, CD3OD) 8 8.94 (s, 1H), 8.53 - 8.61 (m, 1H), 8.37 (s, 1H), 7.92 (dt, J = 1.77, 7.73 Hz, 1H), 7.72 (d, J = 7.83 Hz, 1H), 7.40 (ddd, J = 1.10, 4.98, 7.49 Hz, 1H), 7.37 (d, J = 2.32 Hz, 1H), 7.24 (s, 1H), 7.11 - 7.20 (m, 2H), 7.01 (td, J = 6.92, 15.25 Hz, 1H), 6.63 (d, J = 15.28 Hz, 1H), 5.28 (s, 2H), 4.31 (q, J = 6.97 Hz, 2H), 3.55 (d, J = 6.85 Hz, 2H), 2.84 (br. s„ 4H), 1.74 (quin, J = 5.65 Hz, 4H), 1.56 (t, 7= 6.97 Hz, 5H).

[0819] Cpd. No. 8: (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano- 7-ethoxyquinolin-6-yl)-4-(4-methylpiperazin-l-yl)but-2-enamide was prepared in a manner according to general procedure F by SN2 reaction of VII with 1 -methylpiperazine in NMP (or) CS2CO3 in acetonitrile. Yield 70%; LC-MS calculated for C33H34CIN7O3 [M + H]+= 612.25, found 612.34;1H NMR (400 MHz, CD3OD) 8 8.97 (s, 1H), 8.55 - 8.64 (m, 1H), 8.37 (s, 1H), 7.93 (dt, J = 1.77, 7.73 Hz, 1H), 7.73 (d, J = 7.82 Hz, 1H), 7.42(ddd, J = 1.10, 5.01, 7.58 Hz, 1H), 7.35 (d, J = 2.08 Hz, 1H), 7.20 (s, 1H), 7.10 - 7.18 (m, 2H), 7.00 (td, J = 6.02, 15.34 Hz, 1H), 6.55 (d, J = 15.28 Hz, 1H), 5.28 (s, 2H), 4.30 (q, J = 7.05 Hz, 2H), 3.17 (br. s„ 4H), 2.79 (s, 4H), 2.73 (br. s„ 3H), 1.57 (t, J = 7.03 Hz, 3H).EXAMPLE 6General Procedure E - Preparation of Cpd. Nos. 2 and 29

[0820] 4-(Dimethylamino)butanoyl chloride hydrochloride (0.067 mmol) was added at 0 °C to a suspension of VI (0.045 mmol) in N-methylpyrrolidine. The mixture was then allowed to ambient temperature and stirred for 2 h. The compound was purified by preparative HPLC to yield the Cpd. Nos. 2 and 29.

[0821] Cpd. No. 2: N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7- ethoxyquinolin-6-yl)-4-(dimethylamino)butanamide was prepared in a manner according to general procedure E by coupling between 6-amino-4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile and4-(dimethylamino)butanoyl chloride hydrochloride. Yield 62%; LC-MS calculated for C30H31CIN6O3 [M + H]+= 559.22, found 559.15;1H NMR (400 MHz, CD3OD) 8 8.84 (s, 1H), 8.54 - 8.61 (m, 1H), 8.42 (s, 1H), 7.92 (dt, J = 1.71, 7.76 Hz, 1H), 7.73 (d, J = 7.95 Hz, 1H), 7.38 - 7.44 (m, 2H), 7.33 (s, 1H), 7.16 - 7.25 (m, 2H), 5.30 (s, 2H), 4.34 (q, J = 6.97 Hz, 2H), 2.87 - 2.93 (m, 2H), 2.61 - 2.70 (m, 8H), 2.05 (quin, J = 7.43 Hz, 2H), 1.57 (t, 7= 7.03 Hz, 3H).

[0822] Cpd No. 29: N-(4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4- (dimethylamino)butanamide was prepared in a manner according to general procedure E by coupling between 6-amino-4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile and 4-(dimethylamino)butanoyl chloride hydrochloride. Yield 59%; LC-MS calculated for C35H39CIN6O4 [M + H]+= 643.28, found 643.18;1H NMR (400 MHz, CD3OD) 8 9.16 (s, 1H), 8.77 - 8.83 (m, 2H), 8.49 (dd, J = 2.08, 8.31 Hz, 1H), 7.90 (d, J= 8.31 Hz, 1H), 7.62 (d, J = 2.45 Hz, 1H), 7.41 - 7.48 (m, 2H), 7.34 - 7.40 (m, 1H), 5.47 (s, 2H), 4.43 (q, J = 6.97 Hz, 2H), 4.12 (td, J = 3.00, 11.25 Hz, 2H), 3.57 - 3.67 (m, 2H), 3.22 - 3.30 (m, 3H), 2.76 (t, J = 6.97 Hz, 2H), 2.08 - 2.20 (m, 2H), 1.87 - 2.03 (m, 4H), 1.60 (t, J = 6.97 Hz, 3H).EXAMPLE 7Synthesis of Cpd Nos. 9-11Scheme 4

[0823] Step D.l and Step D.2.- (E)-4-((4-aminobutyl)(methyl)amino)-N-(4-((3-chloro-4- (pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)but-2-enamide (Compound IX). To a solution of Compound VII (1 eq.) in NMP (4 vol.) was added tertbutyl (4-(methylamino)butyl)carbamate (1.1 eq.) and the resulting mixture was stirred at rt for 12 h. The reaction mixture was quenched with trifluoracetic acid and stirred an additional 30 min at room temperature. The compound was purified by preparative HPLC to yield the amine product Compound IX as a light brown oil in 93% yield. LC-MS calculated for C33H36CIN7O3 [M + H]+= 614.27, found 614.25.

[0824] Step D.3: A solution of Compound IX (1 eq.) in DMF (1 mL) was added at room temperature to a solution of acid Biotin (1 eq.) DIPEA (2 eq.) and HATU (1.1 eq.) in DMF (1 mL). The mixture was then stirred at room temperature for 12 h. The compound was purified by preparative HPLC to afford Cpd. No. 9: N-(4-(((E)-4-((4-((3-chloro-4- (pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)amino)-4-oxobut-2- en-l-yl)(methyl)amino)butyl)-5-((3aS,4S,6aR)-2-oxohexahydro-177-thieno[3,4- d]imidazol-4-yl)pentanamide, as a light-yellow solid in 56% yield. LC-MS calculated for C43H50CIN9O5S [M + H]+= 840.34, found 840.29.1H NMR (400 MHz, CD3OD) 8 9.24 (s, 1H), 8.82 (s, 1H), 8.68 (d, J = 4.89 Hz, 1H), 8.13 (dt, J = 1.65, 7.79 Hz, 1H), 7.88 (d, J = 7.82 Hz, 1H), 7.64 (d, J = 2.57 Hz, 1H), 7.60 (dd, J = 5.69, 7.03 Hz, 1H), 7.41 - 7.50(m, 2H), 7.33 (d, J= 8.93 Hz, 1H), 6.96 - 7.09 (m, 1H), 6.82 - 6.92 (m, 1H), 5.44 (s, 2H), 4.38 - 4.57 (m, 3H), 4.30 (dd, J = 4.52, 7.83 Hz, 1H), 4.07 (br. s„ 2H), 3.13 - 3.31 (m, 5H), 2.84 - 3.01 (m, 4H), 2.71 (d, J = 12.72 Hz, 1H), 2.23 (t, J = 7.27 Hz, 2H), 1.54 - 1.84 (m, 11H), 1.40 - 1.50 (m, 2H).

[0825] Step D.4: A solution of Compound IX (1 eq.) in DMF (1 mL) was added at room temperature to a solution of Biotin-PEG4-acid (1 eq.), DIPEA (2 eq.) and HATU (1.1 eq) in DMF (1 mL). The mixture was then stirred at room temperature for 12 h. The compound was purified by preparative HPLC to afford Cpd. No. 10: A-(4-(((E)-4-((4-((3- chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)amino)-4- oxobut-2-en-l-yl)(methyl)amino)butyl)-l-(5-((3aS,4S,6aR)-2-oxohexahydro-177- thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9, 12-tetraoxapentadecan- 15-amide, as a light-yellow solid in 36% yield. LC-MS calculated for C54H71CIN10O10S [M + H]+= 1087.49, found 1087.40.1H NMR (400 MHz, CD3OD) 8 9.27 (s, 1H), 8.83 (s, 1H), 8.75 (d, J = 4.65 Hz, 1H), 8.29 (dt, J = 1.47, 7.83 Hz, 1H), 7.99 (d, J = 7.95 Hz, 1H), 7.72 - 7.86 (m, 1H), 7.66 (d, J = 2.45 Hz, 1H), 7.48 (dd, J = 2.51, 8.74 Hz, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.80 Hz, 1H), 7.02 (td, J = 7.26, 14.95 Hz, 1H), 6.87 (d, J = 15.28 Hz, 1H), 5.51 (s, 2H), 4.42 - 4.55 (m, 3H), 4.32 (td, J = 5.07, 7.70 Hz, 1H), 3.72 - 3.78 (m, 2H), 3.59 - 3.71 (m, 16H), 3.55 (q, J = 5.62 Hz, 2H), 3.36 - 3.40 (m, 2H), 3.28 (t, J = 6.60 Hz, 2H), 3.22 (dd, J = 5.20, 8.01 Hz, 1H), 2.87 - 3.00 (m, 4H), 2.68 - 2.76 (m, 1H), 2.57 (t, J = 6.24 Hz, 1H), 2.47 (t, J = 6.05 Hz, 2H), 2.23 (q, J = 7.46 Hz, 2H), 1.54 - 1.84 (m, 11H), 1.40 - 1.50 (m, 2H)

[0826] Step D.5: A solution of Compound IX (53.4 mg, 0.087 mmol) in DMF (0.5 mL) was added at room temperature to a solution of acid X (30 mg, 0.087 mmol) DIPEA (30.3 |lL, 0.174 mmol) and HATU (39.9 mg, 0.105 mmol) in DMF (1 mL). The mixture was then stirred at room temperature for 16 h. The compound was purified by preparative HPLC to afford Cpd. No. 11: A-(4-(((E)-4-((4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)amino)-4-oxobut-2-en-l- yl)(methyl)amino)butyl)-5-(5-((3aS,4S,6aR)-2-oxohexahydro-177-thieno[3,4-d]imidazol- 4-yl)pentanamido)pentanamide, (21.3 mg, 26% yield) as a light-yellow solid. LC-MS calculated for C48H59CIN10O6S [M + H]+= 939.41, found 939.21.1H NMR (400 MHz, CD3OD) > 9.26 (s, 1H), 8.83 (s, 1H), 8.73 (d, J = 4.89 Hz, 1H), 8.26 (dt, J = 1.59, 7.76 Hz, 1H), 7.96 (d, J = 7.82 Hz, 1H), 7.69 - 7.75 (m, 1H), 7.66 (d, J = 2.69 Hz, 1H), 7.47 (dd, J = 2.69, 8.80 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 9.05 Hz, 1H), 6.97 - 7.08 (m, 1H),6.81 - 6.93 (m, 1H), 5.45 - 5.56 (m, 2H), 4.41 - 4.54 (m, 3H), 4.31 (dd, J= 4.40, 7.82 Hz, 1H), 4.10 (br. s„ 2H), 3.13 - 3.29 (m, 6H), 2.90 - 3.02 (m, 4H), 2.70 (d, J = 12.72 Hz, 1H), 2.15 - 2.29 (m, 4H), 1.38 - 1.83 (m, 18H)Scheme 5x

[0827] Step E.l and Step E.2: 5-(5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4- d]imidazol-4-yl)pentanamido)pentanoic acid (Compound X). Benzyl 5-aminopentanoate hydrogen chloride XI (49.9 mg, 0.205 mmol) was added at room temperature to a solution of Biotin (50 mg, 0.205 mmol), DIPEA (71 pL, 0.409 mmol) and HATU (85.7 mg, 0.226 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 5 h until completion by LCMS analysis. Water and ethyl acetate were added to quench the reaction. The aqueous layer was extracted with ethyl acetate (3x20 mL), and combined organic extracts were washed with water and brine and dried over sodium sulfate and then concentrated in vacuo to afford Compound XII (LC-MS calculated for C22H31N3O4S [M + H]+= 434.21, found 434.01). The crude residue Compound XII was dissolved in methanol under an atmosphere of nitrogen. Palladium on carbon was added, and the reaction vessel was sparged with hydrogen for 15 min and then stirred for a further 12 h at room temperature until the starting material was consumed by LCMS analysis. The reaction mixture was filtered through Celite® and washed with methanol, then concentrated in cacuo, and purified by preparative HPLC to afford the desired Compound X (36.6 mg, 52% yield) as an off white solid. LC-MS calculated for C15H25N3O4S [M + H]+= 344.17, found 344.32EXAMPLE 8Synthesis of A-(4-chloro-3-cyano-7-ethoxy-2-methylquinolin-6-yl)acetamideScheme 6

[0828] Step 1. A mixture of N-(4-amino-2-ethoxyphenyl)acetamide (20.59 mmol), and ethyl (Z)-2-cyano-3-ethoxybut-2-enoate (26.77 mmol) in toluene was refluxed for 16 h. The reaction mixture was allowed to cool to rt, and then the reaction mixture was evaporated under vacuum giving a light brown solid (Yield - 95%) of ethyl (Z)-3-((4- acetamido-3-ethoxyphenyl)amino)-2-cyanobut-2-enoate which was used for the next step without further purification.

[0829] Step 2. To a solution of ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2- cyanobut-2-enoate (19.62 mmol) in Dowtherm was irradiated with micro wave (10 - 15V) at 270 °C for 30 min. The reaction mixture was allowed to cool to rt, and then the precipitated compound was triturated with n-hexane giving a light yellow solid (Yield - 90%) of N-(3-cyano-7-ethoxy-2-methyl-4-oxo-l,4-dihydroquinolin-6-yl)acetamide.

[0830] Step 3. To a solution of N-(3-cyano-7-ethoxy-2-methyl-4-oxo-l,4- dihydroquinolin-6-yl)acetamide (17.54 mmol) in 1, 4-dioxane (50 mL) was added POCI3(87.72 mmol) and then the resulting mixture was refluxed for 5 ~ 6 h. The solvent was concentrated under vacuum and then purified by flash column chromatography giving an off white solid of N-(4-chloro-3-cyano-7-ethoxy-2-methylquinolin-6-yl)acetamide in 80% yield; LC-MS calculated for C15H14CIN3O2 [M + H]+= 304.09, found 304.01;1H NMR (400 MHz, DMSO) 5 9.44 (s, 1H), 9.00 (s, 1H), 7.49 (s, 1H), 4.37 (q, J = 7.0 Hz, 2H), 2.77 (s, 3H), 2.24 (s, 3H), 1.50 (t, J= 7.0 Hz, 3H).EXAMPLE 9Synthesis of N-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)acetamideScheme 7

[0831] Step 1. A mixture of A-(4-amino-2-ethoxyphenyl)acetamide (20.59 mmol), and ethyl (Z)-2-cyano-3-ethoxypent-2-enoate (26.77 mmol) in toluene was refluxed for 16 h. The reaction mixture was allowed to cool to rt, and then the reaction mixture was evaporated under vacuum giving a light brown solid (Yield - 97%) of ethyl (Z)-3-((4- acetamido-3-ethoxyphenyl)amino)-2-cyanopent-2-enoate which was used for the next step without further purification.

[0832] Step 2. To a solution of ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2- cyanopent-2-enoate (19.98 mmol) in Dowtherm was irradiated with microwave (10 - 15V) at 270 °C for 30 min. The reaction mixture was allowed to cool to rt, and then the precipitated compound was triturated with n-hexane giving a light yellow solid (Yield 84%) of N-(3-cyano-7-ethoxy-2-ethyl-4-oxo-l,4-dihydroquinolin-6-yl)acetamide.

[0833] Step 3. To a solution of N-(3-cyano-7-ethoxy-2-ethyl-4-oxo-l,4-dihydroquinolin- 6-yl)acetamide (16.70 mmol) in 1, 4-dioxane (50 mL) was added POCI3 (83.52 mmol) and then the resulting mixture was refluxed for 5 - 6 h. The solvent was concentrated under vacuum and then purified by flash column chromatography giving an off white solid of N-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)acetamide in 65% yield; LC- MS calculated for C16H16CIN3O2 [M + H]+= 318,08 found 318.08;1H NMR (400 MHz, DMSO) 5 9.45 (s, 1H), 9.03 (s, 1H), 7.51 (s, 1H), 4.39 (q, J = 7.0 Hz, 2H), 3.08 (q, J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.5 Hz, 3H).EXAMPLE 10Synthesis of (E)-N-(4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxy-2-methylquinolin-6-yl)-4- (dimethylamino)but-2-enamide (Cpd. No. 24)Scheme 8

[0834] Step 1. Methansulfonic acid (0.197 mmol) was added at room temperature to a suspension of N-(4-chloro-3-cyano-7-ethoxy-2-methylquinolin-6-yl)acetamide (0.066 mmol) and 3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)methoxy)aniline (0.079 mmol) in anhydrous ethyl alcohol. The mixture was then refluxed for 4 ~ 6 h. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to afford 6-amino-4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4- yl)pyridin-3-yl)methoxy)phenyl)amino)-7-ethoxy-2-methylquinoline-3-carbonitrile as a yellow solid in 76% yield. LC-MS calculated for C30H30CIN5O3 [M + H]+= 544.21, found 544.08.

[0835] Step 2. Synthesis of Cpd. No. 24: (E)-4-(dimethylainino)but-2-enoyl chloride hydrochloride (0.067 mmol) was added at 0 °C to a suspension of 6-amino-4-((3-chloro- 4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)methoxy)phenyl)amino)-7 -ethoxy-2- methylquinoline-3-carbonitrile (0.045 mmol) in N- methyl pyrrolidine (0.3 mL). The mixture was then allowed to ambient temperature and stirred for 2 h. The compound was purified by preparative HPLC to yield Cpd. No. 24 as a light yellow solid in 50% yield. LC-MS calculated for C36H39CIN6O4 [M + H]+= 655.28, found 655.50;1H NMR (400 MHz, CD3OD) 8 9.19 (s, 1H), 8.75 - 8.81 (m, 1H), 8.39 (dd, J = 1.83, 8.19 Hz, 1H), 7.81 (d, J = 8.19 Hz, 1H), 7.61 (d, J = 2.45 Hz, 1H), 7.42 - 7.47 (m, 1H), 7.33 - 7.40 (m, 2H), 6.95 - 7.04 (m, 1H), 6.80 - 6.89 (m, 1H), 5.44 (s, 2H), 4.45 (q, J = 6.97 Hz, 2H), 4.08 - 4.16 (m, 2H), 4.04 (d, J= 7.09 Hz, 2H), 3.58 - 3.67 (m, 2H), 3.21 - 3.28 (m, 1H), 2.96 (s, 6H), 2.80 (s, 3H), 1.91 - 2.00 (m, 4H), 1.61 (t, J = 6.97 Hz, 3H).EXAMPLE 11Synthesis of (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7- ethoxy-2-ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 27) Scheme 9

[0836] Step 1. Methansulfonic acid (0.189 mmol) was added at room temperature to a suspension of A-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)acetamide (0.063 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (0.076 mmol) in anhydrous ethyl alcohol. The mixture was then refluxed for 4 - 6 h. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to afford 6- amino-4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-7-ethoxy-2-methylquinoline-3-carbonitrile as a yellow solid in 79% yield. LC-MS calculated for C26H24CIN5O2 [M + H]+= 474.17, found 474.16.

[0837] Step 2. Synthesis of Cpd. No. 27: (E)-A-(4-((3-chloro-4-((6-(tetrahydro-2H- pyran-4-yl)pyridin-3-yl)methoxy)phenyl)amino)-3-cyano-7-ethoxy-2-methylquinolin-6- yl)-4-(dimethylamino)but-2-enamide. ( E) -4-(dimethylamino)but-2-enoy I chloride hydrochloride (0.046 mmol) was added at 0 °C to a suspension of 6-amino-4-((3-chloro- 4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxy-2-ethylquinoline-3-carbonitrile (0.042 mmol) in A-methylpyrrolidine (0.3 mL). The mixture was then allowed to ambient temperature and stirred for 2 h. The compound was purified by preparative HPLC to yield Cpd. No. 27 as a light yellow solid in 62% yield. LC-MS calculated for C32H33CIN6O3 [M + H]+= 585.24, found 585.29;1H NMR (400 MHz, CD3OD) 8 9.18 (s,1H), 8.64 (dd, J = 0.73, 5.01 Hz, 1H), 8.05 (dt, J = 1.65, 7.79 Hz, 1H), 7.82 (d, J= 7.83 Hz, 1H), 7.62 (d, J = 2.57 Hz, 1H), 7.53 (dd, J = 5.20, 6.66 Hz, 1H), 7.38 - 7.45 (m, 2H), 7.31 (d, J= 8.80 Hz, 1H), 6.94 - 7.04 (m, 1H), 6.79 - 6.88 (m, 1H), 5.41 (s, 2H), 4.45 (q, J = 6.93 Hz, 2H), 4.04 (dd, J = 0.86, 7.09 Hz, 2H), 3.10 (q, J = 7.58 Hz, 2H), 2.96 (s, 6H), 1.61 (t, 7 = 6.97 Hz, 3H), 1.44 (t, 7 = 7.64 Hz, 3H).EXAMPLE 12Synthesis of (E)-A-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7- ethoxy-2-methylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 30)Scheme 10

[0838] Step 1. Methansulfonic acid (0.197 mmol) was added at room temperature to a suspension of A-(4-chloro-3-cyano-7-ethoxy-2-methylquinolin-6-yl)acetamide (0.066 mmol) and 3-chloro-4-(pyridin-2-ylmethoxy)aniline (0.079 mmol) in anhydrous ethyl alcohol. The mixture was then refluxed for 4 - 6 h. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to afford 6- amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxy-2-methylquinoline-3-carbonitrile as a yellow solid in 73% yield. LC-MS calculated for C25H22CIN5O2 [M + H]+= 460.16, found 460.18.

[0839] Step 2. Synthesis of Cpd. No. 30: ('E')-4-(dimethylamino)but-2-enoyl chloride hydrochloride (0.048 mmol) was added at 0 °C to a suspension of 6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxy-2-methylquinoline-3-carbonitrile (0.044 mmol) in A-methylpyrrolidine (0.3 mL). The mixture was then allowed to ambient temperature and stirred for 2 h. The compound was purified by preparative HPLC toyield Cpd. No. 30 as a light yellow solid in 68% yield. LC-MS calculated for C31H31CIN6O3 [M + H]+= 571.22, found 571.46;1H NMR (400 MHz, CD3OD) 8 9.18 (s, 1H), 8.63 - 8.69 (m, 1H), 8.07 (dt, J = 1.65, 7.79 Hz, 1H), 7.83 (d, J = 7.82 Hz, 1H), 7.61 (d, J = 2.57 Hz, 1H), 7.53 - 7.58 (m, 1H), 7.42 (dd, J = 2.57, 8.80 Hz, 1H), 7.37 (s, 1H), 7.28 - 7.34 (m, 1H), 6.95 - 7.04 (m, 1H), 6.80 - 6.89 (m, 1H), 5.42 (s, 2H), 4.44 (q, J = 6.97 Hz, 2H), 4.04 (dd, J = 0.86, 7.09 Hz, 2H), 2.96 (s, 6H), 2.80 (s, 3H), 1.61 (t, J= 6.97 Hz, 3H).EXAMPLE 13General Syntheses of Compounds of the Disclosure

[0840] The synthesis of synthetic intermediates and / or Compounds of the Disclosure can be achieved according to Schemes 11-23 using the methods described above and / or methods known in the art.Scheme 11

[0841] Step 1: Sodium hydride (60%, 5.69 mmol) in dry DMF (3 mL) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added appropriate alcohol (2.85 mmol) in anhydrous DMF (2 mL). 2-Chloro-l-fluoro-4- nitrobenzene (2.85 mmol) was added to the above solution and the resulting solution was stirred at rt. Cold water was added slowly to the reaction mixture, and a yellow precipitate resulted. The yellow solid is isolated by vacuum filtration, washed with cold water, and air dried to give the title compound as yellow solid.

[0842] Step 2: A mixture of nitro compound (2.51 mmol), iron (12.56 mmol) and NH4CI (25.11 mmol) in 70% ethanol in water was heated at 70 °C for 1 h. The reaction mixture was allowed to cool to rt, and then filtered over celite®. The filtrate was evaporated under vacuum giving an orange solid which was stirred with EtOAc, and then theresulting mixture was filtered. The filtrate was dried over anhydrous Na2SO4 and evaporated under vacuum to afford the desired amine compound. The crude compound was used for the next step without further purification.

[0843] Step 3: Methansulfonic acid (1.035 mmol) was added at room temperature to a suspension of the corresponding acetamide (0.345 mmol) and the appropriate amine (0.345 mmol) in anhydrous ethyl alcohol. The mixture was then refluxed. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to yield the desired compounds.

[0844] Step 4: (E)-4-(Dimethylamino)but-2-enoyl chloride hydrochloride (0.067 mmol) was added at 0 °C to a suspension of the appropriate amine (0.045 mmol) in N-methylpyrrolidine. The mixture was then allowed to ambient temperature and stirred for ~2 h. The compound was purified by preparative HPLC to yield the desired compounds.Scheme 12

[0845] Methansulfonic acid (1.035 mmol) was added at room temperature to a suspension of the corresponding acetamide (0.345 mmol) and the appropriate amine (0.345 mmol) in anhydrous ethyl alcohol. The mixture was then refluxed. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to yield the desired compounds.

[0846] (E)-4-(Dimethylamino)but"2-enoyl chloride hydrochloride (0.067 mmol) was added at 0 °C to a suspension of the appropriate amine (0.045 mmol) in N- methylpyrrolidine. The mixture was then allowed to ambient temperature and stirred for ~2 h. The compound was purified by preparative HPLC to yield the desired compounds.Scheme 13Scheme 151, 4-dioxane, H2O,90 °C, 12 hScheme 19Cpd. No. 33, R2= -HCpd. No. 34, R2= -CH3Cpd. No. 35, R2= -ClScheme 22EXAMPLE 14Synthesis of N-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)acetamide

[0847] Step 1. Synthesis of ethyl (Z)-2-cyano-3-ethoxypent-2-enoate: Acetic acid (1.3 g, 0.5 eq) was added at room temperature to a solution of ethyl 2-cyanoacetate (5 g, 44.2 mmol, 1.0 eq) in 1,1,1 -triethoxypropane (15.6 g, 88.4 mmol, 2.0 eq). The mixture was then stirred at 125 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo to afford 9.0 g of ethyl (Z)-2-cyano-3-ethoxypent-2-enoate in quantitative yield as a yellow oil. LC-MS calculated for C10H15NO3 [M + H]+= 198.12, found 198.23. The crude compound was used for the next step without further purification.

[0848] Step 2. Synthesis of ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2- cyanopent-2-enoate: To a solution of N-(4-amino-2-ethoxyphenyl)acetamide (2.0 g, 10.3 mmol, 1.0 eq) in toluene (20 mL) was added ethyl (Z)-2-cyano-3-ethoxypent-2-enoate (2.03 g, 10.3 mmol, 1.0 eq) at room temperature. The mixture was then stirred at 90 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo and purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 3.02 g of ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanopent-2- enoate in 85% yield as off white solid. LC-MS calculated for C18H23N3O4 [M + H]+= 346.18, found 346.37.

[0849] Step 3. Synthesis of N-(3-cyano-7-ethoxy-2-ethyl-4-oxo-l,4-dihydroquinolin-6- yl)acetamide: Ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanopent-2-enoate (3.0 g, 8.69 mmol, 1 eq) was dissolved in Dowtherm (15 mL) and then the solution was irradiated under microwave at 260 °C for 2 h. The reaction was cooled to room temperature and triturated with n-hexane to afford 2.2 g of the N-(3-cyano-7-ethoxy-2- ethyl-4-oxo-l,4-dihydroquinolin-6-yl)acetamide in 85% yield as light brown solid. LC- MS calculated for C16H17N3O3 [M + H]+= 300.14, found 300.32. The crude compound was used for the next step without further purification.

[0850] Step 4. Synthesis of N-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6- yl)acetamide: To a solution of N-(3-cyano-7-ethoxy-2-ethyl-4-oxo-l,4-dihydroquinolin- 6-yl)acetamide (2.0 g, 6.69 mmol, 1 eq) in diglyme or 1, 4-dioxane (20 mL) was added phosphorus oxychloride (3.59 g, 23.4 mmol, 3.5 eq). The mixture was then stirred at 100 °C for 1 h. The solution was cooled to ambient temperature, then filtered through celite® and the celite® was washed with diglyme and the filtrate was concentrated in vacuo. The crude compound was quenched with saturated sodium bicarbonate (50 mL) and the compound was extracted with ethyl acetate (3x 100 mL). The combined extracts were washed with brine solutions (50 mL) and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 1.95 g of N-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)acetamide in 92% yield as a white solid. LC-MS calculated for C16H16CIN3O2 [M + H]+= 318.10, found 318.35;1H NMR (400 MHz, CDCI3) 8 9.21 (s, 1H), 8.06 (br. s„ 1H), 7.38 (s, 1H), 4.35 (q, J = 7.05 Hz, 2H), 3.16 (q, J = 7.54 Hz, 2H), 2.32 (s, 3H), 1.61 (t, J = 7.03 Hz, 3H), 1.39 - 1.49 (m, 3H).EXAMPLE 15Synthesis of N-(4-chloro-3-cyano-7-ethoxy-2-methylquinolin-6-yl)acetamide

[0851] Step 1. Synthesis of ethyl (Z)-2-cyano-3-ethoxybut-2-enoate: Acetic acid (1.3 g, 0.5 eq) was added at room temperature to a solution of ethyl 2-cyanoacetate (5 g, 44.2 mmol, 1.0 eq) in 1,1,1 -triethoxy ethane (14.3 g, 88.4 mmol, 2.0 eq). The mixture was then stirred at 125 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo to afford 8.5 g of ethyl (Z)-2-cyano-3-ethoxybut-2-enoate in quantitative yield as a yellow oil. LC-MS calculated for C9H13NO3 [M + H]+= 184.1, found 184.35. The crude compound was used for the next step without further purification.

[0852] Step 2. Synthesis of ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2- cyanobut-2-enoate: To a solution of N-(4-amino-2-ethoxyphenyl)acetamide (2.0 g, 10.3 mmol, 1.0 eq) in toluene (20 mL) was added ethyl (Z)-2-cyano-3-ethoxybut-2-enoate (1.89 g, 10.3 mmol, 1.0 eq) at room temperature. The mixture was then stirred at 90 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo and purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 3.2 g of (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanobut-2-enoate in 94% yield as off white solid. LC-MS calculated for C17H21N3O4 [M + H]+= 332.16, found 332.36.

[0853] Step 3. Synthesis of N-(3-cyano-7-ethoxy-2-methyl-4-oxo-l,4-dihydroquinolin-6- yl)acetamide: Ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanobut-2-enoate (3.0 g, 9.06 mmol, 1 eq) was dissolved in Dowtherm (18 mL) and then the solution was irradiated under microwave at 260 °C for 2 h. The reaction was cooled to room temperature and triturated with n-hexane to afford 2.1 g of the N-(3-cyano-7-ethoxy-2- methyl-4-oxo-l,4-dihydroquinolin-6-yl)acetamide in 82% yield as light green solid. LC- MS calculated for C15H15N3O3 [M + H]+= 286.12, found 286.37. The crude compound was used for the next step without further purification.

[0854] Step 4. Synthesis of N-(4-chloro-3-cyano-7-ethoxy-2-methylquinolin-6- yl)acetamide: To a solution of N-(3-cyano-7-ethoxy-2-methyl-4-oxo-l,4- dihydroquinolin-6-yl)acetamide (2.0 g, 7.0 mmol, 1 eq) in diglyme or 1, 4-dioxane (20 mL) was added phosphorus oxychloride (3.76 g, 24.55 mmol, 3.5 eq). The mixture was then stirred at 100 °C for 1 h. The solution was cooled to ambient temperature, then filtered through celite® and the celite® was washed with diglyme and the filtrate was concentrated in vacuo. The crude compound was quenched with saturated sodium bicarbonate (50 mL) and the compound was extracted with ethyl acetate (3x 100 mL). The combined extracts were washed with brine solutions (50 mL) and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 1.98 g of N-(4-chloro-3-cyano-7-ethoxy-2- methylquinolin-6-yl)acetamide in 93% yield as a white solid. LC-MS calculated for C15H14CIN3O2 [M + H]+= 304.09, found 304.27;1H NMR (400 MHz, DMSO-d6) 8 9.44 (s, 1H), 9.00 (s, 1H), 7.49 (s, 1H), 4.37 (q, J = 6.97 Hz, 2H), 2.77 (s, 3H), 2.24 (s, 3H), 1.50 (t, 7= 6.97 Hz, 3H).EXAMPLE 16Synthesis of N-(4-chloro-3-cyano-7-ethoxy-2-isopropylquinolin-6-yl)acetamideStep 4

[0855] Step 1. Synthesis of ethyl (Z)-2-cyano-3-methoxy-4-methylpent-2-enoate: Acetic acid (1.3 g, 0.5 eq) was added at room temperature to a solution of ethyl 2-cyanoacetate (5 g, 44.2 mmol, 1.0 eq) in l,l,l-trimethoxy-2-methylpropane (14.5 g, 88.4 mmol, 2.0 eq). The mixture was then stirred at 125 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo to afford 8.9 g of ethyl (Z)-2-cyano-3-methoxy- 4-methylpent-2-enoate in quantitative yield as a yellow oil. LC-MS calculated for C10H15NO3 [M + H]+= 198.12, found 198.22. The crude compound was used for the next step without further purification.

[0856] Step 2. Synthesis of ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyano- 4-methylpent-2-enoate: To a solution of N-(4-amino-2-ethoxyphenyl)acetamide (2.0 g, 10.3 mmol, 1.0 eq) in toluene (20 mL) was added ethyl (Z)-2-cyano-3-methoxy-4- methylpent-2-enoate (2.03 g, 10.3 mmol, 1.0 eq) at room temperature. The mixture was then stirred at 90 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo and purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 3.29 g of ethyl (Z)-3-((4-acetamido-3- ethoxyphenyl)amino)-2-cyano-4-methylpent-2-enoate in 89% yield as off white solid. LC-MS calculated for C19H25N3O4 [M + H]+= 360.19, found 359.99.

[0857] Step 3. Synthesis of N-(3-cyano-7-ethoxy-2-isopropyl-4-oxo-l,4- dihydroquinolin-6-yl)acetamide: ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2- cyano-4-methylpent-2-enoate (3.0 g, 8.35 mmol, 1 eq) was dissolved in Dowtherm (18 mL) and then the solution was irradiated under microwave at 260 °C for 2 h. The reaction was cooled to room temperature and triturated with n-hexane to afford 2.25 g of the N-(3- cyano-7-ethoxy-2-isopropyl-4-oxo-l,4-dihydroquinolin-6-yl)acetamide in 86% yield as light green solid. LC-MS calculated for C17H19N3O3 [M + H]+= 314.15, found 314.28. The crude compound was used for the next step without further purification.

[0858] Step 4. Synthesis of N-(4-chloro-3-cyano-7-ethoxy-2-isopropylquinolin-6- yl)acetamide: To a solution of N-(3-cyano-7-ethoxy-2-isopropyl-4-oxo-l,4- dihydroquinolin-6-yl)acetamide (2.0 g, 6.4 mmol, 1 eq) in diglyme or 1, 4-dioxane (20 mL) was added phosphorus oxychloride (3.43 g, 22.35 mmol, 3.5 eq). The mixture was then stirred at 100 °C for 1 h. The solution was cooled to ambient temperature, then filtered through celite® and the celite® was washed with diglyme and the filtrate was concentrated in vacuo. The crude compound was quenched with saturated sodium bicarbonate (50 mL) and the compound was extracted with ethyl acetate (3x 100 mL). The combined extracts were washed with brine solutions (50 mL) and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 1.73 g of N-(4-chloro-3-cyano-7-ethoxy-2- isopropylquinolin-6-yl)acetamide in 82% yield as a white solid. LC-MS calculated for C17H18CIN3O2 [M + H]+= 332.12, found 332.27;1H NMR (400 MHz, DMSO-d6) 8 9.43 (br. s„ 1H), 9.02 (br. s„ 1H), 7.46 (br. s„ 1H), 4.39 (q, J = 6.52 Hz, 2H), 3.47 - 3.53 (m, 1H), 2.24 (s, 3H), 1.50 (t, J = 6.91 Hz, 3H), 1.36 (d, J = 6.60 Hz, 6H).EXAMPLE 17Synthesis of N-(4-chloro-3-cyano-2-cyclopropyl-7-ethoxyquinolin-6-yl)acetamide- 2Z1 -

[0859] Step 1. Synthesis of ethyl (Z)-2-cyano-3-cyclopropyl-3-ethoxyacrylate: Acetic acid (1.3 g, 0.5 eq) was added at room temperature to a solution of ethyl 2-cyanoacetate (5 g, 44.2 mmol, 1.0 eq) in (trimethoxymethyl)cyclopropane (12.92 g, 88.4 mmol, 2.0 eq). The mixture was then stirred at 125 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo to afford 9.3 g of ethyl (Z)-2-cyano-3- cyclopropyl-3-ethoxyacrylate in quantitative yield as a yellow oil. LC-MS calculated for C11H15NO3 [M + H]+= 210.12, found 210.27. The crude compound was used for the next step without further purification.

[0860] Step 2. Synthesis of ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyano- 3-cyclopropylacrylate: To a solution of N-(4-amino-2-ethoxyphenyl)acetamide (2.0 g, 10.3 mmol, 1.0 eq) in toluene (20 mL) was added ethyl (Z)-2-cyano-3-cyclopropyl-3- ethoxyacrylate (2.16 g, 10.3 mmol, 1.0 eq) at room temperature. The mixture was then stirred at 90 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo and purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 2.13 g of ethyl (Z)-3-((4-acetamido-3- ethoxyphenyl)amino)-2-cyano-3-cyclopropylacrylate in 58% yield as light brown solid. LC-MS calculated for C19H23N3O4 [M + H]+= 358.18, found 358.19.

[0861] Step 3. Synthesis of N-(3-cyano-2-cyclopropyl-7-ethoxy-4-oxo-l,4- dihydroquinolin-6-yl)acetamide: Ethyl (Z)-3-((4-acetamido-3-ethoxyphenyl)amino)-2- cyano-3-cyclopropylacrylate (2.0 g, 5.60 mmol, 1 eq) was dissolved in Dowtherm (10 mL) and then the solution was irradiated under microwave at 260 °C for 2 h. The reaction was cooled to room temperature and triturated with n-hexane to afford 1.4 g of the N-(3- cyano-2-cyclopropyl-7-ethoxy-4-oxo-l,4-dihydroquinolin-6-yl)acetamide in 81% yield as light brown solid. LC-MS calculated for C17H17N3O3 [M + H]+= 312.14, found 314.27. The crude compound was used for the next step without further purification.

[0862] Step 4. Synthesis of N-(4-chloro-3-cyano-2-cyclopropyl-7 -ethoxy quinolin-6- yl)acetamide: To a solution of N-(3-cyano-2-cyclopropyl-7-ethoxy-4-oxo-l,4- dihydroquinolin-6-yl)acetamide (1.2 g, 3.86 mmol, 1 eq) in diglyme or 1, 4-dioxane (10 mL) was added phosphorus oxychloride (2.07 g, 13.5 mmol, 3.5 eq). The mixture was then stirred at 100 °C for 1 h. The solution was cooled to ambient temperature, then filtered through celite® and the celite® was washed with diglyme and the filtrate was concentrated in vacuo. The crude compound was quenched with saturated sodium bicarbonate (40 mL) and the compound was extracted with ethyl acetate (3x 70 mL). The combined extracts were washed with brine solutions (30 mL) and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 1.09 g of N-(4-chloro-3-cyano-2-cyclopropyl-7- ethoxyquinolin-6-yl)acetamide in 86% yield as a white solid. LC-MS calculated for C17H16CIN3O2 [M + H]+= 330.10, found 330.15.EXAMPLE 18Synthesis of (R)-N-(4-chloro-3-cyano-2-ethyl-7-((tetrahydrofuran-3-yl)oxy)quinolin-6- yl)acetamide

[0863] Step 1. Synthesis of ethyl (R,Z)-3-((4-acetamido-3-((tetrahydrofuran-3- yl)oxy)phenyl)amino)-2-cyanopent-2-enoate: To a solution of (R)-N-(4-amino-2- ((tetrahydrofuran-3-yl)oxy)phenyl)acetamide (2.0 g, 8.5 mmol, 1.0 eq) in toluene (20 mL) was added ethyl (Z)-2-cyano-3-ethoxypent-2-enoate (1.7 g, 8.5 mmol, 1.0 eq) at room temperature. The mixture was then stirred at 90 °C for 16 h. The solution was cooled to ambient temperature, then concentrated in vacuo and purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 2.36 g of ethyl (R,Z)-3-((4-acetamido-3-((tetrahydrofuran-3-yl)oxy)phenyl)amino)-2-cyanopent-2- enoate in 72% yield as off white solid. LC-MS calculated for C20H25N3O5 [M + H]+= 388.19, found 388.32.

[0864] Step 2. Synthesis of (R)-N-(3-cyano-2-ethyl-4-oxo-7-((tetrahydrofuran-3-yl)oxy)- l,4-dihydroquinolin-6-yl)acetamide: (R,Z)-3-((4-acetamido-3-((tetrahydrofuran-3- yl)oxy)phenyl)amino)-2-cyanopent-2-enoate (2.0 g, 5.17 mmol, 1 eq) was dissolved in Dowtherm (12 mL) and then the solution was irradiated under micro wave at 260 °C for 2 h. The reaction was cooled to room temperature and triturated with n-hexane to afford 1.27 g of the N-(3-cyano-7-ethoxy-2-ethyl-4-oxo-l,4-dihydroquinolin-6-yl)acetamide in 72% yield as light brown solid. LC-MS calculated for C18H19N3O4 [M + H]+= 342.15, found 341.91. The crude compound was used for the next step without further purification.

[0865] Step 3. Synthesis of (R)-N-(4-chloro-3-cyano-2-ethyl-7-((tetrahydrofuran-3- yl)oxy)quinolin-6-yl)acetamide: To a solution of (R)-N-(3-cyano-2-ethyl-4-oxo-7- ((tetrahydrofuran-3-yl)oxy)-l,4-dihydroquinolin-6-yl)acetamide (1.0 g, 2.93 mmol, 1 eq)in diglyme or 1, 4-dioxane (10 mL) was added phosphorus oxychloride (1.57 g, 10.26 mmol, 3.5 eq). The mixture was then stirred at 100 °C for 1 h. The solution was cooled to ambient temperature, then filtered through celite® and the celite® was washed with diglyme and the filtrate was concentrated in vacuo. The crude compound was quenched with saturated sodium bicarbonate (50 mL) and the compound was extracted with ethyl acetate (3x 100 mL). The combined extracts were washed with brine solutions (50 mL) and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 0.88 g of (R)-N-(4- chloro-3-cyano-2-ethyl-7 -((tetrahydrofuran-3-yl)oxy)quinolin-6-yl)acetamide in 84% yield as a pale yellow solid. LC-MS calculated for C18H18CIN3O3 [M + H]+= 360.11, found 359.93;1H NMR (400 MHz, DMSO-d6) 8 9.34 (s, 1H), 9.02 (s, 1H), 7.45 (s, 1H), 5.38 (t, J = 5.32 Hz, 1H), 3.93 - 4.13 (m, 3H), 3.80 (dt, J = 5.01, 8.13 Hz, 1H), 3.39 - 3.47 (m, 1H), 3.06 (q, J= 7.46 Hz, 2H), 2.33 - 2.44 (m, 1H), 2.13 - 2.30 (m, 4H), 1.35 (t, 7 = 7.52 Hz, 3H).EXAMPLE 19Synthesis of (S)-N-(4-chloro-3-cyano-2-ethyl-7-((tetrahydrofuran-3-yl)oxy)quinolin-6- yl) acetamide

[0866] Step 1. Synthesis of ethyl (S,Z)-3-((4-acetamido-3-((tetrahydrofuran-3- yl)oxy)phenyl)amino)-2-cyanopent-2-enoate: To a solution of (S)-N-(4-amino-2- ((tetrahydrofuran-3-yl)oxy)phenyl)acetamide (2.0 g, 8.5 mmol, 1.0 eq) in toluene (20 mL) was added ethyl (Z)-2-cyano-3-ethoxypent-2-enoate (1.7 g, 8.5 mmol, 1.0 eq) at room temperature. The mixture was then stirred at 90 °C for 16 h. The solution wascooled to ambient temperature, then concentrated in vacuo and purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 2.79 g of ethyl (S,Z)-3-((4-acetamido-3-((tetrahydrofuran-3-yl)oxy)phenyl)amino)-2-cyanopent-2-enoate in 85% yield as off white solid. LC-MS calculated for C20H25N3O5 [M + H]+= 388.19, found 388.34.

[0867] Step 2. Synthesis of (S)-N-(3-cyano-2-ethyl-4-oxo-7-((tetrahydrofuran-3-yl)oxy)- l,4-dihydroquinolin-6-yl)acetamide: (S,Z)-3-((4-acetamido-3-((tetrahydrofuran-3- yl)oxy)phenyl)amino)-2-cyanopent-2-enoate (2.0 g, 5.17 mmol, 1 eq) was dissolved in Dowtherm (12 mL) and then the solution was irradiated under micro wave at 260 °C for 2 h. The reaction was cooled to room temperature and triturated with n-hexane to afford 1.39 g of the N-(3-cyano-7-ethoxy-2-ethyl-4-oxo-l,4-dihydroquinolin-6-yl)acetamide in 79% yield as light brown solid. LC-MS calculated for C18H19N3O4 [M + H]+= 342.15, found 342.34. The crude compound was used for the next step without further purification.

[0868] Step 3. Synthesis of (S)-N-(4-chloro-3-cyano-2-ethyl-7-((tetrahydrofuran-3- yl)oxy)quinolin-6-yl)acetamide: To a solution of (S)-N-(3-cyano-2-ethyl-4-oxo-7- ((tetrahydrofuran-3-yl)oxy)-l,4-dihydroquinolin-6-yl)acetamide (1.0 g, 2.93 mmol, 1 eq) in diglyme or 1, 4-dioxane (10 mL) was added phosphorus oxychloride (1.57 g, 10.26 mmol, 3.5 eq). The mixture was then stirred at 100 °C for 1 h. The solution was cooled to ambient temperature, then filtered through celite® and the celite® was washed with diglyme and the filtrate was concentrated in vacuo. The crude compound was quenched with saturated sodium bicarbonate (50 mL) and the compound was extracted with ethyl acetate (3x 100 mL). The combined extracts were washed with brine solutions (50 mL) and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford 0.91 g of (S)-N-(4- chloro-3-cyano-2-ethyl-7 -((tetrahydrofuran-3-yl)oxy)quinolin-6-yl)acetamide in 86% yield as a pale yellow solid. LC-MS calculated for C18H18CIN3O3 [M + H]+= 360.11, found 359.90;1H NMR (400 MHz, DMSO-d6) 8 9.33 (s, 1H), 9.01 (s, 1H), 7.44 (s, 1H), 5.38 (t, J = 5.44 Hz, 1H), 3.91 - 4.16 (m, 3H), 3.80 (dt, J = 5.07, 8.16 Hz, 1H), 3.06 (q, J = 7.50 Hz, 2H), 2.33 - 2.44 (m, 1H), 2.10 - 2.30 (m, 4H), 1.35 (t, J = 7.46 Hz, 3H).EXAMPLE 20Synthesis of Intermediatescr Py

[0869] Step 1. To a solution of 5-nitro-lH-indazole (3.0 g, 18.4 mmol, 1.0 eq) and K2CO3 (5.09 g, 36.8 mmol, 2.0 eq) in DMF (30 mL) was added py-CFhCl (2.6 g, 20.24 mmol, 1.1 eq) at room temperature. The mixture was then stirred at 80 °C for 12 h. The solution was cooled to ambient temperature, then filtered through celite® and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford Isomer A and Isomer B.(Or)

[0870] To a solution of 5-nitro-lH-indazole (3.0 g, 18.4 mmol, 1.0 eq) in DMF (30 mL) was added 60% NaH (1.47 g, 36.8 mmol, 2.0 eq) at 0 °C. The solution was stirred for 10 min at 0 °C. And then py-CFLCl (2.6 g, 20.24 mmol, 1.1 eq) was added to the above reaction solution and stirred for 2 h at rt. The solution was cooled to ambient temperature, then quenched with ice water and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford Isomer A and Isomer B.

[0871] 5-Nitro-l-(pyridin-2-ylmethyl)-lH-indazole. Yield 55%; brown solid; LC-MS calculated for C13H10N4O2 [M + H]+= 255.09, found 255.22;1H NMR (400 MHz, DMSO) 5 8.84 (d, J = 2.2 Hz, 1H), 8.57 - 8.33 (m, 2H), 8.23 (dd, J = 9.3, 2.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.76 (td, J = 7.7, 1.9 Hz, 1H), 7.38 - 7.22 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.86 (s, 2H).

[0872] 5-Nitro-2-(pyridin-2-ylmethyl)-2H-indazole. Yield 31%; brown solid; LC-MS calculated for C13H10N4O2 [M + H]+= 255.09, found 255.22;1H NMR (400 MHz,DMSO) 5 8.97 (d, J = 0.9 Hz, 1H), 8.93 (dd, J = 2.3, 0.7 Hz, 1H), 8.53 (ddd, J = 4.9, 1.9,0.9 Hz, 1H), 8.01 (dd, J = 9.5, 2.3 Hz, 1H), 7.96 (s, 1H), 7.82 (td, J = 7.7, 1.8 Hz, 1H),7.77 (dt, J = 9.4, 0.9 Hz, 1H), 7.39 - 7.27 (m, 2H), 5.86 (s, 2H).

[0873] 5 -Nitro- l-(pyridin-3-ylmethyl)-lH-indazole.Yield 32%; brown solid; LC-MS calculated for C13H10N4O2 [M + H]+= 255.09, found 255.13.

[0874] 5-Nitro-2-(pyridin-3-ylmethyl)-2H-indazole. Yield 25%; brown solid; LC-MS calculated for C13H10N4O2 [M + H]+= 255.09, found 255.13.

[0875] 5 -Nitro-l-(pyridin-4-ylmethyl)-lH-indazole. Yield 29%; brown solid; LC-MS calculated for C13H10N4O2 [M + H]+= 255.09, found 255.13.

[0876] 5 -Nitro-2-(pyridin-4-ylmethyl)-2H-indazole. Yield 22%; brown solid; LC-MS calculated for C13H10N4O2 [M + H]+= 255.09, found 255.13.

[0877] l-((6-Methylpyridin-2-yl)methyl)-5-nitro-lH-indazole.Yield 38%; yellow solid; LC-MS calculated for C14H12N4O2 [M + H]+= 269.11, found 269.01;1H NMR (400 MHz, DMSO) 5 8.84 (dd, J = 2.2, 0.6 Hz, 1H), 8.45 (d, J = 0.9 Hz, 1H), 8.23 (dd, J = 9.3,2.2 Hz, 1H), 7.91 (dt, J = 9.2, 0.8 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 5.80 (s, 2H), 2.41 (s, 3H).

[0878] 2-((6-Methylpyridin-2-yl)methyl)-5-nitro-2H-indazole. Yield 23%; yellow solid; LC-MS calculated for C14H12N4O2 [M + H]+= 269.11, found 269.01;^ NMR (400 MHz, DMSO) 5 8.96 (d, J = 0.9 Hz, 1H), 8.92 (dd, J = 2.3, 0.7 Hz, 1H), 8.01 (dd, J = 9.4,2.3 Hz, 1H), 7.96 (s, 1H), 7.77 (dt, J = 9.5, 0.8 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.05 (dt, J = 7.7, 0.8 Hz, 1H), 5.80 (s, 2H), 2.44 (s, 3H).

[0879] l-((6-Methylpyridin-3-yl)methyl)-5-nitro-lH-indazole. Yield 32%; yellow solid; LC-MS calculated for C14H12N4O2 [M + H]+= 269.11, found 269.01;1H NMR (400 MHz, DMSO) 5 8.83 (dd, J = 2.2, 0.6 Hz, 1H), 8.47 (dd, J = 2.4, 0.8 Hz, 1H), 8.44 (d, J = 0.9 Hz, 1H), 8.24 (dd, J = 9.3, 2.2 Hz, 1H), 8.01 (dt, J = 9.3, 0.8 Hz, 1H), 7.54 (dd, J = 8.0, 2.4 Hz, 1H), 7.23 - 7.13 (m, 1H), 5.76 (s, 2H), 2.41 (s, 3H).

[0880] 2-((6-Methylpyridin-3-yl)methyl)-5-nitro-2H-indazole. Yield 27%; yellow solid; LC-MS calculated for C14H12N4O2 [M + H]+= 269.11, found 269.01;1H NMR (400 MHz, DMSO) 5 8.95 (d, J = 0.9 Hz, 1H), 8.90 (dd, J = 2.2, 0.7 Hz, 1H), 8.55 (dd, J = 2.4, 0.8 Hz, 1H), 8.00 (dd, J = 9.5, 2.3 Hz, 1H), 7.77 (dt, J = 9.4, 0.8 Hz, 1H), 7.68 (dd, J = 8.0, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.75 (s, 2H), 2.44 (s, 3H).

[0881] Step 2. To a solution of appropriate nitro compound (0.79 mmol, 1.0 eq) and NH4CI (0.79 mmol, 1.0 eq) in ethanol (5 mL) was added Fe (3.95 mmol, 5.0 eq) at roomtemperature. The mixture was then stirred at 80 °C for 2 h. The solution was cooled to ambient temperature, then filtered through celite® and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford desired compound.

[0882] l-(Pyridin-2-ylmethyl)-lH-indazol-5-amine. Yield 85%; brown solid; LC-MS calculated for C13H12N4 [M + H]+= 225.12, found 255.01;1H NMR (400 MHz, MeOD) 58.49 (d, J = 5.0 Hz, 1H), 7.85 (s, 1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.41 - 7.17 (m, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.96 (dd, J = 8.9, 2.1 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 5.64 (s, 2H).

[0883] 2-(Pyridin-2-ylmethyl)-2H-indazol-5-amine. Yield 79%; brown solid; LC-MS calculated for C13H12N4 [M + H]+= 225.12, found 255.01;1H NMR (400 MHz, MeOD) 58.50 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.98 (d, J = 1.0 Hz, 1H), 7.71 (td, J = 7.7, 1.8 Hz, 1H), 7.43 (dt, J = 9.1, 0.9 Hz, 1H), 7.28 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H), 7.04 (dt, J = 7.9, 1.0 Hz, 1H), 6.94 (dd, J = 9.1, 2.1 Hz, 1H), 6.85 (dd, J = 2.1, 0.8 Hz, 1H), 5.63 (s, 2H).

[0884] l-(Pyridin-3-ylmethyl)-lH-indazol-5-amine. Yield 72%; brown solid; LC-MS calculated for C13H12N4 [M + H]+= 225.12, found 255.01.

[0885] 2-(Pyridin-3-ylmethyl)-2H-indazol-5-amine. Yield 65%; brown solid; LC-MS calculated for C13H12N4 [M + H]+= 225.12, found 255.01.

[0886] l-(Pyridin-4-ylmethyl)-lH-indazol-5-amine. Yield 68%; brown solid; LC-MS calculated for C13H12N4 [M + H]+= 225.12, found 255.01.

[0887] 2-(Pyridin-4-ylmethyl)-2H-indazol-5-amine. Yield 63%; brown solid; LC-MS calculated for C13H12N4 [M + H]+= 225.12, found 255.01.EXAMPLE 21Synthesis of Intermediates

[0888] Step 1. To a solution of 5-nitro-lH-indole (1.0 g, 6.17 mmol, 1.0 eq) in DMF (10 mL) was added 60% NaH (0.49 g, 12.34 mmol, 2.0 eq) at 0 °C. The solution was stirred for 10 min at 0 °C. Py-CH2C1 (0.86 g, 6.79 mmol, 1.1 eq) was added to the above reaction solution and stirred for 2 h at rt. The solution was cooled to ambient temperature,then quenched with ice water and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate / hexanes (0 - 100%) to afford desired compound.

[0889] 5 -Nitro- l-(pyridin-2-ylmethyl)-lH-indole: Yield 78%; brown solid; LC-MS calculated for C14H11N3O2 [M + H]+= 254.10, found 254.07.

[0890] 5-Nitro-l-(pyridin-3-ylmethyl)-lH-indole. Yield 85%; brown solid; LC-MS calculated for C14H11N3O2 [M + H]+= 254.10, found 254.06.

[0891] 5 -nitro-l-(pyridin-4-ylmethyl)-lH-indole. Yield 82%; brown solid; LC-MS calculated for C14H11N3O2 [M + H]+= 254.10, found 254.06.

[0892] Step 2. To a solution of appropriate nitro compound (0.79 mmol, 1.0 eq) andNH4CI (0.79 mmol, 1.0 eq) in ethanol (5 mL) was added Fe (3.95 mmol, 5.0 eq) at room temperature. The mixture was then stirred at 80 °C for 2 h. The solution was cooled to ambient temperature, then filtered through celite® and concentrated in vacuo. The crude compound was purified by flash silica gel column chromatography in ethyl acetate in hexanes (0 - 100%) to afford desired compound.

[0893] l-(Pyridin-2-ylmethyl)-lH-indol-5-amine. Yield 72%; brown solid; LC-MS calculated for C14H13N3 [M + H]+= 224.12, found 223.94;1H NMR (400 MHz, MeOD) 5 8.59 - 8.26 (m, 1H), 7.61 (td, J = 7.7, 1.8 Hz, 1H), 7.31 (dd, J = 11.9, 2.7 Hz, 2H), 7.27 - 7.17 (m, 2H), 6.93 - 6.74 (m, 2H), 6.57 - 6.36 (m, 1H), 5.41 (s, 2H).

[0894] l-(Pyridin-3-ylmethyl)-lH-indol-5-amine. Yield 74%; brown solid; LC-MS calculated for C14H13N3 [M + H]+= 224.12, found 223.97;1H NMR (400 MHz, MeOD) 5 8.54 (d, J = 37.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 2.1 Hz, 2H), 7.58 - 7.50 (m, 2H), 7.17 (dd, J = 8.7, 2.2 Hz, 1H), 6.68 (dd, J = 3.3, 0.9 Hz, 1H), 5.63 (s, 2H).

[0895] l-(pyridin-4-ylmethyl)-lH-indol-5-amine. Yield 69%; brown solid; LC-MS calculated for C14H13N3 [M + H]+= 224.12, found 223.98.EXAMPLE 22Synthesis of (E)-N-(4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)-4- (dimethylamino)but-2-enamide (Cpd. No. 36)

[0896] Step 1. Methanesulfonic acid (3.0 eq) was added at room temperature to a suspension of N-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)acetamide (1.0 eq) and 3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)methoxy)aniline (1.5 eq) in anhydrous ethyl alcohol. The mixture was then stirred at 70 °C for 6 h. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to afford 6-amino-4-((3-chloro-4-((6-(tetrahydro-2H-pyran-4-yl)pyridin-3- yl)methoxy)phenyl)amino)-7-ethoxy-2-ethylquinoline-3-carbonitrile as a yellow solid in 68% yield. LC-MS calculated for C31H32CIN5O3 [M + H]+= 558.23, found 558.16.

[0897] Step 2. Synthesis of Cpd. No. 36: (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (1.5 eq) was added at 0 °C to a suspension of 6-amino-4-((3-chloro-4-((6- (tetrahydro-2H-pyran-4-yl)pyridin-3-yl)methoxy)phenyl)amino)-7-ethoxy-2- ethylquinoline-3-carbonitrile (1.0 eq) in N- methyl pyrrolidine (6 vol.). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield Cpd. No. 36 as a light yellow solid in 54% yield. LC-MS calculated for C37H41CIN6O4 [M + H]+= 669.30, found 669.30;1H NMR (400 MHz, MeOD) 5 9.20 (s, 1H), 8.89 - 8.76 (m, 1H), 8.55 (dd, J = 8.3, 2.1 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.37 (d, J = 8.9 Hz, 1H), 7.01 (dt, J = 15.3, 7.1 Hz, 1H), 6.86 (dt, J = 15.1, 1.2 Hz, 1H), 5.49 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 4.12 (dt, J = 11.4, 3.2 Hz, 2H), 4.04 (dd, J = 7.1, 1.1 Hz, 2H), 3.68 - 3.55 (m, 2H), 3.09 (q, J = 7.6 Hz, 2H), 2.96 (s, 6H), 2.04 - 1.90 (m, 4H), 1.61 (t, J = 7.0 Hz, 3H), 1.43 (t, 7= 7.6 Hz, 3H).EXAMPLE 23Synthesis of (E)-N-(4-((3-chloro-4-((6-isopropylpyridin-3-yl)methoxy)phenyl)amino)-3- cyano-7-ethoxy-2-ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 39)

[0898] Step 1. Methanesulfonic acid (3.0 eq) was added at room temperature to a suspension of A-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6-yl)acetamide (1.0 eq) and 3-chloro-4-((6-isopropylpyridin-3-yl)methoxy)aniline (1.5 eq) in anhydrous ethyl alcohol. The mixture was then stirred at 70 °C for 6 h. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to afford 6-amino-4-((3-chloro-4-((6-isopropylpyridin-3-yl)methoxy)phenyl)amino)-7- ethoxy-2-ethylquinoline-3-carbonitrile as a yellow solid in 83% yield. LC-MS calculated for C29H30CIN5O2 [M + H]+= 516.22, found 516.19.

[0899] Step 2. Synthesis of Cpd. No. 39: €-4-(dimethylamino)but-2-enoyl chloride hydrochloride (1.5 eq) was added at 0 °C to a suspension of 6-amino-4-((3-chloro-4-((6- isopropylpyridin-3-yl)methoxy)phenyl)amino)-7-ethoxy-2-ethylquinoline-3-carbonitrile (1.0 eq) in / V- methyl pyrrolidine (6 vol.). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield Cpd. No. 39 as a light yellow solid in 62% yield. LC-MS calculated for C35H39CIN6O3 [M + H]+= 627.29, found 627.40;1H NMR (400 MHz, MeOD) 5 9.20 (s, 1H), 8.86 - 8.78 (m, 1H), 8.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.38 (d, J= 8.8 Hz, 1H), 7.00 (dt, J = 15.3, 7.1 Hz,1H), 6.85 (dt, J = 15.2, 1.2 Hz, 1H), 5.50 (s, 2H), 4.45 (q, J = 7.0 Hz, 2H), 4.04 (dd, J = 7.1, 1.2 Hz, 2H), 3.43 - 3.35 (m, 1H), 3.08 (q, J = 7.6 Hz, 2H), 2.96 (s, 6H), 1.61 (t, J = 7.0 Hz, 3H), 1.51 - 1.40 (m, 9H).EXAMPLE 24Synthesis of (E)-N-(4-((3-chloro-4-((6-isopropylpyridin-3-yl)methoxy)phenyl)amino)-3- cyano-7-ethoxy-2-methylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 47)

[0900] Step 1. Methanesulfonic acid (3.0 eq) was added at room temperature to a suspension of N-(4-chloro-3-cyano-7-ethoxy-2-methylquinolin-6-yl)acetamide (1.0 eq) and 3-chloro-4-((6-isopropylpyridin-3-yl)methoxy)aniline (1.5 eq) in anhydrous ethyl alcohol. The mixture was then stirred at 70 °C for 6 h. The solution was cooled to ambient temperature, then concentrated in vacuo, and purified by preparative HPLC to afford 6-amino-4-((3-chloro-4-((6-isopropylpyridin-3-yl)methoxy)phenyl)amino)-7- ethoxy-2-methylquinoline-3-carbonitrile as a yellow solid in 78% yield. LC-MS calculated for C28H28CIN5O2 [M + H]+= 502.20, found 502.16.

[0901] Step 2. Synthesis of Cpd. No. 47: (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (1.5 eq) was added at 0 °C to a suspension of 6-amino-4-((3-chloro-4-((6- isopropylpyridin-3-yl)methoxy)phenyl)amino)-7-ethoxy-2-methylquinoline-3- carbonitrile (1.0 eq) in A-methy 1 pyrrolidine (6 vol.). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield Cpd. No. 47 as a light yellow solid in 73% yield. LC-MS calculated for C34H37CIN6O3 [M + H]+= 613.27, found 613.27;1H NMR (400 MHz, MeOD) 5 9.20 (s,1H), 8.81 (d, J = 2.0 Hz, 1H), 8.57 (dd, J = 8.4, 2.1 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.45 (dd, J = 8.7, 2.5 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.00 (dt, J = 15.2, 7.1 Hz, 1H), 6.85 (dt, 7 = 15.1, 1.2 Hz, 1H), 5.49 (s, 2H), 4.44 (q, 7 = 7.0 Hz, 2H), 4.04 (dd, 7 = 7.2, 1.2 Hz, 2H), 3.43 - 3.35 (m, 1H), 2.96 (s, 6H), 2.79 (s, 3H), 1.61 (t, 7 = 7.0 Hz, 3H), 1.46 (d, 7= 7.0 Hz, 6H).EXAMPLE 25Synthesis of (E)-N-(4-((3-chloro-4-methoxyphenyl)amino)-3-cyano-7-ethoxy-2- methylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 51)

[0902] Synthesis of Cpd. No. 51: ('E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (21.6 mg, 0.12 mmol, 1.5 eq) was added at 0 °C to a suspension of 6- amino-4-((3-chloro-4-methoxyphenyl)amino)-7-ethoxy-2-methylquinoline-3-carbonitrile (30 mg, 0.08 mmol, 1.0 eq) in A^- methyl pyrrolidine (1 mL). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield Cpd. No. 51 (22 mg, 57% yield) as a light yellow solid. LC- MS calculated for C26H28CIN5O3 [M + H]+= 494.20, found 494.18;1H NMR (400 MHz, MeOD) 5 9.16 (s, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.21 (d, J = 8.8 Hz, 1H), 6.99 (dt, J = 15.3, 7.1 Hz, 1H), 6.84 (dt, J = 15.1, 1.2 Hz, 1H), 4.44 (q, 7 = 7.0 Hz, 2H), 4.04 (dd, J = 7.2, 1.2 Hz, 2H), 3.99 (s, 3H), 2.96 (s, 6H), 2.80 (s, 3H), 1.61 (t, J = 7.0 Hz, 3H).EXAMPLE 26Synthesis of (E)-N-(4-((3-chloro-4-methoxyphenyl)amino)-3-cyano-7-ethoxy-2- ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 59)

[0903] Synthesis of Cpd. No. 59: (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (17.4 mg, 0.1 mmol, 1.5 eq) was added at 0 °C to a suspension of 6-amino- 4-((3-chloro-4-methoxyphenyl)amino)-7-ethoxy-2-ethylquinoline-3-carbonitrile (25 mg, 0.06 mmol, 1.0 eq) inmethyl pyrrolidine (1 mL). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield Cpd. No. 59 (25 mg, 78% yield) as a yellow solid. LC-MS calculated for C27H30CIN5O3 [M + H]+= 508.21, found 508.18;1H NMR (400 MHz, MeOD) 5 9.17 (s, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.45 (s, 1H), 7.40 (dd, J = 8.8, 2.6 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 7.00 (dt, J = 15.3, 7.1 Hz, 1H), 6.85 (dt, J = 15.1, 1.2 Hz, 1H), 4.43 (q, J = 7.0 Hz, 2H), 4.04 (dd, J = 7.1, 1.2 Hz, 2H), 3.99 (s, 3H), 3.09 (q, J = 7.6 Hz, 2H), 2.96 (s, 6H), 1.60 (t, 7 = 7.0 Hz, 3H), 1.43 (t, J = 7.6 Hz, 3H).EXAMPLE 27Synthesis of (E)-N-(4-((3-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-3- cyano-7-ethoxy-2-ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 62)

[0904] Synthesis of Cpd. No. 62: (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (17.8 mg, 0.1 mmol, 1.5 eq) was added at 0 °C to a suspension of 6-amino- 4-((3-chloro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-7-ethoxy-2- ethylquinoline-3-carbonitrile (30 mg, 0.064 mmol, 1.0 eq) in A-methylpyrrolidine (1 mL). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield Cpd. No. 62 (23 mg, 62% yield) as a yellow solid. LC-MS calculated for C31H36CIN5O4 [M + H]+= 578.26, found 578.25;1H NMR (400 MHz, MeOD) 5 9.18 (s, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.49 - 7.34 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 6.99 (dt, J = 15.3, 7.1 Hz, 1H), 6.84 (dt, J = 15.2, 1.2 Hz, 1H), 4.79 (dq, J = 7.4, 3.7 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 4.13 - 3.95 (m, 4H), 3.65 (ddd, J = 11.3, 7.5, 3.5 Hz, 2H), 3.09 (q, J = 7.7 Hz, 2H), 2.96 (s, 6H), 2.15 - 2.04 (m, 2H), 1.85 (ddq, J = 13.2, 7.5, 3.6 Hz, 2H), 1.61 (t, J = 7.0 Hz, 3H), 1.43 (t, J = 7.7 Hz, 3H).EXAMPLE 28Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(methylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 63)

[0905] Step 1. Synthesis of N-(3-cyano-7-ethoxy-2-ethyl-4-(methylamino)quinolin-6- yl)acetamide: To a solution of N-(4-chloro-3-cyano-7-ethoxy-2-ethylquinolin-6- yl)acetamide (35 mg, 0.13 mmol, 1 eq) in DMF was added methyl amine (7.9 mg, 0.25, 2 eq). The reaction mixture was stirred at 40 °C for 5 h. The solution was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was evaporated under vacuo. The crude compound was purified by preparative HPLC to afford 41.7 mg of the N-(3-cyano-7-ethoxy-2-ethyl-4-(methylamino)quinolin-6- yl)acetamide as yellow solid in 98% yield. LC-MS calculated for C17H20N4O2 [M + H]+= 313.17, found 313.08.

[0906] Step 2. Synthesis of 6-amino-7-ethoxy-2-ethyl-4-(methylamino)quinoline-3- carbonitrile: A solution of N-(3-cyano-7-ethoxy-2-ethyl-4-(methylamino)quinolin-6- yl)acetamide (40 mg, 0.13 mmol, 1 eq) in Cone. HCI was heated at 50 °C for 12 h. The reaction was quenched with water and purified directly by preparative HPLC to afford 30 mg of the 6-amino-7-ethoxy-2-ethyl-4-(methylamino)quinoline-3-carbonitrile as yellow solid in 86.7% yield. LC-MS calculated for C15H18N4O [M + H]+= 271.16, found 271.09.Step 3. Synthesis of Cpd. No. 63: (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (28.6 mg, 0.16 mmol, 1.5 eq) was added at 0 °C to a suspension of 6- amino-7-ethoxy-2-ethyl-4-(methylamino)quinoline-3-carbonitrile (28 mg, 0.104 mmol, 1.0 eq) in Y- methyl pyrrolidine (1 mL). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield Cpd. No. 63 (32 mg, 81% yield) as a yellow solid. LC-MS calculated for C21H27N5O2 [M + H]+= 382.23, found 382.32;1H NMR (400 MHz, MeOD) 5 9.06 (s, 1H), 7.34 (s, 1H), 7.00 (dt, J = 15.3, 7.1 Hz, 1H), 6.84 (dt, J = 15.2, 1.2 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.04 (dd, J = 7.1, 1.2 Hz, 2H), 3.66 (s, 3H), 3.14 (q, J = 7.7 Hz, 2H), 2.97 (s, 6H), 1.59 (t, J = 7.0 Hz, 3H), 1.50 (t, J= 7.7 Hz, 3H).EXAMPLE 29Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(isopropylamino)quinolin-6-yl)-4- (dimethylamino)but-2-enamide (Cpd. No. 64)68%

[0907] Step 1. Synthesis of N-(3-cyano-7-ethoxy-2-ethyl-4-(isopropylamino)quinolin-6- yl)acetamide: The synthesis of the Step 1 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 1. Yield 78%; yellow solid; LC-MS calculated for C19H24N4O2 [M + H]+= 341.20, found 341.19.Step 2. Synthesis of 6-amino-7-ethoxy-2-ethyl-4-(isopropylamino)quinoline-3- carbonitrile: The synthesis of the Step 2 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 2. Yield 82%; yellow solid; LC-MS calculated for C17H22N4O [M + H]+= 299.19, found 299.12.Step 3. Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(isopropylamino)quinolin-6-yl)- 4-(dimethylamino)but-2-enamide: The synthesis of the Step 3 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 3. Yield 68%;yellow solid; LC-MS calculated for C23H31N5O2 [M + H]+= 410.26, found 410.31;!H NMR (400 MHz, MeOD) 5 9.05 (s, 1H), 7.33 (s, 1H), 7.01 (dt, J = 15.3, 7.1 Hz, 1H), 6.84 (dt, J = 15.2, 1.2 Hz, 1H), 5.11 (hept, J = 6.3 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.05 (dd, J= 7.1, 1.3 Hz, 2H), 3.15 (q, J = 7.7 Hz, 2H), 2.97 (s, 6H), 1.62 - 1.46 (m, 12H).EXAMPLE 30Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 118)

[0908] Step 1. Synthesis of N-(3-cyano-7-ethoxy-2-ethyl-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)quinolin-6-yl)acetamide: The synthesis of the Step 1 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 1. Yield 61%; yellow solid; LC-MS calculated for C22H28N4O3 [M + H]+= 397.23, found 397.12.

[0909] Step 2. Synthesis of 6-amino-7-ethoxy-2-ethyl-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)quinoline-3-carbonitrile: The synthesis of the Step 2 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 2. Yield 61%; yellow solid; LC-MS calculated for C20H26N4O2 [M + H]+= 355.22, found 355.14.

[0910] Step 3. Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(((tetrahydro-2H-pyran- 4-yl)methyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide: The synthesis of the Step 3 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 3. Yield 78%; yellow solid; LC-MS calculated for C26H35N5O3 [M + H]+= 466.28, found 466.29;1H NMR (400 MHz, MeOD) 5 9.07 (s, 1H), 7.35 (s, 1H), 7.00 (dt, J = 15.3, 7.1 Hz, 1H), 6.83 (dt, J = 15.2, 1.2 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H),4.10 - 3.91 (m, 6H), 3.46 (td, J = 11.8, 2.1 Hz, 2H), 3.15 (q, J = 7.6 Hz, 2H), 2.97 (s, 6H), 2.24 (dqd, J= 10.6, 7.2, 3.3 Hz, 1H), 1.85 (ddd, J= 12.9, 4.0, 1.9 Hz, 2H), 1.59 (t, J = 7.0 Hz, 3H), 1.50 (t, J = 7.7 Hz, 5H).EXAMPLE 31Synthesis of (E)-N-(3-cyano-4-(cyclopropylamino)-7-ethoxy-2-ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 119)

[0911] Step 1. Synthesis of N-(3-cyano-4-(cyclopropylamino)-7-ethoxy-2-ethylquinolin- 6-yl)acetamide: The synthesis of the Step 1 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 1. Yield 71%; yellow solid; LC-MS calculated for C19H22N4O2 [M + H]+= 339.18, found 339.17.

[0912] Step 2. Synthesis of 6-amino-4-(cyclopropylamino)-7-ethoxy-2-ethylquinoline-3- carbonitrile: The synthesis of the Step 2 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 2. Yield 84%; yellow solid; LC-MS calculated for C17H20N4O [M + H]+= 297.17, found 297.09.

[0913] Step 3. Synthesis of (E)-N-(3-cyano-4-(cyclopropylamino)-7-ethoxy-2- ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide: The synthesis of the Step 3 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 3. Yield 58%; yellow solid; LC-MS calculated for C23H29N5O2 [M + H]+= 408.24, found 408.33;XH NMR (400 MHz, MeOD) 5 9.10 (s, 1H), 7.37 (s, 1H), 7.00 (dt, J= 15.3, 7.2 Hz, 1H), 6.84 (dt, J = 15.2, 1.2 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.04 (dd, J = 7.1, 1.2 Hz, 2H), 3.42 (tt, J = 7.0, 3.7 Hz, 1H), 3.18 (q, J = 7.8 Hz, 2H), 2.96 (s, 6H), 1.58 (t, J = 7.0 Hz, 3H), 1.51 (t, J = 7.7 Hz, 3H), 1.20 (qd, J = 6.6, 4.3 Hz, 2H), 1.11 (dq, 7 = 7.8, 4.2 Hz, 2H).EXAMPLE 32Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-((tetrahydro-2H-pyran-4- yl)amino)quinolin-6-yl)-4-(4-methylpiperazin-l-yl)but-2-enamide (Cpd. No. 125)

[0914] Step 1. Synthesis of N-(3-cyano-7-ethoxy-2-ethyl-4-((tetrahydro-2H-pyran-4- yl)amino)quinolin-6-yl)acetamide: The synthesis of the Step 1 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 1. Yield 78%; yellow solid; LC-MS calculated for C21H26N4O3 [M + H]+= 383.21, found 383.28.

[0915] Step 2. Synthesis of 6-amino-7-ethoxy-2-ethyl-4-((tetrahydro-2H-pyran-4- yl)amino)quinoline-3-carbonitrile: The synthesis of the Step 2 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 2. Yield 72%; light brown oil; LC-MS calculated for C19H24N4O2 [M + H]+= 341.20, found 341.22.

[0916] Step 3. Synthesis of (E)-4-chloro-N-(3-cyano-7-ethoxy-2-ethyl-4-((tetrahydro- 2H-pyran-4-yl)amino)quinolin-6-yl)but-2-enamide: (E)-4-chlorobut-2-enoyl chloride (24.3 mg, 0.18 mmol, 1.5 eq) was added at 0 °C to a suspension of 6-amino-7-ethoxy-2- ethyl-4-((tetrahydro-2H-pyran-4-yl)amino)quinoline-3-carbonitrile (40 mg, 0.12 mmol, 1.0 eq) in Y- methyl pyrrolidine (1 mL). The mixture was then allowed to ambient temperature and stirred for 1 h. The compound was purified by preparative HPLC to yield (E)-4-chloro-N-(3-cyano-7-ethoxy-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)amino) quinolin-6-yl)but-2-enamide (29 mg, 56% yield) as a yellow solid. LC-MS calculated for C23H27CIN4O3 [M + H]+= 443.19, found 443.27.

[0917] Step 4. Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-((tetrahydro-2H-pyran-4- yl)amino)quinolin-6-yl)-4-(4-methylpiperazin-l-yl)but-2-enamide: 1 -Methylpiperazine (11.3 mg, 0.11 mmol, 2.0 eq) was added at room temperature to a suspension of (E)-4- chloro-N-(3-cyano-7-ethoxy-2-ethyl-4-((tetrahydro-2H-pyran-4-yl)amino)quinolin-6- yl)but-2-enamide (25 mg, 0.06 mmol, 1.0 eq) and CS2CO3 (36.8 mg, 0.11 mmol, 2.0 eq)in acetonitrile (2 mL). The mixture was then stirred at 60 °C for 2 h. The compound was purified by preparative HPLC to yield (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-((tetrahydro- 2H-pyran-4-yl)amino)quinolin-6-yl)-4-(4-methylpiperazin-l-yl)but-2-enamide (19 mg, 67% yield) as a yellow solid. LC-MS calculated for C28H38N6O3 [M + H]+= 507.31, found 507.26;1H NMR (400 MHz, MeOD) 5 9.05 (s, 1H), 7.35 (s, 1H), 7.02 (dt, J = 15.4, 6.2 Hz, 1H), 6.65 (dt, J= 15.3, 1.5 Hz, 1H), 4.98 (dd, J= 7.6, 3.4 Hz, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.14 - 4.05 (m, 2H), 3.61 (td, J = 12.0, 2.0 Hz, 2H), 3.48 (dd, J = 6.3, 1.6 Hz, 2H), 3.40 (s, 4H), 3.16 (q, J = 7.7 Hz, 2H), 2.94 (s, 7H), 2.21 - 2.11 (m, 2H), 2.01 (qd, J= 12.0, 4.4 Hz, 2H), 1.59 (t, J = 7.0 Hz, 3H), 1.50 (t, J = 7.6 Hz, 3H).EXAMPLE 33

[0918] Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(((tetrahydro-2H-pyran-4- yl)methyl)amino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 93)The synthesis was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 3 starting from 6-amino-4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)-7-ethoxy-2-ethylquinoline-3-carbonitrile. Yield 45%; yellow solid; LC-MS calculated for C29H26CIN5O3 [M + H]+= 528.18, found 528.17;1H NMR (400 MHz, MeOD) 5 9.16 (s, 1H), 8.67 (ddd, J = 5.2, 1.7, 0.9 Hz, 1H), 8.11 (td, J = 7.8, 1.7 Hz, 1H), 7.86 (dt, J = 7.9, 1.0 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.59 (ddd, J = 7.7, 5.1, 1.2 Hz, 1H), 7.43 (dd, J = 8.8, 2.6 Hz, 1H), 7.39 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.69 (dd, J = 16.9, 10.2 Hz, 1H), 6.48 (dd, J = 17.0, 1.7 Hz, 1H), 5.89 (dd, J = 10.2, 1.7 Hz, 1H), 5.44 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 3.09 (q, J = 7.6 Hz, 2H), 1.62 (t, J = 7.0 Hz, 3H), 1.44 (t, J= 7.6 Hz, 3H).EXAMPLE 34Synthesis of (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7- ethoxy-2-ethylquinolin-6-yl)but-2-enamide (Cpd. No. 94)

[0919] The synthesis was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 3 starting from 6-amino-4-((3-chloro-4-(pyridin-2- ylmethoxy)phenyl)amino)-7-ethoxy-2-ethylquinoline-3-carbonitrile. Yield 78%; yellow solid; LC-MS calculated for C30H28CIN5O3 [M + H]+= 542.20, found 541.98;1H NMR (400 MHz, MeOD) 5 9.13 (s, 1H), 8.67 (ddd, J = 5.1, 1.7, 0.9 Hz, 1H), 8.11 (td, J = 7.8, 1.7 Hz, 1H), 7.86 (dt, 7 = 7.9, 1.1 Hz, 1H), 7.65 - 7.54 (m, 2H), 7.42 (dd, J = 8.7, 2.6 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.08 (dq, J = 15.1, 6.9 Hz, 1H), 6.39 (dt, J = 15.2, 1.7 Hz, 1H), 5.43 (s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.09 (q, J = 7.6 Hz, 2H), 1.97 (dd, 7= 6.9, 1.7 Hz, 3H), 1.62 (t, 7 = 7.0 Hz, 3H), 1.44 (t, 7 = 7.7 Hz, 3H).EXAMPLE 35Synthesis of (E)-N-(4-((3-chloro-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)amino)- 3-cyano-7-ethoxy-2-ethylquinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 95)

[0920] The synthesis was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 3 starting from 6-amino-4-((3-chloro-4-((tetrahydro-2H-pyran-4- yl)methoxy)phenyl)amino)-7-ethoxy-2-ethylquinoline-3-carbonitrile. Yield 61%; light yellow solid; LC-MS calculated for C32H38CIN5O4 [M + H]+= 592.27, found 592.25;1H NMR (400 MHz, MeOD) 5 9.17 (s, 1H), 7.53 (d, 7 = 2.6 Hz, 1H), 7.46 - 7.34 (m, 2H), 7.20 (d, 7 = 8.9 Hz, 1H), 6.99 (dt, 7 = 14.6, 7.1 Hz, 1H), 6.89 - 6.80 (m, 1H), 4.44 (q, 7 = 7.0 Hz, 2H), 4.11 - 3.97 (m, 6H), 3.52 (td, 7 = 11.8, 2.1 Hz, 2H), 3.08 (q, 7 = 7.6 Hz, 2H), 2.96 (s, 6H), 2.25 - 2.14 (m, 1H), 1.84 (ddd, 7 = 12.7, 4.0, 1.9 Hz, 2H), 1.63 - 1.51 (m, 5H), 1.43 (t, 7 = 7.6 Hz, 3H).EXAMPLE 36Synthesis of (E)-N-(4-((3-chloro-4-methoxyphenyl)amino)-3-cyano-7-ethoxy-2- ethylquinolin-6-yl)-4-(piperidin-l-yl)but-2-enamide (Cpd. No. 96)

[0921] Step 1. Synthesis of (E)-4-chloro-N-(4-((3-chloro-4-methoxyphenyl)amino)-3- cyano-7-ethoxy-2-ethylquinolin-6-yl)but-2-enamide: The synthesis of the Step 1 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 125, Step 3 from 6-amino-4-((3-chloro-4-methoxyphenyl)amino)-7-ethoxy-2- ethylquinoline-3-carbonitrile. Yield 48%; yellow solid; LC-MS calculated for C25H24CI2N4O3 [M + H]+= 499.13, found 499.12.

[0922] Step 2. Synthesis of (E)-N-(4-((3-chloro-4-methoxyphenyl)amino)-3-cyano-7- ethoxy-2-ethylquinolin-6-yl)-4-(piperidin-l-yl)but-2-enamide: The synthesis of the Step 2 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 125, Step 4 from Step 1 compound. Yield 52%; light yellow solid; LC-MS calculated for C30H34CIN5O3 [M + H]+= 548.25, found 548.24;1H NMR (400 MHz, MeOD) 5 9.15 (s, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.00 (dt, J = 15.3, 7.2 Hz, 1H), 6.83 (dt, J = 15.2, 1.2 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 4.08 - 3.88 (m, 5H), 3.58 (d, J= 12.1 Hz, 2H), 3.15 - 2.91 (m, 4H), 2.09 - 1.72 (m, 5H), 1.61 (t, J = 7.0 Hz, 4H), 1.44 (t, J= 7.6 Hz, 3H).EXAMPLE 37Synthesis of (E)-N-(4-((3-chloro-4-methoxyphenyl)amino)-3-cyano-7-ethoxy-2- ethylquinolin-6-yl)-4-morpholinobut-2-enamide (Cpd. No. 97)

[0923] The synthesis was carried out in a manner similar to the synthetic procedure used for Cpd. No. 125, Step 4 from (E)-4-chloro-N-(4-((3-chloro-4-methoxyphenyl)amino)-3- cyano-7-ethoxy-2-ethylquinolin-6-yl)but-2-enamide. Yield 71%; yellow solid; LC-MScalculated for C29H32CIN5O4 [M + H]+= 550.22, found 550.16;1H NMR (400 MHz, MeOD) 5 9.16 (s, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.21 (d, J = 8.9 Hz, 1H), 7.01 (dt, J = 15.2, 7.1 Hz, 1H), 6.88 - 6.82 (m, 1H), 4.44 (q, J = 7.0 Hz, 2H), 4.05 (dd, J = 7.2, 1.2 Hz, 2H), 3.99 (s, 6H), 3.48 - 3.33 (m, 4H), 3.09 (q, J = 7.7 Hz, 2H), 1.61 (t, J= 6.9 Hz, 3H), 1.43 (t, J= 7.6 Hz, 3H).EXAMPLE 38Synthesis of (E)-N-(4-((3-chloro-4-methoxyphenyl)amino)-3-cyano-7-ethoxy-2- ethylquinolin-6-yl)-4-(4-methylpiperazin-l-yl)but-2-enamide (Cpd. No. 98)

[0924] The synthesis was carried out in a manner similar to the synthetic procedure used for Cpd. No. 125, Step 4 from (E)-4-chloro-N-(4-((3-chloro-4-methoxyphenyl)amino)-3- cyano-7-ethoxy-2-ethylquinolin-6-yl)but-2-enamide. Yield 82%; yellow solid; LC-MS calculated for C30H35CIN6O3 [M + H]+= 563.26, found 563.25;1H NMR (400 MHz, MeOD) 5 9.15 (s, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.22 (d, J = 8.8 Hz, 1H), 7.00 (dt, J = 15.3, 6.1 Hz, 1H), 6.63 (dt, J = 15.3, 1.6 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 3.99 (s, 3H), 3.54 - 3.34 (m, 6H), 3.09 (q, J = 7.6 Hz, 2H), 3.05 - 2.42 (m, 7H), 1.62 (t, J= 7.0 Hz, 3H), 1.44 (t, J= 7.6 Hz, 3H).EXAMPLE 39Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(phenylamino)quinolin-6-yl)-4-(dimethylamino)but-2-enamide (Cpd. No. 107)

[0925] The synthesis was carried out in a manner similar to the synthetic procedure used for Cpd. No. 63, Step 3 starting from 6-amino-7-ethoxy-2-ethyl-4-(phenylamino)quinoline-3-carbonitrile. Yield 72%; light yellow solid; LC-MS calculatedfor C26H29N5O2 [M + H]+= 444.24, found 443.68;1H NMR (400 MHz, MeOD) 5 9.12 (s, 1H), 7.52 (dd, J = 8.3, 6.7 Hz, 2H), 7.48 - 7.38 (m, 4H), 6.98 (dt, J = 15.2, 7.1 Hz, 1H), 6.88 - 6.81 (m, 1H), 4.44 (q, J = 7.0 Hz, 2H), 4.04 (dd, J = 7.2, 1.2 Hz, 2H), 3.07 (q, J = 7.7 Hz, 2H), 2.96 (s, 6H), 1.62 (t, J= 7.0 Hz, 3H), 1.43 (t, J= 7.6 Hz, 3H).EXAMPLE 40Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(phenylamino)quinolin-6-yl)-4- morpholinobut-2-enamide (Cpd. No. 108)Step 2

[0926] Step 1. Synthesis of (E)-4-chloro-N-(3-cyano-7-ethoxy-2-ethyl-4-(phenylamino)quinolin-6-yl)but-2-enamide: The synthesis of the Step 1 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 125, Step 3 from 6-amino-7-ethoxy-2-ethyl-4-(phenylamino)quinoline-3-carbonitrile. Yield 52%; yellow solid; LC-MS calculated for C24H23CIN4O2 [M + H]+= 435.16, found 435.21.

[0927] Step 2. Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(phenylamino)quinolin- 6-yl)-4-morpholinobut-2-enamide: The synthesis of the Step 2 compound was carried out in a manner similar to the synthetic procedure used for Cpd. No. 125, Step 4 from Step 1 compound. Yield 65%; light yellow solid; LC-MS calculated for C28H31N5O3 [M + H]+= 486.25, found 485.71;1H NMR (400 MHz, MeOD) 5 9.15 (s, 1H), 7.56 - 7.51 (m, 2H), 7.50 - 7.42 (m, 3H), 7.40 (s, 1H), 7.01 (dt, J = 14.6, 7.1 Hz, 1H), 6.84 (d, J = 15.3 Hz, 1H), 4.45 (q, J = 7.0 Hz, 2H), 4.10 - 3.82 (m, 6H), 3.32 (s, 4H), 3.08 (q, J = 7.7 Hz, 2H), 1.62 (t, J = 7.0 Hz, 3H), 1.43 (t, J = 7.6 Hz, 3H).EXAMPLE 41Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(phenylamino)quinolin-6-yl)-4- (piperidin-l-yl)but-2-enamide (Cpd. No. 109)Acetonitrile CS CO

[0928] The synthesis was carried out in a manner similar to the synthetic procedure used for Cpd. No. 125, Step 4 from (E)-4-chloro-N-(3-cyano-7-ethoxy-2-ethyl-4- (phenylamino)quinolin-6-yl)but-2-enamide. Yield 68%; yellow solid; LC-MS calculated for C29H33N5O2 [M + H]+= 484.27, found 483.85;1H NMR (400 MHz, MeOD) 5 9.15 (s, 1H), 7.57 - 7.50 (m, 2H), 7.50 - 7.43 (m, 3H), 7.41 (s, 1H), 6.99 (dt, J = 14.7, 7.2 Hz, 1H), 6.82 (dt, J = 15.1, 1.2 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 4.00 (dd, J = 7.1, 1.2 Hz, 2H), 3.56 (s, 2H), 3.18 - 2.88 (m, 4H), 1.91 (dt, J = 67.5, 15.0 Hz, 5H), 1.61 (t, J = 7.0 Hz, 4H), 1.43 (t, J= 7.6 Hz, 3H).EXAMPLE 42Synthesis of (E)-N-(3-cyano-7-ethoxy-2-ethyl-4-(phenylamino)quinolin-6-yl)-4-(4- methylpiperazin-l-yl)but-2-enamide (Cpd. No. 110)Acetonitrile CS CO[092...

Claims

What is claimed is:

1. A compound having Formula (IX):or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of -O- and -NRa-;Rais selected from the group consisting to hydrogen and C1-C4 alkyl;R1is selected from the group consisting of -CH=CHRlaand -C=CRlb;Rlais selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and -CH2NR8R9;Rlbis selected from the group consisting of hydrogen and C1-C6alkyl;R8is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4-to 7-membered heterocyclo, C2-C12 alkynyl, and (C1-C6alkoxy)C1-C6alkyl;R9is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; orR8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo;R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; andR5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10- membered heteroaryl.

2. The compound claim 1, or a pharmaceutically acceptable salt or solvate thereof, with the following provisos:(i) if R4is cyano and R1is -CH2NR8R9, then R8is hydrogen, C2-C6 alkyl, C3-C6cycloalkyl, optionally substituted 4-to 7-membered heterocyclo, C2-C12 alkynyl, and (Ci- Ce alkoxy )C1-C6alkyl; R9is selected from the group consisting of hydrogen, C1-C6alkyl, and C3-C6cycloalkyl; or R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo; or(ii) if R1is -CH2NR8R9and R8and R9are each methyl, then R4is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, and C3-C6cycloalkyl; or(iii) if R1is -CH2NR8R9, R8and R9are each methyl, and R4is cyano, then R3is C1-C6alkyl or C3-C6cycloalkyl.

3. The compound of claims 1 or 2 having Formula (X):(X), or a pharmaceutically acceptable salt or solvate thereof, wherein:R6ais selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl;R6bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; andR6Cis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl; C1-C4 haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, (optionally substituted 4- to 7-membered heterocyclo)-O-,(aryl)alkyl-O-, and (heteroaryl)alkyl-O-.

4. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein:R6bis hydrogen; andR6Cis selected from the group consisting of:, or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R5ais optionally substituted 5-membered heteroaryl.

7. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XII):(XII), wherein R5bis selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C2-C6 alkenyl, C3-C6cycloalkyl, and optionally substituted 5- or 6- membered heterocyclo.

8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XIII):(XIII).

9. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XIV):(XIV).

10. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, having Formula (XV):(XV).

11. The compound of claims 1 or 2 having Formula (XVI):(XVI),or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of optionally substituted 5- to 7-membered heterocylo and optionally substituted 5- to 10-membered heteroaryl.

12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 7-membered heterocylo.

13. The compound of claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of:

14. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is optionally substituted 5- to 10-membered heteroaryl.

15. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is selected from the group consisting of:

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais hydrogen.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais C1-C4 alkyl.

18. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein Rlais -CH2NR8R9.

19. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9are C1-C6alkyl.

20. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9are methyl.

21. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is optionally substituted 4-to 7-membered heterocyclo.

22. The compound of claim 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is selected from the group consisting of:

23. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is C2-C10 alkynyl.

24. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9taken together with the nitrogen atom to which they are attached form an optionally substituted 5- to 8-membered heterocyclo.

25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R8and R9taken together with the nitrogen atom to which they are attached form:

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -OR7.

27. The compound of claim 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is selected from the group consisting of methyl, ethyl, and propyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is ethyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from the group consisting of hydrogen and C1-C6alkyl.

30. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

31. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is methyl.

32. The compound of claim 29, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is ethyl.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is selected from the group consisting of hydrogen and cyano.

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

35. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is cyano.

36. The compound of any one of claims 3-10 or 15-35, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais selected from the group consisting of hydrogen and halogen.

37. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais hydrogen.

38. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais chloro.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

40. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.41 The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from any one or more of the compounds of Table 1 A and / or Table 2A.

42. The compound of claim 41, or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of:

43. A pharmaceutical composition comprising the compound of any one of claims 1-42 and a pharmaceutically acceptable excipient.

44. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-42 or the pharmaceutical composition of claim 32.

45. The method of claim 44 further comprising administering a therapeutically effective amount one or more immune checkpoint inhibitors to the subject.

46. The method of claim 44, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies, one or more anti-PD-Ll antibodies, one or more anti-CTLA-4 antibodies, one or more anti-LAG3 antibodies, one or more anti-TIM3 antibodies, one or more anti- VISTA antibodies, one or more anti- TIGIT antibodies, or one or more anti-cd47 antibodies, or a combination thereof.

47. The method of claim 46 wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-1 antibodies.

48. The method of claim 47, wherein the one or more anti-PD-1 antibodies comprise nivolumab, pembrolizumab, dostarlimab, retifanlimab, cemiplimab, vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), INCMGA00012 (MGA012), AMP-224, AMP-514 (MED 10680) and / or Acrixolimab (YBL-006).

49. The method any one of claims 46-48, wherein the one or more immune checkpoint inhibitors comprise one or more anti-PD-Ll antibodies.

50. The method of claim 49, wherein the one or more anti-PD-Ll antibodies comprise avelumab, atezolizumab, durvalumab, KN035, and / or cosibelimab (CK-301).

51. The method of any one of claims 46-50, wherein the one or more immune checkpoint inhibitors comprise one or more anti-CTLA-4 antibodies.

52. The method of claim 51, wherein the one or more anti-CTLA-4 antibodies comprise ipilimumab and / or tremelimumab.

53. The method of any one of claims 46-52, wherein the one or more immune checkpoint inhibitors comprise one or more anti-LAG3 antibodies.

54. The method of claim 53, wherein the one or more anti-LAG3 antibodies comprise relatlimab.

55. The method of any one of claims 46-54 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIM3 antibodies.

56. The method of any one of claims 46-55 wherein the one or more immune checkpoint inhibitors comprise one or more anti- VISTA antibodies.

57. The method of any one of claims 46-56 wherein the one or more immune checkpoint inhibitors comprise one or more anti-TIGIT antibodies.

58. The method of any one of claims 46-57 wherein the one or more immune checkpoint inhibitors comprise one or more anti-cd47 antibodies.

59. The method of claim 45 comprising administering a therapeutically effective amount of nivolumab, pembrolizumab, dostarlimab, retifanlimab, or cemiplimab to the subject.

60. The method of claims 45 or 59 comprising administering a therapeutically effective amount of avelumab, atezolizumab, or durvalumab to the subject.

61. The method of any one of claims 44-60, wherein the cancer is any one or more of the cancers of Table 2 and / or Table 3.

62. A method of inhibiting adenosine deaminase acting on RNA 1 (ADAR1) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 43.

63. A method of providing immuno-oncology therapy to a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 43.

64. A method of sensitizing tumor response to immunotherapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 43.

65. The method of claim 64, wherein the tumor is resistant to immune checkpoint blockade.

66. The method of any one of claims 62-65 comprising administering to the subject a therapeutically effective amount of Neratinib:

67. A kit for carrying out the method of any one of claims 44-66, the kit comprising: (i) a compound having Formula (IX), or a pharmaceutically acceptable salt or solvate thereof; and (ii) a label with instructions for how to use the kit.

68. A kit for carrying out the method of any one of claims 44-66, the kit comprising: (i) one or more immune checkpoint inhibitors; and (ii) a label with instructions for how to use the kit.

69. A kit for carrying out the method of any one of claims 44-66, the kit comprising: (i) a compound having Formula (IX), or a pharmaceutically acceptable salt or solvate thereof; (ii) one or more immune checkpoint inhibitors; and (iii) a label with instructions for how to use the kit.

70. The kit of any one of claims 67-69, wherein the label is approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China Food and Drug Administration (CFDA), or the Japanese Ministry of Health Labor and Welfare (MHLW).

71. A compound having Formula (VIII):or a pharmaceutically acceptable salt or solvate thereof, wherein:R10is selected from the group consisting of chloro and -N(H)R5;R11is selected from the group consisting of hydrogen and -C(=O)CH3;R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; andR5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10- membered heteroaryl.

72. A compound having Formula (XVIII):(XVIII), or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from the group consisting of -O- and -NRa-;Rais selected from the group consisting to hydrogen and C1-C4 alkyl;LG is a leaving group;R2is selected from the group consisting of hydrogen, halo, C1-C6alkyl, and -OR7;R7is selected from the group consisting of C1-C6alkyl, optionally substituted C3-C6cycloalkyl, (optionally substituted C3-C6cycloalkyl)C1-C6-alkyl, (C1-C6alkoxy)C1-C6alkyl, optionally substituted 4- to 7-membered heterocyclo, and (optionally substituted 4-to 7-membered heterocyclo)C1-C6alkyl;R3is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl;R4is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, and C3-C6cycloalkyl; andR5is selected from the group consisting of hydrogen, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 4- to 7-membered heterocyclo, optionally substituted aryl, (heterocyclo)alkyl, and optionally substituted 5- to 10- membered heteroaryl.

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