Compounds for targeted degradation of BRD9

Abstract

BRD9 protein degrading compounds, or pharmaceutically acceptable salts thereof, are provided for the treatment of conditions mediated by BRD9, including but not limited to abnormal cell proliferation.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of March 5, 2021, application number 202180019698.X, and invention name “Compounds for targeted degradation of BRD9”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 985,774, filed March 5, 2020, and U.S. Provisional Application No. 63 / 061,659, filed August 5, 2020. The entire contents of these applications are incorporated herein by reference for all purposes. Technical Field

[0004] The present invention provides BRD9 degrading compounds for therapeutic applications as further described herein. Background Art

[0005] Bromodomain-containing proteins (BRDs) such as BRD9 are proteins that recognize acetylated lysine residues such as those on the N-terminus of histones. BRDs are evolutionarily conserved and are present in a variety of nuclear proteins, including HATs (GCN5, PCAF), ATP-dependent chromatin remodeling complexes (BAZ1B), helicases (SMARCA), methyltransferases (MLL, ASH1L), transcriptional coactivators (TRIM / TIF1, TAF), transcription mediators (TAF1), nuclear scaffold proteins (PB1), and the BET family. (Muller S, Filippakopoulos P, Knapp S., Bromodomains as therapeutic targets, Expert Rev Mol Med. 2011, 13 (29)). Bromodomain-containing proteins have many functions related to transcriptional mediation and coactivation, so they are involved in cell proliferation.

[0006] Studies have also shown that BRD9 is preferentially used by cancers carrying SMARCB1 abnormalities, such as malignant rhabdoid tumors and several specific types of sarcomas. Complexes containing BRD9 bind to active promoters and enhancers simultaneously, whereby they contribute to gene expression. Loss of BRD9 leads to changes in gene expression associated with apoptosis regulation, translation, and developmental regulation. BRD9 is essential for the proliferation of SMARCB1-deficient cancer cell lines, indicating that it is a therapeutic target for these deadly cancers. (Xiaofeng Wang et al., "BRD9 defines a SWI / SNF sub-complex and constitutes aspecific vulnerability in malignant rhabdoid tumors," Nature Communications, 2019, 10(1881)). BRD9 is also a key target required in acute myeloid leukemia, "Nature Chemical Biology, 2016, 101038 / nchembio.2115". In addition to its role as a functionally dependent regulator of BRD9 in certain cancers, BRD9 also plays a key role in immune cells as a regulator of regulatory T cells (Tregs) via transcriptional control of Foxp3 target genes,” BioRxiv, 10.1101 / 2020.02.26.964981.

[0007] Studies have also shown that the newly discovered non-canonical BAF (ncBAF) complex is a distinct entity composed of a unique combination of subunits compared to the classical BAF (cBAF) and polybrominated (pBAF) complexes. (Alpsoy, A. & Dykhuizen, E.C. Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI / SNF chromatin remodeling subcomplexes. J Biol Chem 293, 3892–3903 (2018)). Notably, BRD9 selectively binds to the non-canonical BAF (ncBAF) complex, while SMARCB1 is absent. In the context of SMARCB1 perturbation (cBAF complex expulsion, deletion, truncation, inactivation), the function of the cBAF complex is impaired, resulting in a unique so-called synthetic lethal dependence on the function of the ncBAF complex. Furthermore, BRD9 is essential for ncBAF complex function, and therefore, BRD9 is uniquely dependent in SMARCB1 perturbation cancers (Michel, BC et al. An-canonical SWI / SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol 20, 1–11 (2018) and Brien, GL et al. Targeted degradation of BRD9 reverses oncogenic gene expression in synovialsarcoma. Elife 7, e41305 (2018)).

[0008] Bromodomain-containing protein 7 (BRD7) is also a subunit of PBAF SWI / SNF. Publications describing BRD7 and ligands for BRD7 and BRD9 include: Pérez-Salvia M. et al., “Bromodomain inhibitors and cancer therapy: From structures to applications” (Epigenetics. 2017; 12(5): 323–339; 99); and Clark PGK et al., “Discovery and Synthesis of the First Selective BRD7 / 9 Bromodomain Inhibitor” (Angew Chem Weinheim BergstrGer. 2015, 127(21): 6315–6319).

[0009] Because of the role of BRD9 in cancer proliferation, there has been interest in developing BRD9 inhibitors for the treatment of cancer, including those described in WO 2014 / 114721; WO 2016 / 077375; WO 2016 / 077378; WO 2016 / 139361; WO 2019 / 152440; Martin LJ et al., “Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor” (Journal of Medicinal Chemistry 2016, 59, 4462-4475); NH et al., “Discovery of 1-BRD9, a selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition” (Journal of Medicinal Chemistry 2015, 59, 1425-1439); and Clack et al., “Biotinylated 1-BRD9 Inhibitors” (Journal of Medicinal Chemistry 2016, 59, 1425-1439). Paper by P. et al. (Angewandte Chemie, 2015, 127, 6315-6319).

[0010] Research on protein degradation compounds with an E3 ligase binding portion and a BRD9 binding portion has also been reported, wherein the BRD9 binding ligand binds to BRD9 and brings it to the ligase for ultimate degradation by the proteasome. See, for example, WO 2017 / 223452, WO 2019 / 152440, WO 2019 / 246423, WO 2019 / 246430, WO 2020 / 051235, WO 2020 / 106915, WO 2020 / 160192, WO 2020 / 160193, WO 2020 / 160196, and WO 2021 / 022163.

[0011] Patent applications filed by C4 Therapeutics, Inc. that describe compounds capable of binding to E3 ubiquitin ligases and degrading target proteins include: WO / 2020 / 132561, titled “Targeted Protein Degradation”; WO / 2019 / 204354, titled “Spirocyclic Compounds”; WO / 2019 / 099868, titled “Degraders snd Degrons for Targeted Protein Degradation”; WO / 2018 / 237026, titled “N / O-Linked Degrons and Degronimers for Protein Degradation”; WO 2017 / 197051, titled “Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation”; WO 2017 / 197055, titled “Heterocyclic Degronimers for Target Protein Degradation”; and WO 2018 / 237026, titled “N / O-Linked Degrons and Degronimers for Protein Degradation”. Target Protein Degradation”; WO 2017 / 197036 titled “C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation”; and WO 2017 / 197056 titled “Bromodomain Targeting Degronimers for Target Protein Degradation”.

[0012] Other patent applications describing protein degradation compounds include:

[0013] WO 2015 / 160845; WO 2016 / 105518; WO 2016 / 118666; WO 2016 / 149668; WO 2016 / 197032; WO 2016 / 197114; WO 2017 / 007612; WO 2017 / 011371; WO 2017 / 011590; WO 2017 / 030814; WO 2017 / 046036; WO 2017 / 176708; WO 2017 / 176957; WO 2017 / 180417; WO 2018 / 053354; WO 2018 / 071606; WO 2018 / 102067;WO 2018 / 102725;WO 2018 / 118598;WO 2018 / 119357;WO 2018 / 119441;WO 2018 / 119448;WO 2018 / 140809;WO2018 / 144649;WO 2018 / 119448;WO 2018 / 226542; WO 2019 / 023553; WO / 2019 / 195201; WO2019 / 199816; and WO / 2019 / 099926.

[0014] Because BRD9 plays an important role in cancer, there remains a need for new compounds and methods for treating disorders mediated by BRD9. Summary of the Invention

[0015] Provided are compounds that degrade bromodomain-containing protein 9 (BRD9) via the ubiquitin proteasome pathway (UPP), their uses, and manufacture. The present invention provides compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, comprising a "targeting ligand" that binds to BRD9, an E3 ligase binding moiety (typically via a cereblon subunit), and a linker that covalently links the targeting ligand to the E3 ligase binding moiety. In certain embodiments, the targeting ligand is moiety B of the formula described below, the linker is moiety L, and the remainder of the molecule is the E3 ligase binding moiety.

[0016] By degrading BRD9, the compounds of the present invention can inhibit the formation of BAF complexes containing BRD9 and thereby reduce cell proliferation. Some cancers are more dependent on BAF complexes containing BRD9 than healthy cells, and therefore these cancers, such as acute myeloid leukemia, rhabdoid tumors, synovial sarcoma, and multiple myeloma, can be effectively treated with the compounds of the present invention.

[0017] The compounds of the present invention provided herein, or pharmaceutically acceptable salts thereof, and / or pharmaceutically acceptable compositions thereof, can be used to treat disorders mediated by a selected target protein bound to a targeting ligand, such as a BRD9-containing or alternatively a BRD7-containing or another BRD-containing protein.

[0018] In some embodiments, a method of treating a patient suffering from a disorder mediated by BRD9 is provided, comprising administering to the patient (typically a human) an effective amount of one or more compounds as described herein, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0019] In one aspect, the present invention provides a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI:

[0020]

[0021]

[0022] or a pharmaceutically acceptable salt thereof;

[0023] in

[0024] Each a is independently 0, 1 or 2;

[0025] Each y is independently 0, 1, or 2;

[0026] X 3 、X 4 、X 5 and X 6 Selected from N, CH and CR 3 , where X 3 、X 4 、X 5 and X 6 No more than 3 of them are N;

[0027] X 7 N or CH;

[0028] X 8 and X 9 is independently selected at each occurrence from N and CH; wherein X 8 or X 9 At least one of them is CH;

[0029] or X 8 and X 9 Each occurrence is independently selected from N, CH or COR 7 ; where X 8 or X 9 At least one of them is CH or COR 7 ;

[0030] X 12 is a 5-membered heteroaryl group having 1, 2 or 3 atoms independently selected from N, O and S, wherein X 12 Optionally 1, 2 or 3 independently selected from R 3 substituted by a group;

[0031] X 17 is aryl, heteroaryl, bicyclic or cycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a substituent;

[0032] Q 1 is independently selected at each occurrence from NH, N(alkyl), N(haloalkyl), CH2, O, and S; wherein if X 7 is N, then Q 1 is CH2;

[0033] R is independently selected at each occurrence from hydrogen, C1-C4 haloalkyl, C1-C4 alkyl, fluorine, chlorine, bromine, iodine, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, and CBr3;

[0034] R 1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or cycloalkyl;

[0035] R 3 is independently selected at each occurrence from hydrogen, hydroxy, alkoxy, C1-C4 alkyl, C1-C4 haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine;

[0036] B is selected from B 1 and B 2 ;

[0037] B 1 Selected from:

[0038]

[0039] X 10 C(R 7 )2, C(O) or O;

[0040] X 11 is a heterocyclic ring, a heteroaryl ring, an aryl ring, a cycloalkyl ring or a bicyclic ring, X 11 Each of the groups is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group;

[0041] or X 10 and X 11 Together

[0042] X 13 、X 14 、X 15 and X 16 Independently selected from N, CH and CR 4 , where X 13 、X 14 、X 15 and X 16 No more than 3 of them are N;

[0043] Each R 4 independently selected from hydrogen, aryl, heteroaryl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkyl, fluorine, chlorine, bromine and iodine;

[0044] The two R 4 The groups may optionally be combined to form a fused ring, wherein the fused ring is optionally substituted with 1, 2 or 3 R substituents, such that Non-limiting examples include Two of the R 4 The groups combine to form pyrrole;

[0045] R 5 is hydrogen, C1-C4 alkyl, allyl, crotyl, alkenyl, alkynyl, haloalkyl or cycloalkyl;

[0046] Each R 6 independently selected from hydrogen, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 haloalkyl, fluorine, chlorine, bromine and iodine;

[0047] Each R 7 are independently hydrogen or C1-C4 alkyl;

[0048] R 8 is hydrogen, C1-C4 alkyl, allyl, crotyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; and

[0049] L is a divalent linking group, for example a divalent linking group of formula LI.

[0050] Each combination of variables, substituents, embodiments, and compounds resulting from such combinations is considered to be specifically and individually disclosed, as such depictions are merely for spatial convenience and are not intended to describe only one genus or even a subgenus of compounds.

[0051] In certain embodiments, L is a linker of the formula:

[0052]

[0053] in,

[0054] X 1 and X 2 independently selected at each occurrence from a bond, a heterocycle, NR 2 、C(R 2 )2, O, C(O) and S;

[0055] R 2 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne;

[0056] R 20 、R 21 、R 22 、R 23 and R 24 independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-C(R 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 substituted by a substituent;

[0057] R 26 is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and

[0058] R 40and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxy, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle and cycloalkyl.

[0059] In one aspect, the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI is a compound having an E3 ubiquitin ligase targeting ligand linked to a BRD9 targeting ligand, which functions to recruit target proteins, typically for degradation via a cereblon-containing E3 ubiquitin ligase.

[0060] In certain embodiments, a method of treatment is provided, comprising administering to a patient, e.g., a human, an effective amount of a compound of Formula I, II, III, IV, V, or VI, optionally in a pharmaceutically acceptable carrier. For example, in one embodiment, a compound of Formula I, II, III, IV, V, or VI is administered to a human to treat cancer, e.g., synovial sarcoma. In one embodiment, a compound of the invention is administered to a patient to treat synovial sarcoma. In one embodiment, a compound of the invention is administered to a patient with SS18-SSX translocation carcinoma. In one embodiment, a compound of the invention is administered to a patient with metastatic synovial sarcoma. In one embodiment, a compound of the invention is administered to a patient with malignant rhabdoid tumor. In one embodiment, a compound of the invention is administered to a patient with epithelioid sarcoma.

[0061] In certain embodiments, the targeting ligand (Part B) binds to BRD9 and is used in the treatment of BRD9-mediated disorders. In other embodiments, the targeting ligand (Part B) binds to a different bromodomain-containing protein and is used in the treatment of BRD-mediated disorders. In an alternative embodiment, the compounds of the invention are used in the treatment of non-BRD-mediated disorders.

[0062] In certain embodiments, the compounds of the invention provide multiple advantages over traditional treatments with BRD9 ligands, for example, the BRD9 degrading compounds of the invention can a) overcome resistance in some cases; b) prolong the kinetics of drug action by destroying the protein, thereby requiring resynthesis of the protein even after the compound is metabolized; c) target all functions of a protein at once rather than a specific catalytic activity or binding event; d) expand the number of drug targets by including all proteins for which ligands can be developed rather than proteins whose activity may be affected by small molecule inhibitors, antagonists, or agonists; and / or e) have increased potency compared to inhibitors due to the potential for small molecules to act in a catalytic manner.

[0063] In certain embodiments, when a targeting ligand is administered alone, the compounds of the invention will inhibit the growth of cells or reduce the viability of cells at a GI50 value that is lower than the GI50 of the targeting ligand.

[0064] In certain embodiments, compounds of the invention provide improved efficacy and / or safety relative to known BRD9 inhibitors.

[0065] In certain embodiments, the compounds of the invention are more effective in the treatment of BRD9-mediated disorders than the targeting ligand moiety alone.

[0066] In certain embodiments, treatment of a BRD9-mediated disorder requires lower concentrations of a compound described herein compared to the targeting ligand moiety alone.

[0067] In certain embodiments, the compounds of the invention have fewer side effects in the treatment of BRD9-mediated disorders compared to the targeting ligand moiety alone.

[0068] In certain embodiments, treatment of a BRD9-mediated disorder requires a less frequent dosing regimen of a compound described herein compared to the targeting ligand moiety alone.

[0069] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for inhibiting or preventing a disorder mediated by a bromodomain protein or for regulating or decreasing the amount of a bromodomain-containing protein.

[0070] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in the manufacture of a medicament for treating or preventing a disease in which BRD9 plays a role.

[0071] In certain embodiments, the compounds as described herein are useful for treating disorders involving abnormal cell proliferation, such as tumors or cancers, in which BRD9 is an oncoprotein or a signaling mediator of an abnormal cell proliferation pathway and its degradation reduces abnormal cell growth.

[0072] In certain embodiments, the compounds as described herein are useful as therapeutic agents when administered to a patient in an effective amount to treat medical conditions treatable with thalidomide, pomalidomide, or lenalidomide.

[0073] In certain embodiments, the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI have at least one desired isotopic substitution of an atom in an amount above the natural abundance of that isotope, ie, enriched.

[0074] In one embodiment, the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI comprises deuterium or multiple deuterium atoms.

[0075] Other features and advantages of the present application will become apparent from the following detailed description.

[0076] Therefore, the present invention includes at least the following features:

[0077] (a) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI as described herein, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof;

[0078] (b) a method for treating a BRD9-mediated disorder, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI as described herein, or a pharmaceutically acceptable salt thereof;

[0079] (c) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof, for use in treating a disorder mediated by BRD9, such as abnormal cell proliferation such as a tumor or cancer;

[0080] (d) Use of an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, in treating a patient or normal human being in need thereof suffering from a BRD9-mediated disorder, such as abnormal cell proliferation such as a tumor or cancer;

[0081] (e) Use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt or isotopic derivative (including a deuterated derivative) thereof, in the manufacture of a medicament for treating a BRD9-mediated disorder, such as abnormal cell proliferation such as a tumor or cancer;

[0082] (f) a pharmaceutical composition comprising an amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt or isotopic derivative thereof, effective for treating a patient; and optionally a pharmaceutically acceptable carrier or diluent;

[0083] (g) compounds of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI as described herein, as mixtures of enantiomers or diastereomers (as relevant), including as racemates;

[0084] (h) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as described herein, in enantiomerically or diastereomerically enriched form, as the case may be, including isolated enantiomers or diastereomers (i.e., greater than 85%, 90%, 95%, 97%, or 99% pure); and

[0085] (i) A method for preparing a therapeutic product containing an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI as described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 Figure 1 is a graph of tumor volume after treatment with compound 172, demonstrating a potent effect in a synovial sarcoma xenograft model. The x-axis is time since the start of treatment measured in days, and the y-axis is time in mm. 3 is the unit measurement of tumor volume.

[0087] Figure 2 Graph showing protein degradation of compound 172. The x-axis represents the dose measured in nanomolar (nM) and the y-axis represents the protein degradation level of each corresponding protein, BRD9, BRD7, and BRD4, measured by HiBiT luminescence readout.

[0088] Figure 3 The figure shows the dose-response degradation of various proteins in Yamato-SS cells, a human cell line derived from synovial sarcoma (Stem Cells 2010; 28: 1119-1131), by Western blotting under the action of compound 172.

[0089] Figure 4 This is a confluence graph showing the time course of growth inhibition in Yamato-SS cells under the action of compound 172. The x-axis is time measured in days and the y-axis is confluence measured as a percentage of the control.

[0090] Figure 5Graph showing the pharmacokinetics (PK) of compound 172 in the Yamato-SS xenograft tumor model. The x-axis is time measured in hours and the y-axis is plasma concentration measured in ng / mL.

[0091] Figure 6 Figure 1 is a graph showing the pharmacokinetics of compound 172 in the Aska-SS xenograft tumor model. The x-axis is time measured in hours and the y-axis is plasma concentration measured in ng / mL. Aska-SS is a human cell line derived from synovial sarcoma (Stem Cells 2010;28:1119-1131).

[0092] Figure 7 Graph showing the dose-dependent response of tumor volume to different concentrations of compound 172 in the Yamato-SS xenograft model, demonstrating its dose-dependent efficacy in the synovial sarcoma model. The x-axis is time measured in days and the y-axis is time in mm. 3 is the unit measurement of tumor volume.

[0093] Figure 8 Graph showing the dose-dependent response of body weight changes in mice to different concentrations of Compound 172 in the Yamato-SS xenograft model. The x-axis is time measured in days, and the y-axis is body weight change measured in percentage.

[0094] Figure 9 Graph showing the tolerability of compound 172 in the SA13412 synovial sarcoma PDX-model. The x-axis is the number of days after treatment start measured in days, and the y-axis is the change in body weight measured in percent.

[0095] Figure 10A and 10B Graphs showing a preclinical scaling dose prediction model for compound 172, used to estimate unbound clearance, half-life, and volume reduction in humans. The x-axis of each graph is body weight measured in kg. The upper left y-axis is clearance measured in mL / hr; the upper right y-axis is unbound clearance measured in mL / hr; the lower left y-axis is volume measured in mL, and the lower right y-axis is unbound volume measured in mL.

[0096] Figure 11 Graph showing selective degradation of BRD9 protein by compound 176. The x-axis is the dose measured in nanomolar (nM) and the y-axis is the protein degradation level of each corresponding protein, BRD9, BRD7, and BRD4, measured by HiBiT luminescence readout.

[0097] Figure 12 Bar graph showing dose-dependent in vivo BRD9 degradation in the Yamato-SS xenograft model with different concentrations of compound 172. The x-axis is concentration and time measured in mg / kg and hours, respectively, and the y-axis is normalized concentration.

[0098] Figure 13 Bar graph showing dose-dependent in vivo BRD9 degradation in the Aska-SS xenograft model with varying concentrations of compound 172. The x-axis represents concentration and time measured in mg / kg and hours, respectively, and the y-axis represents normalized concentration.

[0099] Figure 14 Bar graph comparing the levels of BRD9 remaining in synovial sarcoma tumors at different time points after a single dose of Compound 172. The x-axis is time measured in hours and the y-axis is the percentage of protein remaining.

[0100] Figure 15 Graph illustrating endogenous dose degradation across representative cellular environments for various concentrations of compound 176. Upper left represents a malignant human rhabdoid tumor (A204), upper right represents a human synovial sarcoma (HS-SY-II), lower left represents a human soft tissue sarcoma (SW982, BAF wild type), lower right represents a synovial sarcoma (Yamato SS), all via Western blotting.

[0101] Figure 16 Confluence plots of various concentrations of compound 176. Single-dose long-term growth evaluation of the degradation of selective growth inhibition induced by BAF perturbation in the Yamato-SS model. The x-axis is time measured in days, and the y-axis is confluence measured as a percentage of control.

[0102] Figure 17 The graph is a confluence plot of different concentrations of compound 176, demonstrating the lack of growth inhibition in BAF wild-type synovial sarcoma cells (SW982). The x-axis is time measured in days and the y-axis is confluence measured as a percentage of control.

[0103] Figure 18 Graph illustrating the pharmacokinetics (PK) of compound 176 at various concentrations (PO QD) in the synovial sarcoma CDX (Yamato-SS) model. The x-axis is time measured in hours and the y-axis is tumor PK measured in nanograms / milliliter (ng / mL).

[0104] Figure 19Graph illustrating protein degradation of BRD9 in synovial sarcoma tumors (tumor PD) at varying concentrations (PO QD) of compound 176. The x-axis is time measured in hours and the y-axis is the concentration of compound 176 measured in mg / kg PO QD.

[0105] Figure 20 Graph illustrating protein degradation of BRD9 in synovial sarcoma tumors (tumor PD) treated with different concentrations of PO QDs and compound 176. The x-axis is time measured in hours and the y-axis is the percentage of BRD9 remaining normalized to vehicle and Vinculin.

[0106] Figure 21 Graph showing the efficacy of different concentrations of compound 176 in the synovial sarcoma CDX model (Yamato SS). The x-axis is treatment measured in days and the y-axis is treatment measured in cubic millimeters (mm 3 ) is the tumor volume measured in units of SEM.

[0107] Figure 22 Graph showing the tolerability of different concentrations of compound 176 in the synovial sarcoma CDX model (Yamato SS). The x-axis is treatment measured in days and the y-axis is body weight change measured in percent.

[0108] Figure 23 Graph showing the efficacy of different concentrations of compound 176 in a synovial sarcoma PDX model (SA13412). The x-axis is treatment measured in days and the y-axis is treatment measured in cubic millimeters (mm 3 ) is the tumor volume measured in units of SEM.

[0109] Figure 24 Graph showing the tolerability of different concentrations of Compound 176 in a synovial sarcoma PDX model (SA13412). The x-axis is treatment measured in days and the y-axis is body weight change in percent.

[0110] Figure 25 Representative formulas of the invention are provided. DETAILED DESCRIPTION

[0111] I. Definition

[0112] The compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0113] Compounds of any formula described herein may exist as racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxide isomers; such as rotamers, as if each were specifically described unless the context clearly excludes it.

[0114] The term "a / an" does not represent a limit to quantity, but rather represents that there is at least one of the items mentioned. The term "or" refers to "and / or". Unless otherwise indicated herein, the recording of a range of values ​​is intended only to be used as a shorthand method for individually referring to each individual value falling within the range, and each individual value is incorporated into this specification as if it were individually recorded one by one in this article. The endpoints of all ranges are included within this range and can be independently combined. Unless otherwise indicated herein or clearly contradictory to the context, all methods described herein can be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., "such as") is only intended to better illustrate the present invention and is not intended to limit the scope of the present invention.

[0115] The present invention includes compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI having at least one desired isotope substituted for an atom in an amount greater than the natural abundance of that isotope, i.e., enriched. Isotopes are atoms with the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons.

[0116] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I. In one non-limiting embodiment, isotopically labeled compounds can be used in metabolic studies (using, for example, 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determinations, or radiation therapy for patients. In particular, 18F-labeled compounds may be particularly ideal for PET and SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by the procedures disclosed in the embodiments or in the examples and the preparation methods described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0117] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution refers to that at least one hydrogen is replaced by deuterium. In certain embodiments, at any target position, a kind of isotope is enriched in this isotope with 90,95 or 99% or more. In a non-limiting embodiment, deuterium is enriched in the desired position with 90,95 or 99%.

[0118] In a non-limiting embodiment, the substitution of deuterium atoms for hydrogen atoms can be provided in any compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI. In a non-limiting embodiment, the substitution of deuterium atoms for hydrogen atoms occurs in one or more groups selected from any R or variable, linker and targeting ligand described herein. For example, when any group is or contains (e.g., by substitution) methyl, ethyl or methoxy, the alkyl residue can be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H or OCD3, etc.). In certain other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon can be deuterated.

[0119] The compound of the present invention can form a solvate with a solvent (including water). Therefore, in a non-limiting embodiment, the present invention includes the solvated form of the compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salt) and one or more solvent molecules. The non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted (for example, D2O, d6-acetone, d6-DMSO (dimethyl sulfoxide)). Solvate can be in liquid or solid form.

[0120] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the carbonyl (C=O) group.

[0121] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In a non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more generally 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In a non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, a specific range indicates an alkyl group with each member of the range, and each member of the range is described as an independent substance. For example, as used herein, the term C1-C6 alkyl indicates a straight or branched alkyl group with 1, 2, 3, 4, 5 or 6 carbon atoms and is intended to mean that each of these is described as an independent substance and therefore each subset is considered to be disclosed separately. For example, as used herein, the term C1-C4 alkyl indicates a straight or branched alkyl group with 1, 2, 3 or 4 carbon atoms and is intended to mean that each of these is described as an independent substance. The example of alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when using a term comprising "alk", "cycloalkyl" or "carbocyclic" can be considered as part of the definition, unless the context clearly excludes. For example, but not limited to, the term alkyl, alkoxy, haloalkyl etc. can be considered as including the cyclic form of the alkyl, unless the context clearly excludes.

[0122] In one embodiment, "alkyl" is C1-C 10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl.

[0123] In one embodiment, an "alkyl" group has one carbon.

[0124] In one embodiment, an "alkyl" group has two carbons.

[0125] In one embodiment, an "alkyl" group has three carbons.

[0126] In one embodiment, an "alkyl" group has four carbons.

[0127] In one embodiment, an "alkyl" group has five carbons.

[0128] In one embodiment, an "alkyl" group has six carbons.

[0129] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0130] Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0131] Additional non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl, and sec-hexyl.

[0132] Additional non-limiting examples of "alkyl" include tert-butyl, tert-amyl, and tert-hexyl.

[0133] Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and activated pentyl.

[0134] In an alternative embodiment, the "alkyl" is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0135] In one embodiment, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0136] In one embodiment, a "cycloalkyl" group has three carbons.

[0137] In one embodiment, a "cycloalkyl" group has four carbons.

[0138] In one embodiment, a "cycloalkyl" group has five carbons.

[0139] In one embodiment, a "cycloalkyl" group has six carbons.

[0140] In one embodiment, a "cycloalkyl" group has seven carbons.

[0141] In one embodiment, a "cycloalkyl" group has eight carbons.

[0142] In one embodiment, a "cycloalkyl" group has nine carbons.

[0143] In one embodiment, a "cycloalkyl" group has ten carbons.

[0144] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0145] Additional non-limiting examples of "cycloalkyl" include indane and tetrahydronaphthalene, where the point of attachment of each group is on the cycloalkyl ring.

[0146] For example: is a "cycloalkyl" group.

[0147] However, is an "aryl" group.

[0148] In an alternative embodiment, the "cycloalkyl" is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0149] "Alkenyl" is a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at stable points along the chain. As used herein, a specific range indicates an alkenyl group having each member of the range, each member of which is described as an independent species, as described above for the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also embodies "cis" and "trans" alkenyl geometries, or alternatively, "E" and "Z" alkenyl geometries. In an alternative embodiment, the alkenyl group is optionally substituted. The term "alkenyl" also encompasses cycloalkyl or cycloalkyl groups having at least one point of unsaturation. In an alternative embodiment, an alkenyl group is "optionally" "substituted" with 1, 2, 3, or 4 substituents.

[0150] "Alkynyl" is a branched or straight-chain aliphatic hydrocarbon group with one or more carbon-carbon triple bonds, which may occur at any stable point along the chain. As used herein, a specific range indicates an alkynyl group with each member of the range, each member of which is described as an independent substance, as described above for the alkyl portion. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term "alkynyl" also encompasses cycloalkyl or cycloalkyl groups with at least one triple bond. In an alternative embodiment, "alkynyl" is "optionally" "substituted" by 1, 2, 3, or 4 substituents.

[0151] "Alkylene" is a divalent saturated hydrocarbon. For example, an alkylene group can be 1, 2, 3, 4, 5, 6, 7 to 8 carbon moieties, 1 to 6 carbon moieties, or a specified number of carbon atoms, such as C1-C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene, or C1-C6 alkylene.

[0152] "Alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. For example, alkenylene can be a 2 to 8 carbon moiety, a 2 to 6 carbon moiety, or a specified number of carbon atoms, such as C2-C4 alkenylene.

[0153] "Alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. For example, an alkynylene group can be a 2 to 8 carbon moiety, a 2 to 6 carbon moiety, or a specified number of carbon atoms, such as a C2-C4 alkynylene group.

[0154] "Halo" or "halogen" independently refers to fluorine, chlorine, bromine or iodine.

[0155] "Haloalkyl" refers to a branched or straight-chain alkyl group substituted with one or more of the above-mentioned halogen atoms, up to the maximum permitted number of halogen atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0156] In one embodiment, "haloalkyl" is C1-C 10 haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl and C1-C2 haloalkyl.

[0157] In one embodiment, a "haloalkyl" group has one carbon.

[0158] In one embodiment, a "haloalkyl" group has one carbon and one halogen.

[0159] In one embodiment, a "haloalkyl" group has one carbon and two halogens.

[0160] In one embodiment, a "haloalkyl" group has one carbon and three halogens.

[0161] In one embodiment, a "haloalkyl" group has two carbons.

[0162] In one embodiment, a "haloalkyl" group has three carbons.

[0163] In one embodiment, a "haloalkyl" group has four carbons.

[0164] In one embodiment, a "haloalkyl" group has five carbons.

[0165] In one embodiment, a "haloalkyl" group has six carbons.

[0166] Non-limiting examples of "haloalkyl" include:

[0167] Additional non-limiting examples of "haloalkyl" include:

[0168] Additional non-limiting examples of "haloalkyl" include:

[0169] Additional non-limiting examples of "haloalkyl" include:

[0170] "Chain" refers to a linear chain from which all other long or short chains, or both, may be considered to be pendant. Where two or more chains can be equally considered to be the main chain, "chain" refers to the one that results in the simplest representation of the molecule.

[0171] "Haloalkoxy" indicates a haloalkyl group as described herein attached through an oxygen bridge (the oxygen of the alcohol group).

[0172] "Heterocycloalkyl" is an alkyl group as described herein substituted with a heterocycloalkyl group as described herein.

[0173] "Arylalkyl" is an alkyl group as described herein substituted with an aryl group as described herein.

[0174] Non-limiting examples of "arylalkyl" include:

[0175]

[0176] In one embodiment, "arylalkyl" is

[0177] In one embodiment, "arylalkyl" refers to a 2-carbon alkyl group substituted with an aryl group.

[0178] Non-limiting examples of "arylalkyl" include:

[0179]

[0180] In one embodiment, "arylalkyl" refers to a 3-carbon alkyl group substituted with an aryl group.

[0181] "Heteroarylalkyl" is an alkyl group as described herein substituted with a heteroaryl group as described herein.

[0182] As used herein, "aryl" refers to a radical in an aromatic ring system ("C 6–14A group comprising a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the cyclic array) having 6-14 ring carbon atoms and zero heteroatoms (e.g., "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms still specifies the number of carbon atoms in the aryl ring system. The one or more fused carbocyclic or heterocyclic groups may be 4 to 7 or 5 to 7 membered saturated or partially unsaturated carbocyclic or heterocyclic groups, optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron to form, for example, a 3,4-methylenedioxyphenyl group. In one non-limiting embodiment, the aryl group is pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In certain embodiments, the aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl. The aryl group may be optionally substituted with one or more functional groups including, but not limited to, halogen, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.

[0183] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0184] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0185] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the aromatic ring.

[0186] For example, is an "aryl" group.

[0187] However, It is a "heterocyclic" group.

[0188] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl group, wherein the point of attachment is the aryl ring. Non-limiting examples of "aryl" include dihydroindane and tetrahydronaphthalene, wherein the point of attachment of each group is on the aromatic ring.

[0189] For example, is an "aryl" group.

[0190] However, is a "cycloalkyl" group.

[0191] In an alternative embodiment, "aryl" is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0192] The terms "heterocyclyl," "heterocycle," and "heterocyclyl" include saturated and partially saturated heteroatom-containing ring groups, wherein the heteroatom can be selected from nitrogen, sulfur, and oxygen. Heterocyclic rings include monocyclic 3, 4, 5, 6, 7, 8, 9, or 10-membered rings, and 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16-membered bicyclic ring systems (which may include bridged fused and spirofused bicyclic ring systems). They do not include rings containing -OO-, -OS-, or -SS- moieties. The "heterocycle" group may be optionally substituted with, for example, 1, 2, 3, 4, or more substituents, including, but not limited to, hydroxy, Boc, halogen, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino. Examples of saturated heterocyclic groups include saturated 3, 4, 5 or 6-membered heteromonocyclic groups containing 1, 2, 3 or 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5 or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1, 2 or 3 nitrogen atoms [e.g., morpholinyl]; saturated 3, 4, 5 or 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1, 2 or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic radicals include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1, 2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxanyl, 2,3-dihydro-lH-lλ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, benzo[d]thiazol-2(3H)-onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl and dihydrothiazolyl.

[0193] The terms "heterocyclyl," "heterocycle," and "heterocyclyl" groups also include moieties in which a heterocyclic group is fused / condensed with an aryl or heteroaryl group: such as unsaturated condensed heterocyclic groups containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline; unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms; unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms; and saturated, partially unsaturated, and unsaturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0194] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0195] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0196] In one embodiment, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0197] In one embodiment, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0198] In one embodiment, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0199] Non-limiting examples of "heterocycle" include aziridine, oxirane, thioethane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0200] Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0201] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0202] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0203] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocyclic ring.

[0204] For example, It is a "heterocyclic" group.

[0205] However, is an "aryl" group.

[0206] Non-limiting examples of "heterocycle" also include:

[0207]

[0208] Additional non-limiting examples of "heterocycle" include:

[0209]

[0210] Additional non-limiting examples of "heterocycle" include:

[0211]

[0212] Non-limiting examples of "heterocycle" also include:

[0213]

[0214] Non-limiting examples of "heterocycle" also include:

[0215]

[0216] Additional non-limiting examples of "heterocycle" include:

[0217]

[0218] Additional non-limiting examples of "heterocycle" include:

[0219]

[0220] In an alternative embodiment, the "heterocycle" is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0221] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in the cyclic array) and 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, wherein one or more ring nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing sulfur atoms. an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. Further examples include 8-, 9- or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothiphenyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl and triazolopyridinyl.

[0222] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0223] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0224] Additional non-limiting examples of 5-membered "heteroaryl" groups include:

[0225]

[0226] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0227] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0228]

[0229] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0230] Non-limiting examples of "heteroaryl" groups that are bicyclic include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0231] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0232]

[0233] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0234]

[0235] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0236]

[0237] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0238] Non-limiting examples of "heteroaryl" groups that are bicyclic include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0239] Additional non-limiting examples of "heteroaryl" groups that are bicyclic include:

[0240]

[0241] In an alternative embodiment, the "heteroaryl" is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0242] The term "bicyclic" refers to a ring system in which two rings are fused together and each ring is independently selected from carbocycle, heterocycle, aryl and heteroaryl. Non-limiting examples of bicyclic groups include:

[0243]

[0244] When a divalent residue such as a linker or X 11When the term "bicyclic" is used in the context of, the points of attachment can be on separate rings or on the same ring. In certain embodiments, the two points of attachment are on the same ring. In certain embodiments, the two points of attachment are on different rings. Non-limiting examples of divalent bicyclic groups include:

[0245]

[0246] In an alternative embodiment, the "bicyclic ring" is "optionally" substituted with 1, 2, 3, or 4 substituents.

[0247] The term "optionally substituted" means that the groups herein are substituted with moieties including but not limited to: C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkenyl, C1–C 12 Heterocycloalkyl, C3-C 12 Heterocycloalkenyl, C1-C 10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C1-C 10 Alkylamino, C1–C 10 Dialkylamino, arylamino, diarylamino, C1-C 10 Alkylsulfonylamino, arylsulfonylamino, C1-C 10 Alkyl imino, aryl imino, C1-C 10 Alkylsulfonyl imide, arylsulfonyl imide, hydroxyl, halogen, sulfur, C1-C 10 Alkylthio, arylthio, C1-C 10 Alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylate.

[0248] In an alternative embodiment, any suitable group may be present in the "substituted" or "optionally substituted" position (if indicated to form a stable molecule and meet the desired objectives of the present invention) and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br or I); cyano; hydroxy; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl, including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups, including those having one or more sulfonyl linkages; aminoalkyl, including groups having more than one N atom; aryl (e.g., phenyl, biphenyl, naphthyl, etc., each ring being substituted or unsubstituted); having, for example, 1 to 3 separate arylalkyl, for example, having 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy, for example, having 1 to 3 separate or fused rings, with benzyloxy being an exemplary arylalkoxy group; or saturated or partially unsaturated heterocyclic rings having 1 to 3 separate or fused rings having one or more N, O or S atoms, or heteroaryl having 1 to 3 separate or fused rings having one or more N, O or S atoms, for example, coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl. Such groups may be further substituted, for example, with hydroxy, alkyl, alkoxy, halogen and amino groups.

[0249] In certain embodiments, "optionally substituted" includes one or more substituents independently selected from the group consisting of halogen, hydroxy, amino, cyano, -CHO, -COOH, -CONH2, alkyl (including C1-C6 alkyl), alkenyl (including C2-C6 alkenyl), alkynyl (including C2-C6 alkynyl), -C1-C6 alkoxy, alkanoyl (including C2-C6 alkanoyl), C1-C6 alkyl ester, (mono- and di-C1-C6 C1-C6 alkyl (heteroaryl), -C1-C6 alkyl (C3-C7 cycloalkyl), O-C1-C6 alkyl (C3-C7 cycloalkyl), B (OH) 2, phosphate, phosphonate and haloalkoxy (including C1-C6 haloalkoxy).

[0250] In some embodiments, suitable groups present on "substituted" or "optionally substituted" positions are divalent, including but not limited to oxo (=O), =S, =CH2, etc. Suitable groups on "substituted" or "optionally substituted" positions can be monovalent, divalent, or trivalent, so that they form stable molecules and meet the desired purposes of the present invention.

[0251] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0252] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0253] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0254] In one embodiment, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0255] "Aliphatic" refers to a saturated or unsaturated straight chain, branched or cyclic hydrocarbon. "Aliphatic" is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties, and therefore incorporates each of these definitions. In one embodiment, "aliphatic" is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, monounsaturated, diunsaturated, triunsaturated or polyunsaturated, or can be an alkynyl. Unsaturated aliphatic groups can be cis or trans configurations. In one embodiment, the aliphatic group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one embodiment, the aliphatic group contains 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, a specific range indicates an aliphatic group having each member of the range, and each member of the range is described as an independent substance. For example, the term C1-C6 aliphatic, as used herein, refers to a straight or branched chain alkyl, alkenyl, or alkynyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species. For example, the term C1-C4 aliphatic, as used herein, refers to a straight or branched chain alkyl, alkenyl, or alkynyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups that result in the formation of a stable moiety.

[0256] The term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom in the chain, such as an amine, carbonyl, carboxyl, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom, in place of a carbon atom. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. "Heteroaliphatic" is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1-20 carbon atoms. In one embodiment, the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocyclo-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, and the like.

[0257] "Dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, pellets, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, buccal dosage forms, sublingual dosage forms, topicals, gels, mucosal dosage forms, and the like. "Dosage form" may also include implants, such as optical implants.

[0258] As used herein, an "effective amount" refers to an amount that provides a therapeutic or prophylactic benefit.

[0259] As used herein, "endogenous" refers to any material derived from or produced within an organism, cell, tissue, or system.

[0260] As used herein, the term "exogenous" refers to any material introduced from outside of or generated outside of an organism, cell, tissue, or system.

[0261] As used herein, the term "modulate" refers to mediating a detectable increase or decrease in the level of a response in a patient compared to the patient's level of response in the absence of the treatment or compound and / or compared to the level of response in an otherwise identical but untreated patient. The term encompasses perturbing and / or influencing a natural signal or response, thereby mediating a beneficial therapeutic response in a patient, preferably a human.

[0262] "Parenteral" administration of the pharmaceutical compositions includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection or infusion techniques.

[0263] As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds consisting of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present in a protein or peptide sequence is generally comparable to the maximum number of amino acids found in nature. A polypeptide includes any peptide or protein comprising two or more amino acids linked to each other by peptide bonds. As used herein, the term refers to both short chains, which are also commonly referred to in the art as, for example, peptides, oligopeptides, and oligomers, and longer chains, which are commonly referred to in the art as proteins, of many types. "Polypeptide" includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, and the like. Polypeptides include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0264] As used herein, the term "treating" a disease refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a patient (i.e., palliative treatment) or reducing the cause or effects of the disease or condition (i.e., disease-modifying treatment).

[0265] Throughout this disclosure, various aspects of the invention may be presented in range format. It should be understood that descriptions in range format are for convenience only and should not be construed as limitations on the scope of the invention. Descriptions of ranges should be considered to have specifically disclosed all possible subranges and individual values ​​within that range. For example, a description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0266] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance, such as a carrier. A "pharmaceutical combination" is a combination of at least two active agents, which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any of the conditions described herein.

[0267] As used herein, "pharmaceutically acceptable salts" are derivatives of the disclosed compounds wherein the parent compound is modified by preparing its inorganic and organic, non-toxic, acid or base addition salts. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical, where feasible. Salts of the compounds of the present invention also include solvates of the compounds and compound salts.

[0268] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n -COOH (wherein n is 0-4), etc., or salts prepared using different acids that will produce the same counterion. Additional lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0269] The term "carrier" as applied to the pharmaceutical composition / combination of the present invention refers to a diluent, excipient or vehicle with which the active compound is provided.

[0270] "Pharmaceutically acceptable carrier" means a carrier or excipient that can be used in the preparation of a pharmaceutical composition / combination that is generally safe, non-toxic, and not biologically or otherwise unsuitable for administration to a patient, typically a human. In one embodiment, an excipient acceptable for veterinary use is used.

[0271] A "patient" or "subject" is a human or non-human animal in need of treatment or prevention of any of the conditions described in detail herein, such as conditions modulated by native (wild-type) or modified (non-wild-type) proteins that can be degraded according to the present invention to produce a therapeutic effect. As further described herein, unless the context or wording clearly indicates that the present disclosure is intended to include non-human animals, the term patient or subject generally refers to a human patient or subject. Typically, the patient is a human. In an alternative embodiment, the patient or subject is a non-human animal in need of and responsive to such treatment.

[0272] A "therapeutically effective amount" of a pharmaceutical composition / combination of the present invention means an amount effective to provide a therapeutic benefit such as improvement of symptoms or alleviation or reduction of the disease itself when administered to a patient, typically a human patient.

[0273] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which this application belongs. In the specification, the singular also includes the plural, unless the context clearly provides otherwise. Although methods and materials similar to or equivalent to those described herein can be used in the implementation or test of the application, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. The references cited herein are not considered to be the prior art of the claimed application. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are only illustrative and are not intended to be limiting.

[0274] II. Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, and Formula VI

[0275] In certain embodiments, the structure of the compound is generally selected so that it is sufficiently stable to maintain a shelf life of at least two months, three months, four months, or five months under ambient conditions. To achieve this, each R group described herein must be sufficiently stable to maintain a corresponding required shelf life of at least two months, three months, four months, or five months under ambient conditions. Those of ordinary skill in the art will appreciate the stability of the chemical moieties and will avoid those chemical moieties that are unstable or too reactive under suitable conditions.

[0276] In certain alternative embodiments, compounds of the invention comprising any of the "R" groups described herein may be optionally substituted as described in Section I below. If necessary to achieve the desired effect, the definition results in a stable R moiety and a final compound that makes chemical sense to the skilled artisan and is pharmaceutically acceptable if the final compound is to be used therapeutically. Furthermore, all R groups, with or without optional substituents, should be interpreted in a manner that does not include redundancy (i.e., as known in the art, alkyl substituted by alkyl is redundant; however, for example, alkoxy substituted by alkoxy is not redundant).

[0277] In one aspect, the present invention provides a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI:

[0278]

[0279] or a pharmaceutically acceptable salt thereof;

[0280] wherein all variables are as defined above.

[0281] In certain embodiments, the compounds of the present invention are selected from:

[0282]

[0283]

[0284]

[0285] or a pharmaceutically acceptable salt thereof;

[0286] in

[0287] L D is a divalent linking group, for example, a divalent linking group of formula LDI;

[0288] X 3a 、X 4a 、X 5a and X 6a Selected from N, CH and CR 3 , where X 3b 、X 4b 、X 5b and X 6b No more than 3 of them are N;

[0289] and wherein all other variables are as described herein.

[0290] In certain embodiments, X 3 、X 4 、X 5 and X 6 At most two of them are N.

[0291] In certain embodiments, X 3 、X 4 、X 5 and X 6 All of them are CH.

[0292] In certain embodiments, X 3 、X 4 、X 5 and X 6 One of them is CR 3 ; where R 3 In certain embodiments, R 3 is C1-C4 haloalkyl. In certain embodiments, R 3 It is a C1-C4 alkyl group.

[0293] In certain embodiments, X 3 、X 4 、X 5 and X 6 One of them is CR 3 , where R 3 It is a C1-C4 alkyl group.

[0294] In certain embodiments, X 4 or X 6 is N. In certain embodiments, X 4 and X 6 In certain embodiments, X 4 or X 6 In certain embodiments, X 4 and X 6 All are CH.

[0295] In certain embodiments, X 4 or X 6 CR 3 ; where R 3 is selected from fluorine, chlorine and bromine.

[0296] In certain embodiments, X 4 or X 6 CR 3 , where R 3 Selected from C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2 and CBr3.

[0297] In certain embodiments, X 4 or X 6 CR 3 ; where R 3It is a C1-C4 alkyl group.

[0298] In certain embodiments, X 7 N and Q 1 In certain embodiments, X 7 In certain embodiments, X 7 In certain embodiments, X 7 It is a C1-C4 haloalkyl group.

[0299] In certain embodiments, X 8 and X 9 At least one of them is CH.

[0300] In certain embodiments, X 8 is N.

[0301] In certain embodiments, X 9 is N.

[0302] In certain embodiments, X 8 and X 9 Each of them is CH.

[0303] In certain embodiments, X 10 In certain embodiments, X 10 In certain embodiments, X 10 It is O.

[0304] In certain embodiments, X 11 is a heterocyclic ring containing at least one N, O or S. In certain embodiments, X 11 is a heterocycle, which is a C3-C9 heterocycle containing at least one N, O or S.

[0305] In certain embodiments, X 11 is a bicyclic heterocycle containing at least one N, O, or S. In certain embodiments, the bicyclic heterocycle is fused. In certain embodiments, the bicyclic heterocycle is bridged. In certain embodiments, the bicyclic heterocycle is spirocyclic.

[0306] In certain embodiments, X 11 is a heteroaryl group containing at least one N, O or S.

[0307] In certain embodiments, X 11 It is an aryl group.

[0308] In certain embodiments, X 11 It is a cycloalkyl group.

[0309] In certain embodiments, X 12is a substituted 5-membered heteroaryl group containing at least one N, O or S atom.

[0310] In certain embodiments, X 12 is a substituted 5-membered heteroaryl group containing at least one nitrogen atom.

[0311] In certain embodiments, X 12 is a substituted 5-membered heteroaryl group containing at least two N atoms.

[0312] In certain embodiments, X 12 is an unsubstituted 5-membered heteroaryl group containing at least one N, O or S atom.

[0313] In certain embodiments, X 12 is an unsubstituted 5-membered heteroaryl group containing at least one nitrogen atom.

[0314] In certain embodiments, X 12 is an unsubstituted 5-membered heteroaryl group containing at least two N atoms.

[0315] In certain embodiments, Q 1 In certain embodiments, Q 1 Is O. In certain embodiments, Q 1 is S. In certain embodiments, Q 1 is CH2. In certain embodiments, Q 1 is N(alkyl), wherein the alkyl is C1-C4 alkyl or C1-C4 haloalkyl. 1 is N(haloalkyl), wherein the haloalkyl is C1-C4 haloalkyl.

[0316] In certain embodiments, R is hydrogen. In certain embodiments, R is selected from fluorine, chlorine and bromine. In certain embodiments, R is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2 or CBr3. In certain embodiments, R is C1-C4 alkyl.

[0317] In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2 or CBr3. In certain embodiments, R 1 It is a cycloalkyl group.

[0318] In certain embodiments, R 3In certain embodiments, R 3 In certain embodiments, R 3 is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2 or CBr3. In certain embodiments, R 3 In certain embodiments, R 4 is C1-C4 alkyl. In certain embodiments, R 3 It is a cycloalkyl group.

[0319] In certain embodiments, R 4 In certain embodiments, R 4 In certain embodiments, R 4 is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2 or CBr3. In certain embodiments, R 4 In certain embodiments, R 4 is C1-C4 alkyl. In certain embodiments, R 4 It is a C1-C4 haloalkoxy group.

[0320] In an alternative embodiment, R 4 is selected from the group consisting of hydrogen, aryl, heteroaryl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkyl, hydroxy, amino, fluorine, chlorine, bromine and iodine.

[0321] In certain embodiments, R 5 In certain embodiments, R 5 is C1-C4 alkyl. In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, R 5 In certain embodiments, X 5 It is a cycloalkyl group.

[0322] In certain embodiments, R 6 In certain embodiments, R 6 In certain embodiments, R 6In certain embodiments, R6 is C1-C4 alkyl.

[0323] In certain embodiments, R 7 In certain embodiments, R 7 It is a C1-C4 alkyl group.

[0324] In certain embodiments, R 8 In certain embodiments, R 8 is C1-C4 alkyl. In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, R 8 In certain embodiments, X 8 It is a cycloalkyl group.

[0325] In an alternative embodiment, X 17 is optionally substituted by 1, 2, 3 or 4 independently selected from R 3 A heterocyclic ring substituted with a substituent of 17 Non-limiting examples of heterocyclic groups include pyrrolidine, piperidine, morpholine, thiomorpholine, azepane, tetrahydrofuran, tetrahydropyran, dioxane, thiazane, oxepane, azocane, thioane, and azononane.

[0326] In certain embodiments, Selected from:

[0327]

[0328] In certain embodiments, Selected from:

[0329]

[0330]

[0331] In certain embodiments, Selected from:

[0332]

[0333]

[0334] In certain embodiments, Selected from:

[0335]

[0336] In certain embodiments, Selected from:

[0337]

[0338]

[0339] In certain embodiments, X 1 Selected from:

[0340]

[0341] In certain embodiments, X 12 -LB is selected from:

[0342]

[0343]

[0344]

[0345]

[0346]

[0347] The above X 12 Each of the moieties is optionally replaced by 1 or 2 independently selected R 3 substituted by a substituent.

[0348] In one embodiment, the compound of the present invention is selected from:

[0349]

[0350] In one embodiment, the compound of the present invention is selected from:

[0351]

[0352]

[0353] In one embodiment, the compound of the present invention is selected from:

[0354]

[0355] In one embodiment, the compound of the present invention is selected from:

[0356]

[0357] In certain embodiments, the compounds of the present invention are selected from:

[0358]

[0359]

[0360] or a pharmaceutically acceptable salt thereof.

[0361] In one embodiment, the compound of the present invention is selected from:

[0362]

[0363]

[0364] or a pharmaceutically acceptable salt thereof.

[0365] In one embodiment, the compound of the present invention is selected from:

[0366]

[0367]

[0368]

[0369]

[0370]

[0371] or a pharmaceutically acceptable salt thereof.

[0372] In one embodiment, the compound of the present invention is selected from:

[0373]

[0374]

[0375]

[0376] or a pharmaceutically acceptable salt thereof.

[0377] In one embodiment, the compound of the present invention is selected from:

[0378]

[0379]

[0380]

[0381]

[0382] In one embodiment, the compound of the present invention is selected from:

[0383]

[0384]

[0385]

[0386] In one embodiment, the compound of the present invention is selected from:

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394] In one embodiment, the compound of the present invention is selected from:

[0395]

[0396]

[0397]

[0398] In certain embodiments, Selected from:

[0399]

[0400] In certain embodiments, Selected from:

[0401]

[0402]

[0403] In certain embodiments, Selected from:

[0404]

[0405] In certain embodiments, for:

[0406]

[0407] In certain embodiments, for:

[0408]

[0409] In certain embodiments, Selected from:

[0410]

[0411]

[0412] In certain embodiments, Selected from:

[0413]

[0414] In certain embodiments, Selected from:

[0415]

[0416] In certain embodiments, Selected from:

[0417]

[0418]

[0419] In certain embodiments, compound 172 is

[0420]

[0421] or a pharmaceutically acceptable salt thereof.

[0422] Additional embodiments of the present invention

[0423] 001. In certain embodiments, the compounds of the present invention have the following formula:

[0424]

[0425] 002. The compound of embodiment 1, wherein X 8 is N and X 9 For CH.

[0426] 003. The compound of embodiment 1, wherein X 8 is CH and X 9 is N.

[0427] 004. The compound of embodiment 1, wherein X 8 is CH and X 9 For CH.

[0428] 005. The compound of any one of embodiments 1-4, wherein for

[0429] 006. The compound of any one of embodiments 1-4, wherein for

[0430] 007. The compound of any one of embodiments 1-4, wherein for

[0431] 008. The compound of any one of embodiments 1-7, wherein for

[0432] 009. The compound of any one of embodiments 1-8, wherein R is C1-C4 haloalkyl, C1-C4 alkyl, fluorine, chlorine or bromine.

[0433] 010. The compound according to any one of embodiments 1-8, wherein R is fluoro.

[0434] 011. In certain embodiments, the compounds of the present invention have the following formula:

[0435]

[0436] 012. The compound of embodiment 11, wherein X 17 is optionally substituted by 1, 2, 3 or 4 independently selected from R 3 An aryl group substituted with a substituent.

[0437] 013. The compound of embodiment 12, wherein X 17 It is phenyl.

[0438] 014. The compound of embodiment 11, wherein X 17 is a heteroaryl group or a cycloalkyl group; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 3 substituted by a substituent.

[0439] 015. The compound of any one of embodiments 1-14, wherein Q 1 NH and X 7 For CH.

[0440] 016. The compound of any one of embodiments 1-14, wherein Q 1 is O and X 7 For CH.

[0441] 017. The compound of any one of embodiments 1-14, wherein Q 1 is N(CH3) and X 7 For CH.

[0442] 018. In certain embodiments, the compounds of the present invention have the following formula:

[0443] 019. The compound of any one of embodiments 1-18, wherein X 3 CR 3 .

[0444] 020. The compound of any one of embodiments 1-18, wherein X 3 is N.

[0445] 021. The compound of any one of embodiments 1-18, wherein X 3 For CH.

[0446] 022. The compound of any one of embodiments 1-18, wherein X 3 For CF.

[0447] 023. The compound of any one of embodiments 1-18, wherein X 3 is C(CF3).

[0448] 024. The compound of any one of embodiments 1-18, wherein X 3 is C(Cl).

[0449] 025. The compound of any one of embodiments 1-24, wherein X 5 CR 3 .

[0450] 026. The compound of any one of embodiments 1-24, wherein X 5 is N.

[0451] 027. The compound of any one of embodiments 1-24, wherein X 5 For CH.

[0452] 028. The compound of any one of embodiments 1-24, wherein X 5 For CF.

[0453] 029. The compound of any one of embodiments 1-24, wherein X 5 is C(CF3).

[0454] 030. The compound of any one of embodiments 1-24, wherein X 5 is C(Cl).

[0455] 031. In certain embodiments, the compounds of the present invention have the following formula:

[0456] 032. The compound of embodiment 31, wherein R 1 For hydrogen.

[0457] 033. The compound of embodiment 31, wherein R 1 For CH3.

[0458] 034. The compound of any one of embodiments 1-33, wherein X 4 CR 3 .

[0459] 035. The compound of any one of embodiments 1-33, wherein X 4 is N.

[0460] 036. The compound of any one of embodiments 1-33, wherein X 4 For CH.

[0461] 037. The compound of any one of embodiments 1-33, wherein X 4 For CF.

[0462] 038. The compound of any one of embodiments 1-33, wherein X 4 is C(CF3).

[0463] 039. The compound of any one of embodiments 1-33, wherein X 4 is C(Cl).

[0464] 040. The compound of any one of embodiments 1-39, wherein X 6 CR 3 .

[0465] 041. The compound of any one of embodiments 1-39, wherein X 6 For CH.

[0466] 042. The compound of any one of embodiments 1-39, wherein X 6 For CF.

[0467] 043. The compound of any one of embodiments 1-39, wherein X 6 is C(CF3).

[0468] 044. The compound of any one of embodiments 1-39, wherein X 6 is C(Cl).

[0469] 045. In certain embodiments, the compounds of the present invention have the following formula:

[0470] 046. The compound of embodiment 45, wherein Q 1 NH and X 7 For CH.

[0471] 047. The compound of embodiment 45, wherein Q 1 is O and X 7 For CH.

[0472] 048. The compound of embodiment 45, wherein Q 1 is N(CH3) and X 7 For CH.

[0473] 049. The compound of any one of embodiments 45-48, wherein X 12 is a 5-membered heteroaryl group having 1, 2 or 3 atoms independently selected from N, wherein X 12 Optionally 1, 2 or 3 independently selected from R 3 substituted by a group.

[0474] 050. The compound of any one of embodiments 45-48, wherein X 12 is furan, where X 12 Optionally 1, 2 or 3 independently selected from R 3 substituted by a group.

[0475] 051. The compound of any one of embodiments 1-50, wherein B is B 1 .

[0476] 052. The compound of embodiment 51, wherein B 1 for

[0477] 053. The compound of embodiment 52, wherein R 5 For hydrogen.

[0478] 054. The compound of embodiment 52, wherein R 5 It is a methyl group.

[0479] 055. The compound of embodiment 51, wherein B 1 for

[0480] 056. The compound of embodiment 51, wherein B1 for

[0481] 057. The compound of embodiment 51, wherein B 1 for

[0482] 058. The compound of any one of embodiments 1-50, wherein B is B 2 .

[0483] 059. In certain embodiments, the compounds of the present invention have the following formula:

[0484]

[0485] 060. The compound of embodiment 59, wherein Q 1 NH and X 7 For CH.

[0486] 061. The compound of embodiment 59, wherein Q 1 is O and X 7 For CH.

[0487] 062. The compound of embodiment 59, wherein Q 1 is N(CH3) and X 7 For CH.

[0488] 063. The compound of any one of embodiments 59-62, wherein X 3 CR 3 .

[0489] 064. The compound of any one of embodiments 59-62, wherein X 3 is N.

[0490] 065. The compound of any one of embodiments 59-62, wherein X 3 For CH.

[0491] 066. The compound of any one of embodiments 59-62, wherein X 3 For CF.

[0492] 067. The compound of any one of embodiments 59-62, wherein X 3 is C(CF3).

[0493] 068. The compound of any one of embodiments 59-62, wherein X 3 is C(Cl).

[0494] 069. The compound of any one of embodiments 59-68, wherein X 5 CR 3.

[0495] 070. The compound of any one of embodiments 59-68, wherein X 5 is N.

[0496] 071. The compound of any one of embodiments 59-68, wherein X 5 For CH.

[0497] 072. The compound of any one of embodiments 59-68, wherein X 5 For CF.

[0498] 073. The compound of any one of embodiments 59-68, wherein X 5 is C(CF3).

[0499] 074. The compound of any one of embodiments 59-68, wherein X 5 is C(Cl).

[0500] 075. The compound of any one of embodiments 59-74, wherein X 4 CR 3 .

[0501] 076. The compound of any one of embodiments 59-74, wherein X 4 is N.

[0502] 077. The compound of any one of embodiments 59-74, wherein X 4 For CH.

[0503] 078. The compound of any one of embodiments 59-74, wherein X 4 For CF.

[0504] 079. The compound of any one of embodiments 59-74, wherein X 4 is C(CF3).

[0505] 080. The compound of any one of embodiments 59-74, wherein X 4 is C(Cl).

[0506] 081. The compound of any one of embodiments 59-80, wherein X 6 CR 3 .

[0507] 082. The compound of any one of embodiments 59-80, wherein X 6 For CH.

[0508] 083. The compound of any one of embodiments 59-80, wherein X 6 For CF.

[0509] 084. The compound of any one of embodiments 59-80, wherein X 6 is C(CF3).

[0510] 085. The compound of any one of embodiments 59-80, wherein X 6 is C(Cl).

[0511] 086. The compound of any one of embodiments 58-85, wherein B 2 for

[0512] 087. The compound of embodiment 86, wherein R 5 For hydrogen.

[0513] 088. The compound of embodiment 86, wherein R 5 It is a methyl group.

[0514] 089. The compound of any one of embodiments 58-85, wherein B 2 for

[0515] 090. The compound of any one of embodiments 58-85, wherein B 2 for

[0516] 091. The compound of any one of embodiments 58-85, wherein B 2 for

[0517] 092. The compound of any one of embodiments 58-91, wherein X 11 is a heterocyclic ring, each X 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group.

[0518] 093. The compound of any one of embodiments 58-91, wherein X 11 For double rings, each X 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group.

[0519] 094. The compound of any one of embodiments 58-91, wherein X 11 is heteroaryl, aryl or cycloalkyl, each X 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group.

[0520] 095. The compound of any one of embodiments 58-91, wherein X 11 Selected from:

[0521]

[0522] 096. The compound of any one of embodiments 58-91, wherein X 11 Selected from:

[0523]

[0524] 097. The compound of any one of embodiments 58-91, wherein X 10 and X 11 Together

[0525] 098. The compound of any one of embodiments 58-91, wherein X 10 and X 11 Together

[0526] 099. The compound of any one of embodiments 1-96, wherein X 10 C(R 7 )2.

[0527] 100. The compound of any one of embodiments 1-96, wherein X 10 For CH2.

[0528] 101. The compound of any one of embodiments 1-96, wherein X 10 is C(O).

[0529] 102. The compound of any one of embodiments 1-96, wherein X 10 It is O.

[0530] 103. The compound of any one of embodiments 1-102, wherein X 13 CR 3 .

[0531] 104. The compound of any one of embodiments 1-102, wherein X 13 is N.

[0532] 105. The compound of any one of embodiments 1-102, wherein X 13 For CH.

[0533] 106. The compound of any one of embodiments 1-102, wherein X 13 For CF.

[0534] 107. The compound of any one of embodiments 1-102, wherein X13 is C(CF3).

[0535] 108. The compound of any one of embodiments 1-102, wherein X 13 is C(Cl).

[0536] 109. The compound of any one of embodiments 1-108, wherein X 14 CR 3 .

[0537] 110. The compound of any one of embodiments 1-108, wherein X 14 is N.

[0538] 111. The compound of any one of embodiments 1-108, wherein X 14 For CH.

[0539] 112. The compound of any one of embodiments 1-108, wherein X 14 For CF.

[0540] 113. The compound of any one of embodiments 1-108, wherein X 14 is C(CF3).

[0541] 114. The compound of any one of embodiments 1-108, wherein X 14 is C(Cl).

[0542] 115. The compound of any one of embodiments 1-114, wherein X 15 CR 3 .

[0543] 116. The compound of any one of embodiments 1-114, wherein X 15 is N.

[0544] 117. The compound of any one of embodiments 1-114, wherein X 15 For CH.

[0545] 118. The compound of any one of embodiments 1-114, wherein X 15 For CF.

[0546] 119. The compound of any one of embodiments 1-114, wherein X 15 is C(CF3).

[0547] 120. The compound of any one of embodiments 1-114, wherein X 15 is C(Cl).

[0548] 121. The compound of any one of embodiments 1-120, wherein X16 CR 3 .

[0549] 122. The compound of any one of embodiments 1-120, wherein X 16 For CH.

[0550] 123. The compound of any one of embodiments 1-120, wherein X 16 For CF.

[0551] 124. The compound of any one of embodiments 1-120, wherein X 16 is C(CF3).

[0552] 125. The compound of any one of embodiments 1-120, wherein X 16 is C(Cl).

[0553] 126. The compound of any one of embodiments 1-125, wherein R 8 For hydrogen.

[0554] 127. The compound of any one of embodiments 1-125, wherein R 8 It is a methyl group.

[0555] 128. The compound of any one of embodiments 1-127, wherein L is a linker having the formula:

[0556]

[0557] in,

[0558] X 1 and X 2 independently selected at each occurrence from a bond, a heterocycle, NR 2 、C(R 2 )2, O, C(O) and S;

[0559] R 2 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne;

[0560] R 20 、R 21 、R 22 、R 23 and R 24independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-C(R 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 substituted by a substituent;

[0561] R 26 is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and

[0562] R 40 and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxy, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle and cycloalkyl.

[0563] 129. The compound of embodiment 128, wherein L is a linker having the following formula:

[0564]

[0565] 130. The compound of embodiment 128 or 129, wherein X 1 is the key.

[0566] 131. The compound of embodiment 128 or 129, wherein X 1 It is a heterocyclic ring.

[0567] 132. The compound of embodiment 128 or 129, wherein X 1 NR 2 .

[0568] 133. The compound of embodiment 128 or 129, wherein X1 is C(O).

[0569] 134. The compound of any one of embodiments 128-133, wherein X 2 is the key.

[0570] 135. The compound of any one of embodiments 128-133, wherein X 2 It is a heterocyclic ring.

[0571] 136. The compound of any one of embodiments 128-133, wherein X 2 NR 2 .

[0572] 137. The compound of any one of embodiments 128-133, wherein X 2 is C(O).

[0573] 138. The compound of any one of embodiments 128-137, wherein R 20 is the key.

[0574] 139. The compound of any one of embodiments 128-137, wherein R 20 For CH2.

[0575] 140. The compound of any one of embodiments 128-137, wherein R 20 It is a heterocyclic ring.

[0576] 141. The compound of any one of embodiments 128-137, wherein R 20 It is an aryl group.

[0577] 142. The compound of any one of embodiments 128-137, wherein R 20 It is phenyl.

[0578] 143. The compound of any one of embodiments 128-137, wherein R 20 It is a double ring.

[0579] 144. The compound of any one of embodiments 128-143, wherein R 21 is the key.

[0580] 145. The compound of any one of embodiments 128-143, wherein R 21 For CH2.

[0581] 146. The compound of any one of embodiments 128-143, wherein R 21 It is a heterocyclic ring.

[0582] 147. The compound of any one of embodiments 128-143, wherein R21 It is an aryl group.

[0583] 148. The compound of any one of embodiments 128-143, wherein R 21 It is phenyl.

[0584] 149. The compound of any one of embodiments 128-143, wherein R 21 It is a double ring.

[0585] 150. The compound of embodiment 128, wherein L is a linker having the formula:

[0586]

[0587] 151. The compound of any one of embodiments 128-150, wherein R 22 is the key.

[0588] 152. The compound of any one of embodiments 128-150, wherein R 22 For CH2.

[0589] 153. The compound of any one of embodiments 128-150, wherein R 22 It is a heterocyclic ring.

[0590] 154. The compound of any one of embodiments 128-150, wherein R 22 It is an aryl group.

[0591] 155. The compound of any one of embodiments 128-150, wherein R 22 It is phenyl.

[0592] 156. The compound of any one of embodiments 128-150, wherein R 22 It is a double ring.

[0593] 157. The compound of embodiment 128, wherein L is a linker having the formula:

[0594]

[0595] 158. The compound of any one of embodiments 128-157, wherein R 23 is the key.

[0596] 159. The compound of any one of embodiments 128-157, wherein R 23 For CH2.

[0597] 160. The compound of any one of embodiments 128-157, wherein R 23 It is a heterocyclic ring.

[0598] 161. The compound of any one of embodiments 128-157, wherein R 23 It is an aryl group.

[0599] 162. The compound of any one of embodiments 128-157, wherein R 23 It is phenyl.

[0600] 163. The compound of any one of embodiments 128-157, wherein R 23 It is a double ring.

[0601] 164. The compound of embodiment 128, wherein L is a linker having the formula:

[0602]

[0603] 165. The compound of any one of embodiments 128-164, wherein R 24 is the key.

[0604] 166. The compound of any one of embodiments 128-164, wherein R 24 For CH2.

[0605] 167. The compound of any one of embodiments 128-164, wherein R 24 It is a heterocyclic ring.

[0606] 168. The compound of any one of embodiments 128-164, wherein R 24 It is an aryl group.

[0607] 169. The compound of any one of embodiments 128-164, wherein R 24 It is phenyl.

[0608] 170. The compound of any one of embodiments 128-164, wherein R 24 It is a double ring.

[0609] 171. The compound of any one of embodiments 128-164, wherein R 24 is C(O).

[0610] 172. The compound of any one of embodiments 1-171, wherein L is selected from:

[0611]

[0612] 173. In certain embodiments, compound 172 is

[0613]

[0614] or a pharmaceutically acceptable salt thereof.

[0615] 174. In certain embodiments, compound 172 is

[0616]

[0617] or a pharmaceutically acceptable salt thereof.

[0618] 175. In certain embodiments, compound 172 is

[0619]

[0620] or a pharmaceutically acceptable salt thereof.

[0621] 176. In certain embodiments, compound 172 is

[0622]

[0623] or a pharmaceutically acceptable salt thereof.

[0624] III. Targeting Ligands

[0625] Bromodomains (BRDs) are protein interaction modules that specifically recognize acetylation motifs. BRDs are evolutionarily conserved and are present in a wide variety of nuclear proteins, including HATs (GCN5, PCAF), ATP-dependent chromatin remodeling complexes (BAZ1B), helicases (SMARCA), methyltransferases (MLL, ASH1L), transcriptional coactivators (TRIM / TIF1, TAF), transcription mediators (TAF1), nuclear scaffold proteins (PB1), and the BET family. (Muller S, Filippakopoulos P, Knapp S., Bromodomains as therapeutic targets, Expert Rev Mol Med. 2011, 13(29)).

[0626] Bromodomain-containing protein 7 (BRD7) is similar to BRD9 and is a subunit of the PBAF SWI / SNF. (Pérez-Salvia M., Estellera M., Bromodomain inhibitors and cancer therapy: From structures to applications, Epigenetics. 2017; 12(5): 323–339; P99: Clark PGK et al., Discovery and Synthesis of the First Selective BRD7 / 9 Bromodomain Inhibitor, Angew Chem Weinheim Bergstr Ger. 2015, 127(21): 6315–6319).

[0627] In certain embodiments, moiety B is a targeting ligand directed against a disorder mediated by one or more bromodomain-containing proteins.

[0628] In certain embodiments, moiety B is a targeting ligand for a BRD9-mediated disorder.

[0629] In certain embodiments, moiety B is a targeting ligand for a BRD7-mediated disorder.

[0630] In certain embodiments, B is B1.

[0631] In certain embodiments, B is B2.

[0632] In certain embodiments, B2 is selected from:

[0633]

[0634] where X 18 and X 19 is independently selected from -N- and -CH-, and wherein all other variables are as defined herein.

[0635] In certain embodiments, B2 is selected from:

[0636]

[0637]

[0638] where X 18 and X 19 is independently selected from -N- and -CH-, and wherein all other variables are as defined herein.

[0639] In certain embodiments, B2 is selected from:

[0640]

[0641]

[0642] where X 18 and X 19 is independently selected from -N- and -CH-, and wherein all other variables are as defined herein.

[0643] In certain embodiments, B2 is selected from:

[0644]

[0645]

[0646] where X 18 and X 19 is independently selected from -N- and -CH-, and wherein all other variables are as defined herein.

[0647] In certain embodiments, B1 is selected from the group consisting of:

[0648]

[0649] In certain embodiments, B1 is selected from the group consisting of:

[0650]

[0651]

[0652] In certain embodiments, B1 is selected from the group consisting of:

[0653]

[0654]

[0655]

[0656] In certain embodiments, B1 is selected from the group consisting of:

[0657]

[0658]

[0659] In certain embodiments, B 2 Selected from:

[0660]

[0661]

[0662] In certain embodiments, B 2 Selected from:

[0663]

[0664]

[0665] In certain embodiments, B2 is selected from:

[0666]

[0667]

[0668] In certain embodiments, B2 is selected from:

[0669]

[0670]

[0671] In certain embodiments, B2 is selected from:

[0672]

[0673]

[0674]

[0675] In certain embodiments, B2 is selected from:

[0676]

[0677]

[0678]

[0679] In certain embodiments, B1 is

[0680] In certain embodiments, X 11 Selected from:

[0681]

[0682] In certain embodiments, X 11 Selected from:

[0683]

[0684] In certain embodiments, X 11 Selected from:

[0685]

[0686] In certain embodiments, X 11 Selected from:

[0687]

[0688]

[0689] IV. Connectors

[0690] The compounds of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI as described herein, or pharmaceutically acceptable salts thereof, include a linker. Linker (L or L D ) is a chemically stable divalent group that can link the E3 ligase binding moiety to the targeting ligand. According to the present invention, any desired linker as described herein can be used, as long as the resulting compound has a stable shelf life of at least 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form and is itself pharmaceutically acceptable.

[0691] Linkers as described herein can be used in either orientation, ie, either with the left end attached to the E3 ligase binding moiety and the right end attached to the targeting linker, or with the left end attached to the targeting linker and the right end attached to the E3 ligase binding moiety.

[0692] In certain embodiments, the linker is a bond.

[0693] In certain embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, or 20 or more carbon atoms, wherein one or more carbons may be replaced with a heteroatom such as O, N, S, or P.

[0694] In certain embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive atoms in the chain. For example, the chain can include one or more ethylene glycol units, which can be continuous, partially continuous, or discontinuous (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units).

[0695] In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 continuous chains that may have branches, which branches may independently be alkyl, aryl, heteroaryl, alkenyl or alkynyl, aliphatic, heteroaliphatic, cycloalkyl, or heterocyclic substituents.

[0696] In other embodiments, the joint may comprise one or more of ethylene glycol, propylene glycol, lactic acid and / or glycolic acid or be composed of one or more of ethylene glycol, propylene glycol, lactic acid and / or glycolic acid. Typically, propylene glycol increases hydrophobicity, while propylene glycol increases hydrophilicity. Lactic acid segments tend to have longer half-lives than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties and ethylene glycol and propylene glycol are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain desired half-life and hydrophilicity. In some aspects, these units can be flanked or interspersed with other moieties as needed, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocycle, cycloalkyl, etc., to obtain suitable pharmaceutical properties.

[0697] In certain embodiments, L is a linker selected from:

[0698]

[0699] In one aspect, the linker (L) is selected from a moiety of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, Formula LVII, Formula LVIII, Formula IX, and Formula LX:

[0700]

[0701] in,

[0702] X 1 and X 2 independently selected at each occurrence from a bond, a heterocycle, NR 2 、C(R 2 )2, O, C(O) and S;

[0703] R 2 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne;

[0704] R 20 、R 21 、R 22 、R 23 and R 24 independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-C(R 40 R40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 substituted by a substituent;

[0705] R 26 is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and

[0706] R 40 and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxy, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocycle), -N(alkyl)SO2(aryl, heteroaryl or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle and cycloalkyl.

[0707] In certain embodiments, L D is a linker selected from the group consisting of:

[0708]

[0709] In one aspect, the linker (L D ) is selected from a moiety of formula LDI, formula LDII, formula LDIII, formula LDIV, formula LDV, formula LDVI, and formula LDVII:

[0710]

[0711] All variables are as described in this article.

[0712] The following are the connectors that can be used in the present invention (L or L D Based on this detailed description, those skilled in the art will understand how to use the full range of linkers that will achieve the objectives of the present invention.

[0713] Non-limiting examples of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, or Formula LVII include:

[0714]

[0715]

[0716] Non-limiting examples of Formula LDI, Formula LDII, Formula LDIII, Formula LDIV, Formula LDV, Formula LDVI, or Formula LDVII include:

[0717]

[0718]

[0719] In one embodiment, X 1 Connected to B. In another embodiment, X 2 Connect to B.

[0720] R 20 、R 21 、R 22 、R 23 and R 24 Some non-limiting examples include:

[0721]

[0722] R 20 、R 21 、R 22 、R 23 and R 24 Additional non-limiting examples of moieties include:

[0723]

[0724] R 20 、R 21 、R 22 、R 23 and R 24 Additional non-limiting examples of moieties include:

[0725]

[0726] In further embodiments, the linker moiety is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 ethylene glycol units, or an optionally substituted alkyl group interspersed with optionally substituted O, N, S, P or Si atoms.

[0727] In certain embodiments, the linker is flanked, substituted, or interspersed with aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic groups.

[0728] In certain embodiments, the linker can be asymmetric or symmetric.

[0729] In certain embodiments, the linker can be a non-linear chain and can be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[0730] In any of the embodiments of the compounds described herein, the linker group can be any suitable moiety as described herein.

[0731] In certain embodiments, the linker is selected from:

[0732]

[0733] In certain embodiments, the linker (L or L D ) is selected from:

[0734]

[0735] In certain embodiments, the linker (L or L D ) is selected from:

[0736]

[0737] In certain embodiments, the linker (L or L D ) is selected from:

[0738]

[0739]

[0740] In certain embodiments, the linker (L or L D ) is selected from:

[0741]

[0742]

[0743] In certain embodiments, the linker (L or L D ) is selected from:

[0744]

[0745] In certain embodiments, the linker drawn above is attached on the left side to the B group. In other embodiments, the linker drawn above is attached on the right side to the B group.

[0746] In certain embodiments, the compounds of the present invention are selected from:

[0747]

[0748]

[0749] or a pharmaceutically acceptable salt thereof.

[0750] V. Additional Non-Limiting Examples of Compounds of the Invention

[0751] In certain embodiments, the compounds of the present invention are selected from:

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758] In certain embodiments, the compounds of the present invention are selected from:

[0759]

[0760]

[0761] In certain embodiments, the compounds of the present invention are selected from:

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790] In certain embodiments, the compounds of the present invention are selected from:

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797] In certain embodiments, the compounds of the present invention are selected from:

[0798]

[0799]

[0800]

[0801]

[0802] In certain embodiments, the compounds of the present invention are selected from:

[0803]

[0804]

[0805]

[0806] In certain embodiments, the compounds of the present invention are selected from:

[0807]

[0808] In certain embodiments, the compounds of the present invention are selected from:

[0809]

[0810]

[0811] In certain embodiments, the compounds of the present invention are selected from:

[0812]

[0813] In certain embodiments, the compounds of the present invention are selected from:

[0814]

[0815] Non-limiting examples of compounds of the present invention include:

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824] Non-limiting examples of compounds of the present invention include:

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833] Non-limiting examples of compounds of the present invention include:

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841] Non-limiting examples of compounds of the present invention include:

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849] Non-limiting examples of compounds of the present invention include:

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857] Non-limiting examples of compounds of the present invention include:

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865] Non-limiting examples of compounds of the present invention include:

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873] Non-limiting examples of compounds of the present invention include:

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881] Non-limiting examples of compounds of the present invention include:

[0882]

[0883]

[0884]

[0885]

[0886]

[0887] In certain embodiments, the compounds of the present invention are:

[0888]

[0889] or a pharmaceutically acceptable salt thereof.

[0890] In certain embodiments, the compounds of the present invention are:

[0891]

[0892] or a pharmaceutically acceptable salt thereof.

[0893] In certain embodiments, the compounds of the present invention are:

[0894]

[0895] or a pharmaceutically acceptable salt thereof.

[0896] In certain embodiments, the compounds of the present invention are:

[0897]

[0898] or a pharmaceutically acceptable salt thereof.

[0899] In certain embodiments, the compounds of the present invention are:

[0900]

[0901] or a pharmaceutically acceptable salt thereof.

[0902] In certain embodiments, the compounds of the present invention are:

[0903]

[0904] or a pharmaceutically acceptable salt thereof.

[0905] In certain embodiments, the compounds of the present invention are:

[0906]

[0907] or a pharmaceutically acceptable salt thereof.

[0908] In certain embodiments, the compounds of the present invention are:

[0909]

[0910] or a pharmaceutically acceptable salt thereof.

[0911] In certain embodiments, the compounds of the present invention are:

[0912]

[0913] or a pharmaceutically acceptable salt thereof.

[0914] In certain embodiments, the compounds of the present invention are:

[0915]

[0916] or a pharmaceutically acceptable salt thereof.

[0917] In certain embodiments, the compounds of the present invention are:

[0918]

[0919] or a pharmaceutically acceptable salt thereof.

[0920] In certain embodiments, the compounds of the present invention are:

[0921]

[0922] or a pharmaceutically acceptable salt thereof.

[0923] In certain embodiments, the compounds of the present invention are:

[0924]

[0925] or a pharmaceutically acceptable salt thereof.

[0926] In certain embodiments, the compounds of the present invention are:

[0927]

[0928] or a pharmaceutically acceptable salt thereof.

[0929] Non-limiting BRD9 degradation embodiments

[0930] In certain embodiments, compounds of the invention are characterized by having a BRD binding (K) of less than 200 nM. i In certain embodiments, compounds of the invention are characterized by having a BRD binding (K) of less than 100 nM. i ).

[0931] In certain embodiments, the compounds of the present invention are characterized by having FP-E3 binding (K d In certain embodiments, the compounds of the present invention are characterized by having FP-E3 binding (K d ).

[0932] In certain embodiments, compounds of the invention are characterized by less than 10 nM BRD9 degradation at 2 hours and / or less than 10% K after 17 hours. endo .

[0933] In certain embodiments, the compounds of the invention are characterized by having a BRD9 degradation kinetic K of less than 20 nM. pc .

[0934] In certain embodiments, the compounds of the invention are characterized by greater than >999 nM BRD7 degradation and / or greater than 95% E max .

[0935] In certain embodiments, the compounds of the invention are characterized by greater than 1000 nM and less than 5000 nM BRD4 degradation and / or >60% and less than 90% E max .

[0936] In certain embodiments, compounds of the invention are characterized as having >999 nM IKZF1 / SALL4 / GSPT1 degradation.

[0937] In certain embodiments, compounds of the invention are characterized as having a HEPG2 activity of >999 nM. In certain embodiments, compounds of the invention are characterized as having a HEPG2 activity of >10,000 nM.

[0938] In certain embodiments, the compounds of the present invention are characterized by having a SW982 activity (GI) > 1000 nM 50 In certain embodiments, the compounds of the present invention are characterized by having a SW982 activity (GI) > 10,000 nM. 50 ).

[0939] In certain embodiments, the compounds of the present invention are characterized as having a hERG > 30. In certain embodiments, the compounds of the present invention are characterized as having a hERG > 60.

[0940] VI. Treatment Methods

[0941] The compounds as described herein may be used in an effective amount to treat a patient, typically a human patient, in need thereof, suffering from a disorder mediated by BRD9.

[0942] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for treating or preventing cancer or more generally abnormal cell proliferation in a patient, such as a human, in need thereof; wherein the cancer or abnormally proliferating cells contain activated BRD9 or wherein BRD9 inhibition is required to treat or prevent cancer.

[0943] In certain embodiments, the methods comprise administering to a patient in need thereof an effective amount of an active compound as described herein, or a salt thereof, optionally comprising a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another biologically active agent or combination of agents.

[0944] In certain embodiments, the present invention provides a method of treating any of the conditions described herein in a patient in need thereof.

[0945] In other embodiments, an additional therapeutic agent is administered to the patient.In other embodiments, a compound as described herein and an additional therapeutic agent are administered simultaneously or sequentially.

[0946] In certain embodiments, the present application provides a method of preventing any of the conditions described herein in a patient in need thereof.

[0947] In certain embodiments, the patient is a human.

[0948] In certain embodiments, the compounds of the present invention are used to treat refractory conditions, such as refractory cancers. In certain embodiments, the compounds of the present invention are used to treat recurrent conditions, such as recurrent cancers. In further embodiments, the compounds of the present invention are used to treat refractory and recurrent conditions, such as refractory and recurrent cancers. In further embodiments, the compounds of the present invention are used to treat multidrug-resistant conditions, such as multidrug-resistant cancers.

[0949] In certain embodiments, compounds of the invention are used to treat SMARCB1 perturbed cancers, such as SMARCB1 perturbed solid tumors.

[0950] In certain embodiments, the BRD9-mediated disorder is synovial sarcoma, malignant rhabdoid tumor, atypical teratoma or rhabdoid tumor, epithelioid sarcoma, medullary renal carcinoma, epithelioid malignant peripheral nerve sheath tumor, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, chordoma, undifferentiated rhabdoid carcinoma of the pancreas, basaloid carcinoma of the nasal cavity and paranasal sinuses, or rhabdoid carcinoma of the gastrointestinal tract.

[0951] In certain embodiments, the BRD9-mediated disorder is synovial sarcoma.

[0952] In certain embodiments, the BRD9-mediated disorder is malignant rhabdoid tumor.

[0953] In certain embodiments, the BRD9-mediated disorder is an atypical teratoma or a rhabdoid tumor.

[0954] In certain embodiments, the BRD9-mediated disorder is epithelioid sarcoma.

[0955] In certain embodiments, the BRD9-mediated disorder is renal medullary carcinoma.

[0956] In certain embodiments, the BRD9-mediated disorder is epithelioid malignant peripheral nerve sheath tumor.

[0957] In certain embodiments, the BRD9-mediated disorder is myoepithelial carcinoma.

[0958] In certain embodiments, the BRD9-mediated disorder is extraskeletal myxoid chondrosarcoma.

[0959] In certain embodiments, the BRD9-mediated disorder is chordoma.

[0960] In certain embodiments, the BRD9-mediated disorder is undifferentiated rhabdoid carcinoma of the pancreas.

[0961] In certain embodiments, the BRD9-mediated disorder is sinonasal basaloid carcinoma.

[0962] In certain embodiments, the BRD9-mediated disorder is rhabdoid carcinoma of the gastrointestinal tract.

[0963] As inhibitors of BRD9, the compounds and compositions of the present application are particularly useful for treating or lessening the severity of diseases, disorders, or conditions in which bromodomain proteins are associated with the disease, disorder, or condition.

[0964] In one aspect, the present invention provides a method of treating or lessening the severity of a disease, disorder, or condition in which a bromodomain protein is associated with a disease state.

[0965] Another aspect of the present invention provides a method for inhibiting or reducing the amount of bromodomain proteins in a patient in need thereof, comprising administering an effective amount of a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0966] Another aspect of the present invention provides a method for treating a disorder mediated by a bromodomain protein, comprising administering to a patient in need thereof an effective amount of a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0967] Another aspect of the present invention provides a method for treating or preventing a proliferative disease, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0968] In some embodiments, the disease is mediated by BRD9. In other embodiments, BRD9 plays a role in the initiation or development of the disease.

[0969] In certain embodiments, BRD9-mediated disorders include benign growths, metastases, neoplasms, tumors, solid tumors, rhabdoid tumors, malignant rhabdoid tumors, carcinomas, leukemias, cancers, abnormal cell proliferation, graft-versus-host rejection, amyloid diseases, proteinopathies, fibrotic disorders, inflammation, arthritis, pulmonary disorders, and immune disorders.

[0970] In certain embodiments, the conditions treated by the present invention are conditions associated with the SS18-SSX fusion protein. In certain embodiments, the conditions treated by the present invention are conditions associated with the SS18 protein. In certain embodiments, the conditions treated by the present invention are conditions associated with the SSX protein.

[0971] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0972] In certain embodiments, the BRD9-mediated disorder is abnormal cell proliferation, including but not limited to a tumor or cancer, or a myelo- or lymphoproliferative disorder such as a B-cell or T-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferative disorder.

[0973] In certain embodiments, the hematological cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia , promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL) 2 and / or CL6 rearrangement / overexpression [double and triple hit lymphoma], myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma (including bortezomib-resistant mantle cell lymphoma).

[0974] Solid tumors that can be treated with the compounds described herein include, but are not limited to: lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); breast cancer, including inflammatory breast cancer, ER-positive breast cancer (including tamoxifen-resistant ER-positive breast cancer), and triple-negative breast cancer; colon cancer; midline cancer; liver cancer; kidney cancer; prostate cancer (including castration-resistant prostate cancer (CRPC)); brain cancer, including glioma, glioblastoma, neuroblastoma, and medulloblastoma (including MYC-amplified medulloblastoma); colorectal cancer; Wilm's tumor; Ewing's sarcoma; rhabdomyosarcoma; ependymoma; head and neck cancer; melanoma; squamous cell carcinoma; ovarian cancer; pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PanNET); osteosarcoma; giant cell tumor of bone; thyroid cancer; bladder cancer; urothelial carcinoma; vulvar cancer; cervical cancer; endometrial cancer; mesothelioma; esophageal cancer; salivary gland cancer; gastric cancer; nasopharyngeal cancer; cheek cancer; oral cancer; GIST (gastrointestinal stromal tumor); NUT-midline carcinoma; testicular cancer; squamous cell carcinoma; hepatocellular carcinoma (HCC); MYCN-driven solid tumors; and NUT-midline carcinoma (NMC).

[0975] In further embodiments, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0976] In further embodiments, the disease or condition is soft tissue sarcoma, skeletal sarcoma, or osteosarcoma.

[0977] In further embodiments, the disease or condition is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningeal sarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0978] In certain embodiments, the disorder is a bone, muscle, tendon, cartilage, nerve, fat, or angiosarcoma.

[0979] In a further embodiment, the disease or disorder is multiple myeloma.

[0980] In a further embodiment, the disease or condition is synovial sarcoma. The connection between synovial sarcoma and BRD9 has been described in the literature. For example, Brien et al., entitled "Targeted degradation of BRD9 reversesoncogenic gene expression in synovial sarcoma," describes the high sensitivity of synovial sarcoma tumors to administration of BRD9 degraders. Similarly, Michel et al., entitled "A non-canonical SWI / SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation," describes the role of BAF in synovial sarcoma and the role of BRD9 in synovial sarcoma proliferation.

[0981] In certain embodiments, the BRD9-mediated disorder is an inflammatory disease, including but not limited to asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

[0982] In other embodiments, the disease or condition is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neurological inflammation, allergic reactions, pain, neuropathic pain, fever, pulmonary conditions, lung inflammation, adult respiratory distress, chronic inflammatory lung disease and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative disease, gastric ulcers, autoimmune diseases, graft-host reaction and allograft rejection, cancer, leukemia, lymphoma, colorectal cancer , brain cancer, bone cancer, tumors of epithelial cell origin (epithelial cancer), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell carcinoma, prostate cancer, renal cell carcinoma and other known cancers affecting epithelial cells throughout the body, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis (including neoplasia, metastasis, central nervous system disorders), central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy or B-cell lymphoma.

[0983] In other embodiments, a pharmaceutical composition comprising a compound as described herein and an additional therapeutic agent is administered simultaneously or sequentially.

[0984] In other embodiments, the disease or condition is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, solid tumor, blood cancer, or solid cancer.

[0985] In some embodiments, the method is for treating or preventing a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases. In other embodiments, the condition is selected from a proliferative disorder.

[0986] In certain embodiments, the BRD9-mediated disorder is an immune disorder, including but not limited to an autoimmune disorder such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes.

[0987] One aspect of the present application provides compounds that can be used to treat diseases, conditions, and patients characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer; ovarian cancer; cervical cancer; prostate cancer; testicular cancer, genitourinary tract cancer; esophageal cancer; laryngeal cancer, glioblastoma; neuroblastoma; stomach cancer; keratoacanthomas of the skin; epidermoid carcinoma, large cell carcinoma, small cell carcinoma, adenocarcinoma of the lung; bone cancer; colon cancer; colorectal cancer; adenoma; pancreatic cancer, adenocarcinoma; follicular carcinoma, undifferentiated carcinoma, papillary carcinoma of the thyroid; seminoma, melanoma; sarcoma; bladder cancer; liver cancer and biliary tract cancer; kidney cancer; bone marrow disorders; lymphoid disorders, Hodgkin's disease, hairy cell cancer; buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer; small intestine cancer; colorectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer; chronic myeloid leukemia (CML) and leukemia. The term "cancer" includes, but is not limited to, myeloma, lymphoma, or a cancer selected from gastric cancer, renal cancer, or / and the following cancers: head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma, and lung cancer.

[0988] The term "cancer" refers to any cancer caused by the proliferation of malignant cells, such as a tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc. For example, cancer includes, but is not limited to, mesothelioma, leukemia and lymphoma such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV) such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodysplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms tumor, bone tumors and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (such as oral cancer, laryngeal cancer, nasopharyngeal cancer and esophageal cancer), genitourinary tract cancer (such as prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancer (such as small cell lung cancer and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin syndrome (such as medulloblastoma or meningioma), and liver cancer.

[0989] Additional exemplary forms of cancer include, but are not limited to, skeletal or smooth muscle cancer, stomach cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0990] Compounds described herein can be used to prevent, treat, and study additional cancers such as colon cancer, familial adenomatous polyposis carcinoma, and hereditary non-polyposis colorectal cancer, or melanoma. In addition, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary thyroid cancer and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, testicular cancer, urethral cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral primitive neuroectodermal tumors, gallbladder cancer, bronchogenic carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of the present application, the present application provides use of one or more compounds as described herein in the manufacture of a medicament for treating cancer, including but not limited to various types of cancer disclosed herein.

[0991] In some embodiments, the compounds of the present application can be used to treat cancers such as colorectal cancer, thyroid cancer, breast cancer and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia and systemic mast cell disease. In some embodiments, the compounds as described herein can be used to treat hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia and acute lymphoblastic leukemia (ALL).

[0992] In one embodiment, the compounds as described herein or their corresponding pharmaceutically acceptable salts or isotopic derivatives can be used in an effective amount to treat a host, such as a human, suffering from a lymphoma or a lymphocyte or myeloproliferative disorder or abnormality. For example, the compounds as described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host can suffer from a non-Hodgkin's lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; autoimmune blastic lymphoma; blastic NK cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); diffuse small cleaved cell lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic leukemia; cutaneous T-cell lymphoma; diffuse large B cell Lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenstrom's macroglobulinemia.

[0993] In another embodiment, the compounds as described herein, or their corresponding pharmaceutically acceptable salts or isotopic derivatives, can be used in an effective amount to treat a patient, e.g., a human, suffering from Hodgkin's lymphoma, such as, but not limited to: nodular sclerosis classical Hodgkin's lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL.

[0994] The present application also includes the treatment or prevention of cell proliferative disorders such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesions that a pathologist can identify during a biopsy. The compounds can be administered for the purpose of preventing the hyperplasia, dysplasia, or precancerous lesion from progressing or becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0995] As inhibitors of BRD9 protein, the compounds and compositions of the present application can also be used in biological samples. One aspect of the present application is to inhibit protein activity in a biological sample, the method comprising contacting the biological sample with a compound or composition as described herein. As used herein, the term "biological sample" refers to an in vitro or ex vivo sample, including but not limited to cell culture or an extract thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. The inhibition of protein activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include but are not limited to blood transfusion, organ transplantation, and biological sample storage.

[0996] Another aspect of the present application is the study of BRD9 proteins in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such proteins; and the comparative evaluation of novel protein inhibitors. Examples of such uses include, but are not limited to, bioassays, such as enzyme assays and cell-based assays.

[0997] The activity of the compounds and compositions of the present application as BRD9 inhibitors can be measured in vitro, in vivo or in cell lines. In vitro assays include determinations of the inhibition of the ATPase activity of the enzyme activity or activated protein. Alternative in vitro assays quantify the ability of inhibitors to bind to bromodomain proteins and can be measured by radiolabeling the inhibitor before binding, separating the inhibitor / bromodomain complex and measuring the amount of radiolabeled binding or by performing a competition experiment in which a new inhibitor is incubated with a bromodomain bound to a known radioligand. The detailed conditions for determining the compounds used as inhibitors of various bromodomain proteins in the present application will be described in the examples below.

[0998] In accordance with the foregoing, the present application also provides a method for preventing or treating any of the above-mentioned diseases or conditions in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as described herein, or its enantiomer, diastereomer, or stereoisomer, or a pharmaceutically acceptable salt, hydrate, or solvate. For any of the above uses, the required dosage will vary depending on the mode of administration, the specific patient to be treated, and the desired effect.

[0999] VII. Combination Therapy

[1000] Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or pharmaceutically acceptable salts thereof, can be used alone or in combination in an effective amount to treat a patient, such as a human, suffering from a disorder or a BRD9-mediated disorder as described herein.

[1001] The disclosed compounds described herein can be used in an effective amount alone or in combination with another compound of the invention or another biologically active agent or a second therapeutic agent to treat a patient, such as a human, suffering from a disorder including, but not limited to, those described herein.

[1002] The term "biologically active agent" is used to describe an agent other than a compound selected according to the present invention that can be used in combination or in conjunction with a compound of the present invention to achieve a desired therapeutic outcome. In one embodiment, the compound of the present invention and the biologically active agent are administered in such a manner that they are active in vivo over overlapping time periods, for example, having Cmax, Tmax, AUC, or other pharmacokinetic parameters that overlap over time periods. In another embodiment, a compound of the present invention and a biologically active agent are administered to a patient in need thereof and do not have overlapping pharmacokinetic parameters, however, one has a therapeutic impact on the therapeutic efficacy of the other.

[1003] In one aspect of this embodiment, the bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, as non-limiting examples, including PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig inhibitors of T- cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors. In certain aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[1004] PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor, thereby inhibiting immunosuppression, include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby inhibiting immunosuppression, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[1005] In certain embodiments, the checkpoint inhibitor is selected from nivolumab / Pembrolizumab / and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS936559, a PDL2 / lg fusion protein such as AMP 224, or an inhibitor of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof.

[1006] In another embodiment, one of active compounds described herein can be combined with an effective dose of an estrogen inhibitor or alternately used in an effective dose to treat abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer, and the estrogen inhibitor includes but is not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader or another form of part or complete estrogen antagonist or agonist. Partial estrogen antagonists such as raloxifene and tamoxifen retain some estrogen-like effects, including estrogen-like stimulation to uterine growth, and in some cases, the estrogen-like effect in breast cancer progression, which actually stimulates tumor growth. On the contrary, fulvestrant, a complete estrogen antagonist, does not have an estrogen-like effect on the uterus and is effective in tamoxifen-resistant tumors.

[1007] Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176, assigned to Astra Zeneca; WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US 2013 / 0178445, assigned to Olema Pharmaceuticals; U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810; and US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138.

[1008] Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprolide, cetrorelix, allylestradiol, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone acetate, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.

[1009] Other estrogen ligands that can be used according to the present invention are described in U.S. Patent Nos. 4,418,068, 5,478,847, 5,393,763, and 5,457,117; WO 2011 / 156518; U.S. Patent Nos. 8,455,534 and 8,299,112; U.S. Patent Nos. 9,078,871, 8,853,423, 8,703,810; US 2015 / 0005286; WO 2014 / 205138; US 2016 / 0175289; US 2015 / 0258080; WO 2014 / 191726; WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US6821989; US2002 / 0128276; US 6777424; US2002 / 0016340; US 6326392; US 6756401; US2002 / 0013327; US 6512002; US 6632834; US2001 / 0056099; US 6583170; US 6479535; WO1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497; US 5880137; WO 2012 / 048058 and WO 2007 / 087684.

[1010] In another embodiment, the active compounds described herein can be combined with an effective amount of an androgen (such as testosterone) inhibitor or administered in an effective amount in alternation to treat abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer, and the androgen inhibitor includes but is not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, the prostate cancer or testicular cancer is androgen-resistant.

[1011] Non-limiting examples of anti-androgenic compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299, 112. Additional non-limiting examples of anti-androgenic compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[1012] In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[1013] In one embodiment, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), omotinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HK I-272; PB272); avitinib (AC0010), EAI045, tasotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[1014] In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, trastuzumab emtansine, and pertuzumab.

[1015] In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ocrelizumab.

[1016] In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tofacitinib.

[1017] In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R )-4-(dimethylamino)-1-phenylsulfonylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide)(navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate mesylate), (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-4-methoxypyrrol-2-ylidene]indolemethanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxo- ethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Oblimersen).

[1018] In one embodiment, the bioactive agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

[1019] Examples of PI3 kinase inhibitors include, but are not limited to, wortmannin, demethylgliocillin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine -9-yl] pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butanehydrogen (S)-methylphosphonate; or methyl (oxo){[(2R)-1-phenoxy-2-butane]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyl oxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridyl}benzenesulfonamide)(omipalisib), TGX-221((±)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771(2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-lH-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193((R)-2-((l-(7- (methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR 245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinaz), AS252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[ 4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile)(dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[ [(4-(4-pyridyl)-6-quinolyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-3 17. PI-3065, PI-103, NU7441 (KU-57788), HS173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-9 3. AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422).

[1020] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica TM)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), diphenylaminopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics) (see U.S. Patent Publication No. 2011 / 0117073, which is incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline- 6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity, for example, those disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, the entire contents of which are incorporated herein by reference.

[1021] Syk inhibitors include, but are not limited to, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxy-1-yl)-1 ... ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate, sodium salt of fotantinib ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate, sodium salt of BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N- (4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), P RT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine- 2,4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al.Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety), myricetin (see Singh et al.Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire text of which is incorporated herein), Morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire text of which is incorporated herein).

[1022] In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEAl 19 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2, 3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R051267 66 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridinyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinane-2-yl) ) methyl) benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl) amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, bimetinib, SL-327, TAK-733, PD318088.

[1023] In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), Sorafenib Tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline- benzimidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine The drugs included 2,4-dione, 5-chloro-4-nitropropane-5-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane-5-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane-5-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane-5-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane-5-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane-5-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane-5-nitropropane-2-nitropropane-3-nitropropane-4-nitropropane

[1024] In one embodiment, the biologically active agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifosine, (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502 and miltefosine (a FLT-3 inhibitor), including but not limited to P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076 and KW-2449, or a combination thereof.

[1025] In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include, but are not limited to, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinob (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S) -N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib), refametinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), P D-0325901 (N-[(2R)-2,3-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R051267 66 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridinyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[1026] In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[1027] In one embodiment, the bioactive agent is a HSP inhibitor.HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and Radicol.

[1028] Additional biologically active compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF TRAP antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-ETU, nolatrexed, AZD2171, batabulin, atumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, patozuzuril, oblimersen, tesitumumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, RTA 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, celecoxib; PD0325901, AZD-6244, capecitabine Tadalafil, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab,IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprorelin acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, erbitux, EK B-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG), doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone acetate, cytarabine, dacarbazine, dactinomycin, daunorubicin diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, nitrogen mustard, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis- Retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neivastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitamin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without polyoxyethylene castor oil,Docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM3363 72, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronic acid, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab Monoclonal antibody, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, daunorubicin liposomal, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, PEG filgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[1029] In certain embodiments, the compound is administered in combination with ifosfamide.

[1030] In one embodiment, the bioactive agent is selected from but not limited to imatinib mesylate Dasatinib Nilotinib Bosutinib Trastuzumab Trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib Gefitinib Erlotinib Cetuximab Panitumumab Vandetanib Vemurafenib Vorinostat Romidepsin Bexarotene alitretinoin retinoic acid Carfilzomib (Kyprolis™), pralatrexate Bevacizumab Aflibercept Sorafenib Sunitinib Pazopanib Regorafenib and cabozantinib (Cometriq™).

[1031] In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[1032] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents), which include any agent that is detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer drugs include: vincristine or liposome vincristine Daunorubicin (daunorubicin or ) or doxorubicin Cytosine arabinoside (ara-C or ), L-asparaginase or PEG-L-asparaginase (pegaspargase or ), etoposide (VP-16), teniposide 6-Mercaptopurine (6-MP or ), methotrexate, cyclophosphamide Prednisone, dexamethasone (Decatetron), imatinib Dasatinib Nilotinib Bosutinib and ponatinib (Iclusig TM ).

[1033] Examples of additional suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, dactinomycin D, doxorubicin, aldesleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), betamethasone sodium phosphate, and betamethasone acetate. , bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, Cyclothosphamide, cytarabine, cytarabine, cytochalasin B, Cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin hydrochloride, daunorubicin citrate, denileukindiftitox), dexrazoxane, dibromomannitol, dihydroxy anthracin dione, docetaxel, dolasetron mesylate, doxorubicin hydrochloride, dronabinol, Escherichia coli L-asparaginase, cephalothin, epoetin-α, Erwinia lactone L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide aurantium factor, etoposide phosphate, filgrastim, floxuridine, fluconazole , fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine hydrochloride, glucocorticoids, goserelin acetate, gramicidin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon α-2b, irinotecan hydrochloride, letrozole, leucovorin calcium, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytansinoid, nitrogen mustard hydrochloride, medroxyprogesterone acetate, medroxyprogesterone acetate, Melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron hydrochloride, paclitaxel, pamidronate disodium, pentostatin, pilocarpine hydrochloride, prinomycin, polyphenytoin 20 with carmustine implant, porfimer sodium, procaine, procarbazine hydrochloride, propranolol, rituximab, sarmustine, streptozotocin, tamoxifen, purple Taxol, teniposide, teniposide, tenoposide, testolactone, tetracaine, thioepa, chlorambucil, thioguanine, thiotepa, topotecan hydrochloride, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[1034] In some embodiments, the compound of the present invention is administered in combination with chemotherapeutic agents (for example, cytotoxic agents or other chemical compounds that can be used to treat cancer). The example of chemotherapeutic agent includes alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complex, anthracene dione substituted urea, methyl hydrazine derivatives, adrenocortical inhibitor, adrenocortical hormone, progesterone, estrogen, anti-estrogen, androgen, anti-androgen and gonadotropin-releasing hormone analog. Also included are 5-fluorouracil (5-FU), folinic acid (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel.Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; chlorpromazine such as benzodepa, carboquinone, metodepa, and uredopa; ethyleneimines and methylmelamines, including hexamethylmelamine, trothamide, triethylenephosphoramide, triethylenethiophosphoramide, and trihydroxymethylmelamine; annonacetic acid lactones (particularly bratacin and bratacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adolesine, carzelesine, and biszelesine); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189, and CB1-TM1); eleuthrin. erobin); pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthiazolin, cholephosphamide, estramustine, ifosfamide, mechlorethamine, oxazolidinone hydrochloride, melphalan, mechlorethamine, phenylephrine, phenylephrine, trofosfamide, uracil mustard; nitroureas such as carmustine, chlorozolin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediynes (e.g., calicheamicins, especially calicheamicin gamma 11 and calicheamicin omega 11) (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); anthracyclines, including dynemicins A; bisphosphonates, such as clodronate; esperamicin; and the new anticancer chromophore and related chromoprotein enediyne antibiotic chromophores), aclarubicin, actinomycin, authramycin, azaserine, bleomycin, actinomycin C, carabicin, carminomycin, carmomycin, chromomycin, actinomycin D, daunorubicin, detoximum iodide, 6-diazo-5-oxo-L-norleucine,. (doxorubicin, including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolidoxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin, mitomycins such as mitomycin C, mycophenolic acid nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, triferric doxorubicin, rhodorubicin, streptomycin, streptozocin tuberculin, ubenimex, zoloft, doxycycline; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as leucovorin, methotrexate, pteroyltriglutamate, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxil oxadiazine, enocitabine, floxuridine; androgens such as calutosterone, hydroxymethylandrosterone propionate, epithioandrostol, melastane, and testolactone; antiadrenal agents such as aminoglutethimide, mantotan, and trilostane; folic acid supplements such as folinic acid; aceglucosamine; aldophosphamide glycoside; aminolevulinic acid; eniluracil; acridinium; bestrabucil; bisantrene; edatrexate; defofamine; demeclocycline; diazocine; iloni Elfomithine; hydroxypyridine acetate; epothilone; etogluconol; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansine alkaloids such as maytansine and ansamitocin; mitoguanidine; mitoxantrone; mopidanmol; diamine nitrazepam; pentostatin; nitrogen mustard; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; cytochrome; sifoloxicam; spirogermanamine; tenuazonic acid; triazinon; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2mycin, verracurin A, baculozolin A, and serpentin); urethane; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g., (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), Cremophor-free albumin engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL) and docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; Noanto; Teniposide; Edatrexate; Daunorubicin; Aminopterin; Xeloda; Ibadronate; Irinotecan (e.g., CPT-1 1); Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be mixed for administration in combination with the compounds of the present invention. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18: 233a (1999) and Douillard et al., Lancet 355 (9209): 1041-1047 (2000).

[1035] Additional therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, edamasumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, trastuzumab, seleximab ... Ni, fentolimumab, atacicept, rituximab, alemtuzumab, aldesleukin, atezolizumab, tocilizumab, temsirolimus, everolimus, rucamumab, dacillinam, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanspiramycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, Belinostat, panobinostat, mapatumumab, lexalimumab, dulanamine, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin Platinum (Eloxatin), PD0332991, ribociclib (LEE011), pomacequinolone (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necituzumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[1036] In one embodiment, the additional treatment is a monoclonal antibody (MAb). Some MAbs stimulate an immune response, thereby destroying cancer cells. Similar to antibodies naturally produced by B cells, these MAbs may "coat" the surface of cancer cells, thereby triggering the immune system to destroy them. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cell receptors, thereby preventing the signaling that leads to new blood vessel growth. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), while trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.

[1037] In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, for example, cyclosporine or an ascomycin, such as cyclosporine A. FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, e.g., rapamycin or its derivatives, e.g., sirolimus Everolimus Temsirolimus, zotarolimus, umamiolimus-7, umamiolimus-9, rapamycin analogs such as lidaformolimus, azathioprine, campath 1H, S1P receptor modulators such as fingolimod or its analogs, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, such as the sodium salt, or a prodrug thereof, such as mycophenolate mofetil OKT3 (ORTHOCLONE ), prednisone, Buquina sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, treperolimus, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab Daclizumab Mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZASM 981 (pimecrolimus, ), CTLA4lg (Abatacept), Belacept, LFA3lg, Etanercept (by Immunex Sold), Adalimumab Infliximab Anti-LFA-1 antibody, natalizumab Enmoluzumab, golimumab, antithymocyte immunoglobulin, cilizumab, afacept, efalizumab, podesand, mesalamine, doxepin, codeine phosphate, benoxicam, fenbufen, naproxen, diclofenac, etodolac, and indomethacin, aspirin, and ibuprofen.

[1038] In some embodiments, the bioactive agent is a therapeutic agent that is a biologic used in cancer treatment, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)). In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab. In some embodiments, the biologic is an immunoglobulin-based biologic, for example, a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. Such agents include (rituximab); (daclizumab); (basiliximab); (palivizumab); (infliximab); (trastuzumab); (gemtuzumab ozogamicin); (alemtuzumab); (ibritumomab tiuxetan); (adalimumab); (omalizumab); (tositumomab-l-131); (efalizumab); (cetuximab); (bevacizumab); (natalizumab); (tocilizumab); (panitumumab); (ranibizumab); (iculizumab); (certolizumab); (golimumab); (canakinumab); (ustekinumab); (ofatumumab); (denosumab); (motuzumab); (Raxicumab); (belimumab); (ipilimumab); (Bentuximab); (Pertuzumab); (enmetazuzumab); and (Otuzumab). Also included are antibody-drug conjugates.

[1039] Combination therapy may include therapeutic agents that are non-drug therapies. For example, the compound may be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical resection of tumor tissue.

[1040] In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent can be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, up to 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days before or after the second therapeutic agent.

[1041] In certain embodiments, the second therapeutic agent is administered with a different dosage schedule than the compound of the present invention. For example, the second therapeutic agent can have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent can have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments, both the first and second therapeutic agents have a treatment holiday.

[1042] VIII. Pharmaceutical Compositions

[1043] The compounds of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI as described herein can be administered as pure chemicals, but are more typically administered as pharmaceutical compositions comprising an amount effective for a patient, typically a human, in need of such treatment to treat any of the conditions described herein. Thus, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for any use described herein. The pharmaceutical composition may contain the compound or salt as the sole active agent, or in alternative embodiments, the compound and at least one additional active agent.

[1044] Typically, the compositions of the present invention will be administered in a therapeutically effective amount by any accepted mode of administration. Suitable dosage ranges depend on numerous factors such as the severity of the disease to be treated, the age and relative health of the experimenter, the effectiveness of the compound used, route of administration and form, the indications for which administration is directed, and the preference and experience of the relevant doctor. Those of ordinary skill in the art of treating such diseases will be able to determine the therapeutically effective amount of the compositions of the present invention for a given disease without excessive experimentation and relying on personal knowledge and the disclosure of the application.

[1045] In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples include dosage forms having at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

[1046] In an alternative embodiment, a patient can be treated with a low-dose therapy. For example, the pharmaceutical composition can be in a dosage form containing from about 0.1 μg to about 2000 μg, from about 10 μg to about 1000 μg, from about 100 μg to about 800 μg, or from about 200 μg to about 600 μg of the active compound. Examples include dosage forms having at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or its salt.

[1047] In some embodiments, the compounds disclosed herein or as used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, the compounds disclosed herein or as used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days or longer.

[1048] In certain embodiments, the compounds of the invention are administered once a day, twice a day, three times a day, or four times a day.

[1049] In certain embodiments, the compounds of the present invention are administered orally once a day. In certain embodiments, the compounds of the present invention are administered orally twice a day. In certain embodiments, the compounds of the present invention are administered orally three times a day. In certain embodiments, the compounds of the present invention are administered orally four times a day.

[1050] In certain embodiments, the compounds of the present invention are administered intravenously once a day. In certain embodiments, the compounds of the present invention are administered intravenously twice a day. In certain embodiments, the compounds of the present invention are administered intravenously three times a day. In certain embodiments, the compounds of the present invention are administered intravenously four times a day.

[1051] In some embodiments, the compounds disclosed herein or as used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, the compounds disclosed herein or as used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days or longer.

[1052] In certain embodiments, the compounds of the invention are administered once a day, twice a day, three times a day, or four times a day.

[1053] In certain embodiments, the compounds of the present invention are administered orally once a day. In certain embodiments, the compounds of the present invention are administered orally twice a day. In certain embodiments, the compounds of the present invention are administered orally three times a day. In certain embodiments, the compounds of the present invention are administered orally four times a day.

[1054] In certain embodiments, the compounds of the present invention are administered intravenously once a day. In certain embodiments, the compounds of the present invention are administered intravenously twice a day. In certain embodiments, the compounds of the present invention are administered intravenously three times a day. In certain embodiments, the compounds of the present invention are administered intravenously four times a day.

[1055] In some embodiments, the compounds disclosed herein or as used as described are administered once a week (QW), twice a week (BIW), or three times a week (TIW). In some embodiments, the compounds disclosed herein or as used as described are administered at least once a week for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days or longer.

[1056] In certain embodiments, a compound of the invention is administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week.

[1057] In certain embodiments, the compounds of the present invention are administered orally once a week. In certain embodiments, the compounds of the present invention are administered orally twice a week. In certain embodiments, the compounds of the present invention are administered orally three times a week. In certain embodiments, the compounds of the present invention are administered orally four times a week.

[1058] In certain embodiments, the compounds of the present invention are administered intravenously once a week. In certain embodiments, the compounds of the present invention are administered intravenously twice a week. In certain embodiments, the compounds of the present invention are administered intravenously three times a week. In certain embodiments, the compounds of the present invention are administered intravenously four times a week.

[1059] In some embodiments, the compounds of the invention are administered with a treatment holiday between treatment cycles. For example, the compounds can have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

[1060] The pharmaceutical composition may also comprise an active compound and an additional active agent in a molar ratio. For example, the pharmaceutical composition may contain an anti-inflammatory agent or immunosuppressant in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.

[1061] These compositions can contain any amount of active compound to achieve the desired result, for example, 0.1 to 99 weight percent (wt.%) of the compound, typically at least about 5 weight % of the compound. Some embodiments contain from about 25 weight % to about 50 weight % or from about 5 weight % to about 75 weight % of the compound.

[1062] The composition of medicine or therapeutically effective amount is delivered to the patient. Exact effective amount will vary with the patient, and will depend on species, age, size and health status of the experimenter, the nature and degree of the patient being treated, the advice of the treating physician and the therapeutic agent or therapeutic agent combination selected for use. The effective amount of a given situation can be determined by routine experiments. For the purposes of the present disclosure, in at least one administration, the therapeutic amount can be, for example, in the range of about 0.01mg / kg to about 250mg / kg body weight, more generally about 0.1mg / kg to about 10mg / kg. How many administrations can be used to reduce and / or alleviate the signs, symptoms or the cause of disease under consideration to the experimenter, or cause any other desired changes in the biological system. When desired, enteric-coated preparations with a sustained or controlled release administration suitable for active ingredient can be prepared.

[1063] In certain embodiments, the dosage is in the range of about 0.01-100 mg / kg of patient body weight, for example, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 10 mg / kg g, 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 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg.

[1064] The pharmaceutical formulation is preferably in unit dosage form. In such a dosage form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation containing discrete quantities of the formulation, such as tablets, capsules, and powders packaged in vials or ampoules. Alternatively, the unit dosage form can itself be a capsule, tablet, cachet, or lozenge, or it can be an appropriate amount of any of these in packaged form.

[1065] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[1066] Therefore, the compositions of the present disclosure can be administered in pharmaceutical formulations, including pharmaceutical formulations suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous), injection, inhalation or spray, intraaortic, intracranial, subdermal, intraperitoneal, subcutaneous or other administration means containing conventional pharmaceutically acceptable carriers. Typical administration methods are oral, topical or intravenous administration, using a convenient daily dosing regimen that can be adjusted according to the degree of pain.

[1067] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semisolid or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions, pastes, gels, sprays, aerosols, foams, or oils, injectable or infusible solutions, transdermal patches, subcutaneous patches, inhalation preparations, medical devices, suppositories, buccal or sublingual preparations, parenteral preparations or eye drops, etc., preferably in a unit dosage form suitable for single administration of a precise dose.

[1068] Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing appropriate amounts of the active ingredient, e.g., an effective amount to achieve the desired purpose. The composition will comprise an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and may also contain other agents, adjuvants, diluents, buffers, etc.

[1069] The carrier includes an excipient and a diluent and must be of sufficiently high purity and sufficiently low toxicity to make it suitable for administration to the patient being treated. The carrier may be inert or may have its own pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of administration material for each unit dose of the compound.

[1070] Classes of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, excipients, emulsifiers, flavorings, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tableting agents, wetting agents, or solidifying materials.

[1071] Some carriers may be listed in more than one category, for example, a vegetable oil may be used as a lubricant in some formulations and as a diluent in others.

[1072] Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc, petrolatum, lanolin, polyethylene glycol, alcohols, transdermal enhancers, and vegetable oils. The pharmaceutical composition may contain optional active agents that do not substantially interfere with the activity of the compounds of the invention.

[1073] The compound of the present invention can be used as a pharmaceutical composition or as a preparation of a pharmaceutical composition. The compound of the present invention can be used as a pharmaceutical composition or as a preparation of a pharmaceutical composition. Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, etc. Depending on the needs of the therapeutic target, the compound can be provided in the form of, for example, solids, liquids, spray-dried materials, microparticles, nanoparticles, controlled release systems, etc. Excipients suitable for non-liquid formulations are also well known to those skilled in the art. A detailed discussion of pharmaceutically acceptable excipients and salts can be obtained in Remington's Pharmaceutical Sciences (18th edition) (Easton, Pennsylvania: Mack Publishing Company, 1990).

[1074] In addition, auxiliary substances, such as wetting agents or emulsifiers, biological buffer substances, surfactants, etc., may be present in such vehicles. The biological buffer can be any pharmacologically acceptable solution that provides the desired pH for the formulation, i.e., a pH within the physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, and the like.

[1075] For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Compositions for liquid pharmaceutical administration can be prepared, for example, by dissolving, dispersing, or otherwise dissolving the active compound as described herein and optional pharmaceutical adjuvants in an excipient such as water, saline, aqueous dextrose, glycerol, ethanol, or the like to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, cited above.

[1076] In yet another embodiment, the use of a permeation enhancer excipient is provided, comprising polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, polyacrylic acid); and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[1077] In certain embodiments, the excipient is selected from butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[1078] Pharmaceutical compositions / combinations can be formulated for oral administration. For oral administration, the compositions are typically in the form of tablets, capsules, soft gel capsules, or can be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use may contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. Typically, the compositions of the present disclosure can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrants, and colorants can also be introduced into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[1079] When a liquid suspension is used, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc., as well as with an emulsifier and suspending agent. If desired, flavoring agents, colorants and / or sweeteners may also be added. Other optional components incorporated into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[1080] For ocular delivery, the compounds can be administered as desired, for example, by intravitreal, intrastromal, intracameral, subfascial, subretinal, retrobulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericorneal, or lacrimal injection, or through mucus, mucin, or mucosal barriers, in an immediate or controlled release manner or via an ocular device.

[1081] Parenteral formulations can be prepared in conventional forms, or prepared as liquid solutions or suspensions, solid forms suitable for dissolving or being suspended in liquids before injection, or prepared as emulsions. Typically, suitable carriers, dispersants or wetting agents and suspending agents are used to prepare sterile injectable suspensions according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in acceptable nontoxic parenteral acceptable diluents or solvents. Adoptable acceptable vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils, fatty esters or polyols are typically used as solvents or suspension media. In addition, parenteral administration can relate to the use of slow-release or sustained-release systems to maintain constant dosage levels.

[1082] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions, which can contain antioxidants, buffers, antibacterials and solutes that make the preparation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which can include suspending agents, solubilizers, thickeners, stabilizers and preservatives. Administration via some parenteral routes can involve introducing the preparation of the present disclosure into the patient's body by a needle or catheter, which is driven by a sterile syringe or some other mechanical devices such as a continuous infusion system. The preparation provided by the present disclosure can be administered using a syringe, an injector, a pump or any other device recognized in the art for parenteral administration.

[1083] Preparations for parenteral administration according to the present disclosure include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. They may be sterilized, for example, by filtering through a bacteria retaining filter, by introducing a sterilizing agent into the composition, by irradiating the composition or by heating the composition. They may also be manufactured using sterilized water or some other sterile injectable media before use.

[1084] Sterile injectable solutions are prepared by introducing the desired amount of one or more compounds of the present disclosure into a suitable solvent along with the various other ingredients listed above as needed and then sterilizing by filtration. Typically, dispersions are prepared by introducing various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, typical preparation methods are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic and sterilized with sodium chloride.

[1085] Alternatively, the pharmaceutical compositions of the present disclosure can be administered in the form of suppositories for rectal administration. Suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[1086] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents.

[1087] Preparations for buccal administration include tablets, lozenges, gels, etc. Alternatively, buccal administration can be achieved using a transmucosal delivery system well known to those skilled in the art. Compounds of the present disclosure can also be delivered by skin or mucosal tissue using a conventional transdermal drug delivery system, i.e., a transdermal "patch," wherein agents are typically contained in a laminated structure used as a drug delivery device to be fixed to body surface. In such a structure, pharmaceutical compositions are typically contained in a layer or "reservoir" below the upper backing layer. Laminated devices may contain a single reservoir, or they may contain a plurality of reservoirs. In one embodiment, the reservoir comprises a polymer matrix of a pharmaceutically acceptable contact adhesive material, which is used to fix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxanes, polyisobutylene, polyacrylates, polyurethanes, etc.

[1088] Alternatively, the drug-containing reservoir and the skin contact adhesive exist as separate and different layers, and the adhesive below the reservoir can be a polymer matrix as described above, or can be a liquid or gel reservoir, or can take other forms. The backing layer that serves as the upper surface of the device in these laminates plays the role of the main structural element of the laminate structure and provides very large flexibility for the device. The material selected for the backing layer should be substantially impermeable to the active agent and any other material present.

[1089] Compositions of the present disclosure can be formulated for aerosol administration, particularly for respiratory tract administration, including intranasal administration. Compounds can for example generally have a small particle size of for example about 5 microns or less. Such particle size can be obtained by means known in the art, for example by micronization. Active ingredient is provided in a pressurized package together with a suitable propellant such as chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases. Aerosols can also conveniently contain surfactants such as lecithin. The dosage of the medicine can be controlled by a metering valve.

[1090] Alternatively, the active ingredient can be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dose form, for example in capsules or cartridges of, for example, gelatin or blister packs, from which the powder can be administered with the aid of an inhaler.

[1091] Formulations suitable for rectal administration are generally presented as unit-dose suppositories. These suppositories can be prepared by mixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[1092] In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the modes of administration defined above.

[1093] In certain embodiments, the pharmaceutical composition is suitable for transdermal administration and can be in the form of a discrete patch suitable for maintaining close contact with the epidermis of the recipient for a long time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3(6):318(1986)) and are typically in the form of an optionally buffered aqueous solution of the active compound.

[1094] In one embodiment, a microneedle patch or device is provided for delivering drugs through or into biological tissue, particularly the skin. The microneedle patch or device allows for delivery of drugs through or into the skin or other tissue barriers at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[1095] Preparations suitable for administration to the lung can be delivered by a single / multiple dose dry powder inhaler (DPI) driven by a wide range of passive breath drives and active power drives. The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable lung delivery devices depends on parameters such as the properties of the drug and its preparation, site of action, and the pathophysiology of the lung.

[1096] Many methods and devices for drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications (incorporated herein by reference in their entireties). Examples include US 8,192,408 entitled "Ocular trocar assembly" (Psivida Us, Inc.); US 7,585,517 entitled "Transcleral delivery" (Macusight, Inc.); US 5,710,182 and US 5,795,913 entitled "Ophthalmic composition" (Santen OY); US 8,663,639 entitled "Formulations for treating ocular diseases and conditions", US 8,486,960 entitled "Formulations and methods for vascular permeability-related diseases or conditions", US 8,367,097 and US 8,927,005 entitled "Liquid formulations for treatment of diseases or conditions", US 7,455,855 entitled "Delivering substance and drug delivery system using the same" (Santen Pharmaceutical Co., Ltd.); WO / 2011 / 050365 entitled “Conformable Therapeutic Shield For Vision and Pain” and WO / 2009 / 145842 entitled “Therapeutic Device for Pain Management and Vision” (Forsight Labs, LLC); US 9,066,779 and US 8,623,395 entitled “Implantable therapeutic device”, WO / 2014 / 160884 entitled “Ophthalmic Implant for Delivering Therapeutic Substances”, US 8,399,006, US 8,277,830, US 8,795,712, US 8,808,727, US 8,298,578 and WO / 2010 / 088548, WO / 2014 / 152959 and US20140276482 entitled “Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant”, US 8,905,963 and US 9,033,911 entitled “Injector apparatus and method for drug delivery”, WO / 2015 / 057554 entitled “Formulations and Methods for Increasing or Reducing Mucus”, US 8,715,712 and US 8,939 entitled “Ocular insert apparatus and methods”,948, WO / 2013 / 116061 entitled “Insertion and Removal Methods and Apparatus for Therapeutic Devices”, WO / 2014 / 066775 entitled “Ophthalmic System for Sustained Release of Drug to the Eye”, WO / 2015 / 085234 and WO / 2012 / 019176 entitled “Implantable Therapeutic Device”, WO / 2012 / 065006 entitled “Methods and Apparatus to determine Porous Structures for Drug Delivery”, WO / 2010 / 141729 entitled “Anterior Segment Drug Delivery”, WO / 2011 / 050327 entitled “Corneal Denervation for Treatment of Ocular Pain”, WO / 2013 / 066775 entitled “Ophthalmic System for Sustained Release of Drug to the Eye”, WO / 2014 / 066775 entitled “Ophthalmic System for Sustained Release of Drug to the Eye”, WO / 2015 / 085234 and WO / 2012 / 019176 entitled “Implantable Therapeutic Device”, Device”, WO / 2013 / 022801 entitled “Subconjunctival Implant for Posterior Segment Drug Delivery”, WO / 2012 / 019047 entitled “Therapeutic Agent Formulations for Implanted Devices”, WO / 2012 / 068549 entitled “Combined Delivery Methods and Apparatus”, WO / 2012 / 019139 entitled “Ocular Insert Apparatus and Methods”, WO / 2013 / 040426 entitled “Injector Apparatus and Method for Drug Delivery”, WO / 2012 / 019136 entitled “Injector Apparatus and Method for Drug Delivery”, WO / 2013 / 040247 entitled “Fluid Exchange Apparatus and Methods” (For Sight Vision 4,Inc.); US / 2014 / 0352690 entitled “Inhalation Device with Feedback System”, US 8,910,625 and US / 2015 / 0165137 (Vectura GmbH); US 6,948,496 entitled “Inhalers”, US / 2005 / 0152849 entitled “Powders comprising anti-adherent materials for use in dry powder inhalers”, US 6,582,678, US 8,137,657, US / 2003 / 0202944 and US / 2010 / 0330188 entitled “Carrier particles for use in dry powder inhalers”, US 6,221,338, US 6,989,155 entitled “Powders”, US / 2007 / 0043030 entitled “Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation”, US 7,845,349 entitled “Inhaler”, US / 2012 / 0114709 and US 8,101,160 entitled “Formulations for Use in Inhaler Devices”, US / 2013 / 0287854 entitled “Compositions and Uses”, US / 2014 / 0037737 and US 8,580,306 entitled “Particles for Use in a Pharmaceutical Composition”, US / 2015 / 0174343 entitled “Mixing Channel for an Inhalation Device”, US / 2016 / 0174344 entitled “Method of making particles US 7,744 for use in a pharmaceutical composition”855 and US / 2010 / 0285142, US 7,541,022, US / 2009 / 0269412 and US / 2015 / 0050350 entitled “Pharmaceutical formulations for dry powder inhalers” (Vectura Limited).

[1097] Additional non-limiting examples of how to deliver active compounds are provided in WO / 2015 / 085251 entitled “Intracameral Implant for Treatment of an Ocular Condition” (Envisia Therapeutics, Inc.); WO / 2011 / 008737 entitled “Engineered Aerosol Particles, and Associated Methods”; WO / 2013 / 082111 entitled “Geometrically Engineered Particles and Methods for Modulating Macrophage or Immune Responses”; WO / 2009 / 132265 entitled “Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates”; WO / 2010 / 099321 entitled “Interventional drug delivery system and associated methods”; WO / 2011 / 050969 entitled “Polymer particle composite having high fidelity order, size, and WO / 2008 / 100304 titled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Technologies, Inc. and University of North Carolina at Chapel Hill); WO / 2010 / 009087 (Liquidia) titled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) and WO / 2009 / 132206 entitled “Compositions and Methods for Intracellular Delivery and Release of Cargo”, WO / 2007 / 133808 entitled “Nano-particles for cosmetic applications”, WO / 2007 / 056561 entitled “Medical device, materials, and methods”, WO / 2010 / 065748 entitled “Method for producing patterned materials”, and WO / 2007 / 081876 entitled “Nanostructured surfaces for biomedical / biomaterial applications and processes thereof” (Liquidia Technologies, Inc.).

[1098] Additional non-limiting examples of drug delivery devices and methods include, for example, US20090203709 (Abbott Laboratories), entitled “Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor”; US20050009910, entitled “Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of aprodrug”; US20130071349, entitled “Biodegradable polymers for lowering intraocular pressure”; US8,481,069, entitled “Tyrosine kinase microspheres”; US8,465,778, entitled “Method of making tyrosine kinase microspheres”; US Pat. No. 5,826,979, entitled “Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods”; and US Pat. No. 5,826,979, entitled “Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods.” 8,409,607, US 8,512,738 and US 2014 / 0031408, entitled “Biodegradable intravitreal tyrosine kinase implants”, US 2014 / 0294986, entitled “Microsphere Drug Delivery System for Sustained Intraocular Release”, US 8,911,768, entitled “Methods For Treating Retinopathy With Extended Therapeutic Effect” (Allergan, Inc.); US 6,495,164, entitled “Preparation of injectable suspensions having improved injectability” (Alkermes Controlled Therapeutics, Inc.); WO 2014 / 047439 entitled “Biodegradable Microcapsules Containing Filling Material” (Akina, Inc.); WO 2010 / 132664 entitled “Compositions And Methods For Drug Delivery” (Baxter International Inc. Baxter Healthcare SA); US 20120052041 entitled “Polymeric nanoparticles with enhanced drug loading and methods of use thereof” (The Brigham and Women's Hospital, Inc.); US 20140178475, US 20140248358 and US 20140249158 entitled “Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same” (BIND Therapeutics, Inc.); US 20140178475, US 20140248358 and US 20140249158 entitled “Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same” (BIND Therapeutics, Inc.); US 5,869,103 (Danbiosyst UK Ltd.); US 8628801 (Universidad de Navarra) titled "Pegylated Nanoparticles"; US2014 / 0107025 (Jade Therapeutics, LLC) titled "Ocular drug delivery system"; titled "Agent delivery system comprised of microparticles and biodegradable gel with an improved releasing profile and methods of use US 6,287,588 entitled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles" (Macromed, Inc.); US 6,007,845 and US 5,578,325 entitled “Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers” (Massachusetts Institute of Technology); US20040234611, US20080305172, US20120269894 and US20130122064 entitled “Ophthalmic depot formulations for periocular or subconjunctival administration” (Novartis Ag); US 6,413,539 entitled “Block polymer” (Poly-Med, Inc.); US20070071756 entitled “Delivery of an agent to ameliorate inflammation” (Peyman); US20080305172, US20120269894 and US20130122064 entitled “Ophthalmic depot formulations for periocular or subconjunctival administration” (Novartis Ag); US 6,413,539 entitled “Block polymer” (Poly-Med, Inc.); US20080305172, US20120269894 and US20130122064 ... US20080166411 (Pfizer, Inc.) titled "Drugs Comprising Nanoparticles"; US 6,706,289 (PR Pharmaceuticals, Inc.) titled "Methods and compositions for enhanced delivery of bioactive molecules"; and US 8,663,674 (Surmodics) titled "Microparticlecontaining matrices for drug delivery".

[1099] IX. General Synthesis

[1100] The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared using the following schemes.

[1101] For convenience, compounds of the present invention having stereocenters may be drawn without stereochemistry. One skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following:

[1102] i) Physical separation of crystals - a technique in which macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the individual enantiomers are present, i.e. the material is a conglomerate and the crystals are visually distinct;

[1103] ii) Simultaneous crystallization - a technique whereby the individual enantiomers are crystallized separately from a solution of the racemate, which is possible only when the enantiomers are present as aggregates in the solid state;

[1104] iii) Enzymatic resolution - a technique that allows for the partial or complete separation of racemates by exploiting the different reaction rates of the enantiomers with enzymes;

[1105] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one step in the synthesis uses an enzymatic reaction to obtain the enantiomerically pure desired enantiomer or an enriched synthetic precursor of the desired enantiomer;

[1106] v) Chemical asymmetric synthesis - a synthetic technique in which the desired enantiomer is synthesized from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved by chiral catalysts or chiral auxiliaries;

[1107] vi) Diastereoisomer separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization, based on their now more distinct structural differences, followed by removal of the chiral auxiliary to yield the desired enantiomer;

[1108] vii) Primary and secondary asymmetric transformations - rapid equilibrium of the diastereomers from the racemate to produce a numerical preponderance of the diastereomer from the desired enantiomer in solution, wherein preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium so that ultimately, in principle, all of the material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomers;

[1109] viii) Kinetic resolution - This technique involves the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by utilizing the different reaction rates of enantiomers with chiral non-racemic reagents or catalysts under kinetic conditions;

[1110] ix) Enantiospecific synthesis from non-racemic precursors - synthetic techniques where the desired enantiomer is obtained from achiral starting materials and where the stereochemical integrity is not compromised or is only minimally compromised during the synthetic process;

[1111] x) Chiral liquid chromatography - a technique for separating the enantiomers of a racemate in a liquid mobile phase by virtue of their differential interactions with the stationary phase (including vial chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to stimulate differential interactions;

[1112] xi) Chiral gas chromatography - a technique for volatilizing racemates and separating enantiomers by means of their differential interaction in a gaseous mobile phase with a column containing a stationary non-racemic chiral adsorbent phase;

[1113] xii) Extraction with chiral solvents - a technique for separating enantiomers by virtue of the preferential solubility of one enantiomer in a specific chiral solvent;

[1114] xiii) Transport across chiral membranes – a technique where the racemate is brought into contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the membrane barrier. The separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through;

[1115] xiv) In one embodiment simulated moving bed chromatography is used. A wide variety of chiral stationary phases are commercially available.

[1116] X. Synthesis of Building Blocks for the Invention

[1117] Synthesis of 4-(3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

[1118]

[1119] Step 1: A stirred solution of anhydrous potassium phosphate (2.74 g, 12.92 mmol) in THF (150 mL) and water (5 mL) was purged with argon for 15 minutes. Then, 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (3.0 g, 8.62 mmol) and 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3.78 g, 12.92 mmol) were added to the reaction mixture and purged with argon for 15 minutes. 1310584-14-5(XPhos-Pd-G2) (338.60 mg) was added to the reaction mixture, purged with argon for 10 minutes, and stirred at 70 ° C for 16 hours. The reaction progress was monitored by LCMS & TLC. After the reaction was completed, the residue was filtered through celite and purified by column chromatography (reverse phase, 0.1% formic acid / acetonitrile) to give 2,6-dimethoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]benzaldehyde (41-1) (2.1 g, 4.24 mmol, yield 49.26%), LC-MS (ES + ):m / z 434.25[M+H] +

[1120] Step 2: To a stirred solution of 2,6-dimethoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]benzaldehyde (41-1) (500 mg, 1.15 mmol) and tert-butyl piperazine-1-carboxylate (257.81 mg, 1.38 mmol) in DCE (3 ml) and MeOH (2 ml) at 0°C was added acetic acid (32.99 uL, 576.76 mmol) and stirring was continued at room temperature for 4 hours. Sodium triacetoxyborohydride (488.96 mg, 2.31 mmol) was added to the reaction mixture at 0°C and stirring was continued at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude compound was purified by column chromatography (Davisil silica, 0-50% ethyl acetate / petroleum ether) to give tert-butyl 4-(2,6-dimethoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzyl)piperazine-1-carboxylate (41-3) (500 mg) as a colorless solid. LC-MS (ES) + ):m / z604.44[M+H] +

[1121] Step 3: To a stirred solution of tert-butyl 4-[[2,6-dimethoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]phenyl]methyl]piperazine-1-carboxylate (41-3) (0.88 g, 1.46 mmol) in DCM (10 mL) was added trifluoroacetic acid (2.25 ml, 29.15 mmol) and the reaction was stirred at 70 °C for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was dried via rotary evaporation and co-distilled with acetonitrile and toluene. The crude compound was triturated with diethyl ether to afford 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-6-methyl-1H-pyrazolo[3,4-c]pyridin-7-one (1-4) (800 mg, 68.21% yield, 76% purity). LC-MS (ES + ):m / z 384.35[M+H] +

[1122] Synthesis of 4-(3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (Alternative Route)

[1123]

[1124] Step-1: To a stirred solution of 4-bromo-2,6-dimethoxy-benzaldehyde B2-1 (15 g, 61.21 mmol) and tert-butyl piperazine-1-carboxylate (11.40 g, 61.21 mmol) in dry dichloromethane (350 mL) was added acetic acid (3.68 g, 61.21 mmol, 3.50 mL) at 0°C. The reaction mixture was stirred at 0°C for 3 hours. Sodium triacetoxyborohydride (25.95 g, 122.42 mmol) was added to the reaction mixture in one portion at 0°C. The reaction mixture was allowed to slowly warm to room temperature over 1 hour and stirred at room temperature for an additional 9 hours. After completion of the reaction, the reaction mixture was quenched with water (500 mL) and extracted with DCM (2 x 500 mL). The organic layers were combined, further washed with brine (1×250 mL), dried over anhydrous Na 2 SO 4 , and concentrated to give a crude product, which was purified by column chromatography using silica gel (100 / 200 mesh) and eluted with 30-40% EtOAc / hexane to give tert-butyl 4-[(4-bromo-2,6-dimethoxy-phenyl)methyl]piperazine-1-carboxylate (20.5 g, 48.38 mmol, 79.03% yield, 98.01% purity) as a light yellow pasty solid. 1H NMR (400 MHz, CDCl 3 ): δ 6.72 (s, 2H), 3.82 (s, 6H), 3.73 (s, 2H), 3.55 (s, 4H), 2.62 (s, 4H), 1.44 (s, 9H). LC-MS (ES) + ):m / z 415[M+H] + .

[1125] Step-2: To a stirred solution of tert-butyl 4-[(4-bromo-2,6-dimethoxy-phenyl)methyl]piperazine-1-carboxylate (15 g, 36.12 mmol) in 1,4-dioxane (350 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (13.76 g, 54.17 mmol) at room temperature under argon atmosphere, followed by potassium acetate (10.63 g, 108.35 mmol, 6.77 mL). The reaction mixture was repeatedly degassed with argon and cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; and iron (1.47 g, 1.81 mmol) were added in one portion under argon atmosphere. The reaction mixture was again repeatedly degassed with argon and then heated at 100° C. for 12 hours. After the completion of the reaction, the reaction mixture is cooled to room temperature and filtered through diatomaceous earth, washed with ethyl acetate (300mL). The concentrated filtrate is dissolved in ethyl acetate (500mL) and washed with water (2 × 100mL), salt solution (1 × 100mL), and dried over anhydrous Na2SO4, concentrated to give a crude product. The crude product is further purified by column chromatography using silica gel (100 / 200 mesh) and eluted under 40-50% EtOAc / hexane to give 4-[[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-tert-butyl carboxylate (12g, 25.69mmol, 71.14% yield, 99% purity). 1HNMR (400MHz, CDCl3) δ6.99 (s, 2H), 3.85 (s, 6H), 3.74 (s, 2H), 3.39 (t, J = 5.0Hz, 4H), 2.46 (t, J = 5.0Hz, 4H), 1.43 (s, 9H), 1.35 (s, 12H). LC MS: Boric acid: RT: 1.26min=381.41[M+H] + and borate: RT: 1.75 min = 463.48 [M+H] + Note: LCMS indicated 41% boronic acid material and 58% boronate material.

[1126] Step-3: To a stirred solution of 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (1.0 g, 2.87 mmol) in water (10 mL) and THF (30 mL) were added tert-butyl 4-[[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate 5 (1.33 g, 2.87 mmol) and K3PO4 (1.52 g, 7.18 mmol). The resulting solution was degassed with nitrogen for 15 minutes, followed by the addition of XPhos-Pd-G2 (112.98 mg, 143.60 umol). After the addition of the catalyst, the reaction mixture was heated at 80°C for 6 hours while being monitored by LCMS and TLC. The reaction was filtered through a pad of celite, washed with EtOAc (50 mL), and the filtrate was evaporated to give a crude product. The crude compound was purified by (silica gel 100-200 mesh, 60-70% EtOAc / petroleum ether) to give tert-butyl 4-[[2,6-dimethoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]phenyl]methyl]piperazine-1-carboxylate 7 (0.75 g, 1.22 mmol, 42.58% yield, 98.44% purity) as an off-white solid. 1 H NMR (400MHz, CDCl3) δ8.35(s,1H),7.70(s,1H),7.31(d,J=2Hz,2H),6.86(d,J=2Hz,2H),6.61(s,2H),5.50(s, 2H),4.15(s,2H),3.83(s,6H),3.78(s,3H),3.68(s,3H),3.58(m,4H),2.98–2.96(m,4H)1.44(s,9H); LC-MS(ES) + ):m / z 604.44[M+H] + .

[1127] Step-4: To a stirred solution of tert-butyl 4-[[2,6-dimethoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]phenyl]methyl]piperazine-1-carboxylate (0.75 g, 1.24 mmol) in CHCl (2 mL) was added 4 M dioxane / HCl (0.4 ml, 12.4 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 4 hours while monitoring by TLC. The reaction mixture was concentrated to obtain the crude compound. The crude compound was triturated with ether (50 × 2) and n-pentane (20 × 2) to give 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one HCl salt (0.65 g, 1.19 mmol, 95.50% yield, 98.57% purity) as a white solid. It was used in the next step without any purification.

[1128] Step-5: A stirred solution of 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (1.63 g, 3.24 mmol) in TFA (2.49 mL, 32.37 mmol) was stirred and heated at 70°C for 4 hours while monitoring by TLC. After completion, the reaction mixture was concentrated and the crude compound was triturated with diethyl ether (100 × 2) to give 4-[3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl]-6-methyl-1H-pyrazolo[3,4-c]pyridin-7-one TFA salt (1.6 g, 3.14 mmol, yield 96.95%, purity 97.57%) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ13.77(s,1H),8.97(bs,2H)8.22(s,1H),7.63(s,1H),6.98(s,2H)4.25(bs,2H),3.94(s,6H),3.63(s,3H),3.39 -3.40(bs,8H); LC-MS(ES + ):m / z 384.28[M+H] + .

[1129] Synthesis of 2,6-dimethoxy-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde

[1130]

[1131] To a stirred solution of compound 2,6-dimethoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]benzaldehyde (1.0 g, 2.31 mmol) was added TFA (2.63 g, 23.07 mmol, 1.78 mL) at 0 ° C and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after completion, the reaction mixture was concentrated to provide a crude compound. The crude compound was purified by reverse phase using 0.1% TFA and ACN to give 2,6-dimethoxy-4-(6-methyl-7-oxo-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde (0.9 g, 1.90 mmol, yield 82.16%, purity 90%, 061) as a brown solid. The desired compound was confirmed by LCMS. ), LC-MS (ES + ):m / z 314.2[M+H] +

[1132] Synthesis of 2-chloro-6-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde

[1133]

[1134] Step-1: To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-c]pyridin-7-one (4 g, 10.12 mmol) and 4-bromo-2-chloro-6-methoxy-benzaldehyde (2.27 g, 9.11 mmol) in THF (20.00 mL) was added a solution of potassium acetate (2.98 g, 30.36 mmol, 1.90 mL) in water (7 mL). Argon was then purged for 20 minutes, followed by the addition of cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; and iron (413.22 mg, 506.00 umol) and degassed. The mixture was heated to 70° C. for 4 hours. The reaction was monitored by TLC. Then, the reaction mixture was diluted with water and extracted with ethyl acetate, and the organic layer was washed with brine solution, separated, dried over Na2SO4, and concentrated. The crude product was purified by Biotage using 50% EA / PE to give 2-chloro-6-methoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]benzaldehyde (1.1 g, 2.51 mmol, yield 24.82%, light yellow solid), LC-MS (ES) + ):m / z 438.30[M+H] +

[1135] Step-2: To the compound 2-chloro-6-methoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]benzaldehyde (0.25 g, 570.94 umol) was added trifluoroacetic acid 99% (2.96 g, 25.96 mmol, 2 mL). The reaction mixture was heated at 70 ° C for 1 hour. The completion of the reaction was monitored by TLC and LCMS. After the completion of the reaction, the excess TFA was removed in vacuo and the crude product was washed with diethyl ether (2×5 mL) to give 2-chloro-6-methoxy-4-(6-methyl-7-oxo-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde (0.21 g, 470.97 umol, yield 82.49%, purity 96.83%, 061) as a light brown solid. LC-MS (ES + ):m / z 318.27[M+H] +

[1136] Synthesis of 2-chloro-6-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde

[1137]

[1138] To a stirred solution of 2-chloro-6-methoxy-4-(6-methyl-7-oxo-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde (0.3 g, 694.85 μmol, 0.61) in 1,4-dioxane (5 mL) was added 2-methylbut-2-ene (389.85 mg, 5.56 mmol). A mixture of sodium chlorite (314.22 mg, 3.47 mmol) and sodium dihydrogen phosphate (1.67 g, 13.90 mmol) was then slowly added to the reaction mixture and allowed to stir at room temperature for 1 hour. Upon completion, the reaction mass was directly evaporated under reduced pressure. The crude product was purified by using reverse phase. The desired product was eluted with 30% ACN / (1% FA / water) to give 2-chloro-6-methoxy-4-(6-methyl-7-oxo-1H-pyrazolo[3,4-c]pyridin-4-yl)benzoic acid (100 mg, 282.39 umol, 40.64% yield, 94.24% purity) as a light brown solid. LC-MS (ES + ):m / z 334.32[M+H] +

[1139] Synthesis of 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid

[1140]

[1141] Step-1: To a solution of 4-bromo-2-(trifluoromethoxy)benzaldehyde (5 g, 18.59 mmol) in 1,4-dioxane (120 mL) was added bis(pinacolato)diboron (7.08 g, 27.88 mmol) and potassium acetate (5.47 g, 55.76 mmol) and degassed with argon for 20 minutes. Finally, Pd(dppf)Cl2.DCM complex (0.758 g, 0.929 mmol) was added, degassed with argon again for 10 minutes and stirred at 90°C for 16 hours while monitoring the reaction by TLC and LCMS. Upon completion, the reaction mass was filtered through a pad of celite. The crude product was quenched with water (200 ml) and extracted with EtOAc (2 x 200 ml). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to give the crude compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)benzaldehyde (5 g, yield 51.07%, purity 60%) as a brown solid. LC-MS (ES + ):m / z 233.94[MH] - (boric acid substance)

[1142] Step-2: To a stirred solution of 5-bromo-1,3,4-trimethyl-pyridin-2-one (3 g, 13.88 mmol) in THF (80 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)benzaldehyde (4.39 g, 13.88 mmol) and K3PO4 (4.72 g, 34.71 mmol, 2.02 mL) dissolved in water (20 mL). The resulting solution was degassed with argon for 20 minutes, followed by the addition of XPhos-Pd-G2 (0.544 g, 0.694 mmol), degassed again with argon for 10 minutes, and stirred at 75°C for 4 hours while monitoring by LCMS and TLC. The reaction mixture was filtered through a pad of celite, washed with EtOAc (100 mL), and the filtrate was evaporated to give a crude product. The crude compound was purified by silica gel (100-200 mesh, 60-70% EtOAc / petroleum ether) to give 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde 5 (3.5 g, yield 74.14%, purity 95.67%) as a light yellow solid. LC-MS (ES + ):m / z 326.30[M+H] +

[1143] Step-3: To a stirred solution of 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde (3.5 g, 10.76 mmol) in THF (130 mL) was added 2-methyl-2-butene (6.04 g, 86.08 mmol, 9.12 mL) at 25° C., followed by the addition of sodium chlorite (4.87 g, 53.80 mmol) and sodium dihydrogen phosphate (25.82 g, 215.20 mmol) dissolved in water (70 mL), and the mixture was stirred at room temperature for 3 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated to half the amount to give a crude product, which was purified by trituration with methanol and then washed with water to give 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzoic acid (2.3 g, 6.44 mmol, yield 59.87%, purity 95.58%). LC-MS (ES + ):m / z 342.12[M+H] +

[1144] Synthesis of 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid (alternative route)

[1145]

[1146] Step-1: To a mixture of B4-4 (10 g, 35.1 mmol, 1 eq) and B2Pin2 (13.4 g, 52.6 mmol, 1.5 eq) in N,N-dimethylformamide (150 mL) were added potassium acetate (17.2 g, 175 mmol, 5 eq) and Pd(dppf)Cl2 (2.57 g, 3.5 mmol, 0.1 eq) at 15°C under a nitrogen atmosphere. The mixture was stirred at 80°C for 15 hours; after the reaction was completed as monitored by HPLC, the reaction mixture was cooled to room temperature; the mixture was concentrated in vacuo to remove part of the solvent; the residue was diluted with water (200 mL) and extracted with ethyl acetate (100 mL×2). The organic layers were combined, washed with brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to give a residue; the residue was triturated with petroleum ether (50 V), the suspension was filtered, and the filter cake was dried in vacuo to give the product as a white solid (8.5 g, 73% yield). 1 H NMR (400MHz, CDCl3) δ7.98 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 1.29 (s, 12H).

[1147] Step-2: To a mixture of B4-5 (5 g, 23.1 mmol, 1 eq.) and compound-9 (8.45 g, 25.5 mmol, 1.1 eq.) in dioxane (60 mL) was added water (20 mL), sodium carbonate (6.13 g, 57.9 mmol, 2.5 eq.), and Pd(dppf)Cl2 (847 mg, 1.16 mmol, 0.05 eq.) at 10°C under a nitrogen atmosphere. The mixture was stirred at 80°C for 13 hours. The mixture was concentrated in vacuo to remove dioxane; the aqueous phase was then extracted with ethyl acetate (100 mL x 2). The aqueous phase was acidified to pH 5 with HCl (2N) to precipitate a solid. The suspension was filtered, and the solid was dried in vacuo; the solid was triturated with ethyl acetate (10 mL) to give the product as a white solid (5.5 g, 67% yield). 1 H NMR (400MHz, MeOD-d4) δ8.03(d,J=7.9Hz,1H),7.50(s,1H),7.41(dd,J=8.0,1.3Hz,1H),7.35(s,1H),3.60(s,3H),2.17(s,3H),2.13(s,3H).

[1148] Synthesis of 4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2-(trifluoromethoxy)benzaldehyde

[1149]

[1150] To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)benzaldehyde (Compound-3) (3.98 g, 12.60 mmol) in dry THF (80 mL) at room temperature under argon atmosphere was added 4-bromo-2-methyl-2,7-naphthyridin-1-one (3 g, 12.60 mmol), followed by potassium phosphate (K 3 PO 4 ) (6.69 g, 31.51 mmol) dissolved in water (20 mL) and the resulting mixture was purged with argon for up to 30 minutes. 1310584-14-5 (Xphos Pd G 2 ) (0.495 g, 0.63 mmol) was then added and the resulting mixture was heated to reflux at 75° C. for up to 4 hours. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was allowed to reach room temperature and diluted with ice-cold water (100 mL), the resulting solid was filtered off and dried under high vacuum to give a crude product, which was triturated with n-pentane (100 mL) to give a solid mixture, which was again refluxed in methanol (80 mL) and filtered to give 4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2-(trifluoromethoxy)benzaldehyde (2.5 g, 6.54 mmol, 51.36% yield, 92% purity) as a brown solid. LC-MS (ES + ):m / z 349.51[M+H] +

[1151] Synthesis of 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde

[1152]

[1153] Step-1: To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde and 4-bromo-2-chloro-6-methoxy-benzaldehyde (3.85 g, 15.43 mmol) in 1,4-dioxane (40 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.70 g, 18.52 mmol) at room temperature under an argon atmosphere, followed by potassium acetate (3.79 g, 38.58 mmol). The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; and iron (0.63 g, 0.77 mmol) were added in one portion under an argon atmosphere. The reaction mixture was again repeatedly degassed with argon and then heated to reflux at 90° C. for 4 hours. After the reaction is completed, the reaction mixture is cooled to room temperature and filtered through diatomaceous earth, washed with ethyl acetate (200mL). The filtrate is concentrated to obtain a residual material. The residual material is dissolved in ethyl acetate (200mL) and washed with water (2×50mL), brine (1×50mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product is purified by column chromatography using silica gel (100 / 200 mesh) and eluted under 30-40% EtOAc / hexane to obtain 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4g, yield 83.04%, purity 95%) as a light yellow solid. LC-MS (ES + ):m / z[M+H] + 215.13 (corresponding boric acid species observed)

[1154] Step-2: To a stirred mixture of 5-bromo-1,3,4-trimethyl-pyridin-2-one (1 g, 4.63 mmol) and 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 2 (2.06 g, 6.94 mmol) in dioxane (15 mL) and water (5 mL) in a sealed tube at room temperature was added potassium phosphate (2.46 g, 11.57 mmol), and the resulting mixture was purged with argon for 10 minutes. Cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; iron (0.18 g, 0.23 mmol) were added to the reaction mixture, which was again degassed with argon for 5 minutes and then heated at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (100 mL). The organic layer was separated from the filtrate and concentrated to give a crude product, which was purified by column chromatography using silica gel (100 / 200 mesh) and eluted with 60% EtOAc / petroleum ether to give 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde (0.920 g, yield 61.76%, purity 95%). LC-MS (ES + ):m / z 306.31[M+H] +

[1155] Synthesis of 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid

[1156]

[1157] To a stirred solution of 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde (500 mg, 1.64 mmol) in THF (25 mL) was added dropwise 2-methyl-2-butene (917.50 mg, 13.08 mmol) at 0°C, followed by the addition of sodium chlorite (739.48 mg, 8.18 mmol) in a single portion and the addition of sodium dihydrogen phosphate (3.92 g, 32.71 mmol) dissolved in water (20 mL) dropwise. The reaction mixture was slowly warmed to room temperature over 30 minutes and stirred at room temperature for an additional 6 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated to obtain a crude product, which was purified by trituration with water / methanol and the precipitated solid was filtered and dried thoroughly to obtain 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid (400 mg, yield 70.90%, purity 93.26%) as an off-white solid. LC-MS (ES + ):m / z322.12[M+H]+

[1158] Synthesis of 2-chloro-6-methoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde

[1159]

[1160] To a stirred solution of 4-bromo-2-methyl-2,7-naphthyridin-1-one (1 g, 4.18 mmol) in dry THF (40 mL) in a sealed tube was added 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.24 g, 4.18 mmol) at room temperature, followed by the addition of tripotassium phosphate (2.22 g, 10.46 mmol) dissolved in water (10 mL) under an argon atmosphere. The reaction mixture was repeatedly degassed with argon and Pd-Xphos-G2 catalyst (0.16 g, 0.20 mmol) was added to the reaction mixture in one portion. The reaction mixture was again degassed with argon and then heated at 80°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (100 mL). The organic layer was separated from the filtrate and concentrated to obtain the crude product. The crude product was purified by column chromatography using a gradient of 0.1% FA / water and acetonitrile as eluent to give 2-chloro-6-methoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (0.30 g, yield 21.46%, purity 85.97%) as an off-white solid. LC-MS (ES + ):m / z 329.17[M+H] +

[1161] Synthesis of 2-chloro-4-(7-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-6-methoxybenzoic acid

[1162]

[1163] To a stirred solution of 2-chloro-4-(7-fluoro-2-methyl-1-oxo-4-isoquinolinyl)-6-methoxy-benzaldehyde (0.17 g, 0.49 mmol) in THF (25 mL) at 0°C was added 2-methyl-2-butene (0.27 g, 3.93 mmol), followed by dropwise addition of sodium chlorite (0.22 g, 2.46 mmol) and sodium dihydrogen phosphate (1.18 g, 9.83 mmol) dissolved in water (10 mL). The reaction mixture was slowly warmed to room temperature over 30 minutes and stirred at room temperature for 12 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated to half the volume to obtain a crude product, which was purified by trituration with methanol / water to give 2-chloro-4-(7-fluoro-2-methyl-1-oxo-4-isoquinolinyl)-6-methoxy-benzoic acid (0.12 g, yield 64.09%, purity 95%) as a white solid. LC-MS (ES + ):m / z 362.25[M+H] +

[1164] Synthesis of 2-fluoro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde

[1165]

[1166] Step-1: To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde (7 g, 30.04 mmol) in 1,4-dioxane (300 mL) at room temperature under an argon atmosphere was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (11.44 g, 45.06 mmol), followed by potassium acetate (8.84 g, 5.63 mL). The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; and iron (1.23 g, 1.50 mmol) were added in one portion under an argon atmosphere. The reaction mixture was again repeatedly degassed with argon and then heated to reflux at 90°C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (200 mL). The filtrate was concentrated to give a residual substance. The residual substance was dissolved in ethyl acetate (300 mL) and washed with water (2×100 mL), brine (1×50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was ground with pentane (500 mL), stirred thoroughly and filtered through diatomaceous earth. The filtrate was concentrated to give a solid, which was slurried with hexane (25 mL), filtered, washed with hexane (10 mL), and dried thoroughly to give the product 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4.1 g, yield 46.29%, purity 95%) as a light brown solid. LC-MS (ES + ):m / z199.17[M+H] + (The corresponding boronic acid species were observed)

[1167] Step-2: To a stirred solution of 5-bromo-1,3,4-trimethylpyridin-2(1H)-one (1 g, 4.63 mmol) in dry THF (50 mL) in a sealed tube at room temperature was added 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.30 g, 4.63 mmol), followed by the addition of tripotassium phosphate (2.46 g, 11.57 mmol) dissolved in water (15 mL) under an argon atmosphere. The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; and iron (0.18 g, 0.23 mmol) were added to the reaction mixture in one portion. The reaction mixture was again degassed with argon and then heated at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (100 mL). The organic layer was separated from the filtrate and concentrated to give a crude product. The crude product was purified by column chromatography using silica gel (100 / 200 mesh) and eluted under 4-5% MeOH / EtOAc to give 2-fluoro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde (0.45 g, yield 32.40%, purity 96.40%) as an off-white solid. LC-MS (ES + ):m / z 290.52[M+H] +

[1168] Synthesis of 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde

[1169]

[1170] To a stirred solution of 4-bromo-2-methyl-2,7-naphthyridin-1-one (2 g, 8.37 mmol) in dry THF (50 mL) in a sealed tube at room temperature was added 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.34 g, 8.37 mmol), followed by the addition of tripotassium phosphate (4.44 g, 20.91 mmol) dissolved in water (15 mL) under an argon atmosphere. The reaction mixture was repeatedly degassed with argon and Pd-Xphos-G2 catalyst (0.32 g, 0.41 mmol) was added to the reaction mixture in one portion. The reaction mixture was again degassed with argon and then heated at 80°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (100 mL). The organic layer was separated from the filtrate and concentrated to obtain the crude product. The crude product was purified by column chromatography using a gradient of 0.1% FA / water and acetonitrile as eluent to give 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde 7 (1.90 g, yield 72.15%, purity 99.21%) as an off-white solid. LC-MS (ES + ):m / z 313.14[M+H] +

[1171] Synthesis of 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzoic acid

[1172]

[1173] To a stirred solution of 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde 7 (0.40 g, 1.28 mmol) in THF (15 mL) was added 2-methyl-2-butene (0.71 g, 10.25 mmol) at 0°C, followed by sodium chlorite (0.57 g, 6.40 mmol) and sodium dihydrogen phosphate (3.07 g, 25.62 mmol) dissolved in water (10 mL). The reaction mixture was slowly warmed to room temperature over 30 minutes and stirred at room temperature for 6 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated to half the volume to give a crude product, which was purified by trituration with methanol / water to give 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzoic acid (0.22 g, 50.46% yield, 96.44% purity) as an off-white solid. LC-MS (ES + ):m / z 329.22[M+H] +

[1174] Synthesis of 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde

[1175]

[1176] Step-1: To a stirred solution of 4-bromo-2,6-dimethoxy-benzaldehyde (10 g, 40.80 mmol) in 1,4-dioxane (300 mL) at room temperature under an argon atmosphere was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (15.54 g, 61.21 mmol), followed by potassium acetate (12.01 g, 122.41 mmol). The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphine; dichloromethane; dichloropalladium; and iron (1.67 g, 2.04 mmol) were added in one portion under an argon atmosphere. The reaction mixture was again repeatedly degassed with argon and then heated under reflux at 95°C for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (200 mL). The filtrate is concentrated to obtain residual material.The residual material is dissolved in ethyl acetate (500mL) and washed with water (2 × 100mL), brine (1 × 50mL), and dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The crude product is purified by column chromatography using silica gel (100 / 200 mesh) and eluted under 30-40% EtOAc / petroleum ether to obtain 2,6- dimethoxy -4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) benzaldehyde 2 (7g, yield 55.79%, purity 95%) as a light brown solid.

[1177] Step-2: To a stirred solution of 5-bromo-1,3,4-trimethyl-pyridin-2-one (2 g, 9.26 mmol) in dry THF (50 mL) in a sealed tube at room temperature was added 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 2 (2.70 g, 9.26 mmol), followed by the addition of tripotassium phosphate (4.91 g, 23.14 mmol) dissolved in water (15 mL) under an argon atmosphere. The reaction mixture was repeatedly degassed with argon, and XPhos-PdG2 catalyst (0.36 g, 0.46 mmol) was added to the reaction mixture in one portion. The reaction mixture was again degassed with argon and then refluxed at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (100 mL). The organic layer was separated from the filtrate and concentrated. The crude product was purified by reverse phase column chromatography using a gradient of 0.1% FA / water and acetonitrile as eluent to give 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridinyl)benzaldehyde (1.45 g, 4.63 mmol, purity 96.22%) as an off-white solid. LC-MS (ES + ):m / z 302.27[M+H] +

[1178] Synthesis of 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid

[1179]

[1180] To a stirred solution of 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde (1 g, 3.32 mmol) in THF (50 mL) was added 2-methyl-2-butene (1.86 g, 26.55 mmol) dropwise at 0° C., followed by sodium chlorite (1.50 g, 16.59 mmol) and sodium dihydrogen phosphate (7.96 g, 66.37 mmol) in water (20 mL). The reaction mixture was slowly warmed to room temperature over 30 minutes and stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was concentrated to 1 / 4 of the total volume and the precipitated colorless solid was filtered, washed with water (10 mL), and fully dried to obtain 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid (0.65 g, yield 59.90%, purity 97.04%) as a white solid. LC-MS (ES + ):m / z 318.32[M+H] +

[1181] Synthesis of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde

[1182]

[1183] To a stirred solution of 4-bromo-2-methyl-2,7-naphthyridin-1-one (2 g, 8.37 mmol) in dry THF (50 mL) in a sealed tube at room temperature was added 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.44 g, 8.37 mmol), followed by the addition of tripotassium phosphate (4.44 g, 20.91 mmol) dissolved in water (20 mL) under an argon atmosphere. The reaction mixture was repeatedly degassed with argon, and Pd-Xphos-G2 catalyst (0.32 g, 0.41 mmol) was added to the reaction mixture in one portion. The reaction mixture was again degassed with argon and then refluxed at 80°C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through celite, washing with ethyl acetate (100 mL). The organic layer was separated from the filtrate and concentrated to obtain the crude product. The crude product was purified by column chromatography using silica gel (100 / 200 mesh) and eluted with 4-5% MeOH / EtOAc to give 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (1.8 g, yield 64.42%, purity 97.10%) as a light yellow solid. LC-MS (ES + ):m / z 325.29[M+H] +

[1184] Synthesis of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzoic acid

[1185]

[1186] To a stirred solution of 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (0.35 g, 1.08 mmol) in THF (25 mL) was added 2-methyl-2-butene (0.60 g, 8.64 mmol) dropwise at 0° C., followed by sodium chlorite (0.48 g, 5.40 mmol) and sodium dihydrogen phosphate (2.59 g, 21.60 mmol) in water (20 mL). The reaction mixture was slowly warmed to room temperature over 30 minutes and stirred at room temperature for an additional 12 hours. After the reaction was completed, the reaction mixture was concentrated to 1 / 4 of the total volume and the precipitated colorless solid was filtered, washed with water (10 mL) and fully dried to obtain 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzoic acid 8 (0.28 g, yield 62.95%, purity 82.64%) as an off-white solid. LC-MS (ES + ):m / z 341.29[M+H] + .

[1187] Synthesis of 2-ethoxy-5-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde

[1188]

[1189] Step-1: To a solution of 4-bromo-2-hydroxy-5-methoxy-benzaldehyde (505 mg, 2.19 mmol) in DMF (4.89 mL) was added granular potassium carbonate (906.24 mg, 6.56 mmol, 395.74 uL), followed by the addition of iodoethane (340.90 mg, 2.19 mmol, 175.72 uL) at room temperature and stirred under an argon atmosphere for 5 hours. After completion of the reaction, the mixture was quenched by pouring into water (50 mL) and then extracted with ethyl acetate (50 mL×3). The organic layer was washed with LiCl (5% w / v in water, 50 mL), then dried over brine (50 mL), Na2SO4, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 4:6) to give 4-bromo-2-ethoxy-5-methoxybenzaldehyde as a white solid. Yield - 504 mg, 89%; LC-MS (ES + ):m / z 260.0[M+H] + .

[1190] Step-2: Initially, cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (112.96 mg, 154.38 umol), 1-2 4-bromo-2-ethoxy-5-methoxy-benzaldehyde (400 mg, 1.54 mmol), bis(pinacolato)diboron (470.44 mg, 1.85 mmol), potassium acetate (454.54 mg, 4.63 mmol, 289.52 uL) were charged in a MW vial (2-5 mL), suspended in 1,4-dioxane (5.89 mL) under argon atmosphere and heated at 140 °C in MW for 40 minutes. To the suspension was then added 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (134.62 mg, 386.63 umol) and potassium carbonate (2 M, 2 equivalents) under argon and reheated at 120 ° C for 30 minutes, then checked by LCMS. After completion of the reaction, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL) and then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue, which was purified by flash column chromatography (hexane: ethyl acetate 1: 0 to 0: 1) to give 2-ethoxy-5-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde as a mixture of positional isomers. Yield - 599 mg, 82%; LC-MS (ES + ):m / z 448.5[M+H] + .

[1191] Synthesis of 4-(2,5-dichloro-4-(piperazine-1-carbonyl)phenyl)-1-(4-methoxybenzyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

[1192]

[1193] Step-1: Initially, 4-bromo-2,5-dichloro-benzoic acid (609 mg, 2.26 mmol), tert-butyl piperazine-1-carboxylate (462.27 mg, 2.48 mmol, 45.96 uL), DIPEA (583.23 mg, 4.51 mmol, 786.02 uL), and HATU (943.71 mg, 2.48 mmol) were charged into a vial. The reactants were then dissolved in DMF (6.69 mL) and stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with water and then extracted with EA (3 x 10 mL). The organic layer was washed with LiCl (5% w / v in water, 50 mL), then dried over brine (50 mL), Na2SO4, filtered, and concentrated to a residue that was purified via flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to afford tert-butyl 4-(4-bromo-2,5-dichlorobenzoyl)piperazine-1-carboxylate as a white solid. Yield - 535 mg, 54%; LC-MS (ES) + ):m / z 339.0[M+H] + .

[1194] Step-2: Initially, cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (79.83 mg, 109.1 umol), tert-butyl 4-(4-bromo-2,5-dichloro-benzoyl)piperazine-1-carboxylate (478 mg, 1.09 mmol), bis(pinacolato)diboron (332.45 mg, 1.31 mmol), potassium acetate (321.21 mg, 3.27 mmol) were charged in a MW vial (2-5 mL), suspended in 1,4-dioxane (5.89 mL) under argon atmosphere and heated at 140 °C in MW for 40 min. To the suspension was then added 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (417.86 mg, 1.20 mmol) and potassium carbonate (2M, 2 equivalents) under argon and reheated at 120°C for 30 minutes before checking by LCMS. After completion of the reaction, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL) and then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give tert-butyl 4-[2,5-dichloro-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]benzoyl]piperazine-1-carboxylate as a mixture of positional isomers. Yield - 736 mg, 100%; LC-MS (ES+): m / z 626.5 [M+H] + .

[1195] Step-3: Initially, tert-butyl 4-[2,5-dichloro-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]benzoyl]piperazine-1-carboxylate (736 mg, 1.17 mmol) was dissolved in DCM (5.69 mL), and then TFA (267.89 mg, 2.35 mmol, 181.01 uL) was added dropwise, and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated to dryness and co-evaporated with DCM (10 mL×2), then concentrated to a TFA salt and used in the next step without further purification. Yield: 752 mg, 100%; LC-MS (ES+): m / z 526.4 [M+H] + .

[1196] Synthesis of 4-(2-chloro-5-methoxy-4-(piperazin-1-ylmethyl)phenyl)-1-(4-methoxybenzyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

[1197]

[1198] Step-1: Initially, 4-bromo-5-chloro-2-methoxy-benzaldehyde (782 mg, 3.13 mmol) and tert-butyl 2-piperazine-1-carboxylate (642.16 mg, 3.45 mmol) were charged into a reaction vial and dissolved in 1,2-DCE (10.45 mL), followed by the addition of sodium triacetoxyborohydride 95% (1.99 g, 9.40 mmol) in one portion. The reaction mixture was allowed to stir at room temperature and monitored by LCMS. After completion of the reaction, the mixture was concentrated to dryness and purified via flash column chromatography (DCM:MeOH until 10%) to obtain tert-butyl 4-[(4-bromo-5-chloro-2-methoxy-phenyl)methyl]piperazine-1-carboxylate. Yield-1.01 g, 77%; LC-MS (ES + ):m / z 421.3[M+H] + .

[1199] Step-2: Initially, cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (127.78 mg, 174.63 umol), tert-butyl 4-[(4-bromo-5-chloro-2-methoxy-phenyl)methyl]piperazine-1-carboxylate (733 mg, 1.75 mmol), bis(pinacolato)diboron (532.15 mg, 2.10 mmol), potassium acetate (514.16 mg, 5.24 mmol, 327.49 uL) were charged in a MW vial (2-5 mL), suspended in 1,4-dioxane (2.58 mL) under argon atmosphere and heated at 140 °C in MW for 40 min. To the suspension was then added 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (134.62 mg, 386.63 umol) and potassium carbonate (2 M, 2 equivalents) under argon and reheated at 120 ° C for 30 minutes, then checked by LCMS. After completion of the reaction, the mixture was filtered through a celite pad and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL), then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue, which was purified by flash column chromatography (hexane: ethyl acetate 1: 0 to 0: 1) to give tert-butyl 4-[[5-chloro-2-methoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]phenyl]methyl]piperazine-1-carboxylate as a mixture of positional isomers. Yield - 751 mg, 71%; LC-MS (ES + ):m / z 608.5[M+H] + .

[1200] Step-3: Initially, tert-butyl 4-[[5-chloro-2-methoxy-4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]phenyl]methyl]piperazine-1-carboxylate (751 mg, 1.23 mmol) was dissolved in DCM (5.69 mL), followed by the addition of TFA (281.62 mg, 2.47 mmol, 190.28 uL), and the mixture was allowed to stir overnight. After completion of the reaction, the mixture was concentrated to dryness and co-evaporated with DCM (10 mL×2), then concentrated to a TFA salt and used in the next step without further purification. Yield-768 mg, 100%; LC-MS (ES) + ):m / z 508.5[M+H] + .

[1201] Synthesis of 1-(4-methoxybenzyl)-6-methyl-4-(4-(piperazin-1-ylmethyl)-3-(trifluoromethoxy)phenyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

[1202]

[1203] Step-1: Initially, tert-butyl piperazine-1-carboxylate (761.58 mg, 4.09 mmol, 303.70 uL) and 4-bromo-2-(trifluoromethoxy)benzaldehyde (1000 mg, 3.72 mmol) were charged into a reaction vial and dissolved in 1,2-DCE (6.88 mL), followed by the addition of sodium triacetoxyborohydride 95% (1.18 g, 5.58 mmol) in one portion. The reaction mixture was allowed to stir at room temperature and monitored by LCMS. After completion of the reaction, the mixture was concentrated to dryness and purified via flash column chromatography (hexane / EA until 50%) to obtain tert-butyl 4-[[4-bromo-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate. Yield-1.60 g, 97%; LC-MS (ES + ):m / z 441.3[M+H] + .

[1204] Step-2: Initially, cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (131.93 mg, 180.30 umol), tert-butyl 4-[[4-bromo-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate (792 mg, 1.80 mmol), bis(pinacolato)diboron (549.42 mg, 2.16 mmol), potassium acetate (530.85 mg, 5.41 mmol, 338.12 uL) were charged in a MW vial (2-5 mL), suspended in 1,4-dioxane (2.58 mL) under argon atmosphere and heated at 140 °C in MW for 40 min. To the suspension was then added 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (134.62 mg, 386.63 umol) and potassium carbonate (2 M, 2 equivalents) under argon and reheated at 120 ° C for 30 minutes, then checked by LCMS. After completion of the reaction, the mixture was filtered through a celite pad and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL) and then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue, which was purified by flash column chromatography (hexane: ethyl acetate 1: 0 to 0: 1) to give tert-butyl 4-[[4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate as a mixture of positional isomers. Yield - 798 mg, 71%; LC-MS (ES + ):m / z 628.6[M+H] + .

[1205] Step-3: Initially, tert-butyl 4-[[4-[1-[(4-methoxyphenyl)methyl]-6-methyl-7-oxo-pyrazolo[3,4-c]pyridin-4-yl]-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate (798 mg, 1.27 mmol) was dissolved in DCM (5.69 mL), followed by the addition of TFA (2.90 g, 25.43 mmol, 1.96 mL), and the mixture was allowed to stir overnight. After completion of the reaction, the mixture was concentrated to dryness and co-evaporated with DCM (10 mL×2), then concentrated to a TFA salt and used in the next step without further purification. Yield-815 mg, 100%; LC-MS (ES) + ):m / z 528.6[M+H] + .

[1206] Synthesis of 2-(2,2-difluoroethoxy)-5-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde

[1207]

[1208] Step-1: To a solution of 4-bromo-2-hydroxy-5-methoxy-benzaldehyde (622 mg, 2.69 mmol) in DMF (6.01 mL) was added granular potassium carbonate (1.12 g, 8.08 mmol, 487.43 uL), followed by the addition of 1,1-difluoro-2-iodo-ethane (516.75 mg, 2.69 mmol, 237.04 uL) at room temperature and heated to 90° C. under an argon atmosphere with stirring for 48 hours. After completion of the reaction, the mixture was quenched by pouring into water (50 mL) and then extracted with ethyl acetate (50 mL×3). The organic layer was washed with LiCl (5% w / v in water, 50 mL), then dried over brine (50 mL), Na2SO4, filtered and concentrated to a residue which was purified via flash column chromatography (hexane:ethyl acetate 1:0 to 4:6) to afford 4-bromo-2-(2,2-difluoroethoxy)-5-methoxy-benzaldehyde as a white solid. Yield - 349 mg, 44%; LC-MS (ES) + ):m / z 295.1[M+H] + .

[1209] Step-2: Initially, cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (69.43 mg, 94.89 umol), 4-bromo-2-(2,2-difluoroethoxy)-5-methoxy-benzaldehyde (280 mg, 948.90 umol), bis(pinacolato)diboron (289.16 mg, 1.14 mmol), potassium acetate (279.38 mg, 2.85 mmol, 177.95 uL) were charged in a MW vial (2-5 mL), suspended in 1,4-dioxane (2.58 mL) under argon atmosphere and heated at 140 °C in MW for 40 minutes. Then, 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (134.62 mg, 386.63 umol) and potassium carbonate (2M, 2 equivalents) were added to the suspension under argon and reheated at 120° C. for 30 minutes, then checked by LCMS. After completion of the reaction, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL) and then with brine (50 mL), dried over Na2SO4, filtered, and concentrated to a residue, which was purified via flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to provide 2-(2,2-difluoroethoxy)-5-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde as a mixture of positional isomers. Yield - 462 mg, 100%; LC-MS (ES) + ):m / z 484.5[M+H] + .

[1210] Synthesis of 2-Isopropoxy-5-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde

[1211]

[1212] Step-1: To a solution of 4-bromo-2-hydroxy-5-methoxy-benzaldehyde (556 mg, 2.41 mmol) in DMF (5.34 mL) was added granular potassium carbonate (997.77 mg, 7.22 mmol, 435.71 uL), followed by the addition of 2-iodopropane (409.08 mg, 2.41 mmol, 240.64 uL) at room temperature and stirred under an argon atmosphere for 5 hours. After completion of the reaction, the mixture was quenched by pouring into water (50 mL) and then extracted with ethyl acetate (50 mL×3). The organic layer was washed with LiCl (5% w / v in water, 50 mL), then dried over brine (50 mL), Na2SO4, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 4:6) to give 4-bromo-2-isopropoxy-5-methoxy-benzaldehyde as a white solid. Yield 573 mg, 87%; LC-MS (ES + ):m / z 273.0[M+H] + .

[1213] Step-2: Initially, cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (127.52 mg, 174.28 umol), 4-bromo-2-isopropoxy-5-methoxy-benzaldehyde (476 mg, 1.74 mmol), bis(pinacolato)diboron (531.08 mg, 2.09 mmol), potassium acetate (513.13 mg, 5.23 mmol, 326.83 uL) were charged in a MW vial (2-5 mL), suspended in 1,4-dioxane (2.58 mL) under argon atmosphere and heated at 140 °C in MW for 40 minutes. To the suspension was then added 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (134.62 mg, 386.63 umol) and potassium carbonate (2 M, 2 equivalents) under argon and reheated at 120 ° C for 30 minutes, then checked by LCMS. After completion of the reaction, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL) and then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue, which was purified by flash column chromatography (hexane: ethyl acetate 1: 0 to 0: 1) to give 2-isopropoxy-5-methoxy-4-(1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde as a mixture of positional isomers. Yield - 715 mg, 89%; LC-MS (ES + ):m / z 462.9[M+H] + .

[1214] Synthesis of 4-(6-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde

[1215]

[1216] Step-1: Initially, 4-bromo-6-fluoro-2H-isoquinolin-1-one (1000 mg, 4.13 mmol) was dissolved in DMF (38.41 mL) and cooled to 0°C, then sodium hydride (198.29 mg, 8.26 mmol) was added in one portion and the mixture was stirred for 30 minutes. Iodomethane (2.35 g, 16.53 mmol, 1.03 mL) was then added dropwise and the mixture was allowed to stir at ambient temperature overnight. The reaction was then quenched with ice water, the precipitated product was filtered off and washed with plenty of water and then with hexane. The solid was dried to give 4-bromo-2,6-dimethoxy-benzaldehyde. Yield-759 mg, 72%; LC-MS (ES) + ):m / z 256.0[M+H] + .

[1217] Step-2: Cyclopentyl (diphenyl) phosphine; dichloropalladium; iron (59.71 mg, 81.61 umol), 4-bromo-2,6-dimethoxy-benzaldehyde (200 mg, 816.09 umol), bis (pinacolato) diboron (248.68 mg, 979.31 umol), potassium acetate (240.28 mg, 2.45 mmol, 153.04 uL) were initially placed in a MW vial (2-5 mL), suspended in 1,4-dioxane (12.27 mL) under an argon atmosphere, and heated in MW at 140° C. for 40 minutes. 4-Bromo-6-fluoro-2-methyl-isoquinolin-1-one (208.98 mg, 816.09 umol) and potassium carbonate (2M, 2 equivalents) were then added to the suspension under argon and reheated at 120° C. for 30 minutes, followed by LCMS checking. After the reaction was complete, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL), then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 4-(6-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde. Yield - 74 mg, 26%; LC-MS (ES + ):m / z 342.3[M+H] + .

[1218] Synthesis of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)benzaldehyde

[1219]

[1220] Step-1: Initially, 4-bromo-2H-isoquinolin-1-one (1030 mg, 4.13 mmol) was dissolved in DMF (14.21 mL) and cooled to 0°C, then sodium hydride (221.1 mg, 9.21 mmol) was added in one portion and the mixture was stirred for 30 minutes. Iodomethane (2.62 g, 18.42 mmol, 1.15 mL) was then added dropwise and the mixture was stirred at ambient temperature overnight. The reaction was then quenched with ice water, the precipitated product was filtered off and washed with plenty of water and then with hexane. The solid was dried to give 4-bromo-2,6-dimethoxy-benzaldehyde. Yield - 784 mg, 72%; LC-MS (ES) + ):m / z 238.0[M+H] + .

[1221] Step-2: Cyclopentyl (diphenyl) phosphine; dichloropalladium; iron (59.71 mg, 81.61 umol), 4-bromo-2,6-dimethoxy-benzaldehyde (200 mg, 816.09 umol), bis (pinacolato) diboron (248.68 mg, 979.31 umol), potassium acetate (240.28 mg, 2.45 mmol, 153.04 uL) were initially placed in a MW vial (2-5 mL), suspended in 1,4-dioxane (12.27 mL) under argon atmosphere, and heated in MW at 140 ° C. for 40 minutes. Then, 4-bromo-2-methyl-isoquinolin-1-one (194.30 mg, 816.09 umol) and potassium carbonate (2M, 2 equivalents) were added to the suspension under argon and reheated at 120 ° C. for 30 minutes, and then checked by LCMS. After the reaction was complete, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL), then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)benzaldehyde. Yield - 63 mg, 24%; LC-MS (ES + ):m / z 324.3[M+H] + .

[1222] Synthesis of 4-(7-chloro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde

[1223]

[1224] Step-1: Initially 4-bromo-7-chloro-2H-isoquinolin-1-one (916 mg, 3.54 mmol) was dissolved in DMF (38.41 mL) and cooled to 0°C, then sodium hydride (170.07 mg, 7.09 mmol) was added in one portion and the mixture was stirred for 30 minutes. Methyl iodide (2.01 g, 14.17 mmol, 882.39 uL) was then added dropwise and the mixture was allowed to stir at ambient temperature overnight. The reaction was then quenched with ice water, the precipitated product was filtered off and washed with plenty of water and then with hexane. The solid was dried to obtain 4-bromo-2,6-dimethoxy-benzaldehyde. Yield-1.01 g, 100%; LC-MS (ES) + ):m / z 274.0[M+H] + .

[1225] Step-2: Cyclopentyl (diphenyl) phosphine; dichloropalladium; iron (59.71 mg, 81.61 umol), 4-bromo-2,6-dimethoxy-benzaldehyde (200 mg, 816.09 umol), bis (pinacolato) diboron (248.68 mg, 979.31 umol), potassium acetate (240.28 mg, 2.45 mmol, 153.04 uL) were initially placed in a MW vial (2-5 mL), suspended in 1,4-dioxane (12.27 mL) under argon atmosphere, and heated at 140 ° C. in MW for 40 minutes. Then, 4-bromo-7-chloro-2-methyl-isoquinolin-1-one (222.41 mg, 816.09 umol) and potassium carbonate (2M, 2 equivalents) were added to the suspension under argon and reheated at 120 ° C. for 30 minutes, and then checked by LCMS. After the reaction was complete, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL), then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 4-(7-chloro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-2,6-dimethoxybenzaldehyde. Yield - 75 mg, 26%; LC-MS (ES + ):m / z 358.3[M+H] + .

[1226] Synthesis of 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde

[1227]

[1228] Step-1: Initially, 5-bromo-3,4-dimethyl-1H-pyridin-2-one (2 g, 9.90 mmol) was dissolved in DMF (40.57 mL) and cooled to 0°C. Sodium hydride (475.09 mg, 19.80 mmol) was then added in one portion and the mixture was stirred for 30 minutes. Iodomethane (5.62 g, 39.59 mmol, 2.46 mL) was then added dropwise and the mixture was allowed to stir at ambient temperature overnight. The reaction was then quenched with ice water and the mixture was then extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over brine (1×100 mL), Na2SO4, filtered and concentrated to a residue which was purified via flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 4-bromo-2,6-dimethoxy-benzaldehyde. Yield-1.35 g, 63%; LC-MS (ES) + ):m / z215.9[M+H] + .

[1229] Step-2: Cyclopentyl (diphenyl) phosphine; dichloropalladium; iron (59.71 mg, 81.61 umol), 4-bromo-2,6-dimethoxy-benzaldehyde (200 mg, 816.09 umol), bis (pinacolato) diboron (248.68 mg, 979.31 umol), potassium acetate (240.28 mg, 2.45 mmol, 153.04 uL) were initially placed in a MW vial (2-5 mL), suspended in 1,4-dioxane (12.27 mL) under argon atmosphere, and heated at 140 ° C. in MW for 40 minutes. Then, 5-bromo-1,3,4-trimethyl-pyridin-2-one (176.34 mg, 816.09 umol) and potassium carbonate (2M, 2 equivalents) were added to the suspension under argon and reheated at 120 ° C. for 30 minutes, and then checked by LCMS. After the reaction was complete, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL), then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde. Yield - 245 mg, 99%; LC-MS (ES + ):m / z 302.2[M+H] + .

[1230] Synthesis of 4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2,6-dimethoxybenzaldehyde

[1231]

[1232] Step-1: 5-Bromo-3-methyl-1H-pyridin-2-one (1.050 g, 5.58 mmol) was initially dissolved in DMF (17.22 mL) and cooled to 0°C. Sodium hydride (268.03 mg, 11.17 mmol) was then added in one portion and the mixture was stirred for 30 minutes. Iodomethane (3.17 g, 22.34 mmol, 1.39 mL) was then added dropwise and the mixture was allowed to stir at ambient temperature overnight. The reaction was then quenched with ice water and the mixture was then extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over brine (1×100 mL), Na2SO4, filtered and concentrated to a residue which was purified via flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 4-bromo-2,6-dimethoxy-benzaldehyde. Yield-554 mg, 49%; LC-MS (ES) + ):m / z201.9[M+H] + .

[1233] Step-2: Cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (91.36 mg, 124.86 umol), 4-bromo-2,6-dimethoxy-benzaldehyde (306 mg, 1.25 mmol), bis(pinacolato)diboron (380.49 mg, 1.50 mmol), potassium acetate (367.63 mg, 3.75 mmol, 234.16 uL) were initially placed in a MW vial (2-5 mL), suspended in 1,4-dioxane (12.27 mL) under argon atmosphere, and heated in MW at 140° C. for 40 minutes. 5-Bromo-1,3-dimethyl-pyridin-2-one (252.28 mg, 1.25 mmol) and potassium carbonate (2 M, 2 equivalents) were then added to the suspension under argon and reheated at 120° C. for 30 minutes, followed by LCMS checking. After the reaction was complete, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL), then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2,6-dimethoxybenzaldehyde. Yield - 62 mg, 17%; LC-MS (ES + ):m / z 288.2[M+H] + .

[1234] Synthesis of 2-chloro-6-methoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde

[1235]

[1236] Step-1: 4-Bromo-2H-2,7-naphthyridin-1-one (1 g, 4.44 mmol) was initially dissolved in DMF (10.83 mL) and cooled to 0°C. Sodium hydride (213.27 mg, 8.89 mmol) was then added in one portion and the mixture was stirred for 30 minutes. Iodomethane (2.52 g, 17.77 mmol, 1.11 mL) was then added dropwise and the mixture was stirred at ambient temperature overnight. The reaction was then quenched with ice water and the mixture was then extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over brine (1×100 mL), Na2SO4, filtered and concentrated to a residue which was purified via flash column chromatography (hexane:ethyl acetate 1:0 to 0:1) to give 4-bromo-2-methyl-2,7-naphthyridin-1-one. Yield: 811 mg, 76%; LC-MS (ES) + ):m / z 240.9[M+H] + .

[1237] Step-2: Cyclopentyl (diphenyl) phosphine; dichloropalladium; iron (58.66 mg, 80.16 umol), 4-bromo-2-methyl-2,7-naphthyridin-1-one (191.65 mg, 801.64 umol), bis (pinacolato) diboron (244.28 mg, 961.97 umol), potassium acetate (236.02 mg, 2.40 mmol, 150.33 uL) were initially placed in a MW vial (2-5 mL), suspended in 1,4-dioxane (12.27 mL) under argon atmosphere, and heated at 140 ° C. in MW for 40 minutes. Then, 4-bromo-2-chloro-6-methoxy-benzaldehyde (200 mg, 801.64 umol) and potassium carbonate (2M, 2 equivalents) were added to the suspension under argon and reheated at 120 ° C. for 30 minutes, and then checked by LCMS. After the reaction was complete, the mixture was filtered through a pad of celite and washed with DCM / ethyl acetate. The filtrate was washed with water (10 mL), then with brine (50 mL), dried over Na2SO4, filtered and concentrated to a residue w...

Claims

1. A compound selected from Formula I, Formula II, Formula III, Formula IV, Formula V and Formula VI: or a pharmaceutically acceptable salt thereof; in Each a is independently 0, 1 or 2; Each y is independently 0, 1, or 2; X 3 , X 4 , X 5 and X 6 Selected from N, CH and CR 3 , where X 3 , X 4 , X 5 and X 6 No more than 3 of them are N; X 7 N or CH; X 8 and X 9 is independently selected at each occurrence from N and CH; wherein X 8 or X 9 At least one of them is CH; X 12 is a 5-membered heteroaryl group having 1, 2 or 3 atoms independently selected from N, O and S, wherein X 12 Optionally 1, 2 or 3 independently selected from R 3 substituted by a group; X 17 is aryl, heteroaryl, bicyclic or cycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 3 substituted by a substituent; Q 1 is independently selected at each occurrence from NH, N(alkyl), N(haloalkyl), CH2, O, and S; wherein if X 7 is N, then Q 1 is CH2; R at each occurrence is independently selected from hydrogen, C1-C4 haloalkyl, C1-C4 alkyl, fluorine, chlorine, bromine, iodine, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2 and CBr3; R 1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or cycloalkyl; R 3 is independently selected at each occurrence from hydrogen, hydroxy, alkoxy, C1-C4 alkyl, C1-C4 haloalkyl, cycloalkyl, fluorine, chlorine, bromine and iodine; B is selected from B 1 and B 2 ; B 1 Selected from: B 2 Selected from: X 10 C(R 7 )2, C(O) or O; X 11 is a heterocyclic ring, a heteroaryl ring, an aryl ring, a cycloalkyl ring or a bicyclic ring, X 11 Each of the groups is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group; or X 10 and X 11 Together we form X 13 , X 14 , X 15 and X 16 Independently selected from N, CH and CR 4 , where X 13 , X 14 , X 15 and X 16 No more than 3 of them are N; Each R 4 independently selected from hydrogen, aryl, heteroaryl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkyl, fluorine, chlorine, bromine and iodine; The two R 4 The groups may optionally be combined to form a fused ring, wherein the fused ring is optionally substituted with 1, 2 or 3 R substituents, thus, Non-limiting examples include Two of the R 4 The groups combine to form pyrrole; R 5 is hydrogen, C1-C4 alkyl, allyl, crotyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; Each R 6 independently selected from hydrogen, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 haloalkyl, fluorine, chlorine, bromine and iodine; Each R 7 are independently hydrogen or C1-C4 alkyl; R 8 is hydrogen, C1-C4 alkyl, allyl, crotyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; and L is a divalent linking group.

2. The compound according to claim 1, wherein L is a linker having the formula: in, X 1 and X 2 is independently selected at each occurrence from a bond, a heterocycle, NR 2 , C(R 2 )2, O, C(O) and S; R 2 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R 20 , R 21 , R 22 , R 23 and R 24 is independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-C(R 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 substituted by a substituent; R 26 is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and R 40 and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxy, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and cycloalkyl.

3. The compound according to claim 1, which has the formula:

4. The compound according to claim 3, wherein X 8 is N and X 9 For CH.

5. The compound according to claim 3, wherein X 8 is CH and X 9 is N.

6. The compound according to claim 3, wherein X 8 is CH and X 9 For CH.

7. A compound according to any one of claims 3 to 6, wherein for 8. A compound according to any one of claims 3 to 6, wherein for 9. A compound according to any one of claims 3 to 6, wherein for 10. A compound according to any one of claims 3 to 9, wherein for 11. The compound according to any one of claims 3 to 11, wherein R is C1-C4 haloalkyl, C1-C4 alkyl, fluorine, chlorine or bromine.

12. A compound according to any one of claims 3 to 11, wherein R is fluorine.

13. The compound according to claim 1, which has the formula:

14. The compound according to claim 13, wherein X 17 is optionally 1, 2, 3 or 4 independently selected from R 3 An aryl group substituted with a substituent.

15. The compound according to claim 14, wherein X 17 It is phenyl.

16. The compound according to claim 13, wherein X 17 is a heteroaryl group or a cycloalkyl group; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 3 substituted by a substituent.

17. A compound according to any one of claims 3 to 16, wherein Q 1 NH and X 7 For CH.

18. A compound according to any one of claims 3 to 16, wherein Q 1 is O and X 7 For CH.

19. A compound according to any one of claims 3 to 16, wherein Q 1 is N(CH3) and X 7 For CH.

20. The compound of claim 1, which has the formula:

21. A compound according to any one of claims 3 to 20, wherein X 3 CR 3 .

22. A compound according to any one of claims 3 to 20, wherein X 3 is N.

23. A compound according to any one of claims 3-20, wherein X 3 For CH.

24. A compound according to any one of claims 3-20, wherein X 3 For CF.

25. A compound according to any one of claims 3-20, wherein X 3 is C(CF3).

26. A compound according to any one of claims 3-20, wherein X 3 is C(Cl).

27. A compound according to any one of claims 3 to 26, wherein X 5 CR 3 .

28. A compound according to any one of claims 3 to 26, wherein X 5 is N.

29. A compound according to any one of claims 3 to 26, wherein X 5 For CH.

30. A compound according to any one of claims 3-26, wherein X 5 For CF.

31. A compound according to any one of claims 3-26, wherein X 5 is C(CF3).

32. A compound according to any one of claims 3-26, wherein X 5 is C(Cl).

33. The compound of claim 1, which has the formula:

34. The compound according to claim 33, wherein R 1 For hydrogen.

35. The compound according to claim 33, wherein R 1 For CH3.

36. A compound according to any one of claims 3 to 35, wherein X 4 CR 3 .

37. A compound according to any one of claims 3 to 35, wherein X 4 is N.

38. A compound according to any one of claims 3-35, wherein X 4 For CH.

39. A compound according to any one of claims 3-35, wherein X 4 For CF.

40. A compound according to any one of claims 3-35, wherein X 4 is C(CF3).

41. A compound according to any one of claims 3-35, wherein X 4 is C(Cl).

42. A compound according to any one of claims 3-41, wherein X 6 CR 3 .

43. A compound according to any one of claims 3-41, wherein X 6 For CH.

44. A compound according to any one of claims 3-41, wherein X 6 For CF.

45. A compound according to any one of claims 3-41, wherein X 6 is C(CF3).

46. ​​A compound according to any one of claims 3-41, wherein X 6 is C(Cl).

47. The compound of claim 1, which has the formula:

48. The compound according to claim 47, wherein Q 1 NH and X 7 For CH.

49. The compound according to claim 47, wherein Q 1 is O and X 7 For CH.

50. The compound according to claim 47, wherein Q 1 is N(CH3) and X 7 For CH.

51. A compound according to any one of claims 47-50, wherein X 12 is a 5-membered heteroaryl group having 1, 2 or 3 atoms independently selected from N, wherein X 12 Optionally 1, 2 or 3 independently selected from R 3 substituted by a group.

52. A compound according to any one of claims 47-50, wherein X 12 is furan, where X 12 Optionally 1, 2 or 3 independently selected from R 3 substituted by a group.

53. according to the compound described in any one of claims 3-55, wherein B is B 1 .

54. The compound according to claim 53, wherein B 1 for 55. The compound according to claim 54, wherein R 5 For hydrogen.

56. The compound according to claim 54, wherein R 5 It is methyl.

57. The compound according to claim 53, wherein B 1 for 58. The compound according to claim 53, wherein B 1 for 59. The compound according to claim 53, wherein B 1 for 60. A compound according to any one of claims 3-52, wherein B is B 2 .

61. The compound of claim 1, which has the formula:

62. The compound according to claim 61, wherein Q 1 NH and X 7 For CH.

63. The compound according to claim 61, wherein Q 1 is O and X 7 For CH.

64. The compound according to claim 61, wherein Q 1 is N(CH3) and X 7 For CH.

65. A compound according to any one of claims 61-64, wherein X 3 CR 3 .

66. A compound according to any one of claims 61-64, wherein X 3 is N.

67. A compound according to any one of claims 61-64, wherein X 3 For CH.

68. A compound according to any one of claims 61-64, wherein X 3 For CF.

69. A compound according to any one of claims 61-64, wherein X 3 is C(CF3).

70. A compound according to any one of claims 61-64, wherein X 3 is C(Cl).

71. A compound according to any one of claims 61-70, wherein X 5 CR 3 .

72. A compound according to any one of claims 61-70, wherein X 5 is N.

73. A compound according to any one of claims 61-70, wherein X 5 For CH.

74. A compound according to any one of claims 61-70, wherein X 5 For CF.

75. A compound according to any one of claims 61-70, wherein X 5 is C(CF3).

76. A compound according to any one of claims 61-70, wherein X 5 is C(Cl).

77. A compound according to any one of claims 61-76, wherein X 4 CR 3 .

78. A compound according to any one of claims 61-76, wherein X 4 is N.

79. A compound according to any one of claims 61-76, wherein X 4 For CH.

80. A compound according to any one of claims 61-76, wherein X 4 For CF.

81. A compound according to any one of claims 61-76, wherein X 4 is C(CF3).

82. A compound according to any one of claims 61-76, wherein X 4 is C(Cl).

83. A compound according to any one of claims 61-76, wherein X 6 CR 3 .

84. A compound according to any one of claims 61-76, wherein X 6 For CH.

85. A compound according to any one of claims 61-76, wherein X 6 For CF.

86. A compound according to any one of claims 61-76, wherein X 6 is C(CF3).

87. A compound according to any one of claims 61-76, wherein X 6 is C(Cl).

88. according to the compound described in any one of claims 60-87, wherein B 2 for 89. The compound according to claim 88, wherein R 5 For hydrogen.

90. The compound according to claim 88, wherein R 5 It is methyl.

91. according to the compound described in any one of claims 60-87, wherein B 2 for 92. according to the compound described in any one of claims 60-87, wherein B 2 for 93. according to the compound described in any one of claims 60-87, wherein B 2 for 94. according to the compound described in any one of claims 60-93, wherein X 11 is a heterocyclic ring, each X 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group.

95. A compound according to any one of claims 60-93, wherein X 11 For a double ring, each X 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group.

96. A compound according to any one of claims 60-93, wherein X 11 is heteroaryl, aryl or cycloalkyl, each X 11 The group is optionally substituted by 1, 2, 3 or 4 independently selected R 3 substituted by a group.

97. A compound according to any one of claims 60-93, wherein X 11 Selected from:

98. A compound according to any one of claims 60-93, wherein X 11 Selected from:

99. A compound according to any one of claims 60-93, wherein X 10 and X 11 Together we form 100. A compound according to any one of claims 60-93, wherein X 10 and X 11 Together we form 101. A compound according to any one of claims 3-98, wherein X 10 C(R 7 )2.

102. A compound according to any one of claims 3-98, wherein X 10 For CH2.

103. A compound according to any one of claims 3-98, wherein X 10 is C(O).

104. A compound according to any one of claims 3-98, wherein X 10 is O.

105. A compound according to any one of claims 3-104, wherein X 13 CR 3 .

106. A compound according to any one of claims 3-104, wherein X 13 is N.

107. A compound according to any one of claims 3-104, wherein X 13 For CH.

108. A compound according to any one of claims 3-104, wherein X 13 For CF.

109. A compound according to any one of claims 3-104, wherein X 13 is C(CF3).

110. A compound according to any one of claims 3-104, wherein X 13 is C(Cl).

111. A compound according to any one of claims 3-110, wherein X 14 CR 3 .

112. A compound according to any one of claims 3-110, wherein X 14 is N.

113. A compound according to any one of claims 3-110, wherein X 14 For CH.

114. A compound according to any one of claims 3-110, wherein X 14 For CF.

115. A compound according to any one of claims 3-110, wherein X 14 is C(CF3).

116. A compound according to any one of claims 3-110, wherein X 14 is C(Cl).

117. A compound according to any one of claims 3-116, wherein X 15 CR 3 .

118. A compound according to any one of claims 3-116, wherein X 15 is N.

119. A compound according to any one of claims 3-116, wherein X 15 For CH.

120. A compound according to any one of claims 3-116, wherein X 15 For CF.

121. A compound according to any one of claims 3-116, wherein X 15 is C(CF3).

122. A compound according to any one of claims 3-116, wherein X 15 is C(Cl).

123. A compound according to any one of claims 3-122, wherein X 16 CR 3 .

124. A compound according to any one of claims 3-122, wherein X 16 For CH.

125. A compound according to any one of claims 3-122, wherein X 16 For CF.

126. A compound according to any one of claims 3-122, wherein X 16 is C(CF3).

127. A compound according to any one of claims 3-122, wherein X 16 is C(Cl).

128. A compound according to any one of claims 3-127, wherein R 8 For hydrogen.

129. A compound according to any one of claims 3-127, wherein R 8 It is methyl.

130. A compound according to any one of claims 3-129, wherein L is a linker having the formula: in, X 1 and X 2 is independently selected at each occurrence from a bond, a heterocycle, NR 2 , C(R 2 )2, O, C(O) and S; R 2 is independently selected at each occurrence from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne; R 20 , R 21 , R 22 , R 23 and R 24 is independently selected at each occurrence from a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR 2 -、-NR 2 C(O)-, -O-, -S-, -NR 2 -、-C(R 40 R 40 )-、-P(O)(OR 26 )O-、-P(O)(OR 26 )-, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid and carbocyclic; each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R 40 substituted by a substituent; R 26 is independently selected at each occurrence from hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and R 40 and independently at each occurrence selected from hydrogen, alkyl, alkene, alkyne, fluorine, bromine, chlorine, hydroxy, alkoxy, azide, amino, cyano, -NH(aliphatic, including alkyl), -N(aliphatic, including alkyl)2, -NHSO2(aliphatic, including alkyl), -N(aliphatic, including alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic and cycloalkyl.

131. The compound of claim 130, wherein L is a linker having the formula:

132. The compound according to claim 130 or 131, wherein X 1 is the key.

133. The compound according to claim 130 or 131, wherein X 1 It is a heterocyclic ring.

134. The compound according to claim 130 or 131, wherein X 1 NR 2 .

135. The compound according to claim 130 or 131, wherein X 1 is C(O).

136. A compound according to any one of claims 130-135, wherein X 2 is the key.

137. A compound according to any one of claims 130-135, wherein X 2 It is a heterocyclic ring.

138. A compound according to any one of claims 130-135, wherein X 2 NR 2 .

139. A compound according to any one of claims 130-135, wherein X 2 is C(O).

140. A compound according to any one of claims 130-139, wherein R 20 is the key.

141. A compound according to any one of claims 130-139, wherein R 20 For CH2.

142. A compound according to any one of claims 130-139, wherein R 20 It is a heterocyclic ring.

143. A compound according to any one of claims 130-139, wherein R 20 It is an aromatic group.

144. according to the compound described in any one of claims 130-139, wherein R 20 It is phenyl.

145. A compound according to any one of claims 130-139, wherein R 20 It is a double ring.

146. A compound according to any one of claims 130-145, wherein R 21 is the key.

147. A compound according to any one of claims 130-145, wherein R 21 For CH2.

148. A compound according to any one of claims 130-145, wherein R 21 It is a heterocyclic ring.

149. according to the compound described in any one of claims 130-145, wherein R 21 It is an aromatic group.

150. A compound according to any one of claims 130-145, wherein R 21 It is phenyl.

151. according to the compound described in any one of claims 130-145, wherein R 21 It is a double ring.

152. The compound of claim 130, wherein L is a linker having the formula:

153. A compound according to any one of claims 130-152, wherein R 22 is the key.

154. according to the compound described in any one of claims 130-152, wherein R 22 For CH2.

155. A compound according to any one of claims 130-152, wherein R 22 It is a heterocyclic ring.

156. A compound according to any one of claims 130-152, wherein R 22 It is an aromatic group.

157. A compound according to any one of claims 130-152, wherein R 22 It is phenyl.

158. A compound according to any one of claims 130-152, wherein R 22 It is a double ring.

159. The compound of claim 130, wherein L is a linker having the formula:

160. A compound according to any one of claims 130-159, wherein R 23 is the key.

161. A compound according to any one of claims 130-159, wherein R 23 For CH2.

162. A compound according to any one of claims 130-159, wherein R 23 It is a heterocyclic ring.

163. A compound according to any one of claims 130-159, wherein R 23 It is an aromatic group.

164. according to the compound described in any one of claims 130-159, wherein R 23 It is phenyl.

165. A compound according to any one of claims 130-159, wherein R 23 It is a double ring.

166. The compound of claim 130, wherein L is a linker having the formula:

167. A compound according to any one of claims 130-166, wherein R 24 is the key.

168. A compound according to any one of claims 130-166, wherein R 24 For CH2.

169. A compound according to any one of claims 130-166, wherein R 24 It is a heterocyclic ring.

170. A compound according to any one of claims 130-166, wherein R 24 It is an aromatic group.

171. A compound according to any one of claims 130-166, wherein R 24 It is phenyl.

172. A compound according to any one of claims 130-166, wherein R 24 It is a double ring.

173. A compound according to any one of claims 130-166, wherein R 24 is C(O).

174. A compound according to any one of claims 3-173, wherein L is selected from:

175. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

176. A compound selected from Table 2 or a pharmaceutically acceptable salt thereof.

177. A pharmaceutical composition comprising a compound according to any one of claims 1-176 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

178. A method of treating a disorder mediated by BRD9, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

179. The method of claim 178, wherein the patient is a human.

180. A compound according to any one of claims 1-176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a BRD9-mediated disorder.

181. Use of a compound according to any one of claims 1-176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a BRD9-mediated disorder.

182. Use of a compound according to any one of claims 1-176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for treating a BRD9-mediated disorder.

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