Compounds for targeted degradation of BRD9

Abstract

To provide new compounds and methods for treating disorders mediated by BRD9.SOLUTION: To provide BRD9 proteolytic compounds or pharmaceutically acceptable salts thereof for the treatment of disorders mediated by BRD9. For example, the following compounds are shown.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 985,774, filed March 5, 2020, and U.S. Provisional Patent Application No. 63 / 061,659, filed August 5, 2020, the entireties of which are incorporated herein by reference for all purposes.

[0002] The present invention provides BRD9 degrading compounds for therapeutic uses as further described herein. [Background technology]

[0003] Bromodomain-containing proteins (BRDs), such as BRD9, recognize acetylated lysine residues, such as those at 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), transcriptional mediators (TAF1), nuclear scaffolding proteins (PB1), and the BET family (Non-Patent Document 1). Bromodomain-containing proteins have numerous functions related to transcriptional mediation and coactivation, and are therefore involved in cell proliferation.

[0004] Studies have also shown that BRD9 is preferentially used in cancers with SMARCB1 abnormalities, such as malignant rhabdoid tumors and some specific types of sarcomas. BRD9-containing complexes bind to both active promoters and enhancers, where they contribute to gene expression. Loss of BRD9 leads to changes in gene expression related to apoptosis regulation, translation, and developmental regulation. BRD9 is essential for the growth of SMARCB1-deficient cancer cell lines, suggesting it may be a therapeutic target for these lethal cancers (Non-Patent Document 2). BRD9 is also a critical target required for acute myeloid leukemia (Non-Patent Document 3). In addition to its role as a functional dependency in certain cancers, BRD9 also plays a crucial role in immune cells as a regulator of regulatory T cells (Tregs) through transcriptional regulation of Foxp3 target genes (Non-Patent Document 4).

[0005] Furthermore, studies have shown that the newly identified non-canonical BAF (ncBAF) complex is distinct and composed of a unique combination of subunits compared to the canonical BAF (cBAF) and polybromo (pBAF) complexes (Non-Patent Document 5). Notably, BRD9 is selectively incorporated into the non-canonical BAF (ncBAF) complex in the absence of SMARCB1. Under SMARCB1-disrupted conditions (eviction, deletion, truncation, or inactivation of the cBAF complex), the function of the cBAF complex is impaired, resulting in a unique, so-called synthetic lethal dependency on the function of the ncBAF complex. In this case, because BRD9 is essential for the function of the ncBAF complex, BRD9 exhibits unique dependency in SMARCB1-disrupted cancers (Non-Patent Document 6 and Non-Patent Document 7).

[0006] Bromodomain-containing protein 7 (BRD7) is also a subunit of PBAF SWI / SNF. Literatures describing BRD7 and ligands for BRD7 and BRD9 include Non-Patent Document 8 and Non-Patent Document 9.

[0007] Due to the role of BRD9 in cancer growth, it has been described in patent documents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. There is interest in developing BRD9 inhibitors for the treatment of cancers, including those affected by BRD9.

[0008] Studies have also been reported on proteolytic compounds that have an E3 ligase-binding moiety and a BRD9-binding moiety, where the BRD9-binding ligand binds to BRD9 and directs it to the ligase for eventual degradation by the proteasome (see, e.g., U.S. Patent No. 6,223,262; ... and U.S. Patent No. 6,223,262).

[0009] A patent application filed by C4 Therapeutics, Inc. describing compounds capable of binding to E3 ubiquitin ligases and targeting proteins for degradation includes the phrase "target protein degradation." Patent document 15 entitled "Targeted Protein Degradation" and patent document 16 entitled "Spirocyclic Compounds" and "Degradation Solutions for Targeted Protein Degradation" are also included. Patent document 17, entitled "Degraders and Degronimers for Targeted Protein Degradation," patent document 18, entitled "N / O-Linked Degrons and Degronimers for Protein Degradation," patent document 19, entitled "Amine-Linked C3-Glutarimide Degronimers for Targeted Protein Degradation," patent document 20, entitled "Heterocyclic Degronimers for Targeted Protein Degradation," and patent document 21, entitled "N / O-Linked Degronimers and Degronimers for Targeted Protein Degradation." Patent document 21, entitled "Spirocyclic Degronimers for Target Protein Degradation," patent document 22, entitled "C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation," and patent document 23, entitled "Bromo-C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation." Bromodomain Targeting Degronimers for Target Protein This includes U.S. Patent No. 5,929,633 entitled "Polymer Degradation."

[0010] Other patent applications describing proteolytic compounds include U.S. Patent No. 6,263,629, ... [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2014 / 114721 [Patent Document 2] International Publication No. 2016 / 077375 [Patent Document 3] International Publication No. 2016 / 077378 [Patent Document 4] International Publication No. 2016 / 139361 [Patent Document 5] International Publication No. 2019 / 152440 [Patent Document 6] International Publication No. 2017 / 223452 [Patent Document 7] International Publication No. 2019 / 246423 [Patent Document 8] International Publication No. 2019 / 246430 [Patent Document 9] International Publication No. 2020 / 051235 [Patent Document 10] International Publication No. 2020 / 106915 [Patent Document 11] International Publication No. 2020 / 160192 [Patent Document 12] International Publication No. 2020 / 160193 [Patent Document 13] International Publication No. 2020 / 160196 [Patent Document 14] International Publication No. 2021 / 022163 [Patent Document 15] International Publication No. 2020 / 132561 [Patent Document 16] International Publication No. 2019 / 204354 [Patent Document 17] International Publication No. 2019 / 099868 [Patent Document 18] International Publication No. 2018 / 237026 [Patent Document 19] International Publication No. 2017 / 197051 [Patent Document 20] International Publication No. 2017 / 197055 [Patent Document 21] International Publication No. 2017 / 197036 [Patent Document 22] International Publication No. 2017 / 197046 [Patent Document 23] International Publication No. 2017 / 197056 [Patent Document 24] International Publication No. 2015 / 160845 [Patent Document 25] International Publication No. 2016 / 105518 [Patent Document 26] International Publication No. 2016 / 118666 [Patent Document 27] International Publication No. 2016 / 149668 [Patent Document 28] International Publication No. 2016 / 197032 [Patent Document 29] International Publication No. 2016 / 197114 [Patent Document 30] International Publication No. 2017 / 007612 [Patent Document 31] International Publication No. 2017 / 011371 [Patent Document 32] International Publication No. 2017 / 011590 [Patent Document 33] International Publication No. 2017 / 030814 [Patent Document 34] International Publication No. 2017 / 046036 [Patent Document 35] International Publication No. 2017 / 176708 [Patent Document 36] International Publication No. 2017 / 176957 [Patent Document 37] International Publication No. 2017 / 180417 [Patent Document 38] International Publication No. 2018 / 053354 [Patent Document 39] International Publication No. 2018 / 071606 [Patent Document 40] International Publication No. 2018 / 102067 [Patent Document 41] International Publication No. 2018 / 102725 [Patent Document 42] International Publication No. 2018 / 118598 [Patent Document 43] International Publication No. 2018 / 119357 [Patent Document 44] International Publication No. 2018 / 119441 [Patent Document 45] International Publication No. 2018 / 119448 [Patent Document 46] International Publication No. 2018 / 140809 [Patent Document 47] International Publication No. 2018 / 144649 [Patent Document 48] International Publication No. 2018 / 226542 [Patent Document 49] International Publication No. 2019 / 023553 [Patent Document 50] International Publication No. 2019 / 195201 [Patent Document 51] International Publication No. 2019 / 199816 [Patent Document 52] International Publication No. 2019 / 099926 [Non-patent literature]

[0012] [Non-Patent Document 1] Muller S, Filippakopoulos P, Knapp S., Bromodomains as therapeutic targets, Expert Rev Mol Med. 2011, 13(29) [Non-patent document 2] Xiaofeng Wang et. al., "BRD9 defines a SWI / SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors," Nature Communications, 2019, 10 (1881) [Non-patent document 3] Nature Chemical Biology, 2016, 101038 / nchembio.2115 [Non-patent document 4] BioRxiv, 10.1101 / 2020.02.26.964981 [Non-patent document 5] Alpsoy, A. & Dykhuizen, EC 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) [Non-patent document 6] Michel, BC et al. A non-canonical SWI / SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol 20, 1-11 (2018) [Non-Patent Document 7] Brien, GL et al. Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. Elife 7, e41305 (2018) [Non-patent document 8] Perez-Salvia M. et al, "Bromodomain inhibitors and cancer therapy: From structures to applications" Epigenetics. 2017; 12(5): 323-339; 99 [Non-Patent Document 9] 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 [Non-Patent Document 10] Martin LJ et. al., (Journal of Medicinal Chemistry 2016, 59, 4462-4475) "Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor" [Non-Patent Document 11] Theodoulou NH et. al., (Journal of Medicinal Chemistry 2015, 59, 1425-1439) "Discovery of I-BRD9, a selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition" [Non-Patent Document 12] Clack P. et. al., (Angewandte Chemie, 2015, 127, 6315-6319) Summary of the Invention [Problem to be solved by the invention]

[0013] Due to the important role that BRD9 plays in cancer, there remains a need for new compounds and methods to treat disorders mediated by BRD9. [Means for solving the problem]

[0014] Provided are compounds that degrade bromodomain-containing protein 9 (BRD9) via the ubiquitin proteasome pathway (UPP), as well as their uses and production. The invention provides compounds of Formula I, II, III, IV, V, or VI, which include 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 following formula, the linker is moiety L, and the remainder of the molecule is the E3 ligase binding moiety:

[0015] The compounds of the present invention can inhibit the formation of BRD9-containing BAF complex by degrading BRD9, thereby reducing cell proliferation.Some cancers are more dependent on BRD9-containing BAF complex than healthy cells, and therefore these cancers, such as acute myeloid leukemia, rhabdoid tumor, synovial sarcoma and multiple myeloma, can be effectively treated with the compounds of the present invention.

[0016] The compounds of the 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, e.g., BRD9 or alternatively, BRD7 or another BRD-containing protein, that binds to a targeting ligand.

[0017] In some embodiments, methods are provided for treating a patient having a disorder mediated by BRD9, comprising administering to the patient, typically a human, an effective amount of one or more compounds described herein, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutically acceptable composition.

[0018] In one aspect, the present invention provides a compound of formula I, formula II, formula III, formula IV, formula V or formula VI : [ka] (In the formula, 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 are N, CH and CR 3 where X is selected from the group consisting of 3 , X 4 , X 5 and X 6 Three or fewer of these are N, X 7 is N or CH, X 8 and X9 are each independently selected from the group consisting of N and CH, 8 or X 9 at least one of is CH, or X 8 and X 9 are each independently N, CH, or COR 7 where X is selected from the group consisting of 8 or X 9 At least one of the following is CH or COR 7 and X 12 is a 5-membered heteroaryl group having 1, 2, or 3 atoms independently selected from N, O, and S, where X 12 is R 3 optionally substituted with one, two, or three groups independently selected from X 17 is aryl, heteroaryl, bicyclic, or cycloalkyl, each of which is R 3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Q 1 is independently selected in each occurrence from the group consisting of NH, N(alkyl), N(haloalkyl), CH, O, and S; 7 If N, then Q 1 is CH2, and R is independently in each occurrence hydrogen, C1-C4 haloalkyl, C1-C4 alkyl, fluorine, chlorine, bromine, iodine, CH2F, CHF2, CF3, CH2Cl, CHCl2, selected from the group consisting of CCl3, CH2Br, CHBr2 and CBr3; R 1 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or cycloalkyl, and R 3 is independently selected in each occurrence from the group consisting of hydrogen, hydroxyl, alkoxy, C1-C4 alkyl, C1-C4 haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine; B is B 1 and B 2 is selected from B 1 teeth, [ka] is selected from the group consisting of B 2 teeth, [ka] is selected from the group consisting of X 10 is C(R 7 )2, C(O) or O, X 11 is a heterocycle, heteroaryl, aryl, cycloalkyl, or bicycle, and X 11 Each of the groups is R 3 optionally substituted with one, two, three, or four groups independently selected from or X 10 and X 11 together, [ka] Forming X 13 , X 14 , X 15 and X 16 are independently N, CH and CR 4 where X is selected from the group consisting of 13 , X 14 , X 15 and X 16 Three or fewer of these are N, Each R 4 are independently hydrogen, aryl, heteroaryl, C1-C4 alkoxy, C1-C4 selected from haloalkyl, C1-C4 haloalkoxy, C1-C4 alkyl, fluorine, chlorine, bromine, and iodine; where two R on adjacent carbon atoms 4 The groups may optionally be joined to form a fused ring, which is optionally substituted with one, two, or three R substituents, such that: [ka] Non-limiting examples of 4 groups are linked to form a pyrrole, [ka] are listed, R 5 is hydrogen, C1-C4 alkyl, allyl, crotyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; Each R 6 are 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; L is a divalent linking group, for example, a divalent linking group of formula LI), or a pharmaceutically acceptable salt thereof.

[0019] Any combination of variables, substituents, embodiments, and compounds resulting from these combinations are considered to be specifically and individually disclosed, as such descriptions are merely for convenience of space and are not intended to describe only a genus or even a subgenus of compounds.

[0020] In certain embodiments, L has the formula: [ka] (In the formula, X 1 and X 2 are, in each occurrence, independently a bond, a heterocycle, or NR 2 , C(R 2 )2, O, C(O) and S; R 2is independently selected in each occurrence from the group consisting of 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 are, in each occurrence, independently a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -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, glycolic, and carbocyclic, each of which is selected from the group consisting of R 40 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 26 is independently selected in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 40is in each occurrence independently selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, —NH(aliphatic including alkyl), —N(aliphatic including alkyl), —NHSO(aliphatic including alkyl), —N(aliphatic including alkyl)SOalkyl, —NHSO(aryl, heteroaryl, or heterocyclic), —N(alkyl)SO(aryl, heteroaryl, or heterocyclic), —NHSOalkenyl, —N(alkyl)SOalkenyl, —NHSOalkynyl, —N(alkyl)SOalkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl.

[0021] In one aspect, a 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, and functions to recruit a target protein for degradation, typically via a cereblon-containing E3 ubiquitin ligase.

[0022] In certain embodiments, methods of treatment are provided that include administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, optionally in a pharmaceutically acceptable carrier, to a patient, e.g., a human, in need thereof. For example, in one embodiment, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI is administered to a human to treat cancer, e.g., synovial sarcoma. In one embodiment, a compound of the present invention is administered to a patient to treat synovial sarcoma. In one embodiment, a compound of the present invention is administered to a patient with an SS18-SSX translocation cancer. In one embodiment, a compound of the present invention is administered to a patient with metastatic synovial sarcoma. In one embodiment, a compound of the present invention is administered to a patient with malignant rhabdoid tumor. In one embodiment, a compound of the present invention is administered to a patient with epithelioid sarcoma.

[0023] In certain embodiments, the targeting ligand (B moiety) binds to BRD9 and is used to treat a BRD9-mediated disorder. In other embodiments, the targeting ligand (B moiety) binds to a different bromodomain-containing protein and is used to treat a BRD-mediated disorder. In alternative embodiments, the compounds of the invention are used to treat a non-BRD-mediated disorder.

[0024] In certain embodiments, the compounds of the present invention offer multiple advantages over conventional treatments with BRD9 ligands, for example, the BRD9 degrading compounds of the present invention may a) overcome resistance in certain cases, b) extend the kinetics of drug effect by disrupting the protein, thereby requiring protein resynthesis even after the compound is metabolized, c) target all functions of the protein at once rather than specific catalytic activities or binding events, d) increase 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 catalytically.

[0025] In certain embodiments, the compounds of the present invention inhibit cell growth or reduce cell viability with a GI50 value that is lower than the GI50 of the targeting ligand when the targeting ligand is administered alone.

[0026] In certain embodiments, the compounds of the present invention provide improved efficacy and / or safety profiles compared to known BRD9 inhibitors.

[0027] In certain embodiments, the compounds of the invention are more effective than the targeting ligand moiety alone in treating a BRD9-mediated disorder.

[0028] In certain embodiments, lower concentrations of the compounds described herein are required to treat a BRD9-mediated disorder than the targeting ligand moiety alone.

[0029] In certain embodiments, the compounds of the present invention have fewer side effects than the targeting ligand moiety alone in treating a BRD9-mediated disorder.

[0030] In certain embodiments, a less frequent dosing regimen of a compound described herein is required to treat a BRD9-mediated disorder than the targeting ligand moiety alone.

[0031] 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 modulating or reducing the amount of a bromodomain-containing protein.

[0032] 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.

[0033] In certain embodiments, the compounds described herein are useful for treating disorders involving abnormal cell proliferation, such as tumors or cancer, where BRD9 is an oncogenic protein or a signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell growth.

[0034] In certain embodiments, the compounds described herein are useful as therapeutic agents when administered in an effective amount to a patient for the treatment of medical disorders that can be treated with thalidomide, pomalidomide, or lenalidomide.

[0035] In certain embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI has an isotopic substitution of at least one desired atom at an amount greater than the natural abundance of the isotope, i.e., enriched.

[0036] In one embodiment, the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI includes one deuterium atom or multiple deuterium atoms.

[0037] Other features and advantages of the present application will be apparent from the following detailed description.

[0038] To this end, the present invention includes at least the following features: (a) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as described herein a compound or a pharmaceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives), (b) a method of 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 described herein, or a pharmaceutically acceptable salt thereof; (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 thereof (including deuterated derivatives), for use in the treatment of a disorder mediated by BRD9, e.g., abnormal cell growth such as a tumor or cancer; (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 the treatment of a patient, typically a human, in need of such treatment, having a BRD9-mediated disorder, e.g., abnormal cell proliferation such as a tumor or cancer; (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 thereof (including deuterated derivatives) in the manufacture of a medicament for the treatment of a BRD9-mediated disorder, e.g., abnormal cell growth such as a tumor or cancer; (f) a pharmaceutical composition comprising an effective patient therapeutic amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt, isotopic derivative thereof, and optionally a pharmaceutically acceptable carrier or diluent; (g) a compound of formula I, II, III, IV, V or VI as described herein as a mixture of enantiomers or diastereomers (where appropriate), including racemates; (h) enantiomerically or diastereomerically (where appropriate) enriched forms of the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI as described herein, including isolated enantiomers or diastereomers (i.e., greater than 85%, 90%, 95%, 97% or 99% pure), and (i) A process 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 described herein, or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0039] [Figure 1] 1 is a graph of tumor volume following treatment with Compound 172, which shows potent efficacy in a synovial sarcoma xenograft model. The x-axis is time since treatment initiation measured in days, and the y-axis is tumor volume measured in mm. [Figure 2] 1 is a graph of proteolysis by compound 172. The x-axis is dose measured in nanomolar (nM) and the y-axis is proteolysis level measured by HiBiT luminescence readout for each of the proteins BRD9, BRD7, and BRD4. [Figure 3] 1 is a graph showing the dose-response degradation of various proteins by compound 172 in Yamato-SS cells (Stem Cells 2010;28:1119-1131), a human cell line derived from synovial sarcoma, by Western blot. [Figure 4]1 is a confluence graph showing growth inhibition over time in Yamato-SS cells by compound 172. The x-axis is time measured in days and the y-axis is confluence measured as a percentage of the control. [Figure 5] 1 is a graph 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. [Figure 6] 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). [Figure 7] 1 is a graph showing the dose-dependent response of tumor volume to various concentrations of Compound 172 in a Yamato-SS xenograft model, demonstrating its dose-dependent efficacy in a synovial sarcoma model. The x-axis is time measured in days and the y-axis is tumor volume measured in mm. [Figure 8] 1 is a graph showing the dose-dependent response of mouse weight change to various concentrations of Compound 172 in a Yamato-SS xenograft model. The x-axis is time measured in days and the y-axis is weight change measured in percentage. [Figure 9] 1 is a graph showing the tolerability of Compound 172 in the SA13412 synovial sarcoma PDX model. The x-axis is the number of days since the start of treatment measured in days, and the y-axis is the change in body weight measured in percentage. [Figure 10]10A and 10B are graphs showing preclinical scaling dose prediction models for Compound 172 for estimated human values ​​of unbound clearance, half-life, and degradation volume. 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. [Figure 11] 1 is a graph showing the selective degradation of BRD9 protein by compound 176. The x-axis is dose measured in nanomolar (nM) and the y-axis is the level of proteolysis measured by HiBiT luminescence readout for each of the proteins BRD9, BRD7, and BRD4. [Figure 12] 1 is a bar graph showing dose-dependent in vivo BRD9 degradation in the Yamato-SS xenograft model by various 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. [Figure 13] 1 is a bar graph showing dose-dependent in vivo BRD9 degradation in an Aska-SS xenograft model by various 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. [Figure 14] 1 is a 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 percent protein remaining. [Figure 15] Figure 1 shows the intrinsic dose resolution across representative cellular contexts for various concentrations of compound 176. The upper left represents malignant human rhabdoid tumor (A204), the upper right represents human synovial sarcoma (HS-SY-II), the lower left represents human soft tissue sarcoma (SW982, BAF wild-type), and the lower right represents synovial sarcoma (Yamato SS), all by Western blot. [Figure 16]Figure 10 is a confluence graph for various concentrations of Compound 176. Single-dose long-term growth assessment of the reduction of induced selective growth inhibition in the BAF-perturbed Yamato-SS model. The x-axis is time measured in days and the y-axis is confluence measured as a percentage of control. [Figure 17] 1 is a confluence graph for various concentrations of Compound 176 showing 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 the control. [Figure 18] 1 is a graph showing the pharmacokinetics (PK) of compound 176 at various concentrations (PO QD) in a synovial sarcoma CDX (Yamato-SS) model. The x-axis is time measured in hours and the y-axis is tumor PK measured in nanograms per milliliter (ng / mL). [Figure 19] 1 is a graph showing the proteolysis of BRD9 (tumor PD) in synovial sarcoma tumors by various 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. [Figure 20] 1 is a graph showing the proteolysis (tumor PD) of BRD9 in synovial sarcoma tumors by varying concentrations of PO QDs of Compound 176. The x-axis is time measured in hours and the y-axis is remaining BRD9 normalized to vehicle and vinculin measured in percentage. [Figure 21] 1 is a graph showing the efficacy of various concentrations of Compound 176 in a synovial sarcoma CDX model (Yamato SS). The x-axis is treatment measured in days, and the y-axis is mean tumor volume + SEM measured in cubic millimeters (mm). [Figure 22] 1 is a graph showing the tolerability of various concentrations of Compound 176 in a synovial sarcoma CDX model (Yamato SS). The x-axis is treatment measured in days and the y-axis is body weight change measured in percentage. [Figure 23]1 is a graph showing the efficacy of various concentrations of Compound 176 in a synovial sarcoma PDX model (SA13412). The x-axis is treatment measured in days and the y-axis is mean tumor volume + SEM measured in cubic millimeters (mm). [Figure 24] 1 is a graph showing the tolerability of various 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 measured in percentage. [Figure 25] FIG. 1 shows a representative formula of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0040] I. Definition Compounds are described using their proper names. Unless otherwise defined, 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.

[0041] Compounds of any formula described herein may be in the form of isomers, such as a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or rotamer, as if each were specifically stated, unless clearly excluded by context.

[0042] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein by reference as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better illustrate the invention. and does not represent a limitation on the scope of the invention unless otherwise stated.

[0043] The present invention includes compounds of Formula I, II, III, IV, V, or VI having isotopic substitution of at least one desired atom at greater than the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but different number of neutrons.

[0044] Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 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's In one non-limiting embodiment, the isotopically labeled compounds are used in metabolic studies (e.g., 14 C), reaction kinetic studies (e.g.2 H or 3 H), drug or substrate tissue distribution assays or radiation treatment of patients, including detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). 18 F-labeled compounds are particularly desirable for PET or SPECT studies Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by following the procedures disclosed in the schemes or in the examples and preparations below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0045] Isotopic substitution, e.g., deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced with deuterium. In certain embodiments, the isotope is enriched to 90%, 95%, or 99% or more at any position of interest. In one non-limiting embodiment, deuterium is enriched to 90%, 95%, or 99% at the desired position.

[0046] In one non-limiting embodiment, the replacement of a hydrogen atom with a deuterium atom can occur in any compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI. In one non-limiting embodiment, the replacement of a hydrogen atom with a deuterium atom occurs in one or more groups selected from any of R or variable moieties, linkers, and targeting ligands described herein. For example, an alkyl residue can be deuterated if any of the groups is methyl, ethyl, or methoxy, or contains these, for example, by substitution (such as, in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3). In certain other embodiments, an unsubstituted carbon can be deuterated when two substituents combine to form a ring.

[0047] The compounds of the present invention can form solvates with solvents (including water). Thus, in one non-limiting embodiment, the present invention includes compounds in solvated form. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. 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 may be isotopically substituted, for example, DO, d6-acetone, d6-DMSO (dimethyl sulfoxide). The solvate may be in liquid or solid form.

[0048] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH is attached through the carbon of the carbonyl (C=O) group.

[0049] "Alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, an alkyl 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 non-limiting embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. As used herein, specified ranges refer to alkyl groups with each member of the range stated as a separate species. For example, as used herein, the term C1-C6 alkyl refers to straight- or branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as a separate species, and thus each subset is considered separately disclosed. For example, the term C1-C4 alkyl as used herein is intended to refer to straight or branched chain alkyl groups having 1, 2, 3, or 4 carbon atoms, each of which is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In alternative embodiments, alkyl groups are optionally substituted. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, "alk" includes Where a term is used, "cycloalkyl" or "carbocyclic" can be included as part of its definition unless the context clearly excludes it. For example, without limitation, the terms alkyl, alkoxy, haloalkyl, etc. can all be considered to include cyclic forms of alkyl unless the context clearly excludes it.

[0050] In one embodiment, "alkyl" is C1-C 10alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl.

[0051] In one embodiment, an "alkyl" contains 1 carbon.

[0052] In one embodiment, an "alkyl" contains 2 carbons.

[0053] In one embodiment, the "alkyl" contains 3 carbons.

[0054] In one embodiment, the "alkyl" contains 4 carbons.

[0055] In one embodiment, the "alkyl" contains 5 carbons.

[0056] In one embodiment, an "alkyl" contains 6 carbons.

[0057] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0058] Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0059] Additional non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0060] Additional non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0061] Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0062] In alternative embodiments, the "alkyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0063] In one embodiment, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0064] In one embodiment, the "cycloalkyl" has 3 carbons.

[0065] In one embodiment, the "cycloalkyl" has 4 carbons.

[0066] In one embodiment, the "cycloalkyl" has 5 carbons.

[0067] In one embodiment, the "cycloalkyl" has 6 carbons.

[0068] In one embodiment, the "cycloalkyl" has 7 carbons.

[0069] In one embodiment, the "cycloalkyl" has 8 carbons.

[0070] In one embodiment, the "cycloalkyl" has 9 carbons.

[0071] In one embodiment, the "cycloalkyl" has 10 carbons.

[0072] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0073] Additional non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the cycloalkyl ring.

[0074] for example, [ka] is a "cycloalkyl" group.

[0075] however, [ka] is an "aryl" group.

[0076] In alternative embodiments, the "cycloalkyl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0077] An "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at any stable point along the chain. As used herein, a specified range refers to an alkenyl group with each member of the range described as a separate species, as described above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also encompasses "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. In alternative embodiments, alkenyl groups are optionally substituted. The term "alkenyl" also encompasses cycloalkyl or cycloalkyl groups having at least one point of unsaturation. In alternative embodiments, "alkenyl" is "optionally substituted" with one, two, three, or four substituents.

[0078] "Alkynyl" refers to a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain. As used herein, the specified ranges are alkyl groups with each member of the range described as an independent species, as described above for the alkyl moiety. "alkynyl" refers to an alkynyl group. 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 alternative embodiments, the alkynyl group is optionally substituted. The term "alkynyl" also encompasses cycloalkyl or cycloalkyl groups having at least one triple bond. In alternative embodiments, the "alkynyl" is "optionally substituted" with one, two, three, or four substituents.

[0079] "Alkylene" is a divalent saturated hydrocarbon. Alkylene can be, for example, a 1, 2, 3, 4, 5, 6, 7, or 8 carbon moiety, a 1-6 carbon moiety, or a designated number of carbon atoms, such as C1 or C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene, or C1-C6 alkylene.

[0080] An "alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. The alkenylene can be, for example, a 2-8 carbon portion, a 2-6 carbon portion, or a specified number of carbon atoms, for example, a C2-C4 alkenylene.

[0081] An "alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. The alkynylene can be, for example, a 2-8 carbon portion, a 2-6 carbon portion, or a specified number of carbon atoms, for example, a C2-C4 alkynylene.

[0082] "Halo" and "halogen" refer independently to fluorine, chlorine, bromine, or iodine.

[0083] "Haloalkyl" refers to a branched or straight-chain alkyl group substituted with one or more of the above-mentioned halo atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups 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 have been replaced with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0084] 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 or C2 haloalkyl.

[0085] In one embodiment, the "haloalkyl" has 1 carbon.

[0086] In one embodiment, a "haloalkyl" has 1 carbon and 1 halogen.

[0087] In one embodiment, a "haloalkyl" has 1 carbon and 2 halogens.

[0088] In one embodiment, the "haloalkyl" has 1 carbon and 3 halogens.

[0089] In one embodiment, the "haloalkyl" has 2 carbons.

[0090] In one embodiment, the "haloalkyl" has 3 carbons.

[0091] In one embodiment, the "haloalkyl" has 4 carbons.

[0092] In one embodiment, the "haloalkyl" has 5 carbons.

[0093] In one embodiment, the "haloalkyl" has 6 carbons.

[0094] Non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0095] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0096] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0097] Additional non-limiting examples of "haloalkyl" include: [ka] Examples include:

[0098] "Chain" refers to a linear chain from which all other chains, long or short, or both, can be considered pendant. Where two or more chains can equally be considered the main chain, "chain" refers to that which leads to the simplest representation of the molecule.

[0099] "Haloalkoxy" refers to a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).

[0100] "Heterocycloalkyl" refers to an alkyl group, as described herein, substituted with a heterocyclo group, as described herein.

[0101] An "arylalkyl" is an alkyl group, as described herein, substituted with an aryl group, as described herein.

[0102] Non-limiting examples of "arylalkyl" include: [ka] Examples include:

[0103] In one embodiment, "arylalkyl" is [ka] is.

[0104] In one embodiment, "arylalkyl" refers to a two-carbon alkyl group substituted with an aryl group.

[0105] Non-limiting examples of "arylalkyl" include: [ka] Examples include:

[0106] In one embodiment, "arylalkyl" refers to a 3-carbon alkyl group substituted with an aryl group.

[0107] "Heteroarylalkyl" refers to an alkyl group, as described herein, substituted with a heteroaryl group, as described herein.

[0108] As used herein, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms within the aromatic ring system ("C6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl," e.g., anthracyl. "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocyclyl groups may be 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated carbocyclyls, optionally containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron, forming, 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 alternative embodiments, 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, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.

[0109] In one embodiment, "aryl" is a six-carbon aromatic group (phenyl).

[0110] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0111] In one embodiment, an "aryl" is a six-carbon aromatic group fused to a heterocycle, where the point of attachment is on the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the aromatic ring.

[0112] for example, [ka] is an "aryl" group.

[0113] however, [ka] is a "heterocyclic" group.

[0114] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl, where the point of attachment is on the aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the aromatic ring.

[0115] for example, [ka] is an "aryl" group.

[0116] however, [ka] is a "cycloalkyl" group.

[0117] In alternative embodiments, "aryl" may be "aryl" with 1, 2, 3, or 4 substituents. be arbitrarily substituted."

[0118] The terms "heterocyclyl," "heterocycle," and "heterocyclo" include saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur, and oxygen. Heterocycles 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 spiro-fused bicyclic ring systems). Heterocycles do not include rings containing -OO-, -OS-, or -SS- moieties. The above "heterocycle" groups may be optionally substituted with one, two, three, four, or more substituents, including, but not limited to, hydroxyl, Boc, halo, 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), and 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 radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2, These include, but are not limited to, 4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, 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.

[0119] The terms "heterocyclyl," "heterocycle," and "heterocyclo" groups also include moieties in which a heterocycle radical is fused / condensed with an aryl or heteroaryl radical, for example, unsaturated fused heterocyclic groups containing 1, 2, 3, 4, or 5 nitrogen atoms, e.g., indoline, isoindoline, unsaturated fused heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated fused heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated, and unsaturated fused heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0120] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0121] In one embodiment, "heterocycle" refers to a cyclic ring having one nitrogen, one oxygen, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0122] In one embodiment, a "heterocycle" is a ring system having two nitrogens and three, four, five, six, seven or more nitrogen atoms. refers to a cyclic ring having 8 carbon atoms.

[0123] In one embodiment, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0124] In one embodiment, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0125] Non-limiting examples of "heterocycles" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0126] Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0127] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0128] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0129] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the point of attachment of each group is on the heterocycle.

[0130] for example, [ka] is a "heterocyclic" group.

[0131] however, [ka] is an "aryl" group.

[0132] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0133] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0134] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0135] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0136] Non-limiting examples of "heterocycle" include: [ka] Other examples include:

[0137] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0138] Additional non-limiting examples of "heterocycle" include: [ka] Examples include:

[0139] In alternative embodiments, the "heterocycle" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0140] The term "heteroaryl" refers to a mono- or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi-electrons shared in a cyclic arrangement and 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S) in which the ring nitrogen and sulfur atom(s) are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Examples include unsaturated 5- or 6-membered heteromonocyclyl groups containing one, two, three or four nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, 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 an oxygen atom, such as pyranyl, 2-furyl, 3-furyl; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, such as Examples of unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms include, but are not limited to, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl). Additional 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, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl.

[0141] In one embodiment, a "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0142] 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.

[0143] Additional non-limiting examples of 5-membered "heteroaryl" groups include: [ka] Examples include:

[0144] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0145] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include: [ka] Examples include:

[0146] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0147] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0148] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0149] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0150] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0151] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0152] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0153] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] Examples include:

[0154] In alternative embodiments, the "heteroaryl" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0155] The term "bicyclic" refers to a ring system in which two rings are fused together, each ring being independently selected from carbocycle, heterocycle, aryl, and heteroaryl. Non-limiting examples of bicyclic groups include: [ka] Examples include:

[0156] The term "bicyclic" refers to the linker or X 11 When used in connection with a divalent residue such as, the points of attachment can be on separate rings or on the same ring. In certain embodiments, both points of attachment are on the same ring. In certain embodiments, both points of attachment are on different rings. Non-limiting examples of bivalent bicyclic groups include: [ka] Examples include:

[0157] In alternative embodiments, the "bicycle" is "optionally substituted" with 1, 2, 3, or 4 substituents.

[0158] The term "optionally substituted" refers 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 Alkyl sulfone amino, aryl sulfone amino, C1-C 10 Alkylimino, arylimino, C1-C 10 Alkyl sulfonimino, aryl sulfonimino, hydroxyl, halo, thio, C1-C 10 Alkylthio, arylthio, C1-C 10It refers to the substitution of groups herein with moieties including, but not limited to, alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, amidino, guanidine, ureido, cyano, nitro, azido, acyl, thioacyl, acyloxy, carboxyl, and carboxylic acid ester.

[0159] In an alternative embodiment, any suitable groups may be present at the "substituted" or, where indicated, "optionally substituted" positions that will form a stable molecule and fulfill the desired objectives of the invention, such as halogen (which may independently be F, Cl, Br, or I); cyano; hydroxyl; nitro; azido; alkanoyl (e.g., C2-C6 alkanoyl groups); carboxamido; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, such as phenoxy; thioalkyl, including those with one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups, including those with one or more sulfonyl linkages; aminoalkyl groups, including groups with two or more N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, etc., where each ring is either substituted or unsubstituted); and groups having, for example, 1 to 3 separated or fused rings and 6 to about 14 or 18 ring carbon atoms. (benzyl is an example of an arylalkyl group); arylalkoxy having, for example, 1 to 3 separated or fused rings (benzyloxy is an example of an arylalkoxy group); or saturated or partially unsaturated heterocycle having 1 to 3 separated or fused rings with one or more N, O, or S atoms, or heteroaryl having 1 to 3 separated or fused rings with one or more N, O, or S atoms, such as coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, thiazinyl, 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.

[0160] In certain embodiments, "optionally substituted" includes halogen, hydroxyl, 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 alkylamino)C0-C2 alkyl, C1-C6 haloal. and haloalkoxy, including C1-C6 haloalkoxy, hydroxyC1-C6 alkyl, ester, carbamate, urea, sulfonamide, -C1-C6 alkyl(heterocyclo), C1-C6 alkyl(heteroaryl), -C1-C6 alkyl(C3-C7 cycloalkyl), O-C1-C6 alkyl(C3-C7 cycloalkyl), B(OH), phosphate, phosphonate, and haloalkoxy, including C1-C6 haloalkoxy.

[0161] In some embodiments, suitable groups present in the "substituted" or "optionally substituted" position are divalent groups including, but not limited to, oxo (=O), =S, =CH, etc. Suitable groups in the "substituted" or "optionally substituted" position can be monovalent, divalent, or trivalent groups that form a stable molecule and meet the desired objectives of the present invention.

[0162] In one embodiment, a group described herein that may be substituted with 1, 2, 3 or 4 substituents is substituted with 1 substituent.

[0163] In one embodiment, a group described herein that may be substituted with 1, 2, 3 or 4 substituents is substituted with 2 substituents.

[0164] In one embodiment, a group described herein that may be substituted with 1, 2, 3 or 4 substituents is substituted with 3 substituents.

[0165] In one embodiment, a group described herein that may be substituted with 1, 2, 3 or 4 substituents is substituted with 4 substituents.

[0166] "Aliphatic" refers to a saturated or unsaturated straight-chain, branched, or cyclic hydrocarbon. As used herein, "aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and encompasses each of these definitions. In one embodiment, "aliphatic" is used to refer to an aliphatic group having 1 to 20 carbon atoms. The aliphatic chain can be, for example, monounsaturated, diunsaturated, triunsaturated, or polyunsaturated, or alkynyl. Unsaturated aliphatic groups can be in a cis or trans configuration. In one embodiment, an 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, an aliphatic group contains 1 to about 8 carbon atoms. In certain embodiments, an aliphatic group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. As used herein, a specified range refers to an aliphatic group with each member of the range described as a separate species. For example, the term C1-C6 aliphatic, as used herein, refers to a linear or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as a separate species. For example, the term C1-C4 aliphatic, as used herein, refers to a linear or branched alkyl, alkenyl, or alkynyl group having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as a separate species. In one embodiment, an aliphatic group is substituted with one or more functional groups to form a stable moiety.

[0167] The term "heteroaliphatic" refers to an aliphatic moiety that contains at least one heteroatom in place of a carbon atom in the chain, such as amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atom. In one embodiment, the heteroatoms are nitrogen only. In one embodiment, the heteroatoms are oxygen only. In one embodiment, the heteroatoms are sulfur only. "Heteroaliphatic," as used herein, includes, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to refer to heteroaliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched, or unbranched) having 1 to 20 carbon atoms. In one embodiment, heteroaliphatic groups are optionally substituted to form stable moieties. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, and the like.

[0168] "Dosage form" means a unit dose of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal dosage forms, sublingual dosage forms, topical dosage forms, gels, mucosal dosage forms, etc. "Dosage form" can also include implants, such as optical implants. do.

[0169] "Effective amount," as used herein, means an amount that provides a therapeutic or prophylactic effect.

[0170] As used herein, "endogenous" refers to any substance from or produced within an organism, cell, tissue, or system.

[0171] As used herein, the term "exogenous" refers to any substance introduced from or produced outside an organism, cell, tissue, or system.

[0172] The term "modulate," as used herein, means to mediate a detectable increase or decrease in the level of a response in a patient compared to the level of the response in the patient in the absence of the treatment or compound, and / or compared to the level of the response in an otherwise identical, but untreated, patient. This term encompasses disrupting and / or affecting an intrinsic signal or response to mediate a beneficial therapeutic response in a patient, preferably a human.

[0173] "Parenteral" administration of pharmaceutical compositions includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im) or intrasternal injection, or infusion techniques.

[0174] As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed 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 typically similar to that found in nature. A polypeptide includes any peptide or protein containing two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, commonly referred to in the art as peptides, oligopeptides, and oligomers, as well as longer chains, of which there are many varieties, generally referred to in the art as proteins. "Polypeptide" specifically includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, and fusion proteins. A polypeptide includes natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0175] "Treating" a disease, as that term is used herein, means reducing the frequency or severity of at least one sign or symptom of the disease or disorder experienced by a patient (i.e., palliative treatment) or reducing the cause or effects of the disease or disorder (i.e., disease-modifying treatment).

[0176] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is for convenience only and should not be construed as limiting the scope of the invention. The description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range. For example, description of a range such as 1 to 6 should be considered to specifically disclose 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, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This is true regardless of the broadness of the range.

[0177] As used herein, a "pharmaceutical composition" is a composition that contains at least one active agent and at least one other substance, such as a carrier. "Pharmaceutical combinations" are combinations that can be combined in a single dosage form or given together in separate dosage forms. and a combination of at least two active agents capable of treating any of the disorders described herein. It is recommended that an active agent be used in combination with this product.

[0178] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by making non-toxic inorganic and organic acid or base addition salts thereof. Salts of the present compounds can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (such as hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical when practical. Salts of the present compounds also include solvates of the compounds and salts of the compounds.

[0179] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids, and quaternary ammonium salts. 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, and nitric acid, as well as salts derived from 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, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n Included are salts prepared from organic acids such as —COOH, where n is 0 to 4, or with a different acid that produces the same counterion. Additional suitable salts are listed, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418. (1985).

[0180] The term "carrier" used in pharmaceutical compositions / combinations of the invention refers to a diluent, excipient, or vehicle provided with an active compound.

[0181] "Pharmaceutically acceptable carrier" means a carrier or excipient useful in preparing a pharmaceutical composition / combination that is generally safe, non-toxic, and not biologically or otherwise unsuitable for administration to a patient, usually a human. In one embodiment, an excipient acceptable for veterinary use is used.

[0182] A "patient" or "subject" is a human or non-human animal in need of treatment or prevention of any of the disorders specifically described herein that are modulated, for example, by a native (wild-type) or modified (non-wild-type) protein that can be degraded in accordance with the present invention to provide a therapeutic effect. As further explained herein, the terms patient or subject typically refer to a human patient or subject unless it is clear from the context or wording that the disclosure is intended to include non-human animals. Typically, the patient is a human. In alternative embodiments, the patient or subject is a non-human animal in need of and responsive to such therapy.

[0183] A "therapeutically effective amount" of a pharmaceutical composition / combination of the invention means an amount that, when administered to a patient, typically a human patient, is effective to bring about a therapeutic effect, such as amelioration of symptoms or reduction or diminishment of the disease itself.

[0184] Unless otherwise defined, 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 application belongs. In the present specification, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to this application. In the case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0185] II. Compounds of Formula I, Formula II, Formula III, Formula IV, Formula V and Formula VI In certain embodiments, the structure of the compound is typically selected to be sufficiently stable to maintain a shelf life of at least 2, 3, 4, or 5 months under ambient conditions. To achieve this, each of the R groups described herein must be sufficiently stable to maintain the corresponding desired shelf life of at least 2, 3, 4, or 5 months under ambient conditions. Those skilled in the art are familiar with the stability of chemical moieties and can avoid those that are unstable or overly reactive under appropriate conditions.

[0186] In certain alternative embodiments, compounds of the invention containing any of the "R" groups described herein may be optionally substituted as described below in Section I. The definitions are provided to allow for stable R moieties and for the routineer to determine the desired effect. and, in the case of a final compound for therapy, is pharmaceutically acceptable. Also, all R groups, with or without optional substituents, should be construed as non-redundant (i.e., as known in the art, alkyl substituted with alkyl is redundant, but, for example, alkoxy substituted with alkoxy is not).

[0187] In one aspect, the present invention provides compounds of formula I, formula II, formula III, formula IV, formula V and formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined above.

[0188] In certain embodiments, the compounds of the present invention are [ka] TIFF2026001008000040.tif214170TIFF2026001008000041.tif105170 (in the formula, L D is a divalent linking group, for example a divalent linking group of formula LDI, X 3a , X 4a , X 5a and X 6a are N, CH and CR 3 where X is selected from the group consisting of 3b , X 4b , X 5b and X 6b Three or fewer of these are N, All other variables are as described herein) or a pharmaceutically acceptable salt thereof.

[0189] In certain embodiments, X 3 , X 4 , X 5 and X 6 At most two of them are N.

[0190] In certain embodiments, X 3 , X 4 , X 5 and X 6 All of these are CH.

[0191] In certain embodiments, X 3 , X 4 , X 5 and X 6 One of them is CR 3 where R 3is selected from the group consisting of fluoro, chloro, and bromo. In certain embodiments, R 3 is C1-C4 haloalkyl. In certain embodiments, R 3 is C1-C4 alkyl.

[0192] In certain embodiments, X 3 , X 4 , X 5 and X 6 One of them is CR 3 where R 3 is C1-C4 alkyl.

[0193] In certain embodiments, X 4 or X 6 is N. In certain embodiments, X 4 and X 6 are both N. In certain embodiments, X 4 or X 6 is CH. In certain embodiments, X 4 and X 6 are both CH.

[0194] In certain embodiments, X 4 or X 6 is CR 3 where R 3 is selected from the group consisting of fluoro, chloro and bromo.

[0195] In certain embodiments, X 4 or X 6 is CR 3 where R 3 is selected from the group consisting of C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, and CBr3.

[0196] In certain embodiments, X 4 or X 6 is CR 3 where R 3is C1-C4 alkyl.

[0197] In certain embodiments, X 7 is N and Q 1 is CH2. In certain embodiments, X 7 is CH. In certain embodiments, X 7 is C1-C4 alkyl. In certain embodiments, X 7 is C1-C4 haloalkyl.

[0198] In certain embodiments, X 8 and X 9 At least one of the is CH.

[0199] In certain embodiments, X 8 is N.

[0200] In certain embodiments, X 9 is N.

[0201] In certain embodiments, X 8 and X 9 Each of these is CH.

[0202] In certain embodiments, X 10 is CH2. In certain embodiments, X 10 is C(O). In certain embodiments, X 10 is O.

[0203] In certain embodiments, X 11 is a heterocycle containing at least one N, O, or S. In certain embodiments, X 11 is a heterocycle, and is a C3 to C9 heterocycle containing at least one N, O or S.

[0204] In certain embodiments, X 11is 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.

[0205] In certain embodiments, X 11 contains at least one N, O or S It is heteroaryl.

[0206] In certain embodiments, X 11 is aryl.

[0207] In certain embodiments, X 11 is cycloalkyl.

[0208] In certain embodiments, X 12 is a substituted 5-membered heteroaryl containing at least one N, O, or S atom.

[0209] In certain embodiments, X 12 is a substituted 5-membered heteroaryl containing at least one N atom.

[0210] In certain embodiments, X 12 is a substituted 5-membered heteroaryl containing at least two N atoms.

[0211] In certain embodiments, X 12 is an unsubstituted 5-membered heteroaryl containing at least one N, O, or S atom.

[0212] In certain embodiments, X 12 is an unsubstituted 5-membered heteroaryl containing at least one N atom.

[0213] In certain embodiments, X 12is an unsubstituted 5-membered heteroaryl containing at least two N atoms.

[0214] In certain embodiments, Q 1 is NH. 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), where alkyl is C1-C4 alkyl or C1-C4 haloalkyl. In certain embodiments, Q 1 is N(haloalkyl), where haloalkyl is C1-C4 haloalkyl.

[0215] In certain embodiments, R is hydrogen. In certain embodiments, R is selected from the group consisting of fluoro, chloro, and bromo. 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.

[0216] In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is selected from the group consisting of fluoro, chloro, and bromo. In this case, R 1 is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In certain embodiments, R 1 is cycloalkyl.

[0217] In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3is selected from the group consisting of fluoro, chloro, and bromo. In certain embodiments, R 3 is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In certain embodiments, R 3 is C1-C4 alkoxy. In certain embodiments, R 4 is C1-C4 alkyl. In certain embodiments, R 3 is cycloalkyl.

[0218] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is selected from the group consisting of fluoro, chloro, and bromo. In certain embodiments, R 4 is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In certain embodiments, R 4 is C1-C4 alkoxy. In certain embodiments, R 4 is C1-C4 alkyl. In certain embodiments, R 4 is C1-C4 haloalkoxy.

[0219] In an alternative embodiment, R 4 is selected from hydrogen, aryl, heteroaryl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkyl, hydroxyl, amino, fluorine, chlorine, bromine and iodine.

[0220] In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C1-C4 alkyl. In certain embodiments, R 5 is allyl. In certain embodiments, R 5 is crotyl. In certain embodiments, R 5is alkenyl. In certain embodiments, R 5 is alkynyl. In certain embodiments, R 5 is haloalkyl. In certain embodiments, R 5 is cycloalkyl.

[0221] In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is selected from the group consisting of fluoro, chloro, and bromo. In certain embodiments, R 6 is C1-C4 haloalkyl, CH2F, CHF2, CF3, CH2Cl, CHCl2, CCl3, CH2Br, CHBr2, or CBr3. In certain embodiments, R 6 is C1-C4 alkyl.

[0222] In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C4 alkyl.

[0223] In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is C1-C4 alkyl. In certain embodiments, R 8 is allyl. In certain embodiments, R 8 is crotyl. In certain embodiments, R 8 is alkenyl. In certain embodiments, R 8 is alkynyl. In certain embodiments, R 8 is haloalkyl. In certain embodiments, R 8 is cycloalkyl.

[0224] In an alternative embodiment, X 17 is R 3 X is a heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from17 Non-limiting examples of heterocyclic groups include pyrrolidine, piperidine, morpholine, thiomorpholine, azepane, tetrahydrofuran, tetrahydropyran, dioxane, thiane, oxepane, azocane, thioane, and azonane.

[0225] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0226] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0227] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0228] In certain embodiments, [ka] teeth, [ka] is selected from the group consisting of:

[0229] In certain embodiments, [ka] teeth, [ka] TIFF2026001008000052.tif30170.

[0230] In certain embodiments, X 1 teeth, [ka] is selected from the group consisting of:

[0231] In certain embodiments, X 12 -LB is [ka] TIFF2026001008000055.tif210170TIFF2026001008000056.tif226170TIFF2026001008000057.tif201170TIFF2026001008000058.tif102170 (wherein, 12 Each of the parts is R 3 and optionally substituted with one or two substituents independently selected from:

[0232] In one embodiment, the compound of the present invention is [ka] is selected from.

[0233] In one embodiment, the compound of the present invention is [ka] is selected from.

[0234] In one embodiment, the compound of the present invention is [ka] is selected from.

[0235] In one embodiment, the compound of the present invention is [ka] is selected from.

[0236] In certain embodiments, the compounds of the present invention are [ka] TIFF2026001008000064.tif200170TIFF2026001008000065.tif104170 or a pharmaceutically acceptable salt thereof.

[0237] In one embodiment, the compound of the present invention is [ka] TIFF2026001008000067.tif190170TIFF2026001008000068.tif92170 or a pharmaceutically acceptable salt thereof.

[0238] In one embodiment, the compound of the present invention is [ka] TIFF2026001008000070.tif199170TIFF2026001008000071.tif193170TIFF2026001008000072.tif193170TIFF2026001008000073.tif195170 or a pharmaceutically acceptable salt thereof.

[0239] In one embodiment, the compound of the present invention is [ka] TIFF2026001008000075.tif212170TIFF2026001008000076.tif107170 or a pharmaceutically acceptable salt thereof.

[0240] In one embodiment, the compound of the present invention is [ka] Selected from TIFF2026001008000078.tif200170TIFF2026001008000079.tif202170TIFF2026001008000080.tif101170.

[0241] In one embodiment, the compound of the present invention is [ka] Selected from TIFF2026001008000082.tif189170TIFF2026001008000083.tif95170.

[0242] In one embodiment, the compound of the present invention is [ka] Selected from TIFF2026001008000085.tif196170TIFF2026001008000086.tif197170TIFF2026001008000087.tif200170TIFF2026001008000088.tif197170TIFF2026001008000089.tif201170TIFF2026001008000090.tif97170.

[0243] In one embodiment, the compound of the present invention is [ka] Selected from TIFF2026001008000092.tif213170TIFF2026001008000093.tif213170.

[0244] In certain embodiments, [ka] teeth, [ka] is selected from.

[0245] In certain embodiments, [ka] teeth, [ka] is selected from.

[0246] In certain embodiments, [ka] teeth, [ka] is selected from.

[0247] In certain embodiments, [ka] teeth, [ka] is.

[0248] In certain embodiments, [ka] teeth, [ka] is.

[0249] In certain embodiments, [ka] teeth, [ka] Selected from TIFF2026001008000106.tif163170.

[0250] In certain embodiments, [ka] teeth, [ka] is selected from.

[0251] In certain embodiments, [ka] teeth, [ka] is selected from.

[0252] In certain embodiments, [ka] teeth, [ka] is selected from.

[0253] In certain embodiments, compound 172 is [ka] or a pharmaceutically acceptable salt thereof.

[0254] Additional Embodiments of the Invention In certain embodiments, the compounds of the present invention have the formula: [ka] It is of the type. 002.X 8 is N and X 9 The compound of embodiment 1, wherein is CH. 003.X 8 is CH and X 9 The compound of embodiment 1, wherein is N. 004.X 8 is CH and X 9 The compound of embodiment 1, wherein is CH. 005. [ka] but, [ka] The compound of any one of embodiments 1-4, wherein 006. [ka] but, [ka] The compound of any one of embodiments 1-4, wherein 007. [ka] but, [ka] The compound of any one of embodiments 1-4, wherein 008. [ka] but, [ka] The compound of any one of embodiments 1-7, wherein The compound of any one of embodiments 1-8, wherein R is C1-C4 haloalkyl, C1-C4 alkyl, fluorine, chlorine, or bromine. 010. The compound of any one of embodiments 1-8, wherein R is fluorine. In certain embodiments, the compounds of the present invention have the formula: [ka] It is of the type. 012.X 17 R 3 and optionally 1, 2, 3, or 4 substituents independently selected from 12. The compound of embodiment 11, wherein the aryl group is optionally substituted. 013.X 17 The compound of embodiment 12, wherein is phenyl. 014.X 17 are heteroaryl or cycloalkyl groups, each of which is R 3 The compound of embodiment 11, optionally substituted with 1, 2, 3, or 4 substituents independently selected from: 015.Q 1 is NH and X 7 The compound of any one of embodiments 1-14, wherein is CH. 016.Q 1 is O and X 7 The compound of any one of embodiments 1-14, wherein is CH. 017.Q 1 is N(CH3) and X 7 The compound of any one of embodiments 1-14, wherein is CH. In certain embodiments, the compounds of the present invention have the formula: [ka] It is of the type. 019.X 3 is CR 3 The compound of any one of embodiments 1-18, wherein 020.X 3 The compound of any one of embodiments 1-18, wherein is N. 021.X 3 The compound of any one of embodiments 1-18, wherein is CH. 022.X 3 The compound of any one of embodiments 1-18, wherein is CF. 023.X 3 The compound of any one of embodiments 1-18, wherein is C(CF3). 024.X 3 The compound of any one of embodiments 1-18, wherein is C(Cl). 025.X 5 is CR 3 The compound of any one of embodiments 1-24, wherein 026.X 5 The compound of any one of embodiments 1-24, wherein is N. 027.X 5 The compound of any one of embodiments 1-24, wherein is CH. 028.X 5 The compound of any one of embodiments 1-24, wherein is CF. 029.X 5 The compound of any one of embodiments 1-24, wherein is C(CF3). 030.X 5 The compound of any one of embodiments 1-24, wherein is C(Cl). 031. In certain embodiments, the compounds of the present invention have the formula: [ka] It is of the type. 032.R 1 32. The compound of embodiment 31, wherein is hydrogen. 033.R 1 32. The compound of embodiment 31, wherein is CH3. 034.X 4 is CR 3 The compound of any one of embodiments 1-33, wherein 035.X 4 The compound of any one of embodiments 1-33, wherein is N. 036.X 4 The compound of any one of embodiments 1-33, wherein is CH. 037.X 4 The compound of any one of embodiments 1-33, wherein is CF. 038.X 4 The compound of any one of embodiments 1-33, wherein is C(CF3). 039.X 4 The compound of any one of embodiments 1-33, wherein is C(Cl). 040.X 6 is CR 3 The compound of any one of embodiments 1-39, wherein 041.X 6 The compound of any one of embodiments 1-39, wherein is CH. 042.X 6 The compound of any one of embodiments 1-39, wherein is CF. 043.X 6 The compound of any one of embodiments 1-39, wherein is C(CF3). 044.X 6 The compound of any one of embodiments 1-39, wherein is C(Cl). 045. In certain embodiments, the compounds of the present invention have the formula: [ka] It is of the type. 046.Q 1 is NH and X 7 46. ​​The compound of embodiment 45, wherein is CH. 047.Q 1 is O and X 7 46. ​​The compound of embodiment 45, wherein is CH. 048.Q 1 is N(CH3) and X 746. ​​The compound of embodiment 45, wherein is CH. 049.X 12 is a 5-membered heteroaryl group having 1, 2, or 3 atoms independently selected from N, where X 12 is R 3 The compound of any one of embodiments 45-48, optionally substituted with one, two or three groups independently selected from: 050.X 12 is franc, where X 12 is R 3 The compound of any one of embodiments 45-48, optionally substituted with one, two or three groups independently selected from: 051.B is B 1 The compound of any one of embodiments 1-50, wherein 052.B 1 but, [ka] 52. The compound of embodiment 51, wherein 053.R 5 53. The compound of embodiment 52, wherein is hydrogen. 054.R 5 53. The compound of embodiment 52, wherein is methyl. 055.B 1 but, [ka] 52. The compound of embodiment 51, wherein 056.B 1 but, [ka] 52. The compound of embodiment 51, wherein 057.B 1 but, [ka] 52. The compound of embodiment 51, wherein 058.B is B 2 The compound of any one of embodiments 1-50, wherein 059. In certain embodiments, the compounds of the present invention have the formula: [ka] It is of the type. 060.Q 1 is NH and X 7 60. The compound of embodiment 59, wherein is CH. 061.Q 1 is O and X 7 60. The compound of embodiment 59, wherein is CH. 062.Q 1 is N(CH3) and X 7 60. The compound of embodiment 59, wherein is CH. 063.X 3 is CR 3 The compound of any one of embodiments 59-62, wherein 064.X 3 The compound of any one of embodiments 59-62, wherein is N. 065.X 3 The compound of any one of embodiments 59-62, wherein is CH. 066.X 3 The compound of any one of embodiments 59-62, wherein is CF. 067.X 3 The compound of any one of embodiments 59-62, wherein is C(CF3). 068.X 3 The compound of any one of embodiments 59-62, wherein is C(Cl). 069.X 5 is CR 3 The compound of any one of embodiments 59-68, wherein 070.X 5 The compound of any one of embodiments 59-68, wherein is N. 071.X 5 The compound of any one of embodiments 59-68, wherein is CH. 072.X 5 The compound of any one of embodiments 59-68, wherein is CF. 073.X 5The compound of any one of embodiments 59-68, wherein is C(CF3). 074.X 5 The compound of any one of embodiments 59-68, wherein is C(Cl). 075.X 4 is CR 3 The compound of any one of embodiments 59-74, wherein 076.X 4 The compound of any one of embodiments 59-74, wherein is N. 077.X 4 The compound of any one of embodiments 59-74, wherein is CH. 078.X 4 The compound of any one of embodiments 59-74, wherein is CF. 079.X 4 The compound of any one of embodiments 59-74, wherein is C(CF3). 080.X 4 The compound of any one of embodiments 59-74, wherein is C(Cl). 081.X 6 is CR 3 The compound of any one of embodiments 59-80, wherein 082.X 6 The compound of any one of embodiments 59-80, wherein is CH. 083.X 6 The compound of any one of embodiments 59-80, wherein is CF. 084.X 6 The compound of any one of embodiments 59-80, wherein is C(CF3). 085.X 6 The compound of any one of embodiments 59-80, wherein is C(Cl). 086.B 2 but, [ka] The compound of any one of embodiments 58-85, wherein 087.R 1 87. The compound of embodiment 86, wherein is hydrogen. 088.R 587. The compound of embodiment 86, wherein is methyl. 089.B 2 but, [ka] The compound of any one of embodiments 58-85, wherein 090.B 2 but, [ka] The compound of any one of embodiments 58-85, wherein 091.B 2 but, [ka] The compound of any one of embodiments 58-85, wherein 092.X 11 is a heterocycle, and this X 11 Each of the groups is R 3 The compound of any one of embodiments 58-91, optionally substituted with 1, 2, 3, or 4 groups independently selected from: 093.X 11 is a bicyclic ring, and this X 11 Each of the groups is R 3 The compound of any one of embodiments 58-91, optionally substituted with 1, 2, 3, or 4 groups independently selected from: 094.X 11 is heteroaryl, aryl or cycloalkyl, and X 11 Each of the groups is R 3 The compound of any one of embodiments 58-91, optionally substituted with 1, 2, 3, or 4 groups independently selected from: 095.X 11 but, [ka] The compound of any one of embodiments 58-91, selected from: 096.X 11 but, [ka] The compound of any one of embodiments 58-91, selected from: 097.X 10 and X 11 together, [ka] The compound of any one of embodiments 58 to 91, wherein 098.X 10 and X 11 together, [ka] The compound of any one of embodiments 58 to 91, wherein 099.X 10 is C(R 7 )2. The compound of any one of embodiments 1-96, wherein 100.X 10 The compound of any one of embodiments 1-96, wherein is CH2. 101.X 10 The compound of any one of embodiments 1-96, wherein is C(O). 102.X 10 The compound of any one of embodiments 1-96, wherein 103.X 13 is CR 3 The compound of any one of embodiments 1-102, wherein 104.X 13 The compound of any one of embodiments 1-102, wherein is N. 105.X 13 The compound of any one of embodiments 1-102, wherein is CH. 106.X 13 The compound of any one of embodiments 1-102, wherein is CF. 107.X 13 The compound of any one of embodiments 1-102, wherein is C(CF3). 108.X 13 The compound of any one of embodiments 1-102, wherein is C(Cl). 109.X14 is CR 3 The compound of any one of embodiments 1-108, wherein 110.X 14 The compound of any one of embodiments 1-108, wherein is N. 111.X 14 The compound of any one of embodiments 1-108, wherein is CH. 112.X 14 The compound of any one of embodiments 1-108, wherein is CF. 113.X 14 The compound of any one of embodiments 1-108, wherein is C(CF3). 114.X 14 The compound of any one of embodiments 1-108, wherein is C(Cl). 115.X 15 is CR 3 The compound of any one of embodiments 1-114, wherein 116.X 15 The compound of any one of embodiments 1-114, wherein is N. 117.X 15 The compound of any one of embodiments 1-114, wherein is CH. 118.X 15 The compound of any one of embodiments 1-114, wherein is CF. 119.X 15 The compound of any one of embodiments 1-114, wherein is C(CF3). 120.X 15 The compound of any one of embodiments 1-114, wherein is C(Cl). 121.X 16 is CR 3 The compound of any one of embodiments 1-120, wherein 122.X 16 The compound of any one of embodiments 1-120, wherein is CH. 123.X 16 The compound of any one of embodiments 1-120, wherein is CF. 124.X 16 The compound of any one of embodiments 1-120, wherein is C(CF3). 125.X16 The compound of any one of embodiments 1-120, wherein is C(Cl). 126.R 8 The compound of any one of embodiments 1-125, wherein is hydrogen. 127.R 8 The compound of any one of embodiments 1-125, wherein is methyl. 128.L is the formula: [ka] (In the formula, X 1 and X 2 are, in each occurrence, independently a bond, a heterocycle, or NR 2 , C(R 2 )2, O, C(O) and S; R 2 is independently selected in each occurrence from the group consisting of 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 are, in each occurrence, independently a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -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, glycolic, and carbocyclic, each of which is selected from the group consisting of R 40optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 26 is independently selected in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 40 is, in each occurrence, independently hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, 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, -NHSO2alkenyl The compound of any one of embodiments 1-127, wherein the linker is selected from the group consisting of alkynyl, -N(alkyl)SO2, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl. 129.L is the formula: [ka] 129. The compound of embodiment 128, wherein the linker is 130.X 1 130. The compound of embodiment 128 or 129, wherein is a bond. 131.X 1 130. The compound of embodiment 128 or 129, wherein is a heterocycle. 132.X 1 NR 2 130. The compound of embodiment 128 or 129, wherein 133.X 1 130. The compound of embodiment 128 or 129, wherein is C(O). 134.X 2 The compound of any one of embodiments 128-133, wherein is a bond. 135.X 2The compound of any one of embodiments 128-133, wherein is a heterocycle. 136.X 2 NR 2 The compound of any one of embodiments 128-133, wherein 137.X 2 The compound of any one of embodiments 128-133, wherein is C(O). 138.R 20 The compound of any one of embodiments 128-137, wherein is a bond. 139.R 20 The compound of any one of embodiments 128-137, wherein is CH2. 140.R 20 The compound of any one of embodiments 128-137, wherein is a heterocycle. 141.R 20 The compound of any one of embodiments 128-137, wherein is aryl. 142.R 20 The compound of any one of embodiments 128-137, wherein is phenyl. 143.R 20 The compound of any one of embodiments 128-137, wherein is bicyclic. 144.R 21 The compound of any one of embodiments 128-143, wherein is a bond. 145.R 21 The compound of any one of embodiments 128-143, wherein is CH2. 146.R 21 The compound of any one of embodiments 128-143, wherein is a heterocycle. 147.R 21 The compound of any one of embodiments 128-143, wherein is aryl. 148.R 21 The compound of any one of embodiments 128-143, wherein is phenyl. 149.R 21 The compound of any one of embodiments 128-143, wherein is bicyclic. 150.L is the formula: [ka] 129. The compound of embodiment 128, wherein the linker is 151.R 22 The compound of any one of embodiments 128-150, wherein is a bond. 152.R 22 The compound of any one of embodiments 128-150, wherein is CH2. 153.R 22 The compound of any one of embodiments 128-150, wherein is a heterocycle. 154.R 22 The compound of any one of embodiments 128-150, wherein is aryl. 155.R 22 The compound of any one of embodiments 128-150, wherein is phenyl. 156.R 22 The compound of any one of embodiments 128-150, wherein is bicyclic. 157.L is the formula: [ka] 129. The compound of embodiment 128, wherein the linker is 158.R 23 The compound of any one of embodiments 128-157, wherein is a bond. 159.R 23 The compound of any one of embodiments 128-157, wherein is CH2. 160.R 23 The compound of any one of embodiments 128-157, wherein is a heterocycle. 161.R 23 The compound of any one of embodiments 128-157, wherein is aryl. 162.R 23 The compound of any one of embodiments 128-157, wherein is phenyl. 163.R 23 The compound of any one of embodiments 128-157, wherein is bicyclic. 164.L is the formula: [ka] 129. The compound of embodiment 128, wherein the linker is 165.R 24 The compound of any one of embodiments 128-164, wherein is a bond. 166.R 24 The compound of any one of embodiments 128-164, wherein is CH2. 167.R 24 The compound of any one of embodiments 128-164, wherein is a heterocycle. 168.R 24 The compound of any one of embodiments 128-164, wherein is aryl. 169.R 24 The compound of any one of embodiments 128-164, wherein is phenyl. 170.R 24 The compound of any one of embodiments 128-164, wherein is bicyclic. 171.R 24 The compound of any one of embodiments 128-164, wherein is C(O). 172.L is, [ka] The compound of any one of embodiments 1-171, selected from:

[0255] In certain embodiments, compound 172 is [ka] or a pharmaceutically acceptable salt thereof.

[0256] In certain embodiments, compound 172 is [ka] or a pharmaceutically acceptable salt thereof.

[0257] In certain embodiments, compound 172 is [ka] or a pharmaceutically acceptable salt thereof.

[0258] In certain embodiments, compound 172 is [ka] or a pharmaceutically acceptable salt thereof.

[0259] III. Targeting Ligands Bromodomains (BRDs) are protein interaction modules that recognize only acetylated motifs. BRDs are evolutionarily conserved and present in diverse nuclear proteins, including HATs (GCN5, PCAF), ATP-dependent chromatin remodeling complexes (BAZ1B), helicases (SMARCA), methyltransferases (MLL, ASH1L), transcriptional coactivators (TRIM / TIF1, TAF), transcriptional mediators (TAF1), nuclear scaffolding proteins (PB1), and the BET family (Non-Patent Document 1).

[0260] Bromodomain-containing protein 7 (BRD7) is similar to BRD9 and is involved in the regulation of PBAF. It is a subunit of SWI / SNF (Non-patent Document 8, Non-patent Document 9).

[0261] In certain embodiments, moiety B is a targeting ligand for disorders mediated by one or more bromodomain-containing proteins.

[0262] In certain embodiments, moiety B is a targeting ligand for a BRD9-mediated disorder. It is Do.

[0263] In certain embodiments, moiety B is a targeting ligand for a BRD7-mediated disorder.

[0264] In certain embodiments, B is B 1 is.

[0265] In certain embodiments, B is B 2 is.

[0266] In certain embodiments, B 2 teeth, [ka] (In the formula, X 18 and X 19 is selected from the group consisting of: -N- and -CH-, and all other variables are as defined herein.

[0267] In certain embodiments, B 2 teeth, [ka] (In the formula, X 18 and X 19 is selected from the group consisting of: -N- and -CH-, and all other variables are as defined herein.

[0268] In certain embodiments, B 2 teeth, [ka] (In the formula, X 18 and X 19 is selected from the group consisting of: -N- and -CH-, and all other variables are as defined herein.

[0269] In certain embodiments, B 2 teeth, [ka] (In the formula, X 18 and X 19 is selected from the group consisting of: -N- and -CH-, and all other variables are as defined herein.

[0270] In certain embodiments, B 1 teeth, [ka] is selected from the group consisting of:

[0271] In certain embodiments, B 1 teeth, [ka] is selected from the group consisting of:

[0272] In certain embodiments, B 1 teeth, [ka] TIFF2026001008000157.tif222170TIFF2026001008000158.tif182170.

[0273] In certain embodiments, B 1 teeth, [ka] TIFF2026001008000160.tif107170.

[0274] In certain embodiments, B 2 teeth, [ka] is selected from the group consisting of:

[0275] In certain embodiments, B 2 teeth, [ka] TIFF2026001008000163.tif66170.

[0276] In certain embodiments, B 2 teeth, [ka] Selected from TIFF2026001008000165.tif252170.

[0277] In certain embodiments, B 2 teeth, [ka] Selected from TIFF2026001008000167.tif140170.

[0278] In certain embodiments, B 2 teeth, [ka] Selected from TIFF2026001008000169.tif211170TIFF2026001008000170.tif89170.

[0279] In certain embodiments, B 2 teeth, [ka] Selected from TIFF2026001008000172.tif215170TIFF2026001008000173.tif206170TIFF2026001008000174.tif80170.

[0280] In certain embodiments, B 1 teeth, [ka] is.

[0281] In certain embodiments, X 11teeth, [ka] is selected from the group consisting of:

[0282] In certain embodiments, X 11 teeth, [ka] is selected from the group consisting of:

[0283] In certain embodiments, X 11 teeth, [ka] is selected from the group consisting of:

[0284] In certain embodiments, X 11 teeth, [ka] is selected from the group consisting of:

[0285] IV. Linkers The linker is included in the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI described herein, or a pharmaceutically acceptable salt thereof. D ) is a chemically stable divalent group that attaches the E3 ligase binding moiety to the targeting ligand. In accordance with the present invention, any desired linker described herein can be used so 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. .

[0286] The linkers described herein can be used in either orientation, i.e., the left end is linked to an E3 ligase binding moiety and the right end is linked to a targeting linker, or the left end is linked to a targeting linker and the right end is linked to an E3 ligase binding moiety.

[0287] In certain embodiments, the linker is a bond.

[0288] In certain embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, or 20 or more carbon atoms, in which one or more carbons may be replaced by a heteroatom such as O, N, S, or P.

[0289] 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 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ethylene glycol units), which can be consecutive, partially consecutive, or discontinuous.

[0290] In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains, which may have branches that may independently be alkyl, aryl, heteroaryl, alkenyl or alkynyl, aliphatic, heteroaliphatic, cycloalkyl, or heterocyclic substituents.

[0291] In other embodiments, the linker may comprise or consist of one or more of ethylene glycol, propylene glycol, lactic acid, and / or glycolic acid. Generally, propylene glycol adds hydrophobicity, while propylene glycol adds hydrophilicity. Lactic acid segments tend to have longer half-lives than glycolic acid segments. Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to achieve the desired half-life and hydrophilicity. In certain embodiments, these units may be flanked or interspersed with other moieties, such as aliphatic, e.g., alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve appropriate drug properties.

[0292] In certain embodiments, L is [ka] is a linker selected from

[0293] In one aspect, the linker (L) is selected from the group consisting of Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, Formula LVII, Formula LVIII, Formula IX and Formula LX: [ka] (In the formula, X 1 and X 2 are, in each occurrence, independently a bond, a heterocycle, or NR 2 , C(R 2 )2, O, C(O) and S; R 2is independently selected in each occurrence from the group consisting of 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 are, in each occurrence, independently a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, or -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, glycolic, and carbocyclic, each of which is selected from the group consisting of R 40 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 26 is independently selected in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R 40 is, in each occurrence, independently hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, 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, -NHSO2alkenyl alkynyl, -N(alkyl)SO2, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl moieties.

[0294] In certain embodiments, L D teeth, [ka] is a linker selected from

[0295] In one aspect, the linker (L D ) are formula LDI, formula LDII, formula LDIII, formula LDIV, formula LDV, formula LDVI, and formula LDVII: [ka] wherein all variables are as described herein.

[0296] The following are linkers (L or L) that can be used in the present invention: D Based on this elaboration, one skilled in the art will understand how to use the full range of linkers to achieve the objectives of the present invention.

[0297] Non-limiting examples of formula LI, formula LII, formula LIII, formula LIV, formula LV, formula LVI or formula LVII include: [ka] Examples include:

[0298] Non-limiting examples of formula LDI, formula LDII, formula LDIII, formula LDIV, formula LDV, formula LDVI or formula LDXII include: [ka] Examples include:

[0299] In one embodiment, X 1 is attached to B. In another embodiment, X 2 attaches to B.

[0300] R 20 , R 21 , R 22 , R 23 and R 24 Non-limiting examples of moieties include: [ka] Examples include:

[0301] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of moieties include: [ka] Examples include:

[0302] R 20 , R 21 , R 22 , R 23 and R 24 Additional non-limiting examples of moieties include: [ka] Examples include:

[0303] In additional embodiments, the linker moiety is at least one, at least two, or An optionally substituted (poly)ethylene glycol having 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.

[0304] In certain embodiments, the linker may be flanked, substituted, or interspersed with aryl, phenyl, benzyl, alkyl, alkylene, or heterocyclic groups.

[0305] In certain embodiments, the linker may be asymmetric or symmetric.

[0306] In certain embodiments, the linker may be a non-linear chain and may be or include an aliphatic or aromatic or heteroaromatic cyclic moiety.

[0307] In any of the compound embodiments described herein, the linker group can be any suitable moiety described herein.

[0308] In certain embodiments, the linker is [ka] is selected from the group consisting of:

[0309] In certain embodiments, the linker (L or L D )teeth, [ka] is selected from the group consisting of:

[0310] In certain embodiments, the linker (L or L D )teeth, [ka] is selected from the group consisting of:

[0311] In certain embodiments, the linker (L or L D )teeth, [ka] is selected from the group consisting of:

[0312] In certain embodiments, the linker (L or L D )teeth, [ka] is selected from the group consisting of:

[0313] In certain embodiments, the linker (L or L D )teeth, [ka] is selected from.

[0314] In certain embodiments, the linker depicted above is attached to the left of the B group. In other embodiments, the linker depicted above is attached to the right of the B group.

[0315] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof is selected from.

[0316] V. Additional Non-Limiting Examples of Compounds of the Invention In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026001008000197.tif202170TIFF2026001008000198.tif213170TIFF2026001008000199.tif210170TIFF2026001008000200.tif172170TIFF2026001008000201.tif212170TIFF2026001008000202.tif77170.

[0317] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026001008000204.tif176170TIFF2026001008000205.tif136170.

[0318] In certain embodiments, the compounds of the present invention are [ka] TIFF2026001008000207.tif223170TIFF2026001008000208.tif197170TIFF2026001008000209.tif222170TIFF2026001008000210.tif175170T IFF2026001008000211.tif202170TIFF2026001008000212.tif229170TIFF2026001008000213.tif211170TIFF2026001008000214.tif209170TI FF2026001008000215.tif205170TIFF2026001008000216.tif233170TIFF2026001008000217.tif230170TIFF2026001008000218.tif197170TIF F2026001008000219.tif209170TIFF2026001008000220.tif189170TIFF2026001008000221.tif197170TIFF2026001008000222.tif187170TIFF 2026001008000223.tif208170TIFF2026001008000224.tif228170TIFF2026001008000225.tif226170TIFF2026001008000226.tif184170TIFF2 026001008000227.tif219170TIFF2026001008000228.tif205170TIFF2026001008000229.tif230170TIFF2026001008000230.tif231170TIFF20 Selected from 26001008000231.tif218170TIFF2026001008000232.tif186170TIFF2026001008000233.tif215170TIFF2026001008000234.tif190170TIFF2026001008000235.tif175170TIFF2026001008000236.tif189170TIFF2026001008000237.tif213170TIFF2026001008000238.tif245170

[0319] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026001008000240.tif225170TIFF2026001008000241.tif191170TIFF2026001008000242.tif229170TIFF2026001008000243.tif217170TIFF2026001008000244.tif188170TIFF2026001008000245.tif142170

[0320] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026001008000247.tif205170TIFF2026001008000248.tif199170TIFF2026001008000249.tif165170.

[0321] In certain embodiments, the compounds of the present invention are [ka] Selected from TIFF2026001008000251.tif194170TIFF2026001008000252.tif64170.

[0322] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0323] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0324] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0325] In certain embodiments, the compounds of the present invention are [ka] is selected from.

[0326] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000258.tif193170, TIFF2026001008000259.tif182170, TIFF2026001008000260.tif212170, TIFF2026001008000261.tif232170, TIFF2026001008000262.tif215170, TIFF2026001008000263.tif226170, and TIFF2026001008000264.tif154170.

[0327] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000266.tif208170, TIFF2026001008000267.tif219170, TIFF2026001008000268.tif216170, TIFF2026001008000269.tif202170, TIFF2026001008000270.tif192170, TIFF2026001008000271.tif196170, and TIFF2026001008000272.tif150170.

[0328] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000274.tif205170, TIFF2026001008000275.tif194170, TIFF2026001008000276.tif232170, TIFF2026001008000277.tif193170, TIFF2026001008000278.tif191170, and TIFF2026001008000279.tif229170.

[0329] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000281.tif226170, TIFF2026001008000282.tif233170, TIFF2026001008000283.tif229170, TIFF2026001008000284.tif197170, TIFF2026001008000285.tif199170, and TIFF2026001008000286.tif231170.

[0330] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000288.tif195170, TIFF2026001008000289.tif197170, TIFF2026001008000290.tif229170, TIFF2026001008000291.tif193170, TIFF2026001008000292.tif189170, and TIFF2026001008000293.tif229170.

[0331] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000295.tif199170, TIFF2026001008000296.tif194170, TIFF2026001008000297.tif230170, TIFF2026001008000298.tif196170, TIFF2026001008000299.tif190170, and TIFF2026001008000300.tif230170.

[0332] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000302.tif197170, TIFF2026001008000303.tif195170, TIFF2026001008000304.tif231170, TIFF2026001008000305.tif194170, TIFF2026001008000306.tif193170, and TIFF2026001008000307.tif229170.

[0333] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000309.tif202170TIFF2026001008000310.tif198170TIFF2026001008000311.tif231170TIFF2026001008000312.tif197170TIFF2026001008000313.tif188170TIFF2026001008000314.tif229170.

[0334] Non-limiting examples of compounds of the present invention include: [ka] Examples include TIFF2026001008000316.tif218170TIFF2026001008000317.tif216170TIFF2026001008000318.tif215170TIFF2026001008000319.tif108170.

[0335] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0336] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0337] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0338] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0339] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0340] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0341] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0342] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0343] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0344] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0345] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0346] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0347] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0348] In certain embodiments, the compounds of the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0349] Non-limiting BRD9 Degradation Embodiments In certain embodiments, compounds of the present invention have a BRD binding (K i In certain embodiments, the compounds of the present invention are characterized by having a BRD binding (K i ) is characterized by having.

[0350] In certain embodiments, compounds of the present invention have FP-E3 binding (K d In certain embodiments, the compounds of the present invention are characterized by having FP-E3 binding (K) of less than 1000 nM. d ) is characterized by having.

[0351] In certain embodiments, compounds of the invention exhibit less than 10 nM BRD9 degradation at 2 hours and / or less than 10% K after 17 hours. endo The present invention is characterized by having the following.

[0352] In certain embodiments, compounds of the invention have a BRD9 degradation kinetics K of less than 20 nM. pc The present invention is characterized by having the following.

[0353] In certain embodiments, compounds of the present invention exhibit BRD7 degradation of greater than 999 nM and / or an E of greater than 95% after 24 hours. max The present invention is characterized by having the following.

[0354] In certain embodiments, compounds of the present invention exhibit BRD4 degradation of greater than 1000 nM and less than 5000 nM and / or E of greater than 60% and less than 90% after 24 hours. max The present invention is characterized by having the following.

[0355] In certain embodiments, compounds of the invention are characterized by having IKZF1 / SALL4 / GSPT1 degradation of greater than 999 nM.

[0356] In certain embodiments, compounds of the invention are characterized by having a HEPG2 viability greater than 999 nM. In certain embodiments, compounds of the invention are characterized by having a HEPG2 viability greater than 10,000 nM.

[0357] In certain embodiments, compounds of the invention inhibit SW982 viability (GI 1 50 In certain embodiments, compounds of the present invention are characterized by having an SW982 viability (GI) of greater than 10,000 nM. 50 ) is characterized by having.

[0358] In certain embodiments, compounds of the invention are characterized by having a hERG greater than 30. In certain embodiments, compounds of the invention are characterized by having a hERG greater than 60.

[0359] VI. Treatment method The compounds described herein can be used in effective amounts to treat a patient, typically a human patient, in need of treatment, having a disorder mediated by BRD9.

[0360] 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 thereof, for use in the manufacture of a medicament for treating or preventing cancer or more generally abnormal cell proliferation in a patient, e.g., a human, in need of such treatment or prevention, wherein the cancer or abnormally proliferative cells contain activated BRD9 or BRD9 inhibition is required for the treatment or prevention of cancer.

[0361] In certain embodiments, the methods comprise administering to a patient in need thereof an effective amount of an active compound described herein, or a salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of bioactive agents.

[0362] In certain embodiments, the present invention provides methods of treating any of the disorders described herein in a patient in need thereof.

[0363] In other embodiments, the patient is administered an additional therapeutic agent, hi other embodiments, the compound described herein and the additional therapeutic agent are administered simultaneously or sequentially.

[0364] In certain embodiments, the present application provides methods of preventing any of the disorders described herein in a patient in need thereof.

[0365] In certain embodiments, the patient is a human.

[0366] In certain embodiments, compounds of the invention are used to treat refractory disorders, such as refractory cancer. In certain embodiments, compounds of the invention are used to treat recurrent disorders, such as recurrent cancer. In further embodiments, compounds of the invention are used to treat refractory and recurrent disorders, such as refractory and recurrent cancer. In further embodiments, compounds of the invention are used to treat multidrug-resistant disorders, such as multidrug-resistant cancer.

[0367] In certain embodiments, the compounds of the invention are used to treat SMARCB1-perturbed cancers, such as SMARCB1-perturbed solid tumors.

[0368] In certain embodiments, the BRD9-mediated disorder is synovial sarcoma, malignant rhabdoid tumor, atypical teratoid or rhabdoid tumor, epithelioid sarcoma, renal medullary carcinoma, epithelioid malignant peripheral nerve sheath tumor, myoepithelial carcinoma, extraskeletal myxoid chondrosarcoma, chordoma, pancreatic undifferentiated rhabdoid carcinoma, paranasal sinus basaloid carcinoma, or rhabdoid carcinoma of the gastrointestinal tract.

[0369] In certain embodiments, the BRD9-mediated disorder is synovial sarcoma.

[0370] In certain embodiments, the BRD9-mediated disorder is malignant rhabdoid tumor.

[0371] In certain embodiments, the BRD9-mediated disorder is an atypical teratoid or rhabdoid tumor.

[0372] In certain embodiments, the BRD9-mediated disorder is epithelioid sarcoma.

[0373] In certain embodiments, the BRD9-mediated disorder is renal medullary carcinoma.

[0374] In certain embodiments, the BRD9-mediated disorder is epithelioid malignant peripheral nerve sheath tumor.

[0375] In certain embodiments, the BRD9-mediated disorder is myoepithelial carcinoma.

[0376] In certain embodiments, the BRD9-mediated disorder is extraskeletal myxoid chondrosarcoma.

[0377] In certain embodiments, the BRD9-mediated disorder is chordoma.

[0378] In certain embodiments, the BRD9-mediated disorder is pancreatic undifferentiated rhabdoid carcinoma.

[0379] In certain embodiments, the BRD9-mediated disorder is sinonasal basaloid carcinoma.

[0380] In certain embodiments, the BRD9-mediated disorder is rhabdoid carcinoma of the gastrointestinal tract.

[0381] As inhibitors of BRD9, the present compounds and compositions are particularly useful for treating or lessening the severity of diseases, conditions, or disorders where a bromodomain protein is implicated in the disease, condition, or disorder.

[0382] In one aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder in which a bromodomain protein contributes to the pathology.

[0383] Another aspect of the present invention provides a method for inhibiting or reducing the amount of a bromodomain protein in a patient in need thereof, comprising administering an effective amount of a compound described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0384] Another aspect of the present invention provides a method of treating a bromodomain protein-mediated disorder, comprising administering to a patient in need thereof an effective amount of a compound described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0385] Another aspect of the present invention provides a method for treating or preventing a proliferative disease, the method 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.

[0386] In some embodiments, the disease is mediated by BRD9, hi other embodiments, BRD9 plays a role in the development or progression of the disease.

[0387] In certain embodiments, the BRD9-mediated disorder is a benign tumor, metastasis, neoplasm, tumor, solid tumor, rhabdoid tumor, malignant rhabdoid tumor, carcinoma, leukemia, cancer, abnormal cell proliferation, graft-versus-host rejection, amyloid-based proteinopathy, proteinopathy, fibrotic disorder, inflammation, arthritis, pulmonary disorder, and immune disorder. Includes:

[0388] In certain embodiments, the disorder treated by the present invention is an SS18-SSX fusion protein-associated disorder. In certain embodiments, the disorder treated by the present invention is an SS18 protein-associated disorder. In certain embodiments, the disorder treated by the present invention is an SSX protein-associated disorder.

[0389] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0390] In certain embodiments, the BRD9-mediated disorder is an abnormal cell proliferation, including, but not limited to, a tumor or cancer, or a bone marrow or lymphoproliferative disorder such as B-cell or T-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder.

[0391] In certain embodiments, the hematological cancer is selected from 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, and the like. 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 BCL6 rearrangements / overexpression (double-hit and triple-hit lymphomas), myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma including bortezomib-resistant mantle cell lymphoma.

[0392] Solid tumors that can be treated using the compounds described herein include lung cancer, such as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), breast cancer, such as inflammatory breast cancer, ER-positive breast cancer, including tamoxifen-resistant ER-positive breast cancer, and triple-negative breast cancer, colon cancer, midline carcinoma, liver cancer, kidney cancer, prostate cancer, such as castration-resistant prostate cancer (CRPC), brain cancer, such as glioma, glioblastoma, and glioma. These include, but are not limited to, medulloblastoma and medulloblastoma, including MYC-amplified medulloblastoma, colorectal cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, head and neck cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, such as pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (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 carcinoma, buccal 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).

[0393] In a further embodiment, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0394] In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0395] In further embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Kaposi'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.

[0396] In certain embodiments, the disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0397] In a further embodiment, the disease or disorder is multiple myeloma.

[0398] In a further embodiment, the disease or disorder is synovial sarcoma. The association between synovial sarcoma and BRD9 has been described in the literature. For example, Non-Patent Document 7 describes the high sensitivity of synovial sarcoma tumors to the administration of BRD9 degrading agents. Similarly, Non-Patent Document 6 describes the role of BAF in synovial sarcoma and the role of BRD9 in synovial sarcoma growth.

[0399] In certain embodiments, the BRD9-mediated disorder is an inflammatory disease, including, but not limited to, asthma, chronic peptic ulcer disease, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

[0400] In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neuroinflammation, allergies, pain, neuropathic pain, fever, lung disorders, pulmonary inflammation, adult respiratory distress, chronic pulmonary inflammatory 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, ulcer disease, gastric ulcer, autoimmune diseases, graft versus host reaction and allograft rejection, cancer, leukemia, lymphoma, colon cancer, brain cancer, bone cancer, epithelial cell The cancers include neoplasms of epithelial origin (epithelial cancers), 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.

[0401] In other embodiments, the pharmaceutical composition comprising a compound described herein and the additional therapeutic agent are administered simultaneously or sequentially.

[0402] In other embodiments, the disease or disorder is cancer, hi 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, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, squamous cell carcinoma of the head and neck, leukemia, lymphoma, myeloma, solid tumor, hematological cancer or solid tumor.

[0403] In some embodiments, the method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases, while in other embodiments, the condition is selected from a proliferative disorder.

[0404] 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 1 diabetes.

[0405] One aspect of the present application provides compounds useful for treating diseases, disorders, and conditions 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, pharyngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, Included are follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hairy cell carcinoma, buccal cavity and pharyngeal cancer (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, cancers selected from the following: myeloma, lymphoma, or gastric cancer, renal cancer, and / or 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.

[0406] The term "cancer" refers to any cancer caused by the proliferation of malignant new 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), e.g., adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous 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. Further examples include myelodysplastic syndromes, 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 cancers (e.g., oral cancer, laryngeal cancer, nasopharyngeal cancer, and esophageal cancer), genitourinary tract cancers (e.g., prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancer (e.g., 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.

[0407] Further exemplary forms of cancer include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, cancer of the salivary glands, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0408] Additional cancers that the compounds described herein may be useful for prevention, treatment, and research are, for example, colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, gallbladder cancer, bronchial 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, the present application provides the use of one or more compounds described herein in the manufacture of a medicament for the treatment of cancer, including, but not limited to, the various types of cancer disclosed herein.

[0409] In some embodiments, the compounds described herein are useful for treating cancer, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, and myeloproliferative disorders, such as polycythemia vera, thrombocytopenia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds described herein are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0410] In one embodiment, a compound described herein, or its corresponding pharmaceutically acceptable salt thereof, The isotopic salts or isotopic derivatives can be used in effective amounts to treat a host, e.g., a human, having lymphoma, or a lymphocytic or myeloid proliferative disorder or abnormality. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may be suffering from, but not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); small cleaved cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathic type The patient may have T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; non-Hodgkin's lymphoma such as Langerhans cell histiocytosis or Waldenstrom's macroglobulinemia.

[0411] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, or isotopic derivatives, can be used in an effective amount to treat patients, e.g., humans, with Hodgkin lymphoma, such as, but not limited to, nodular sclerosing classical Hodgkin lymphoma (CHL), mixed cellularity CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-predominant Hodgkin lymphoma, or nodular lymphocyte-predominant HL.

[0412] The present application further encompasses the treatment or prevention of cell proliferative disorders, such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that can be recognized by a pathologist in a biopsy. The compounds can be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0413] The compounds and compositions of the present application are also useful in biological samples as inhibitors of the BRD9 protein. One aspect of the present application is to inhibit protein activity in a biological sample. This method involves contacting the biological sample with a compound or composition described herein. As used herein, the term "biological sample" refers to in vitro or ex vivo samples, including, but not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, semen, tears, or other bodily fluids, or extracts thereof. Inhibition of protein activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, and biological specimen storage.

[0414] Another aspect of the present application is the study of BRD9 proteins in biological and pathological phenomena, the study of intracellular signaling pathways mediated by such proteins, and the comparative evaluation of novel protein inhibitors. Examples of such uses include, but are not limited to, biological assays, such as enzymatic assays and cell-based assays.

[0415] The activity of the compounds and compositions herein as BRD9 inhibitors can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either the enzymatic activity or the ATPase activity of the activated protein. Alternative in vitro assays quantitate the ability of an inhibitor to bind to a bromodomain protein by radiolabeling the inhibitor prior to binding, isolating the inhibitor / bromodomain complex, and determining the amount of bound radiolabel, or by performing a competition experiment in which new inhibitors are incubated with bromodomains bound to known radioligands. Detailed conditions for assaying the compounds used in this application as inhibitors of various bromodomain proteins are described in the Examples below.

[0416] In accordance with the above, the present application further provides a method of preventing or treating any of the above diseases or disorders in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. For any of the above uses, the required dosage will vary depending on the method of administration, the particular condition to be treated, and the desired effect.

[0417] VII. Combination Therapy The compounds of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or pharmaceutically acceptable salts thereof, can be used in effective amounts, either alone or in combination, to treat a patient, such as a human, having a disorder described herein or a BRD9-mediated disorder.

[0418] The disclosed compounds described herein can be used in effective amounts alone or in combination with another compound of the invention or another bioactive agent or second therapeutic agent to treat a patient, such as a human, having a disorder, including but not limited to those described herein.

[0419] The term "bioactive agent" is used to describe an agent other than a selected compound according to the present invention that can be used in combination or alternation with a compound of the present invention to achieve a desired outcome of therapy. In one embodiment, a compound of the present invention and a bioactive agent are administered such that they are active in vivo during an overlapping period, e.g., their Cmax, Tmax, AUC, or other pharmacokinetic parameters overlap. In another embodiment, a compound of the present invention and a bioactive agent that do not have overlapping pharmacokinetic parameters, but one has a therapeutic impact on the therapeutic efficacy of the other, are administered to a patient in need thereof.

[0420] In one aspect of this embodiment, the bioactive agent may be, by way of non-limiting example, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a V-domain Ig suppressor of T-cell activation, or a PD-L1 inhibitor. Checkpoint inhibitors, including VISTA inhibitors, small molecules, peptides, Immunomodulatory agents include, but are not limited to, nucleotide or other inhibitors. In certain embodiments, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

[0421] PD-1 inhibitors that bind to the PD-1 receptor, blocking the interaction between PD-1 and PD-L1, and inhibiting immunosuppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, and AMP-224 (AstraZeneca and 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 and inhibit 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, BM-1, BM-2, BM-3, BM-4, BM-5, BM-6, BM-7, BM-8, BM-9, BM-10, BM-11, BM-12, BM-13, BM-14, BM-15, BM-16, BM-17, BM-18, BM-19, BM-20, BM-21, BM-22, BM-23, BM-24, BM-25, BM-26, BM-27, BM-28, BM-31, BM-29, BM-32, BM-33, BM-34, BM-35, BM-46, BM-47, BM-48, BM-49, BM-59, BM-56, BM-57, BM-58, BM-59, BM-59, BM-61, BM-62, BM-63, BM-74, BM-75, BM-86, S-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).

[0422] In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO™, pembrolizumab / KEYTRUDA™, and pidilizumab / CT-011, MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559, PDL2 / lg fusion proteins such as AMP 224, or inhibitors of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0423] In yet another embodiment, one of the active compounds described herein can be administered in an effective amount in combination with or alternating with an effective amount of an estrogen inhibitor, including but not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist, for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer.Partial antiestrogen such as raloxifene and tamoxifen retain some estrogenic effects, including estrogenic stimulation of uterine growth, and in some cases, estrogenic effects during the progression of breast cancer, which actually stimulate tumor growth.In contrast, fulvestrant, a complete antiestrogen, does not have estrogenic effects on the uterus, and is effective in tamoxifen-resistant tumors.

[0424] Non-limiting examples of anti-estrogen compounds include those described in WO 2014 / 19176 assigned to Astra Zeneca, WO 2013 / 0909 assigned to Olema Pharmaceuticals, 21, WO 2014 / 203129, WO 2014 / 203132 and U.S. Patent Application Publication No. 2013 / 0178445, and U.S. Patent Nos. 9,078,871, 8,853,423 and 8,703,810, and U.S. Patent Application Publication Nos. 2015 / 0005286, WO 2014 / 205136 and WO 2014 / 205138.

[0425] Additional non-limiting examples of anti-estrogen compounds include SERMs such as anordrin, bazedoxifene, broparestrol chlorotrianisene, clomiphene citrate, cyclophenyl, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.

[0426] Other estrogen ligands that can be used in accordance with the present invention are described in U.S. Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO 2011 / 156518, U.S. Pat. Nos. 8,455,534 and 8,299,112, U.S. Pat. Nos. 9,078,871; 8,853,423; 8,703,810; U.S. Patent Application Publication No. 2015 / 0005286; and WO 2014 / 205138, U.S. Patent Application Publication No. 2016 / 0175 289, U.S. Patent Application Publication No. 2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO 2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; U.S. Patent No. 6,821,989; U.S. Patent Application Publication No. 2002 / No. 0128276; U.S. Patent No. 6,777,424; U.S. Patent Application Publication No. 2002 / 0016340; U.S. Patent No. 6,326,392; U.S. Patent No. 6,756,401; U.S. Patent Application Publication No. 2002 / 0013327; U.S. Patent No. 6,512,002; U.S. Patent No. 6,632,834; U.S. Patent Application Publication No. 2001 / 0056,099; U.S. Patent No. 6,583,170; U.S. Patent No. 6,479,535; WO 1999 / 024027; U.S. Patent No. 6,005,102; EP 0802184; U.S. Patent No. 5,998,402; U.S. Patent No. 5,780,497, U.S. Patent No. 5,880,137, WO 2012 / 048058 and WO 2007 / 087684.

[0427] In another embodiment, the active compounds described herein can be administered in effective amounts in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor, including, but 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, for the treatment of abnormal tissue of the male reproductive system, such as prostate or testicular cancer. In one embodiment, the prostate or testicular cancer is androgen-resistant.

[0428] Non-limiting examples of anti-androgen 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-androgen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0429] 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.

[0430] 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), olmutinib (Olita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), and tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[0431] In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. Zumab is an example.

[0432] In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tositumomab, and ocrelizumab.

[0433] In one embodiment, the bioactive agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.

[0434] 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-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and venetoclax (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl). [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((trimethylamino)-4-pyridin-1-yl)-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-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((trimethylamino)-4-pyridin-1-yl)-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Ovatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid)), 2-Methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), Pogosin, Ethyl 2- amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-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).

[0435] In one embodiment, the bioactive agent is a kinase inhibitor, hi 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.

[0436] Examples of PI3 kinase inhibitors include wortmannin, demethoxyviridin, 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]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), G SK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d] imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(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-mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([ S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (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[1,2-c]quinaz), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(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 (RG7422 and also known as 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) (gedatricib), 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}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2 ,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-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 sonolicidin, ), LY294002, AZD8186, PF-4989216, piraralisib, GNE-317, PI-3065, PI-103, NU7441 (KU- 57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD648 2, 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).

[0437] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine 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 Application Publication No. 2011 / 0117073, which is incorporated herein by reference 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)propenamide), 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]quinoxalin-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), as well as other molecules capable of inhibiting BTK activity, such as Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, which is incorporated herein by reference in its entirety.

[0438] Syk inhibitors include cerdulatinib (4-(cyclopropylamino) -2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1 H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (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), 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), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazolophenyl)pyrimidine-5-carboxamide) 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, the entire contents of which are incorporated by reference herein), Compound D (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety), PRT060318 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), luteolin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), apigenin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 (incorporated herein by reference in its entirety), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), and morin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety).

[0439] In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are known, such as 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 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY8697 66 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK73 3((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-carboxylate ruboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]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-2yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-733, PD318088.

[0440] In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known, such as vemurafenib (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- NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoalvinyl (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl [N-methyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

[0441] In one embodiment, the bioactive 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; an FLT-3 inhibitor, including but not limited to, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449; or a combination thereof.

[0442] 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 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 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({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-sulfo benzamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-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), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / C Examples of suitable fluorocarbons include, but are not limited to, H4987655 (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).

[0443] In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include: These include, but are not limited to, Reolysin and siG12D LODER.

[0444] In one embodiment, the bioactive agent is an HSP inhibitor, including but not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0445] 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 (mek) inhibitors, VEGF trap antibodies, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edoteca Phosphorus, tetrandrine, rubitecan, tesmilifene, oblimersen , ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, 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, seliciclib; PD0325901, AZD-6244, capecitabine, 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, anastrazole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate lan, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib;Amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, meconium; Loretamine, 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-retinoid acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, enantiotropin, Dostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, ido Idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, Pak Ritaxel, Paclitaxel without Cremophor, 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, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine, hexafluorophosphate These include samethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0446] In certain embodiments, the compound is administered in combination with ifosfamide.

[0447] In one embodiment, the bioactive agent is imatinib mesylate (Gleevac™), dasatinib (Sprycel™), nilotinib (Tasigna™), bosutinib (Bosulif™), trastuzumab (Herceptin™), trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib (Tykerb™), gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), panitumumab (Vectibix™), vandetanib (Caprelsa™), vemurafenib (Z The anti-cancer drug may be selected from, but is not limited to, elboraf™), vorinostat (Zolinza™), romidepsin (Istodax™), bexarotene (Tagretin™), alitretinoin (Panretin™), tretinoin (Vesanoid™), carfilzomib (Kyprolis™), pralatrexate (Folotyn™), bevacizumab (Avastin™), Ziv-aflibercept (Zaltrap™), sorafenib (Nexavar™), sunitinib (Sutent™), pazopanib (Votrient™), regorafenib (Stivarga™), and cabozantinib (Cometriq™).

[0448] In certain embodiments, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[0449] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic drugs, any agent detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anti-cancer drugs include vincristine (Oncovin™) or liposomal vincristine (Marqibo™), daunorubicin (daunomycin or Cerubidine™) or doxorubicin (Adriamycin™), cytarabine (cytosine arabinoside, ara-C or Cytosar™), L-asparaginase (Elspar™) or PEG-L-asparaginase (peguaspargase or Oncaspar™), etho These include fluticasone (VP-16), teniposide (Vumon™), 6-mercaptopurine (6-MP or Purinethol™), methotrexate, cyclophosphamide (Cytoxan™), prednisone, dexamethasone (Decadron), imatinib (Gleevec™), dasatinib (Sprycel™), nilotinib (Tasigna™), bosutinib (Bosulif™), and ponatinib (Iclusig™).

[0450] Examples of additional suitable chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG bacteria (BCG), live) (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, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy anthracin dione, docetaxel, and doracea mesylate Thoron, doxorubicin HCl, dronabinol, Escherichia coli (E. coli) L-asparaginase Estrogen, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrovorum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, ibuprofen Darubicin HCl, Ifosfamide, Interferon alpha-2b, Irinotecan HCl, Letrozole, Leucovorin calcium, Leuprolide acetate, Levamisole HCl, Lidocaine, Lomustine, Maytansinoids, Mechlorethamine HCl, Medroxyprogesterone acetate, Megestrol acetate, Melphalan HCl, Mercaptopurine, Mesna, Methotrexate, Methyltestosterone, Mithramycin, Mitomycin C, Mitotane, Mitoxantrone, Nilutamide, Octreotide acetate, O These include, but are not limited to, indansetron HCl, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCl, plimycin, poriflozan 20 carmustine implant, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0451] In some embodiments, the compounds of the present invention are administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel.Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophytes. cins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquine, fenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin γ11 and calicheamicin ω11 (e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)). substances; dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin Caminomycin, carzinophilin, chromomycin, dactinomycin, daunomycin Rubicin, Detrubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN™ (doxorubicin including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin, and deoxydoxorubicin), Epirubicin Mitomycins such as esorubicin, idarubicin, marcelomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ube antimetabolites such as nimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; florinic acid Folic acid supplements such as aceglatone, aldophosphamide glycosides, aminolevulinic acid, eniluracil, amsacrine, bestravcil, bisantrene, edatrexate, defofamine, demecolcine, diaziquone, elfomithine, elliptinium acetate, epothilone, etoglucide, gallium nitrate, hydroxybenzoates Urea; Lentinan; Lonidamine; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK™ Polysaccharide Complex (JHS Natural Products, Eugene, OR); Razoxane; Rhizoxin; Sizofuran; Spirogermanium; Tenure zolic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as TAXOL™ (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE™, a cremophor-free albumin-modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE™ docetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® Gel Examples of suitable chemotherapeutic agents include mucitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE™ vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan (e.g., CPT-11), the 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 used in cocktails administered 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).

[0452] Additional therapeutic agents that can be administered in combination with the compounds disclosed herein include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol, The following drugs are listed: 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, Lucatumumab, dacetuzumab, HLL1, huN901-DM1, Acip Remod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinstat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, These include talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0453] In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells and induce their destruction by the immune system. 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 VEGF binds to bevacizumab, it cannot interact with its cell receptor, preventing signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending normal growth-promoting signals. They may also induce apoptosis and activate the immune system to destroy tumor cells.

[0454] In one embodiment of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, e.g., cyclosporine A (NEORAL™), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor, such as rapamycin or a derivative thereof, e.g., sirolimus (RAPAMUNE™), everolimus (Certican™), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g., ridaforolimus, azathioprine, campath 1H, an S1P receptor modulator, e.g., fingolimod or an analog thereof, an anti-IL-8 antibody, mycophenolic acid or a salt thereof, e.g., the sodium salt or a prodrug thereof, e.g., mycophenolate mofetil (CELLCEPT™), OKT3 (ORTHOCLONE), or the like. OKT3™), prednisone, ATGAM™, THYMOGLOBULIN™, brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide (ARAVA™), CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT™), daclizumab (ZENAPAX™), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel™), CTLA4Ig (abatacept), belatacept, LFA3Ig, etanercept (Enbrel™ by Immunex) ), adalimumab (Humira™), infliximab (Remicade™), anti-LFA-1 antibody, natalizumab (Antegren™), enlimomab, gavilimomab, anti-thymocyte immunoglobulin, cytomegalovirus (CV-1), cytomegalovirus (CV-2), cytomegalovirus (CV-3), cytomegalovirus (CV-4), cytomegalovirus (CV-5), cytomegalovirus (CV-6), cytomegalovirus (CV-7), cytomegalovirus (CV-8), cytomegalovirus (CV-9), cytomegalovirus (CV-11), cytomegalovirus (CV-12), cytomegalovirus (CV-13), cytomegalovirus (CV-14), cytomegalovirus (CV-15), cytomegalovirus (CV-16), cytomegalovirus (CV-17), cytomegalovirus ( It can be lizumab, alefacept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

[0455] In some embodiments, the bioactive agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-angiogenesis agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN™). In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof), that agonizes a target, stimulates an anti-cancer response, or antagonizes an antigen important to cancer.Such agents include RITUXAN™ (rituximab), ZENAPAX™ (daclizumab), SIMULECT™ (basiliximab), SYNAGIS™ (palivizumab), REMICADE™ (infliximab), HERCEPTIN™ (trastuzumab), MYLOTARG™ (gemtuzumab ozogamicin), CAMPATH™ (alemtuzumab), and HERCEPTIN™ (trastuzumab). Mab), ZEVALIN™ (ibritumomab tiuxetan), HUMIRA™ (adalimumab), XOLAIR™ (omalizumab), BEXXAR™ (tositumomab-l-131), RAPTIVA™ (efalizumab), ERBITUX™ (cetuximab), AVASTIN™ (bevacizumab), TYSABRI™ (natalizumab), ACTEMRA™ (tocilizumab), VECTIBIX™ (panitumumab), LUCENTIS™ (ranibizumab), SOURIS™ (eculizumab), CIMZIA™ (certolizumab pegol), SIMPONI™ (golimumab), ILARIS™ (canakinumab), STELARA™ (ustekinumab), ARZERRA™ (ofatumumab), PROLIA™ (denosine triphosphate), sumab), NUMAX™ (motavizumab), ABTHRAX™ (raxibacumab), BENLYSTA™ (belimumab), YERVOY™ (ipilimumab), ADCETRIS™ (brentuximab vedotin), PERJETA™ (pertuzumab), KADCYLA™ (adotrastuzumab emtansine), and GAZYVA™ (obinutuzumab). Antibody-drug conjugates are also included.

[0456] The combination therapy may also include therapeutic agents that are non-drug treatments, for example, the compound may be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical removal of tumor tissue.

[0457] 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 before or immediately after the second therapeutic agent, 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, 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 to 7 days, 1 to 14 days, 1 to 21 days, or 1 to 30 days before or after the second therapeutic agent.

[0458] In certain embodiments, the second therapeutic agent is administered according to a different dosing schedule from the compound of the present invention. For example, the second therapeutic agent may 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 may 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.

[0459] VIII. Pharmaceutical Compositions The compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI described herein can be administered as the neat chemical, but more typically are administered as the compounds described herein. The compound is administered to a patient, typically a human, in need of such treatment for any of the disorders described as a pharmaceutical composition containing an effective amount. Accordingly, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain only the compound or salt as the active agent, or in alternative embodiments, the compound and at least one additional active agent.

[0460] In general, the compositions of the present disclosure are administered in a therapeutically effective amount by any of the accepted administration methods. The appropriate dosage range depends on numerous factors, including the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication for which administration is intended, and the preferences and experience of the physician involved. Those skilled in the art of treating such diseases can ascertain a therapeutically effective amount of the disclosed compositions for a given disease without undue experimentation, relying on their own knowledge and the disclosure of this application.

[0461] In certain embodiments, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of active compound per unit dosage form, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent. Examples are dosage forms containing at least 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of active compound or a salt thereof.

[0462] In alternative embodiments, patients can be treated with low-dose therapy. For example, the pharmaceutical composition can be in a dosage form containing about 0.1 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 800 μg, or about 200 μg to about 600 μg of the active compound. Examples are dosage forms containing at least 0.1 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of the active compound or a salt thereof.

[0463] In some embodiments, the compounds disclosed or used as described herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, a compound disclosed or used as described herein is administered at least once daily 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 more.

[0464] In certain embodiments, the compounds of the invention are administered once daily, twice daily, three times daily, or four times daily.

[0465] In certain embodiments, the compounds of the invention are orally administered once daily. In certain embodiments, the compounds of the invention are orally administered twice daily. In certain embodiments, the compounds of the invention are orally administered three times daily. In certain embodiments, the compounds of the invention are orally administered three times daily. The compound is administered orally four times daily.

[0466] In certain embodiments, the compound of the present invention is administered intravenously once a day. In certain embodiments, the compound of the present invention is administered intravenously twice a day. In certain embodiments, the compound of the present invention is administered intravenously three times a day. In certain embodiments, the compound of the present invention is administered intravenously four times a day.

[0467] In some embodiments, the compounds disclosed or used as described herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, a compound disclosed or used as described herein is administered at least once daily 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 more.

[0468] In certain embodiments, the compounds of the invention are administered once daily, twice daily, three times daily, or four times daily.

[0469] In certain embodiments, the compound of the present invention is orally administered once a day. In certain embodiments, the compound of the present invention is orally administered twice a day. In certain embodiments, the compound of the present invention is orally administered three times a day. In certain embodiments, the compound of the present invention is orally administered four times a day.

[0470] In certain embodiments, the compound of the present invention is administered intravenously once a day. In certain embodiments, the compound of the present invention is administered intravenously twice a day. In certain embodiments, the compound of the present invention is administered intravenously three times a day. In certain embodiments, the compound of the present invention is administered intravenously four times a day.

[0471] In some embodiments, the compounds disclosed or used as described herein are administered once per week (QW), twice per week (BIW), or three times per week (TIW). In some embodiments, a compound disclosed or used as described herein is 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 more.

[0472] In certain embodiments, the compounds of the invention are administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week.

[0473] In certain embodiments, the compound of the present invention is orally administered once a week. In certain embodiments, the compound of the present invention is orally administered twice a week. In certain embodiments, the compound of the present invention is orally administered three times a week. In certain embodiments, the compound of the present invention is orally administered four times a week.

[0474] 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.

[0475] In some embodiments, the compounds of the invention are administered with a treatment holiday between treatment cycles, for example, the compounds may 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.

[0476] The pharmaceutical composition may contain a molar ratio of the active compound to the additional active agent. For example, the pharmaceutical composition may contain 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 of the anti-inflammatory or immunosuppressant agent.

[0477] These compositions can contain any amount of the active compound that achieves the desired result, for example, 0.1% to 99% by weight (wt%) of the compound, usually at least about 5% by weight of the compound, with some embodiments containing about 25% to about 50% by weight or about 5% to about 75% by weight of the compound.

[0478] A pharmaceutically or therapeutically effective amount of the composition is delivered to the patient. The precise effective amount will vary from patient to patient and will depend on the species, age, size, and health of the subject, the nature and extent of the condition being treated, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. Effective amounts for a given situation can be determined by routine experimentation. For purposes of this disclosure, a therapeutic amount may be, for example, in the range of about 0.01 mg / kg to about 250 mg / kg of body weight in at least one administration, more typically about 0.1 mg / kg to about 10 mg / kg. A subject may receive as many doses as needed to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or to effect any other desired change in a biological system. Where appropriate, formulations may be prepared with enteric coatings suitable for sustained- or controlled-release administration of the active ingredient.

[0479] In certain embodiments, the dose ranges from about 0.01 mg / kg to 100 mg / kg of patient body weight, e.g., 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, 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.

[0480] The pharmaceutical preparation is preferably in unit dosage form. In such dosage form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, where the package contains discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself. There may be any suitable number of any of these in packaged form.

[0481] 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, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, bromide, and the like. Hydrogen chloride, 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, Included are 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 non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0482] As such, the compositions of the present disclosure may be administered in pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, intravaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration, by injection, inhalation or spray, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous administration, or in the form of conventional pharmaceutically acceptable carriers. The compound may be administered by other means containing a suitable carrier. Typical modes of administration are oral, topical or intravenous, using a convenient daily regimen that can be adjusted according to the severity of the affliction.

[0483] Depending on the intended method of administration, the pharmaceutical composition may be in the form of a solid, semi-solid or liquid dosage form, such as a tablet, suppository, pill, capsule, powder, liquid, syrup, suspension, cream, ointment, lotion, paste, gel, spray, aerosol, foam or oil, injectable or infusible solution, transdermal patch, subcutaneous patch, inhalation formulation, medical device, suppository, buccal or sublingual formulation, parenteral formulation, or eye drops, preferably in a unit dosage form suitable for single administration of a precise dosage amount.

[0484] Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing an appropriate amount of the active ingredient, e.g., an amount effective to achieve a desired purpose. The composition contains an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may further include other medicinal agents, adjuvants, diluents, buffers, etc.

[0485] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. Carriers may be inert or may possess medicinal properties in themselves. The amount of carrier used in combination with the compound is sufficient to provide a quantity of material useful for administration per unit dose of the compound.

[0486] 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 agents.

[0487] Some carriers may fall into more than one class; for example, vegetable oils may be used as lubricants in some formulations and as diluents in others.

[0488] Exemplary pharmaceutically acceptable carriers include sugars, starch, cellulose, powdered tragacanth, malt, gelatin, talc, petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and vegetable oils. Any active agent that does not substantially interfere with the activity of the compound may be included in the pharmaceutical composition.

[0489] Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, etc. The compound can be provided in the form of solid, liquid, spray-dried product, microparticles, nanoparticles, controlled release systems, etc., as desired, for example, depending on the purpose of therapy. Suitable excipients for non-liquid formulations are also known to those skilled in the art. A thorough discussion of pharmaceutically acceptable excipients and salts can be found in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

[0490] Additionally, auxiliary substances, such as wetting or emulsifying agents, physiological buffer substances, surfactants, etc., may be present in such vehicles. The physiological buffer may be any solution that is pharmacologically acceptable and provides the formulation with a desired pH, i.e., a pH within the physiologically acceptable range. Examples of buffer solutions include physiological saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, etc.

[0491] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving or dispersing an active compound described herein and any pharmaceutical adjuvants in an excipient, such as water, saline, aqueous dextrose, glycerol, ethanol, or the like, thereby forming a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, 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; see, for example, Remington's Pharmaceutical Sciences, supra.

[0492] In yet another embodiment, there is provided the use of penetration-enhancing excipients including polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin), polyanions (N-carboxymethylchitosan, polyacrylic acid), and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0493] In certain embodiments, the excipient is butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, Selected from sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0494] The pharmaceutical composition / combination can be formulated for oral administration. For oral administration, the composition generally takes the form of a tablet, capsule, softgel capsule, or may be an aqueous or non-aqueous solution, suspension, or syrup. Tablets and capsules are typical oral dosage forms. Oral tablets and capsules can contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also commonly added. Typically, the compositions of the present disclosure can be combined with non-toxic, pharmaceutically acceptable inert carriers for oral use, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Furthermore, suitable binders, lubricants, disintegrating agents, and coloring agents may be incorporated into the mixture, if desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn syrup, natural and synthetic gums such as gum arabic and gum tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. 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.

[0495] 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 emulsifying and suspending agents. Flavoring agents, coloring agents, and / or sweetening agents may be added as needed. Other optional ingredients incorporated into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[0496] For intraocular delivery, the compounds can be administered, for example, by intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, periconeal, or lacrimal injection, or in an immediate or controlled release manner via a mucus, mucin, or mucosal barrier, or by an intraocular device, as desired.

[0497] Parenteral preparations can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents, and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in parenterally acceptable diluents or solvents that are non-toxic to an acceptable extent. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty acid esters, or polyols are conventionally used as solvents or suspending media. In addition, parenteral administration can involve the use of sustained-release or sustained-release systems to maintain a constant level of dosage.

[0498] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Administration via certain parenteral routes may involve introducing the formulations of the present disclosure into the patient's body through a needle or catheter propelled by a sterile syringe or some other mechanical device, such as a continuous infusion system. The formulations provided by the present disclosure are suitable for use in the art-recognized parenteral administration. The drug may be administered using a syringe, infuser, pump, or any other device that is suitable for administration.

[0499] Preparations according to the present disclosure for parenteral administration include aqueous or non-aqueous sterile solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are 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 contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These may be achieved by, for example, filtration through a bacteria-retaining filter, incorporating a sterilizing agent into the composition, or irradiating the composition. Alternatively, the compositions can be sterilized by heating. They can also be prepared using sterile water, or some other sterile injectable medium, immediately before use.

[0500] Sterile injectable solutions are prepared by incorporating the required amount of one or more compounds of the present disclosure into a suitable solvent, optionally containing various other ingredients as listed above, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other required ingredients from those listed above. For sterile powders for preparing sterile injectable solutions, typical preparation methods are vacuum drying and freeze-drying, which produce a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution. 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 of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0501] Alternatively, the pharmaceutical compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the active ingredient 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.

[0502] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents.

[0503] Formulations for buccal administration include tablets, lozenges, gels, and the like. Alternatively, buccal administration can be achieved using transmucosal delivery systems known to those skilled in the art. The compounds of the present disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches," in which the active ingredient is typically contained within a laminated structure that serves as a drug delivery device attached to a body surface. In such structures, the drug composition is typically contained in a layer, or "reservoir," beneath an upper backing layer. The laminated device may contain a single reservoir or multiple reservoirs. In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to attach the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like.

[0504] Alternatively, the drug-containing reservoir and skin contact adhesive may be present as separate and distinct layers, with the adhesive underneath the reservoir, which may be a polymer matrix as described above, or a liquid or gel reservoir, or some other form. The backing layer in these laminates, which forms the top surface of the device, serves as the primary structural element of the laminate structure and provides the device with much of its flexibility. The material selected for the backing layer may be: It should be substantially impermeable to the active agent and any other materials present.

[0505] The compositions of the present disclosure can be formulated for aerosol administration, including intranasal administration, particularly to the respiratory tract. The compound can, for example, generally have a small particle size, for example, about 5 microns or less. Such particle size can be obtained by means known in the art, for example, by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol can conveniently also contain a surfactant, such as lecithin. The dose of drug can be controlled by a metered valve.

[0506] Alternatively, the active ingredient can be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives, for example, hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. For example, the powder composition can be presented in unit dose form in, for example, gelatin capsules or cartridges, or blister packs from which the powder can be administered by inhaler.

[0507] Formulations suitable for rectal administration are typically presented as unit-dose suppositories, which may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0508] In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the administration methods defined above.

[0509] In certain embodiments, pharmaceutical compositions are suitable for transdermal administration and can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.

[0510] In one embodiment, a microneedle patch or device is provided for the delivery of drugs across or into biological tissue, particularly the skin, which allows for drug delivery across or into the skin or other tissue barriers at clinically relevant rates with little or no damage, pain, or irritation to the tissue.

[0511] Formulations suitable for pulmonary administration can be delivered by a wide range of passively and actively powered single / multiple dose dry powder inhalers (DPIs). The most commonly used devices 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 a suitable pulmonary delivery device depends on parameters such as the properties of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0512] Many methods and devices for drug delivery are known in the art. Non-limiting examples are described in the following patents and patent applications, which are incorporated herein by reference in their entirety: U.S. Pat. No. 8,192,408 (Psivida U.S., Inc.), entitled "Ocular trocar assembly"; U.S. Pat. No. 7,585,517 (Macusight, Inc.), entitled "Transcleral delivery"; U.S. Pat. No. 5,710,182 (Ophthalmic composition); and U.S. Pat. No. 5,710,182 (Ophthalmic composition). ,795,913 (Santen OY); "Formulations for treating ophthalmic diseases and conditions" U.S. Patent No. 8,663,666 entitled "Potassium Iodide for Treating Ocular Diseases and Conditions" No. 39, entitled "Formulations and methods for vascular permeability-related diseases or conditions," No. 8,486,960, U.S. Patent No. 8,367, entitled "Liquid formulations for treatment of diseases or conditions"; No. 097 and U.S. Patent No. 8,927,005, U.S. Patent No. 7,455,855 (Santen Pharmaceutical Co., Ltd.) entitled "Delivery substance and drug delivery system using the same"; U.S. Patent No. 7,455,855 (Santen Pharmaceutical Co., Ltd.) entitled "Relief of vision and pain" WO 2011 / 050365 entitled "Conformable Therapeutic Shield For Vision and Pain" and WO 2011 / 050366 entitled "Therapeutic Device for Pain Management and Vision" No. 2009 / 145842 (Forsight Labs, LLC); U.S. Pat. No. 9,066,779 and U.S. Pat. No. 8,623,395, entitled "Implantable therapeutic device"; International Publication No. WO 2014 / 160884, entitled "Ophthalmic Implant for Delivering Therapeutic Substances"; U.S. Pat. No. 6,623,395, entitled "Posterior segment drug delivery"; No. 8,399,006, U.S. Pat. No. 8,277,830, U.S. Pat. No. 8,795,712, U.S. Pat. No. 8,808,727, U.S. Pat. No. 8,298,578, and International Publication No. WO 2010 / 088548, WO 2014 / 152959 entitled "Systems for Sustained Intraocular Delivery of Low Solubility Compounds from a Port Delivery System Implant," and U.S. Patent Application Publication No. 20140276482, entitled "Injector apparatus and method for drug delivery." No. 8,905,963 and U.S. Pat. No. 9,033,911, "Formulations and Methods for Increasing or Reducing Mucus" WO 2015 / 057554 entitled "Ocular insert apparatus and methods," U.S. Pat. No. 8,715,712 entitled "Ocular insert apparatus and methods," and U.S. Pat. No. 8,939,948, entitled "Insertion and Removal Methods and Apparatus for Therapeutic Devices," International Publication No. WO 2008 / 0239948. International Publication No. 13 / 116061, entitled "Ophthalmic System for Sustained Release of Drug to the Eye", International Publication No. 2014 / 066775, entitled "Implantable Therapeutic Device", International Publication No. 2015 / 085234 and International Publication No. 2012 / 019176, entitled "Implantable Therapeutic Device", International Publication No. 2012 / 065006, entitled "Methods and Apparatus to Determine Porous Structures for Drug Delivery", International Publication No. 2010 / 141729, entitled "Anterior Segment Drug Delivery", and "Corneal Denervation for Treatment of Ocular Pain". International Publication No. WO 2011 / 050327 entitled "Small Molecule Delivery with Implantable Therapeutic Device" and International Publication No. WO 2013 / 022801 entitled "Posterior Ocular Drug Delivery" International Publication No. WO 2012 / 019047, entitled "Subconjunctival Implant for Posterior Segment Drug Delivery," and "Clinical Procedures for Implanted Devices," WO 2012 / 068549 entitled "Therapeutic Agent Formulations for Implanted Devices" and WO 2012 / 019139 entitled "Combined Delivery Methods and Apparatus" and "Intraocular Implants" International Publication No. 2013 entitled "Ocular Insert Apparatus and Methods" / 040426, entitled "Injector Apparatus and Method for Drug Delivery," and WO 2012 / 019136, entitled "Fluid Exchange WO 2013 / 040247 (ForSight Vision4, Inc.) entitled "Fluid Exchange Apparatus and Methods"; WO 2013 / 040247 (ForSight Vision4, Inc.) entitled "Inhalation Device with Feedback System"; U.S. Patent Application Publication No. 2014 / 0352690, entitled "Inhalation Device with Feedback System," U.S. Patent No. 8,910,625 and U.S. Patent Application Publication No. 2015 / 0165137 (Vectura GmbH), entitled "Inhalation Device for Use in Aerosol Therapy"; U.S. Patent No. 6,948,496, entitled "Inhalers," U.S. Patent Application Publication No. 2005 / 0152849, entitled "Powders comprising anti-adherent materials for use in dry powder inhalers," and U.S. Patent Application Publication No. 2005 / 0152849, entitled "Dry Powder Inhaler No. 6,582,678 entitled "Carrier particles for use in dry powder inhalers," U.S. Patent No. 8,137,657, U.S. Patent Application Publication Nos. 2003 / 0202944 and 2010 / 0330188, U.S. Patent No. 6,221,338 entitled "Method of producing particles for use in dry powder inhalers," U.S. Patent No. 6,989,155 entitled "Powders," and U.S. Patent No. 6,989,155 entitled "Method of producing particles for use in dry powder inhal ... U.S. Patent Application Publication No. 2007 / 0043030, entitled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation," U.S. Patent No. 7,845,349, entitled "Inhaler," and U.S. Patent No. 7,845,349, entitled "Pharmaceutical compositions for use in inhaler devices." U.S. patent application entitled "Formulations for Use in Inhaler Devices" Publication No. 2012 / 0114709 and U.S. Patent No. 8,101,160, U.S. Patent Application Publication No. 2013 / 028785 entitled "Compositions and Uses" No. 4, U.S. Patent Application Publication No. 2014 / 0037737 entitled "Particles for Use in a Pharmaceutical Composition" and U.S. Patent No. 8, No. 580,306, entitled "Mixing Channel for an Inhalation Device," and U.S. Patent Application Publication No. 2015 / 0174343, entitled "Mixing Channel for Use in Pharmaceutical Compositions." No. 7,744,855 and U.S. Patent Application Publication No. 2010 / 0285142, entitled "Method of making particles for use in a pharmaceutical composition," U.S. Patent No. 7,541,022, entitled "Pharmaceutical formulations for dry powder inhalers," U.S. Patent No. Patent Application Publication No. 2009 / 0269412 and U.S. Patent Application Publication No. 2015 / 0050350 (Vectura Limited).

[0513] Additional non-limiting examples of methods for delivering active compounds are described in the publication entitled "Intracameral Implant for Treatment of an Ocular Condition." WO 2015 / 085251 (Envisia Therapeutics, Inc.) entitled "Engineered Aerosol Particles and Associated Methods"; WO 2011 / 008737 (Geometrically Engineered Particles and Methods for Modulating Macrophages or Immune Responses) International Publication No. WO 2013 / 082111, entitled "For Modulating Macrophage or Immune Responses," International Publication No. WO 2009 / 132265, entitled "Degradable compounds and methods of use thereof, particularly with particle replication in non-wetting templates," International Publication No. WO 2010 / 099321, entitled "Interventional drug delivery system and associated methods," and International Publication No. WO 2010 / 099321, entitled "Polymer particle composite having high fidelity, size and shape particles." International Publication No. WO 2008 / 100304 entitled "Liquidia nanoparticles with high fidelity order, size, and shape" and International Publication No. WO 2007 / 024323 entitled "Nanoparticle fabrication methods, systems, and materials" (Liquidia Nanoparticles). Technologies, Inc. and the University of North Carolina at Chapel Hill); "Controlled Release in the Eye" International Publication No. WO 2010 / 009087 (Liquidia Technologies, Inc. and Eyegate Pharmaceuticals, Inc.) entitled "Iontophoretic Delivery of a Controlled-Release Formulation in the Eye" and "Intracellular Delivery and Release of Cargo"

[0005] Nanoparticles for cosmetic applications are presented in International Publication No. WO 2009 / 132206, entitled "Compositions and Methods for Intracellular Delivery and Release of Cargo," International Publication No. WO 2007 / 133808, entitled "Nano-particles for cosmetic applications," International Publication No. WO 2007 / 056561, entitled "Medical device, materials, and methods," International Publication No. WO 2010 / 065748, entitled "Method for producing patterned materials," and International Publication No. WO 2007 / 081876, entitled "Nanostructured surfaces for biomedical / biomaterial applications and processes thereof" (Liquidia Technologies, Inc.).

[0514] Additional non-limiting examples of drug delivery devices and methods include, for example, U.S. Patent Application Publication No. 200902020, entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor." No. 3709 (Abbott Laboratories); "Subconjunctival or periocular delivery of prodrugs" U.S. Patent No. 6,399,663, entitled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug." Publication No. 20050009910, entitled "Biodegradable polymers for lowering intraocular pressure," U.S. Patent Application Publication No. 20130071349, entitled "Tyrosine kinase microspheres," U.S. Patent No. 8,481,069, entitled "Method of making tyrosine kinase microspheres ... Patent No. 8,465,778, U.S. Patent No. 8,409,607 entitled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods," U.S. Patent No. 8,512,738 entitled "Biodegradable intravitreal tyrosine kinase implants," and U.S. Patent Application Publication No. U.S. Patent Application Publication No. 2014 / 0031408, entitled "Microsphere Drug Delivery System for Sustained Intraocular Release," U.S. Patent Application Publication No. 2014 / 0294986, entitled "Methods For Treating Retinopathy With Extended Therapeutic Effect," and No. 8,911,768 (Allergan, Inc.) entitled "Preparation of injectable suspensions having improved injectability"; U.S. Pat. No. 6,495,164 (Alkermes Controlled Therapeutics, Inc.) entitled "Biodegradable Microcapsules Containing Filling Material"; WO 2014 / 047439 (Akina, Inc.) entitled "Compositions And Methods For Drug Delivery"; International Publication No. WO 2010 / 132664 (Baxter International Inc. Baxter Healthcare SA) entitled "Improved Drug Loading"; "Polymer Nanoparticles and Methods of Use Thereof"; U.S. Patent Application Publication No. 20120052041 (The Brigham and Women's Hospital, Inc.) entitled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof"; U.S. Patent Application Publication No. 20140178475 (The Brigham and Women's Hospital, Inc.) entitled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same ... Publication No. 20140248358 and Publication No. 20140249158 (BIND Therapeutics, Inc.); U.S. Patent No. 5,869,103 (Danbiosyst UK Ltd.) entitled "Polymer microparticles for drug delivery"; U.S. Patent No. 8,628,801 (University of Navarre) entitled "Pegylated Nanoparticles"; U.S. Patent Application Publication No. 2014 / 0107025 (Jade Therapeutics, LL) entitled "Ocular drug delivery system." C); "A composition of microparticles and biodegradable gel with improved release profile" U.S. Patent No. 6,287,588 entitled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof," U.S. Patent No. 6,589,549 (Macromed, Inc.) entitled "Bioactive agent delivering system comprised of microparticles within a biodegradable material to improve release profiles," U.S. Patent No. 6,007,845 and U.S. Patent No. 5,578,325 entitled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers," No. (Massachusetts Institute of Technology); "Ophthalmic Devices for Periocular or Subconjunctival Administration" U.S. Patent Application Publication No. 20040234611, U.S. Patent Application Publication No. 20080305172, U.S. Patent Application Publication No. 20120269894, and U.S. Patent Application Publication No. 20130122064 (Novartis Ag) entitled "Ophthalmic depot formulations for periocular or subconjunctival administration"; U.S. Patent No. 6,413,539 (Poly-Med, Inc.) entitled "Block polymer"; and U.S. Patent No. 6,413,539 (Poly-Med, Inc.) entitled "Delivery of an agent to ameliorate inflammation." U.S. Patent Application Publication No. 20070071756 (Peyman) entitled "Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles"; U.S. Patent Application Publication No. 20080166411 (Pfizer, Inc.) entitled "Methods and compositions for enhanced delivery of bioactive molecules"; U.S. Patent Nos. 6 and 7 (Pfizer, Inc.) entitled "Methods and compositions for enhanced delivery of bioactive molecules"; No. 06,289 (PR Pharmaceuticals, Inc.); and No. 2006,289 (PR Pharmaceuticals, Inc.) entitled "Microparticle containing matrices for drug delivery." No. 8,663,674 (Surmodics).

[0515] IX. General synthesis 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 made using the following scheme:

[0516] Compounds of the present invention that have a stereocenter may be conveniently depicted without stereochemistry. Those 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:

[0517] i) Physical Separation of Crystals - a technique in which visible crystals of the individual enantiomers are manually separated. This technique can be used when crystals of the separate enantiomers are present, i.e. the material is a conglomerate, and the crystals are visually distinguishable.

[0518] ii) Simultaneous crystallization - a technique in which the individual enantiomers are separately crystallized from a solution of the racemate, which is only possible if the enantiomers are conglomerates in the solid state.

[0519] iii) Enzymatic resolution - a technique for partial or complete separation of a racemate by virtue of the difference in reaction rates of the enantiomers with an enzyme.

[0520] iv) Enzymatic Asymmetric Synthesis - a synthetic technique that uses an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enantiomerically enriched synthetic precursor of a desired enantiomer.

[0521] v) Chemical asymmetric synthesis - a synthetic technique in which a desired enantiomer is synthesized from non-chiral precursors under conditions that result in asymmetry (ie, chirality) in the product, which may be achieved by means of chiral catalysts or chiral auxiliaries.

[0522] vi) Diastereomeric separation - a technique in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their more distinct structural differences, followed by removal of the chiral auxiliary to give the desired enantiomer.

[0523] vii) First and second order asymmetric transformations - rapid equilibration of diastereomers derived from the racemate and preponderance of dissolution of the diastereomer derived from the desired enantiomer. This technique results in the preferential crystallization of the diastereomer derived from the desired enantiomer, which disrupts the equilibrium and ultimately converts essentially all of the material from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomer.

[0524] viii) Kinetic Resolution - This technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions.

[0525] ix) Enantiospecific synthesis from non-racemic precursors - during synthesis A synthetic technique that yields a desired enantiomer from non-chiral starting materials with little or no loss of stereochemical integrity.

[0526] x) Chiral Liquid Chromatography - a technique in which enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase (including by chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral material to effect the different interactions.

[0527] xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the enantiomers are separated by their different interactions in a gaseous mobile phase by a column containing a fixed non-racemic chiral adsorbent phase.

[0528] xii) Extraction with chiral solvents- a technique in which enantiomers are separated by selective dissolution of one enantiomer in a particular chiral solvent.

[0529] xiii) Transport across chiral membranes—a technique in which a racemate is placed in 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 a concentration or pressure difference results in preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral properties of the membrane, which allows only one enantiomer of the racemate to pass through.

[0530] xiv) Simulated moving bed chromatography is used in one embodiment. A wide variety of chiral stationary phases are commercially available.

[0531] X. Synthesis of Components Used in the Invention Synthesis of 4-(3,5-dimethoxy-4-(piperazin-1-ylmethyl)phenyl)-6-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one [ka] Step 1: A stirred solution of anhydrous potassium phosphate tribasic (2.74 g, 12.92 mmol) in THF (150 mL) and water (5 mL) was purged with argon for 15 minutes. 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 then added to the reaction mixture, which was then purged with argon for 15 minutes. 1310584-14-5 (XPhos-Pd-G2) (338.60 mg) was added to the reaction mixture, which was then purged with argon for 10 minutes and stirred at 70 °C for 16 hours. The reaction progress was monitored by LCMS and TLC. After completion of the reaction, the residue was filtered through Celite and purified by column chromatography (reverse phase, 0.1% formic acid in 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, 49.26% yield). LC-MS (ES + ): m / z 434.25 [M+H] +

[0532] 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) was added acetic acid (32.99 μL, 576.76 mmol) at 0° C. 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 purified under vacuum. The mixture was concentrated. 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% to 50% ethyl acetate in 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 / z 604.44 [M+H] +

[0533] 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 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was dried by rotary evaporation and co-distilled with acetonitrile and toluene. The crude compound was triturated with diethyl ether to give 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] +

[0534] 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) [ka] Step-1: 4-Bromo-2,6-dimethoxy- in dry dichloromethane (350 mL) To a stirred solution of benzaldehyde B2-1 (15 g, 61.21 mmol) and tert-butyl piperazine-1-carboxylate (11.40 g, 61.21 mmol) 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 h. Sodium triacetoxyboranide (25.95 g, 122.42 mmol) was added in one portion to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to RT slowly over 1 h and stirred at RT for an additional 9 h. After completion of the reaction, the reaction mixture was quenched with water (500 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were further washed with brine (1×250 mL), dried over anhydrous NaSO, and concentrated to give the crude product, which was purified by column chromatography on silica gel (100 / 200 mesh) and the product was 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 pale yellow pasty solid. 1 H NMR (400MHz, CDCl3): 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] + .

[0535] Step 2: To a stirred solution of tert-butyl 4-[(4-bromo-2,6-dimethoxyphenyl)methyl]piperazine-1-carboxylate (15 g, 36.12 mmol) in 1,4-dioxane (350 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (13.76 g, 54.17 mmol) was added, followed by potassium acetate (10.63 g, 108.35 mmol, 6.77 mL) at room temperature under an argon atmosphere. The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphane, dichloromethane, dichloropalladium, and iron (1.47 g, 1.81 mmol) were added in one portion under an argon atmosphere. The reaction mixture was again repeatedly degassed with argon and then heated at 100 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (300 mL). The filtrate was concentrated, and the resulting mass was dissolved in ethyl acetate (500 mL), washed with water (2 × 100 mL), brine (1 × 100 mL), dried over anhydrous NaSO, and concentrated to give the crude product. The crude material was further purified by column chromatography on silica gel (100 / 200 mesh). The product was eluted with 40% to 50% EtOAc / hexane to give tert-butyl 4-[[2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-1-carboxylate (12 g, 25.69 mmol, 71.14% yield, 99% purity) as an off-white pasty solid. 1 H NMR (400MHz, CDCl3) δ 6.99 (s, 2H), 3.85 (s, 6H), 3.74 (s, 2H), 3.39 (t, J=5.0 Hz, 4H), 2.46 (t, J=5.0 Hz, 4H), 1.43 (s, 9H), 1.35 (s, 12H). LC MS: Boronic Acid: RT: 1.26 min=381.41[M+H] + and boronic ester: RT: 1.75 min = 463.48 [M+H] +Note: LCMS shows 41% boronic acid mass and 58% boronic ester mass.

[0536] 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) was 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 KPO (1.52 g, 7.18 mmol). The resulting solution was degassed with nitrogen for 15 minutes, and then XPhos-Pd-G (112.98 mg, 143.60 μmol) was added. 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 the crude material. Purification by HPLC (SHS 100-200, 60% → 70% EtOAc in PET ether) gave 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 (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.70 (s, 1H), 7.31 (d, J=2 Hz, 2H), 6.86 (d, J=2 Hz, 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] + .

[0537] 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 in HCl (0.4 ml, 12.4 mmol) at 0° C., and the reaction mixture was stirred at RT for 4 hours while being monitored by TLC. The reaction mixture was concentrated to give crude compound. The crude compound was triturated with diethyl 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, which was carried on to the next step without purification.

[0538] 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. 1H NMR (400 MHz, DMSO-d6) δ 13.77 (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] + .

[0539] Synthesis of 2,6-dimethoxy-4-(6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-4-yl)benzaldehyde [ka] To a stirred solution of the 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), TFA (2.63 g, 23.07 mmol, 1.78 mL) was added at 0° C., and the reaction mixture was stirred at RT for 16 hours. The progress of the reaction was monitored by TLC, and upon completion, the reaction mixture was concentrated to give the crude compound. 0.1% T The crude compound was purified by reverse phase using FA 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, 82.16% yield, 90% purity, 061) as a brown solid. The desired compound was confirmed by LCMS. LC-MS (ES + ): m / z 314.2 [M+H] +

[0540] 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 [ka] 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 potassium acetate (2.98 g, 30.36 mmol, 1.90 mL) in water (7 mL). The mixture was then purged with argon gas for 20 minutes, followed by the addition of cyclopentyl(diphenyl)phosphane; dichloromethane; dichloropalladium; and iron (413.22 mg, 506.00 μmol) and degassing. The mixture was heated to 70° C. and maintained for 4 hours. The reaction was monitored by TLC. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, separated, dried over Na2SO4, and concentrated. The crude product was purified by Biotage using 50% EA in 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, 24.82% yield, pale yellow solid). LC-MS (ES) + ): m / z 438.30 [M+H] +

[0541] Step-2: 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 μmol) was added with 99% trifluoroacetic acid (2.96 g, 25.96 mmol, 2 mL). The reaction mixture was heated at 70 ° C for 1 hour. Completion of the reaction was monitored by TLC and LCMS. After completion of the reaction, excess TFA was removed under vacuum 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 μmol, 82.49% yield, 96.83% purity, 061) as a light brown solid. LC-MS (ES + ): m / z 318.27 [M+H] +

[0542] 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 [ka] 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, 061) in 1,4-dioxane (5 mL) was added 2-methylbut-2-ene (389.85 mg, 5.56 mmol). Then, a mixture of sodium chlorite (314.22 mg, 3.47 mmol) and sodium dihydrogen phosphate (1.67 g, 13.90 mmol) was slowly added to the reaction mixture and stirred at RT for 1 h. Upon completion, the reaction mass was directly evaporated under reduced pressure. The crude material was purified using reverse phase chromatography. The desired product was eluted with 30% ACN in 1% FA in water to give a light brown solid, 2-chloro-6-methoxy-4-(6-methyl-7-oxo-1H-pyrazolo[3,4-c]pyridin-4-yl)benzoic acid (100 mg, 282.39 μmol, 40.64% yield, 94.24% purity). LC-MS (ES) + ): m / z 334.32 [M+H] +

[0543] Synthesis of 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid [ka] Step 1: To a solution of 4-bromo-2-(trifluoromethoxy)benzaldehyde (5 g, 18.59 mmol) in 1,4-dioxane (120 mL), bis(pinacolato)diboron (7.08 g, 27.88 mmol) and potassium acetate (5.47 g, 55.76 mmol) were added and the mixture was degassed with argon for 20 min. Finally, Pd(dppf)Cl·DCM complex (0.758 g, 0.929 mmol) was added and the mixture was degassed with argon for 10 min. The mixture was degassed and stirred at 90°C for 16 hours while monitoring the reaction by TLC and LCMS. After completion, the reaction mass was filtered through a Celite pad. The crude material was quenched with water (200 mL) and extracted with EtOAc (2 x 200 ml). The combined organic layers were dried over anhydrous NaSO and concentrated to give crude compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)benzaldehyde (5 g, 51.07% yield, 60% purity) as a brown solid. LC-MS (ES + ): m / z 233.94 [MH] - (boronic acid mass)

[0544] 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 KPO (4.72 g, 34.71 mmol, 2.02 mL) dissolved in water (20 mL). The resulting solution was degassed with argon for 20 minutes, and then XPhos-Pd-G (0.544 g, 0.694 mmol) was added, 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 Celite pad, washed with EtOAc (100 mL), and the filtrate was evaporated to give a crude material. The crude compound was purified by silica gel mesh 100-200 (PET ether, 60% → 70% EtOAc) to give 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde 5 (3.5 g, 74.14% yield, 95.67% purity) as a pale yellow solid. LC-MS (ES) + ): m / z 326.30 [M+H] +

[0545] 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 stirring at RT for 3 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated to half its volume to give the crude product, which was purified by trituration with methanol, followed by washing with water to give 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzoic acid (2.3 g, 6.44 mmol, 59.87% yield, 95.58% purity). LC-MS (ES + ): m / z 342.12 [M+H] +

[0546] Synthesis of 2-(trifluoromethoxy)-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid (alternative route) [ka] Step-1: To a mixture of B4-4 (10 g, 35.1 mmol, 1 equiv.) and B2Pin2 (13.4 g, 52.6 mmol, 1.5 equiv.) in N,N-dimethylformamide (150 mL) was added potassium acetate (17.2 g, 175 mmol, 5 equiv.), Pd(dppf) Cl2 (2.57 g, 3.5 mmol, 0.1 equiv) was added at 15 °C under a nitrogen atmosphere. The mixture was stirred at 80 °C for 15 hours. After completion of the reaction, which was monitored by HPLC, the reaction mixture was cooled to room temperature. The mixture was concentrated in vacuo to remove some of the solvent. The residue was diluted in water (200 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were 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 (8.5 g, 73% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.98 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.68 (s, 1H), 1.29 (s, 12H).

[0547] 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) and water (20 mL), sodium carbonate (6.13 g, 57.9 mmol, 2.5 eq.) and Pd(dppf)Cl (847 mg, 1.16 mmol, 0.05 eq.) were added at 10 °C under a nitrogen atmosphere. The mixture was stirred at 80 °C for 13 h. The mixture was concentrated in vacuo to remove dioxane. The aqueous phase was then extracted with ethyl acetate (100 mL × 2). The aqueous phase was acidified to pH 5 with HCl (2 N) 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 (5.5 g, 67% yield) as a white solid. 1 H NMR (400 MHz, MeOD-d4) δ 8.03 (d, J=7.9 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J=8.0, 1.3 Hz, 1H), 7.35 (s, 1H), 3.60 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H).

[0548] Synthesis of 4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)-2-(trifluoromethoxy)benzaldehyde [ka] 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) was added 4-bromo-2-methyl-2,7-naphthyridin-1-one (3 g, 12.60 mmol) at room temperature under an argon atmosphere, followed by potassium phosphate (KPO) (6.69 g, 31.51 mmol) dissolved in water (20 mL), and the resulting mixture was purged with argon gas for up to 30 minutes. After this, 1310584-14-5 (Xphos Pd G2) (0.495 g, 0.63 mmol) was 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 brought to room temperature and diluted with ice-cold water (100 mL), and the resulting solid was collected by filtration and dried under high vacuum to give a crude material, which was triturated with n-pentane (100 mL) to give a solid mixture, which was again refluxed in methanol (80 mL), filtered, and purified 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) was obtained as a brown solid. LC-MS (ES + ): m / z 349.51 [M+H] +

[0549] Synthesis of 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde [ka] Step 1: To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde and 4-bromo-2-chloro-6-methoxybenzaldehyde (3.85 g, 15.43 mmol) in 1,4-dioxane (40 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.70 g, 18.52 mmol) was added, followed by potassium acetate (3.79 g, 38.58 mmol) at room temperature under an argon atmosphere. The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphane, 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 completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (200 mL). The filtrate was concentrated to obtain a residual mass. The residual mass was dissolved in ethyl acetate (200 mL), washed with water (2 x 50 mL), brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography using silica gel (100 / 200 mesh). The product was eluted with 30% to 40% EtOAc / hexane to obtain 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4 g, 83.04% yield, 95% purity) as a pale yellow solid. LC-MS (ES) + ): m / z [M+H] + 215.13 (corresponding boronic acid mass observed)

[0550] 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, potassium phosphate tripotassium (2.46 g, 11.57 mmol) was added at room temperature, and the resulting mixture was purged with argon for 10 minutes. Cyclopentyl(diphenyl)phosphane, dichloromethane, dichloropalladium, and iron (0.18 g, 0.23 mmol) were added to the reaction mixture, and the reaction mixture was again degassed with argon for another 5 minutes before heating at 80 °C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The organic layer was separated from the filtrate and concentrated to give the crude material, which was purified by column chromatography on silica gel (100 / 200 mesh). The product was eluted with 60% EtOAc / Pet ether to give 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde (0.920 g, 61.76% yield, 95% purity). LC-MS (ES + ): m / z 306.31 [M+H] +

[0551] Synthesis of 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid [ka] 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 2-methyl-2-butene (917.50 mg, 13.08 mmol) dropwise at 0 °C, followed by the addition of sodium chlorite (739.48 mg, 8.18 mmol) in one portion and the dropwise addition of sodium dihydrogen phosphate (3.92 g, 32.71 mmol) dissolved in water (20 mL). The reaction mixture was allowed to warm slowly to RT over 30 min and stirred at RT for an additional 6 h. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated directly to give the crude product, which was purified by trituration with water / methanol, and the precipitated solid was filtered and thoroughly dried to give 2-chloro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid (400 mg, 70.90% yield, 93.26% purity) as an off-white solid. LC-MS (ES) + ): m / z 322.12 [M+H] +

[0552] Synthesis of 2-chloro-6-methoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde [ka] 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, 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.24 g, 4.18 mmol) was added at room temperature, followed by the addition of potassium phosphate tribasic (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 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The organic layer was partitioned from the filtrate and concentrated to give the crude material. The eluent gradient was 0.1% FA in water and acetonitrile. The crude product was purified by reverse-phase column chromatography to give 2-chloro-6-methoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (0.30 g, 21.46% yield, 85.97% purity) as an off-white solid. LC-MS (ES + ): m / z 329.17 [M+H] +

[0553] Synthesis of 2-chloro-4-(7-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-6-methoxybenzoic acid [ka] To a stirred solution of 2-chloro-4-(7-fluoro-2-methyl-1-oxo-4-isoquinolyl)-6-methoxy-benzaldehyde (0.17 g, 0.49 mmol) in THF (25 mL) was added 2-methyl-2-butene (0.27 g, 3.93 mmol) at 0 °C, followed by the 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 allowed to warm slowly to RT over 30 min and stirred at RT for 12 h. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated to half the volume to give the crude product, which was purified by trituration with methanol / water to give 2-chloro-4-(7-fluoro-2-methyl-1-oxo-4-isoquinolyl)-6-methoxy-benzoic acid (0.12 g, 64.09% yield, 95% purity) as a white solid. LC-MS (ES + ): m / z 362.25 [M+H] +

[0554] Synthesis of 2-fluoro-6-methoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde [ka] Step 1: To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzaldehyde (7 g, 30.04 mmol) in 1,4-dioxane (300 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (11.44 g, 45.06 mmol), followed by potassium acetate (8.84 g, 5.63 mL) at room temperature under an argon atmosphere. The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphane, dichloromethane, dichloropalladium, and iron (1.23 g, 1.50 mmol) were added. The reaction mixture was 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, filtered through Celite, and washed with ethyl acetate (200 mL). The filtrate was concentrated to give a residual mass. The residual mass was dissolved in ethyl acetate (300 mL), washed with water (2×100 mL), brine (1×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was triturated with pentane (500 mL), stirred thoroughly, and filtered through Celite. The filtrate was concentrated to give a solid, which was slurried with hexane (25 mL), filtered, washed with hexane (10 mL), and thoroughly dried to give the product, 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4.1 g, 46.29% yield, 95% purity) as a light brown solid. LC-MS (ES) + ): m / z 199.17 [M+H] + (Corresponding boronic acid masses were observed)

[0555] 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, 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.30 g, 4.63 mmol) was added at RT, followed by the addition of potassium phosphate tribasic (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)phosphane, 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 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The organic layer was partitioned from the filtrate and concentrated to give the crude material. The crude product was purified by column chromatography on silica gel (100 / 200 mesh). The product was eluted with 4% to 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, 32.40% yield, 96.40% purity) as an off-white solid. LC-MS (ES) + ): m / z 290.52 [M+H] +

[0556] Synthesis of 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde [ka] 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 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) at RT, followed by the addition of potassium phosphate tribasic (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. After degassing, the mixture was heated at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The organic layer was partitioned from the filtrate and concentrated to give the crude material. The crude product was purified by reverse-phase column chromatography using 0.1% FA in water and acetonitrile as an eluent gradient to give 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde 7 (1.90 g, 72.15% yield, 99.21% purity) as an off-white solid. LC-MS (ES + ): m / z 313.14 [M+H] +

[0557] Synthesis of 2-fluoro-6-methoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzoic acid [ka] 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 RT over 30 min and stirred at RT for 6 h. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated to half its volume to give the 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] +

[0558] Synthesis of 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde [ka] Step-1: To a stirred solution of 4-bromo-2,6-dimethoxy-benzaldehyde (10 g, 40.80 mmol) in 1,4-dioxane (300 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (15.54 g, 61.21 mmol); Subsequently, potassium acetate (12.01 g, 122.41 mmol) was added at room temperature under an argon atmosphere. The reaction mixture was repeatedly degassed with argon, and cyclopentyl(diphenyl)phosphane; 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 to reflux at 95° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (200 mL). The filtrate was concentrated to obtain a residual mass. The residual mass was dissolved in ethyl acetate (500 mL), washed with water (2×100 mL), brine (1×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography on silica gel (100 / 200 mesh) and the product was eluted with 30% → 40% EtOAc / Pet ether to give 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 2 (7 g, 55.79% yield, 95% purity) as a light brown solid.

[0559] 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, 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde 2 (2.70 g, 9.26 mmol) was added at RT, followed by the addition of potassium phosphate tribasic (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 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The organic layer was partitioned from the filtrate and concentrated. The resulting crude product was further purified by reverse-phase column chromatography using 0.1% FA in water and acetonitrile as an eluent gradient to give 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-3-pyridyl)benzaldehyde (1.45 g, 4.63 mmol, 96.22% purity) as an off-white solid. LC-MS (ES + ): m / z 302.27 [M+H] +

[0560] Synthesis of 2,6-dimethoxy-4-(1,4,5-trimethyl-6-oxo-1,6-dihydropyridin-3-yl)benzoic acid [ka] 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 the addition of 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 allowed to warm slowly to rt over 30 min and stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was concentrated to one-quarter of the total volume, and the precipitated colorless solid was filtered, washed with water (10 mL), and thoroughly dried to give 2,6-dimethoxy-4-(1,4,5-trimethyl- 6-Oxo-1,6-dihydropyridin-3-yl)benzoic acid (0.65 g, 59.90% yield, 97.04% purity) was obtained as a white solid. LC-MS (ES + ): m / z 318.32 [M+H] +

[0561] Synthesis of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzaldehyde [ka] 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, 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.44 g, 8.37 mmol) was added at room temperature, followed by potassium 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 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (100 mL). The organic layer was partitioned from the filtrate and concentrated to give the crude material. The crude product was purified by column chromatography using silica gel (100 / 200 mesh) and eluted with 4% to 5% MeOH in EtOAc to give 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzaldehyde (1.8 g, 64.42% yield, 97.10% purity) as a pale yellow solid. LC-MS (ES + ): m / z 325.29 [M+H] +

[0562] Synthesis of 2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzoic acid [ka] 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 the addition of 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 stirred for 30 min. The mixture was allowed to warm slowly to rt over a period of time and stirred at rt for an additional 12 h. After completion of the reaction, the reaction mixture was concentrated to ¼ of the total volume, and the precipitated colorless solid was filtered, washed with water (10 mL), and thoroughly dried to give 2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)benzoic acid 8 (0.28 g, 62.95% yield, 82.64% purity) as an off-white solid. LC-MS (ES + ): m / z 341.29 [M+H] +

[0563] 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 [ka] 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 μL), followed by iodoethane (340.90 mg, 2.19 mmol, 175.72 μL) at room temperature and stirring for 5 hours under argon atmosphere. 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 (50 mL of a 5% (w / v) aqueous solution), then brine (50 mL), dried over NaSO, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0 → 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] + .

[0564] Step-2: First, cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (112.96 mg, 154.38 μmol), 4-bromo-2-ethoxy-5-methoxy-benzaldehyde 1-2 (400 mg, 1.54 mmol), bis(pinacolato)diboron (470.44 mg, 1.85 mmol), potassium acetate (454.54 mg, 4.63 mmol, 289.52 μL) were placed in a MW vial (2 mL - 5 mL), suspended in 1,4-dioxane (5.89 mL) under argon atmosphere, and heated at 140 °C for 40 min in a MW vial. The suspension was then added with 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (134.62 mg, 386.63 μmol) under argon along with potassium carbonate (2 M, 2 equiv.) and reheated to 120 °C for 30 min, as confirmed 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), followed by brine (50 mL), NaSO, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0 → 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 regioisomers. Yield—599 mg, 82%; LC-MS (ES + ): m / z 448.5 [M+H] + .

[0565] 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 [ka] Step-1: 4-Bromo-2,5-dichlorobenzoic acid (609 mg, 2.26 mmol), tert-butyl piperazine-1-carboxylate (462.27 mg, 2.48 mmol, 45.96 μL), DIPEA (583.23 mg, 4.51 mmol, 786.02 μL), and HATU (943.71 mg, 2.48 mmol) were initially added to a vial. The reaction mixture was 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 × 10 mL). The organic layer was washed with LiCl (50 mL of a 5% (w / v) aqueous solution), then brine (50 mL), dried over Na2SO4, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0 → 0:1) to give 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] + .

[0566] Step-2: First, cyclopentyl(diphenyl)phosphane, dichloropalladium, iron (79.83 mg, 109.1 μmol), 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 placed in a MW vial (2 mL to 5 mL), suspended in 1,4-dioxane (5.89 mL) under an argon atmosphere, and heated at 140°C for 40 minutes in a MW vial. The suspension was then added with 4-bromo-1-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[3,4-c]pyridin-7-one (417.86 mg, 1.20 mmol) under argon with potassium carbonate (2 M, 2 equivalents) and reheated at 120° C. for 30 minutes, after which the reaction was confirmed 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 diluted with water (10 mL). After washing with HCl, the mixture was washed with brine (50 mL), NaSO, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0→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 regioisomers. Yield—736 mg, 100%; LC-MS (ES) + ): m / z 626.5 [M+H] + .

[0567] Step 3: First, 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 μL) was added dropwise, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated to dryness and co-evaporated with DCM (10 mL × 2), and then concentrated as the TFA salt, which was used in the next step without further purification. Yield: 752 mg, 100%; LC-MS (ES) + ): m / z 526.4 [M+H] + .

[0568] 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 [ka] Step-1: 4-Bromo-5-chloro-2-methoxy-benzaldehyde (782 mg, 3.13 mmol) and tert-butyl piperazine-1-carboxylate 2 (642.16 mg, 3.45 mmol) were initially charged into a reaction vial and dissolved in 1,2-DCE (10.45 mL). 95% sodium triacetoxyborohydride (1.99 g, 9.40 mmol) was then added in one portion. The reaction mixture was stirred at room temperature and monitored by LCMS. After completion of the reaction, the mixture was concentrated to dryness and purified by flash column chromatography (DCM:MeOH up to 10%) to give 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] + .

[0569] Step-2: First, cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (127.78 mg, 174.63 μmol), 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), and potassium acetate (514.16 mg, 5.24 mmol, 327.49 μL) were placed in a MW vial (2 mL - 5 mL), suspended in 1,4-dioxane (2.58 mL) under an argon atmosphere, and heated in a MW vial at 140 °C 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 μmol) under argon along with potassium carbonate (2 M, 2 equiv.) and reheated at 120° C. for 30 min, after which time the reaction was confirmed 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), followed by brine (50 mL), NaSO, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0→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 regioisomers. Yield—751 mg, 71%; LC-MS (ES) + ): m / z 608.5 [M+H] + .

[0570] Step-3: First, 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 μL), and the mixture was stirred overnight. After completion of the reaction, the mixture was concentrated to dryness and co-evaporated with DCM (10 mL × 2), and then concentrated as the TFA salt, which was used in the next step without further purification. Yield: 768 mg, 100%; LC-MS (ES) + ): m / z 508.5 [M+H] + .

[0571] 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 [ka] Step-1: First, tert-butyl piperazine-1-carboxylate (761.58 A mixture of 4-bromo-2-(trifluoromethoxy)benzaldehyde (1000 mg, 3.72 mmol) and 4-bromo-2-(trifluoromethoxy)benzaldehyde (1000 mg, 3.72 mmol) was placed in a reaction vial and dissolved in 1,2-DCE (6.88 mL). Then, 95% sodium triacetoxyborohydride (1.18 g, 5.58 mmol) was added in one portion. The reaction mixture was stirred at room temperature and monitored by LCMS. After completion of the reaction, the mixture was concentrated to dryness and purified by flash column chromatography (hexane / EA up to 50%) to give 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] + .

[0572] Step-2: First, cyclopentyl(diphenyl)phosphane, dichloropalladium, iron (131.93 mg, 180.30 μmol), 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 μL) were placed in a MW vial (2 mL to 5 mL), suspended in 1,4-dioxane (2.58 mL) under an argon atmosphere, and heated at 140 °C in a MW vial 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 μmol) under argon along with potassium carbonate (2 M, 2 equiv.) and reheated at 120° C. for 30 min, after which time the reaction was confirmed 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), followed by brine (50 mL), NaSO, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0→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 regioisomers. Yield—798 mg, 71%; LC-MS (ES) + ): m / z 628.6 [M+H] + .

[0573] Step-3: First, 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 stirred overnight. After completion of the reaction, the mixture was concentrated to dryness and co-evaporated with DCM (10 mL × 2), and then concentrated as the TFA salt, which was used in the next step without further purification. Yield: 815 mg, 100%; LC-MS (ES) + ): m / z 528.6 [M+H] + .

[0574] 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 [ka] 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 μL), followed by 1,1-difluoro-2-iodo-ethane (516.75 mg, 2.69 mmol, 237.04 μL) at room temperature and stirred under argon atmosphere at 90° C. 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 (50 mL of a 5% (w / v) aqueous solution), then brine (50 mL), dried over NaSO, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0 → 4:6) to give 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]+ .

[0575] Step-2: First, cyclopentyl(diphenyl)phosphane, dichloropalladium, iron (69.43 mg, 94.89 μmol), 4-bromo-2-(2,2-difluoroethoxy)-5-methoxy-benzaldehyde (280 mg, 948.90 μmol), bis(pinacolato)diboron (289.16 mg, 1.14 mmol), potassium acetate (279.38 mg, 2.85 mmol, 177.95 μL) were placed in a MW vial (2 mL to 5 mL), suspended in 1,4-dioxane (2.58 mL) under an argon atmosphere, and heated at 140°C for 40 minutes in a MW vial. 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 μmol) under argon along with potassium carbonate (2 M, 2 equiv.) and reheated at 120° C. for 30 min, after which time the reaction was confirmed 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), followed by brine (50 mL), NaSO, filtered, and concentrated to a residue, which was purified by flash column chromatography (hexane:ethyl acetate 1:0→0:1) to give 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 regioisomers. Yie...

Claims

1. Formula I, Formula II, Formula III, Formula IV, Formula V and Formula VI: 【Chemistry 1】 (In the formula, 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 are N, CH and CR ３ where X is selected from the group consisting of ３ , X ４ , X ５ and X ６ Three or fewer of these are N, X ７ is N or CH, X ８ and X ９ are each independently selected from the group consisting of N and CH, ８ or X ９ at least one of is CH; X １２ is a 5-membered heteroaryl group having 1, 2, or 3 atoms independently selected from N, O, and S, where X １２ is R ３ optionally substituted with one, two, or three groups independently selected from X １７ is aryl, heteroaryl, bicyclic, or cycloalkyl, each of which is R ３ optionally substituted with 1, 2, 3, or 4 substituents independently selected from Q １ is independently in each occurrence NH, N(alkyl), N(haloalkyl), CH ２ , O and S, where X ７ If N, then Q １ is CH ２ and R is independently in each case hydrogen, C １ ~C ４ Haloalkyl, C １ ~C ４ Alkyl, fluorine, chlorine, bromine, iodine, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , C.H. ２ Br, CHBr ２ and CBr ３ is selected from the group consisting of R １ is hydrogen, C １ ~C ４ Alkyl, C １ ~C ４ haloalkyl or cycloalkyl, R ３ are independently in each case hydrogen, hydroxyl, alkoxy, C １ ~C ４ Alkyl, C １ ~C ４ selected from the group consisting of haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine; B is B １ and B ２ is selected from B １ teeth, 【Chemistry 2】 is selected from the group consisting of B ２ teeth, 【Transformation 3】 is selected from the group consisting of X １０ is C(R ７ ) ２ , C(O) or O; X １１ is a heterocycle, heteroaryl, aryl, cycloalkyl or bicycle, １１ Each of the groups is R ３ optionally substituted with one, two, three, or four groups independently selected from or X １０ and X １１ together, 【Chemistry 4】 Forming X １３ , X １４ , X １５ and X １６ are independently N, CH, and CR ４ where X is selected from the group consisting of １３ , X １４ , X １５ and X １６ Three or fewer of these are N, Each R ４ are independently hydrogen, aryl, heteroaryl, C １ ~C ４ Alkoxy, C １ ~C ４ Haloalkyl, C １ ~C ４ Haloalkoxy, C １ ~C ４ Alkyl, fluorine, chlorine, bromine and and iodine, where two R on adjacent carbon atoms ４ The groups may optionally be joined to form a fused ring, which is optionally substituted with one, two or three R substituents, such that: 【Transformation 5】 Non-limiting examples of ４ groups are linked to form a pyrrole, 【Transformation 6】 are listed, R ５ is hydrogen, C １ ~C ４ alkyl, aryl, crotyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; Each R ６ are independently hydrogen, C １ ~C ４ Alkoxy, C １ ~C ４ Alkyl, C １ ~C ４ selected from haloalkyl, fluorine, chlorine, bromine and iodine; Each R ７ are independently hydrogen or C １ ~C ４ is alkyl, R ８ is hydrogen, C １ ~C ４ alkyl, aryl, crotyl, alkenyl, alkynyl, haloalkyl or cycloalkyl; and L is a divalent linking group, or a pharmaceutically acceptable salt thereof.

2. L is of the formula: 【Transformation 7】 (In the formula, X １ and X ２ are each independently a bond, a heterocycle, NR ２ , C(R ２ ) ２ , O, C(O) and S; R ２ is independently selected in each occurrence from the group consisting of 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 represents, independently in each occurrence, a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, or —SO ２ -, -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, glycolic, and carbocyclic, each of which is selected from the group consisting of R ４０ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２６ is independently selected in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R ４０ are independently in each case hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH (aliphatic including alkyl), -N (aliphatic including alkyl) ２ , -NHSO ２ (aliphatic containing alkyl), -N(aliphatic containing alkyl)SO ２ Alkyl, -NHSO ２ (aryl, heteroaryl or heterocyclic ring), —N(alkyl)SO ２ (aryl, heteroaryl or heterocyclic ring), —NHSO ２ Alkenyl, -N(alkyl)SO ２ Alkenyl, —NHSO ２ Alkynyl, —N(alkyl)SO ２ 2. The compound of claim 1, wherein the linker is selected from the group consisting of alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl.

3. formula: 【Transformation 8】 2. The compound of claim 1, wherein

4. X ８ is N and X ９ The compound of claim 3, wherein is CH.

5. X ８ is CH and X ９ The compound of claim 3 wherein is N.

6. X ８ is CH and X ９ The compound of claim 3, wherein is CH. 【Request Item 7】 【Chemistry 9】 but, 【Chemistry 10】 The compound according to any one of claims 3 to 6, 【Request Item 8】 【Chemistry 11】 but, 【Chemistry 12】 The compound according to any one of claims 3 to 6, 【Request Item 9】 【Chemistry 13】 but, 【Chemistry 14】 The compound according to any one of claims 3 to 6, 【Request Item 10】 【Chemistry 15】 but, 【Chemistry 16】 The compound according to any one of claims 3 to 9, wherein

11. R is C １ ~C ４ Haloalkyl, C １ ~C ４ The compound according to any one of claims 3 to 11, which is alkyl, fluorine, chlorine or bromine.

12. 12. The compound according to any one of claims 3 to 11, wherein R is fluorine.

13. formula: 【Chemistry 17】 2. The compound of claim 1, wherein

14. X １７ is R ３ 14. The compound of claim 13, wherein the aryl group is optionally substituted with one, two, three, or four substituents independently selected from:

15. X １７ 15. The compound of claim 14, wherein is phenyl.

16. X １７ are heteroaryl or cycloalkyl groups, each of which is R ３ 14. The compound of claim 13, optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

17. Q １ is NH, and X ７ The compound of any one of claims 3 to 16, wherein is CH.

18. Q １ is O and X ７ The compound of any one of claims 3 to 16, wherein is CH.

19. Q １ is N (CH ３ ) and X ７ The compound of any one of claims 3 to 16, wherein is CH.

20. formula: [Chemistry 18] 2. The compound of claim 1, wherein

21. X ３ is CR ３ The compound according to any one of claims 3 to 20,

22. X ３ The compound according to any one of claims 3 to 20, wherein is N.

23. X ３ The compound of any one of claims 3 to 20, wherein is CH.

24. X ３ The compound according to any one of claims 3 to 20, wherein is CF.

25. X ３ is C (CF ３ 21. The compound according to any one of claims 3 to 20, wherein

26. X ３ The compound according to any one of claims 3 to 20, wherein is C(Cl).

27. X ５ is CR ３ The compound according to any one of claims 3 to 26,

28. X ５ The compound of any one of claims 3 to 26, wherein is N.

29. X ５ The compound of any one of claims 3 to 26, wherein is CH.

30. X ５ The compound of any one of claims 3 to 26, wherein is CF.

31. X ５ is C (CF ３ 27. The compound according to any one of claims 3 to 26, wherein

32. X ５ The compound of any one of claims 3 to 26, wherein is C(Cl).

33. formula: 【Chemistry 19】 2. The compound of claim 1, wherein

34. R １ 34. The compound of claim 33, wherein is hydrogen.

35. R １ is CH ３ 34. The compound of claim 33, wherein:

36. X ４ is CR ３ The compound according to any one of claims 3 to 35,

37. X ４ The compound of any one of claims 3 to 35, wherein is N.

38. X ４ The compound of any one of claims 3 to 35, wherein is CH.

39. X ４ The compound of any one of claims 3 to 35, wherein is CF.

40. X ４ is C (CF ３ 36. The compound according to any one of claims 3 to 35, wherein

41. X ４ The compound of any one of claims 3 to 35, wherein is C(Cl).

42. X ６ is CR ３ The compound according to any one of claims 3 to 41,

43. X ６ The compound of any one of claims 3 to 41, wherein is CH.

44. X ６ The compound of any one of claims 3 to 41, wherein is CF.

45. X ６ is C (CF ３ 42. The compound according to any one of claims 3 to 41, wherein

46. X ６ The compound of any one of claims 3 to 41, wherein is C(Cl).

47. formula: 【Chemistry 20】 2. The compound of claim 1, wherein

48. Q １ is NH, and X ７ 48. The compound of claim 47, wherein is CH.

49. Q １ is O and X ７ 48. The compound of claim 47, wherein is CH.

50. Q １ is N (CH ３ ) and X ７ 48. The compound of claim 47, wherein is CH.

51. X １２ is a 5-membered heteroaryl group having 1, 2, or 3 atoms independently selected from N, where X １２ is R ３ 51. The compound of any one of claims 47 to 50, optionally substituted with one, two or three groups independently selected from:

52. X １２ is furan, where X １２ is R ３ 51. The compound of any one of claims 47 to 50, optionally substituted with one, two or three groups independently selected from:

53. B is B １ 56. The compound according to any one of claims 3 to 55,

54. B １ but, 【Chemistry 21】 54. The compound of claim 53, wherein:

55. R ５ 55. The compound of claim 54, wherein is hydrogen.

56. R ５ 55. The compound of claim 54, wherein is methyl.

57. B １ but, 【Chemistry 22】 54. The compound of claim 53, wherein:

58. B １ but, 【Chemistry 23】 54. The compound of claim 53, wherein:

59. B １ but, 【Chemistry 24】 54. The compound of claim 53, wherein:

60. B is B ２ The compound according to any one of claims 3 to 52,

61. formula: 【Chemistry 25】 2. The compound of claim 1, wherein

62. Q １ is NH, and X ７ 62. The compound of claim 61 , wherein is CH.

63. Q １ is O and X ７ 62. The compound of claim 61 , wherein is CH.

64. Q １ is N (CH ３ ) and X ７ 62. The compound of claim 61 , wherein is CH.

65. X ３ is CR ３ 65. The compound according to any one of claims 61 to 64, wherein

66. X ３ The compound of any one of claims 61 to 64, wherein is N.

67. X ３ 65. The compound of any one of claims 61 to 64, wherein is CH.

68. X ３ 65. The compound of any one of claims 61 to 64, wherein is CF.

69. X ３ is C (CF ３ 65. The compound according to any one of claims 61 to 64, wherein

70. X ３ 65. The compound of any one of claims 61 to 64, wherein is C(Cl).

71. X ５ is CR ３ The compound according to any one of claims 61 to 70,

72. X ５ The compound of any one of claims 61 to 70, wherein is N.

73. X ５ 71. The compound of any one of claims 61 to 70, wherein is CH.

74. X ５ The compound of any one of claims 61 to 70, wherein is CF.

75. X ５ is C (CF ３ 71. The compound according to any one of claims 61 to 70, wherein

76. X ５ The compound of any one of claims 61 to 70, wherein is C(Cl).

77. X ４ is CR ３ 77. The compound according to any one of claims 61 to 76, wherein

78. X ４ The compound of any one of claims 61 to 76, wherein is N.

79. X ４ 77. The compound of any one of claims 61 to 76, wherein is CH.

80. X ４ 77. The compound of any one of claims 61 to 76, wherein is CF.

81. X ４ is C (CF ３ 77. The compound according to any one of claims 61 to 76, wherein

82. X ４ 77. The compound of any one of claims 61 to 76, wherein is C(Cl).

83. X ６ is CR ３ 77. The compound according to any one of claims 61 to 76, wherein

84. X ６ 77. The compound of any one of claims 61 to 76, wherein is CH.

85. X ６ 77. The compound of any one of claims 61 to 76, wherein is CF.

86. X ６ is C (CF ３ 77. The compound according to any one of claims 61 to 76, wherein

87. X ６ 77. The compound of any one of claims 61 to 76, wherein is C(Cl).

88. B ２ but, 【Chemistry 26】 The compound according to any one of claims 60 to 87,

89. R ５ 89. The compound of claim 88, wherein is hydrogen.

90. R ５ 89. The compound of claim 88, wherein is methyl.

91. B ２ but, 【Chemistry 27】 The compound according to any one of claims 60 to 87,

92. B ２ but, 【Chemistry 28】 The compound according to any one of claims 60 to 87,

93. B ２ but, 【Chemistry 29】 The compound according to any one of claims 60 to 87,

94. X １１ is a heterocycle, and this X １１ Each of the groups is R ３ 94. The compound of any one of claims 60 to 93, optionally substituted with 1, 2, 3 or 4 groups independently selected from:

95. X １１ is a bicyclic ring, and this X １１ Each of the groups is R ３ 94. The compound of any one of claims 60 to 93, optionally substituted with 1, 2, 3 or 4 groups independently selected from:

96. X １１ is heteroaryl, aryl or cycloalkyl, １１ Each of the groups is R ３ 94. The compound of any one of claims 60 to 93, optionally substituted with 1, 2, 3 or 4 groups independently selected from:

97. X １１ but, 【Transformation 30】 94. The compound according to any one of claims 60 to 93, selected from:

98. X １１ but, 【Chemistry 31】 94. The compound according to any one of claims 60 to 93, selected from:

99. X １０ and X １１ together, 【Chemistry 32】 The compound according to any one of claims 60 to 93, which forms:

100. X １０ and X １１ together, 【Transformation 33】 The compound according to any one of claims 60 to 93, which forms:

101. X １０ is C(R ７ ) ２ 99. The compound according to any one of claims 3 to 98, wherein

102. X １０ is CH ２ 99. The compound according to any one of claims 3 to 98, wherein

103. X １０ The compound of any one of claims 3 to 98, wherein is C(O).

104. X １０ The compound of any one of claims 3 to 98, wherein is O.

105. X １３ is CR ３ The compound according to any one of claims 3 to 104,

106. X １３ The compound of any one of claims 3 to 104, wherein is N.

107. X １３ The compound of any one of claims 3 to 104, wherein is CH.

108. X １３ The compound of any one of claims 3 to 104, wherein is CF.

109. X １３ is C (CF ３ ) The compound according to any one of claims 3 to 104.

110. X １３ The compound of any one of claims 3 to 104, wherein is C(Cl).

111. X １４ is CR ３ The compound according to any one of claims 3 to 110,

112. X １４ The compound of any one of claims 3 to 110, wherein is N.

113. X １４ The compound of any one of claims 3 to 110, wherein is CH.

114. X １４ The compound of any one of claims 3 to 110, wherein is CF.

115. X １４ is C (CF ３ 111. The compound according to any one of claims 3 to 110, wherein

116. X １４ The compound of any one of claims 3 to 110, wherein is C(Cl).

117. X １５ is CR ３ The compound according to any one of claims 3 to 116,

118. X １５ The compound of any one of claims 3 to 116, wherein is N.

119. X １５ The compound of any one of claims 3 to 116, wherein is CH.

120. X １５ The compound of any one of claims 3 to 116, wherein is CF.

121. X １５ is C (CF ３ ) The compound according to any one of claims 3 to 116.

122. X １５ The compound of any one of claims 3 to 116, wherein is C(Cl).

123. X １６ is CR ３ The compound according to any one of claims 3 to 122,

124. X １６ The compound of any one of claims 3 to 122, wherein is CH.

125. X １６ The compound of any one of claims 3 to 122, wherein is CF.

126. X １６ is C (CF ３ ) The compound according to any one of claims 3 to 122.

127. X １６ The compound of any one of claims 3 to 122, wherein is C(Cl).

128. R ８ The compound of any one of claims 3 to 127, wherein is hydrogen.

129. R ８ The compound of any one of claims 3 to 127, wherein is methyl.

130. L is of the formula: 【Transformation 34】 (In the formula, X １ and X ２ are each independently a bond, a heterocycle, NR ２ , C(R ２ ) ２ , O, C(O) and S; R ２ is independently selected in each occurrence from the group consisting of 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 represents, independently in each occurrence, a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, or —SO ２ -, -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, glycolic, and carbocyclic rings, each of which is selected from the group consisting of R ４０ optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２６ is independently selected in each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; R ４０ are independently in each case hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH (aliphatic including alkyl), -N (aliphatic including alkyl) ２ , -NHSO ２ (aliphatic containing alkyl), -N(aliphatic containing alkyl)SO ２ Alkyl, -NHSO ２ (aryl, heteroaryl or heterocyclic ring), —N(alkyl)SO ２ (aryl, heteroaryl or heterocyclic ring), —NHSO ２ Alkenyl, -N(alkyl)SO ２ Alkenyl, —NHSO ２ Alkynyl, —N(alkyl)SO ２ 130. The compound of any one of claims 3 to 129, wherein the linker is selected from the group consisting of alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl.

131. L is of the formula: 【Chemistry 35】 The compound of claim 130, wherein the linker is

132. X １ 132. The compound of claim 130 or 131, wherein is a bond.

133. X １ 132. The compound of claim 130 or 131, wherein is a heterocycle.

134. X １ NR ２ 132. The compound of claim 130 or 131, wherein:

135. X １ 132. The compound of claim 130 or 131, wherein is C(O).

136. X ２ The compound of any one of claims 130 to 135, wherein is a bond.

137. X ２ The compound of any one of claims 130 to 135, wherein is a heterocycle.

138. X ２ NR ２ The compound according to any one of claims 130 to 135,

139. X ２ The compound of any one of claims 130 to 135, wherein is C(O).

140. R ２０ The compound of any one of claims 130 to 139, wherein is a bond.

141. R ２０ is CH ２ The compound according to any one of claims 130 to 139,

142. R ２０ is a heterocycle.

143. R ２０ 140. The compound of any one of claims 130 to 139, wherein is aryl.

144. R ２０ 140. The compound of any one of claims 130 to 139, wherein is phenyl.

145. R ２０ is a bicyclic ring.

146. R ２１ The compound of any one of claims 130 to 145, wherein is a bond.

147. R ２１ is CH ２ The compound according to any one of claims 130 to 145,

148. R ２１ is a heterocycle.

149. R ２１ The compound of any one of claims 130 to 145, wherein is aryl.

150. R ２１ is phenyl.

151. R ２１ The compound of any one of claims 130 to 145, wherein is bicyclic.

152. L is of the formula: 【Transformation 36】 The compound of claim 130, wherein the linker is

153. R ２２ The compound of any one of claims 130 to 152, wherein is a bond.

154. R ２２ is CH ２ The compound according to any one of claims 130 to 152,

155. R ２２ is a heterocycle.

156. R ２２ The compound of any one of claims 130 to 152, wherein is aryl.

157. R ２２ is phenyl.

158. R ２２ is bicyclic.

159. L is of the formula: 【Chemistry 37】 The compound of claim 130, wherein the linker is

160. R ２３ 160. The compound of any one of claims 130 to 159, wherein is a bond.

161. R ２３ is CH ２ The compound according to any one of claims 130 to 159,

162. R ２３ is a heterocycle.

163. R ２３ 160. The compound of any one of claims 130 to 159, wherein is aryl.

164. R ２３ 160. The compound of any one of claims 130 to 159, wherein is phenyl.

165. R ２３ is bicyclic.

166. L is of the formula: 【Transformation 38】 The compound of claim 130, wherein the linker is

167. R ２４ The compound of any one of claims 130 to 166, wherein is a bond.

168. R ２４ is CH ２ The compound according to any one of claims 130 to 166,

169. R ２４ is a heterocycle.

170. R ２４ The compound of any one of claims 130 to 166, wherein is aryl.

171. R ２４ The compound of any one of claims 130 to 166, wherein is phenyl.

172. R ２４ is a bicyclic ring.

173. R ２４ is C(O).

174. L, 【Chemistry 39】 174. The compound of any one of claims 3 to 173, 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. 177. A pharmaceutical composition comprising a compound according to any one of claims 1 to 176, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

178. 177. A method of treating a disorder mediated by BRD9, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

179. 179. The method of claim 178, wherein the patient is a human.

180. 177. A compound according to any one of claims 1 to 176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a BRD9-mediated disorder.

181. 177. Use of a compound according to any one of claims 1 to 176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a BRD9-mediated disorder.

182. 177. Use of a compound according to any one of claims 1 to 176, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a BRD9-mediated disorder.

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