Modulators of BCL6 protein degradation and related methods of use

Abstract

The present disclosure relates to bifunctional compounds, their preparation, and the use of these bifunctional compounds in the treatment of diseases or disorders resulting from the aggregation or accumulation of B-cell lymphoma 6 protein in subjects in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 417,657, filed October 19, 2022, and U.S. Provisional Application No. 63 / 417,628, filed October 19, 2022, the contents of each of which are incorporated by reference in their entirety for all purposes.

[0002] The present disclosure provides imide-based compounds, including bifunctional compounds comprising the same, and related methods of use, that are useful as modulators of targeted ubiquitination, particularly with respect to a variety of polypeptides and other proteins that are degraded and / or otherwise inhibited by the bifunctional compounds of the present disclosure. [Background technology]

[0003] Most small molecule drugs bind closely to enzymes or receptors in well-defined pockets. Targeting protein-protein interactions using small molecules, however, is notoriously challenging due to the large protein contact surfaces and shallow, groove-like, or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and are therefore attractive therapeutic targets. The development of ligands for E3 ligases has proven challenging, in part, due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases.

[0004] One E3 ubiquitin ligase with therapeutic potential is cereblon, a protein encoded by the CRBN gene in humans. Thalidomide and its analogs, such as pomalidomide and lenalidomide, are known to bind to cereblon. These agents bind to cereblon and alter the specificity of the complex, inducing the ubiquitination and degradation of transcription factors essential for multiple myeloma growth. Indeed, high cereblon expression is associated with increased efficacy of imide-based drugs in the treatment of multiple myeloma.

[0005] However, transcription factors, for example, have non-specific effects and cannot completely target and regulate specific classes of proteins. This remains an obstacle to the development of effective anti-cancer drugs. Therefore, a "tunable" small molecule therapeutic agent that activates or enhances the substrate specificity of cereblon and simultaneously targets and specifically regulates a wide range of protein species would be very useful as a therapeutic agent. Summary of the Invention

[0006] The present disclosure describes bifunctional compounds that function to recruit endogenous proteins to E3 ubiquitin ligases for degradation, and methods of their use. In particular, the present disclosure provides bifunctional or proteolysis-inducing chimeric molecular compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds described herein. Further, the present specification provides information on the treatment of various types of cancer, including, for example, breast cancer, ovarian cancer, leukemia, lymphoma, benign lymphoma, malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, synovial sarcoma, meningeal sarcoma, carcinosarcoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B acute lymphoblastic leukemia, pre-B lymphoma, B-cell lymphoma, large B-cell lymphoma, and malignant lymphoma, diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia (ALL), Philadelphia chromosome positive acute lymphoblastic leukemia (ALL), Philadelphia chromosome positive chronic myeloid leukemia (CML), follicular lymphoma, intravascular large B-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), T-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, non-small cell lung cancer, systemic lupus erythematosus (SLE), brain tumor, or central nervous system cancer.

[0007] In one embodiment, the disease or disorder is cancer associated with aberrant BCL6 expression or activity.

[0008] In one embodiment, the disease or disorder is associated with accumulation and aggregation of BCL6.

[0009] In one embodiment, the disease or disorder is a cancer associated with the accumulation and aggregation of BCL6.

[0010] In another aspect, the present description provides methods for identifying the effects of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0011] In one aspect, the present application provides a bifunctional compound of formula (I): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or isotopic derivative thereof, wherein: R 1 is H or C1-C6 alkyl, Q is [ka] and X is N or CH; Y1, Y2, and Y3 each independently represent N or CR. 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl, Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), or -O-(C1-C6 haloalkyl), In the formula, Q [ka] indicates the point of attachment to X or glutaramide.

[0012] In one aspect, the present application provides a bifunctional compound of formula (II): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or isotopic derivative thereof, wherein: R 1a is H or a halogen, R 2a is H or C1-C3 alkyl, X 3a is CHR 3a or C(O), R 3a is H or C1-C3 alkyl, X 4a and X 6a are each independently CH or N, R 5a is H, C1-C3 alkyl, or halogen.

[0013] In one aspect, the present application provides a bifunctional compound of formula (III): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or isotopic derivative thereof, wherein: L is [ka] and X 6b is CHR 6b or C(O), R 6b is H or C1-C3 alkyl, R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R 3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl, X 1b and X 2b are each independently CH or N, and X 1b and X 2bat least one of is N, In the formula, each of L [ka] indicates the point of attachment.

[0014] In one aspect, the present application relates to a bifunctional compound of any of formulas (I) to (III), or a pharmaceutically acceptable salt thereof.

[0015] In one aspect, the present application relates to a bifunctional compound of any of formulas (I) to (III).

[0016] In one aspect, the present application relates to a bifunctional compound of any of Formulas (I)-(III), wherein the compound is as shown in Table 1, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or isotopic derivative thereof.

[0017] In one aspect, the present application relates to a bifunctional compound of any of Formulas (I)-(III), wherein the compound is as shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, the present application relates to a bifunctional compound of any of formulas (I) to (III), wherein the compound is a compound as shown in Table 1.

[0019] In one embodiment, the present application provides a pharmaceutical composition comprising a bifunctional compound described herein and one or more pharmaceutically acceptable excipients.

[0020] In one embodiment, the composition is formulated as a tablet and includes one or more of an emulsifier, a surfactant, a binder, a disintegrant, a glidant, and a lubricant.

[0021] In one embodiment, the composition further comprises an effective amount of at least one additional anti-cancer agent.

[0022] In one embodiment, the present application provides a method of treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound described herein or a therapeutically effective amount of a pharmaceutical composition described herein.

[0023] In one embodiment, a therapeutically effective amount of the bifunctional compound is orally administered to a subject.

[0024] In one embodiment, a therapeutically effective amount of the bifunctional compound is administered to a subject once a day, twice a day, three times a day, or four times a day.

[0025] In one embodiment, a therapeutically effective amount of the bifunctional compound is administered to a subject once daily.

[0026] In one embodiment, a therapeutically effective amount of the bifunctional compound is administered to a subject in one dose, or in two, three, or four divided doses.

[0027] In one embodiment, the therapeutically effective amount of the bifunctional compound is from about 1 mg to about 1000 mg.

[0028] In one embodiment, the therapeutically effective amount of the bifunctional compound is from about 5 mg to about 750 mg.

[0029] In one embodiment, the therapeutically effective amount of the bifunctional compound is from about 10 mg to about 500 mg.

[0030] In one embodiment, the therapeutically effective amount of the bifunctional compound is from about 20 mg to about 250 mg.

[0031] In one embodiment, the subject is in a fed state at the time of administration.

[0032] In one embodiment, the subject is in a fasted state at the time of administration.

[0033] In one embodiment, the method further comprises administering to a subject in need thereof an effective amount of at least one additional anti-cancer agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description herein, serve to explain the principles of the present disclosure. The drawings are solely for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which show exemplary embodiments of the present disclosure. [Brief explanation of the drawings]

[0035] [Figure 1A] Figures 1A and 1B illustrate the general principle of the function of proteolysis-inducing chimeric molecule compounds. Figure 1A shows an exemplary proteolysis-inducing chimeric molecule compound containing a protein-targeting moiety (PTM; rectangle), a cereblon ubiquitin ligase-binding moiety (CLM; triangle), and a linker moiety (black line) that connects or connects the PTM and CLM. Figure 1B illustrates the functional application of the proteolysis-inducing chimeric molecule compounds described herein. Briefly, the CLM recognizes and binds to the E3 ubiquitin ligase cereblon, and the PTM binds and recruits intracellular target proteins, bringing them into close proximity with the cereblon E3 ubiquitin ligase. Typically, the cereblon E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and catalyzes the attachment of ubiquitin to lysines on target proteins via an isopeptide bond (dark circle), either alone or via the E2 protein. Polyubiquitinated proteins (far right) are then targeted for degradation by the cellular proteasome machinery. [Figure 1B]Figures 1A and 1B illustrate the general principle of the function of proteolysis-inducing chimeric molecule compounds. Figure 1A shows an exemplary proteolysis-inducing chimeric molecule compound containing a protein-targeting moiety (PTM; rectangle), a cereblon ubiquitin ligase-binding moiety (CLM; triangle), and a linker moiety (black line) that connects or connects the PTM and CLM. Figure 1B illustrates the functional application of the proteolysis-inducing chimeric molecule compounds described herein. Briefly, the CLM recognizes and binds to the E3 ubiquitin ligase cereblon, and the PTM binds and recruits intracellular target proteins, bringing them into close proximity with the cereblon E3 ubiquitin ligase. Typically, the cereblon E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and catalyzes the attachment of ubiquitin to lysines on target proteins via an isopeptide bond (dark circle), either alone or via the E2 protein. Polyubiquitinated proteins (far right) are then targeted for degradation by the cellular proteasome machinery. DETAILED DESCRIPTION OF THE INVENTION

[0036] Detailed Description definition The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, thereby targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein that, together with or alone with an E2 ubiquitin-conjugating enzyme, attaches ubiquitin to lysine on a target protein, thereby targeting the specific protein substrate for proteasomal degradation. Thus, either in a complex with an E2 ubiquitin-conjugating enzyme or alone, an E3 ubiquitin ligase is involved in the transfer of ubiquitin to a targeted protein. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, a third ubiquitin is attached to the second ubiquitin, and so on. Polyubiquitination marks proteins for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which only one ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation but may instead change their cellular location or function, for example, through binding to other proteins that contain domains capable of ubiquitin binding. Further complicating the issue, additional lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to generate polyubiquitin that is recognized by the proteasome.

[0037] As used herein, "compound," "bifunctional compound," or "compound of the disclosure" refers to the compounds disclosed by the structures in the Tables and Examples below.

[0038] "Halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0039] "C1-C6 alkyl" refers to a straight or branched chain saturated hydrocarbon containing from 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0040] "C1-C6 haloalkyl" refers to a straight or branched chain saturated hydrocarbon containing 1 to 6 carbon atoms substituted with one or more halogens. Examples of C1-C6 haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, and fluoromethyl.

[0041] As used herein with respect to compounds of the present disclosure, "pharmaceutically acceptable salts" refers to salt forms and hydrates of salt forms in which one or more water molecules are present of compounds of the present disclosure. Such salts and hydrate forms retain the biological activity of the compounds of the present disclosure and are not biologically or otherwise undesirable, i.e., exhibit minimal, if any, toxicological effects. Representative "pharmaceutically acceptable salts" include, for example, acetate, anthonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate. , magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methane-bis-2-hydroxy-3-naphthoate, eimbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0042] The term "isomer" refers to salts and / or compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences can be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, salts of the compounds of the present disclosure may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers.

[0043] The compounds of the present disclosure can exist in unsolvated as well as solvated forms, such as, for example, hydrated forms.

[0044] "Solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one of the substances in which water retains its molecular state as HO; such combinations can form one or more hydrates. In hydrates, water molecules are bound through subvalence by intermolecular forces, particularly hydrogen bridges. Solid hydrates contain water in a stoichiometric ratio, so-called water of crystallization, and the water molecules do not necessarily have to be equivalent in terms of their bonding state. Examples of hydrates include sesquihydrates, monohydrates, dihydrates, or trihydrates. Hydrates of salts of compounds of the present disclosure are also suitable.

[0045] As referred to herein, an "isotopic derivative" refers to a compound of the present disclosure that is isotopically enriched or labeled (with respect to one or more atoms of the compound) with one or more stable isotopes. Thus, in this application, compounds of the present disclosure include compounds that are isotopically enriched or labeled with one or more atoms, such as, for example, deuterium.

[0046] As used herein, "treating" refers to the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes the reduction or alleviation of symptoms or complications, or elimination of the disease, condition, or disorder.

[0047] As used herein, "preventing" refers to arresting the onset of symptoms or complications of a disease, condition, or disorder.

[0048] "Administration" refers to the introduction of a drug, such as a compound of the present disclosure, into a subject. The related terms "administer" and "administration of" (and grammatical equivalents) refer to both direct administration, which can be administration to a subject by a medical professional or by the subject's self-administration, and / or indirect administration, which can be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering the drug to the patient.

[0049] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a time that differs from the administration of an additional therapeutic agent) while the therapeutic agents are simultaneously present in the patient's body in some, preferably effective, amount. In certain preferred embodiments, one or more of the present compounds described herein are administered simultaneously in combination with at least one additional bioactive agent, including, particularly, anti-cancer agents. In particularly preferred embodiments, the co-administration of the compounds results in synergistic activity and / or treatment, including anti-cancer activity.

[0050] As used herein, "therapeutically effective amount" means an amount of the free base of a compound of the present disclosure sufficient to treat, ameliorate, or prevent a particular disease (e.g., lymphoma), disease symptom, disorder, or condition, or to exert a detectable therapeutic or inhibitory effect. The effect may be detected by any analytical method known in the art. The effective amount for a particular subject may depend on the subject's weight, size, and health, the nature and extent of the condition, and whether additional therapeutic agents are administered to the subject. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0051] As used herein, "C max " refers to the maximum (peak) plasma concentration of a particular compound observed in a subject after administering a dose of that compound to the subject.

[0052] As used herein, "AUC" refers to the total area under the plasma concentration-time curve, is a measure of exposure to a compound of interest, and is the integral of the concentration-time curve after a single dose or at steady state. AUC is expressed in units of ng*H / mL (ngxH / mL), where "H" refers to time.

[0053] As used herein, "AUC tau " refers to the AUC from time 0 to the end of the dosing interval.

[0054] "AUC 0~24 " means the AUC from 0 hours to 24 hours after administration of a single dose.

[0055] "Extended release" or "CR," as used herein with respect to an oral dosage form, refers to the release of a compound of the present disclosure from the dosage form according to a predetermined profile, which may include when and where release occurs after oral administration, and / or a specified rate of release over a specified period of time.

[0056] "Controlled-release agent," as used herein with respect to oral dosage forms of the present disclosure, refers to one or more substances or materials that modify the release of a compound of the present disclosure from the dosage form. Controlled-release agents can be organic or inorganic, naturally occurring or synthetic, such as polymeric materials, triglycerides, derivatives of triglycerides, fatty acids and salts of fatty acids, talc, boric acid, colloidal silica, and combinations thereof.

[0057] As used herein with respect to dosage forms of the present disclosure, "enteric coating" refers to a pH-dependent material that surrounds a core containing a compound of the present disclosure, and that remains substantially intact in the acidic environment of the stomach, but dissolves in the pH environment of the intestine.

[0058] "Gastric resistance" or "GR" as applied to the CR oral dosage forms described herein means that the release of a compound of the disclosure in the stomach of a subject does not exceed 5%, 2.5%, 1%, or 0.5% of the total amount of the compound of the disclosure in the dosage form.

[0059] As used herein, "oral dosage form" refers to a pharmaceutical product containing a specific amount (dose) of a compound of the present disclosure, or a pharmaceutically acceptable salt and / or solvate thereof, as the active ingredient, and inactive ingredients (excipients), and formulated into a specific configuration suitable for oral administration, such as an oral tablet, liquid, or capsule. In one embodiment, the composition is in the form of a scored tablet.

[0060] The term "carrier" as used in this disclosure encompasses pharmaceutically acceptable excipients and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body.

[0061] The term "about" as part of a quantitative expression, such as "about X," includes any value 10% higher or lower than X, and also includes any number between X-10% and X+10%. Thus, for example, a weight of about 40 g includes weights from 36 to 44 g.

[0062] "Comprising" or "comprises," as applied to a particular dosage form, composition, use, method, or process described or claimed herein, means that the dosage form, composition, use, method, or process includes all of the elements recited in the particular statement or claim, but does not exclude other elements. "Consists essentially of" and "consisting essentially of" mean that the described or claimed composition, dosage form, method, use, or process does not exclude other materials or steps that do not materially affect the recited physical, pharmacological, pharmacokinetic properties, or therapeutic efficacy of the composition, dosage form, method, use, or process. "Consists of" and "consisting of" refer to the exclusion of trace elements of other ingredients and more than substantial method or process steps.

[0063] "Fasted condition" or "fasted state" as used to describe a subject means that the subject has not consumed food for at least 4 hours prior to the time of interest, such as the time of administration of a compound of the present disclosure. In one embodiment, a subject in a fasted state has not consumed food for at least 6, 8, 10, or 12 hours prior to administration of a compound of the present disclosure.

[0064] As used herein to describe a subject, "fed condition" or "fed state" means that the subject has eaten a meal less than 4 hours before the time of interest, such as the time of administering a compound of the present disclosure. In one embodiment, a subject in a fed state has eaten a meal within at least 3, 2, 1, or 0.5 hours before administering a compound of the present disclosure.

[0065] As used herein, the term "anti-cancer agent" is used to describe an anti-cancer agent, or a therapeutic agent co-administered with an anti-cancer agent (e.g., palonosetron), which may be co-administered and / or co-formulated with a compound of the present disclosure to treat cancer as well as side effects associated with cancer treatment. These agents include, for example, everolimus, venetoclax, palbociclib, tazemetostat, apelisib, olaparib, MK2206, ibrutinib, acalabrutinib, bendamustine, prednisone, cyclophosphamide, gemcitabine, polatuzumab, upadacitinib, abrocitinib, panobinostat, 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, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 modulators, Bcl-2 inhibitors, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, EGFR TK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 or 2 inhibitors, focal adhesion kinase inhibitors, MAP kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, erlotinib, dasatinib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cilengitide, Jaimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Lucanton, LY317615, Neurajiab, Vitespam, 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, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; Amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (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, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab , streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine , vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bolus Lutezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone 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 alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-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, hexamethylmelamine, bexarotene, toxin These include momab, 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.

[0066] In one embodiment, the anticancer agent is temozolomide, capecitabine, irinotecan, tamoxifen, anastrazole, exemestane, letrozole, DES, estradiol, estrogen, bevacizumab, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroprogesterone caproate, raloxifene, megestrol acetate, carboplatin, cisplatin, dacarbazine, methotrexate, vinblastine, vinorelbine, topotecan, finasteride, arzoxifene, fulvestrant, prednisone, abiraterone, Selected from the group consisting of enzalutamide, apalutamide, darolutamide, sipuleucel-T, pembrolizumab, nivolumab, cemiplimab, atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), docetaxel (Taxotere), cabazitaxel (Jevtana), mitoxantrone (Novantrone), estramustine (Emcyt), docetaxel, ketoconazole, histrelin, triptorelin, buserelin, cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, and zoledronate.

[0067] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0068] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0069] The terms "patient" and "subject" are used interchangeably herein and refer to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0070] In one embodiment, the subject is a human.

[0071] In one embodiment, the subject is a human diagnosed with multiple myeloma.

[0072] In one embodiment, the subject is a human diagnosed with lymphoma.

[0073] In one embodiment, the subject is a human diagnosed with B-cell non-Hodgkin's lymphoma, large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, intravascular large B-cell lymphoma, B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, or non-small cell lung cancer. Compounds of the Disclosure

[0074] In one aspect, the present application relates to bifunctional or multifunctional compounds useful for controlling protein activity by inducing target protein degradation. In some embodiments, the bifunctional compounds comprise an E3 ubiquitin ligase-binding moiety and a protein-targeting moiety, preferably linked via a linker moiety, as otherwise described herein, wherein the E3 ubiquitin ligase-binding moiety is linked to the protein-targeting moiety, the E3 ubiquitin ligase-binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), and the target protein moiety recognizes the target protein, such that degradation of the target protein occurs when the target protein is brought into proximity with the ubiquitin ligase, resulting in a reduction / inhibition of the target protein's action and control of protein levels. In certain embodiments, the bifunctional compounds comprise a CLM and a PTM, e.g., covalently, directly, or indirectly linked to a chemical linker, L, which can be represented as follows: PTM-L-CLM

[0075] CLM recognizes and binds to cereblon, an E3 ubiquitin ligase. PTM is a small protein-binding moiety that binds to and recruits intracellular target proteins or polypeptides, bringing them into close proximity with CLM to affect target protein degradation, resulting in ubiquitination of the target protein. In certain embodiments, the PTM is a B-cell lymphoma 6 protein (BCL6) targeting moiety.

[0076] In one aspect, for the compounds described herein, the PTM has the following chemical structure: [ka] wherein the PTM [ka] indicates the point of attachment to L.

[0077] In some embodiments, for the compounds described herein, L has the following chemical structure: [ka] wherein L is [ka] indicates the point of attachment to the PTM or CLM.

[0078] In some embodiments of the compounds described herein, the CLM has the following chemical structure: [ka] wherein CLM [ka] indicates the point of attachment to L.

[0079] In one aspect, the present application provides a bifunctional compound of formula (I): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or isotopic derivative thereof, wherein R 1 is H or C1-C6 alkyl, Q is [ka] and X is N or CH; Y1, Y2, and Y3 each independently represent N or CR. 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl, Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), or -O-(C1-C6 haloalkyl), In the formula, Q [ka] indicates the point of attachment to X or glutaramide.

[0080] In one aspect, the present application provides a bifunctional compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or C1-C6 alkyl, Q is [ka] and X is N or CH; Y1, Y2, and Y3 each independently represent N or CR. 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl, Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), or -O-(C1-C6 haloalkyl), In the formula, Q [ka] indicates the point of attachment to X or glutaramide.

[0081] In one aspect, the present application relates to a bifunctional compound of formula (I): [ka] During the ceremony, R 1 is H or C1-C6 alkyl, Q is [ka] and X is N or CH; Y1, Y2, and Y3 each independently represent N or CR. 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl, Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), or -O-(C1-C6 haloalkyl), In the formula, Q [ka] indicates the point of attachment to X or glutaramide.

[0082] In some embodiments, R 1is hydrogen. In some embodiments, R 1 is methyl.

[0083] In some embodiments, Q is [ka] is.

[0084] In some embodiments, Q is [ka] is.

[0085] In some embodiments, Q is [ka] is.

[0086] In some embodiments, Q is [ka] is.

[0087] In some embodiments, Q is [ka] is.

[0088] In some embodiments, Q is [ka] is.

[0089] In some embodiments, Q is [ka] is.

[0090] In some embodiments, Y 1 , Y 2 , and Y 3 are each CH.

[0091] In some embodiments, one of Y1, Y2, and Y3 is N and the other two of Y1, Y2, or Y3 are CH. In some embodiments, Y1 is N and Y2 and Y3 are CH. In some embodiments, Y2 is N and Y1 and Y3 are CH. In some embodiments, Y3 is N and Y1 and Y2 are CH.

[0092] In some embodiments, two of Y1, Y2, and Y3 are N and the other of Y1, Y2, or Y3 is CH. In some embodiments, Y1 and Y2 are N and Y3 is CH. In some embodiments, Y1 and Y3 are N and Y2 is CH. In some embodiments, Y2 and Y3 are N and Y1 is CH.

[0093] In some embodiments, Z 1 and Z 2 are each N.

[0094] In some embodiments, Z1 and Z2 are each CH.

[0095] In some embodiments, Z1 is N and Z2 is CH.

[0096] In some embodiments, Z 1 is CH and Z 2 is N.

[0097] In some embodiments, X is N. In some embodiments, X is CH.

[0098] In some embodiments, R 2 is H, methyl, ethyl, or isopropyl.

[0099] In some embodiments, R 2 is H.

[0100] In some embodiments, R 2 is methyl, ethyl, or isopropyl.

[0101] In some embodiments, R 2 is methyl.

[0102] In some embodiments, R 2 is ethyl.

[0103] In some embodiments, R 2 is isopropyl.

[0104] In some embodiments, each R 3 is independently hydrogen, methyl, fluoro, or methoxy.

[0105] In one aspect, the present application provides a bifunctional compound of formula (II): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or isotopic derivative thereof, wherein R 1a is H or halogen, and R 2a is H or C1-C3 alkyl, X 3a is CHR 3a or C(O), R 3a is H or C1-C3 alkyl, X 4a and X 6a are each independently CH or N, R 5a is H, C1-C3 alkyl, or halogen.

[0106] In one aspect, the present application provides a bifunctional compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1a is H or a halogen, R 2a is H or C1-C3 alkyl, X3a is CHR 3a or C(O), R 3a is H or C1-C3 alkyl, X 4a and X 6a are each independently CH or N, R 5a is H, C1-C3 alkyl, or halogen.

[0107] In one aspect, the present application relates to a bifunctional compound of formula (II): [ka] During the ceremony, R 1a is H or a halogen, R 2a is H or C1-C3 alkyl, X 3a is CHR 3a or C(O), R 3a is H or C1-C3 alkyl, X 4a and X 6a are each independently CH or N, R 5a is H, C1-C3 alkyl, or halogen.

[0108] In some embodiments, the compound of Formula (II) is a compound of Formula (II-a): [ka] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound of Formula (II) is a compound of Formula (II-a).

[0110] In some embodiments, the compound of Formula (II) is a compound of Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), or Formula (II-j): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound of Formula (II) is a compound of Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), or Formula (II-j).

[0112] In some embodiments, R 1a is H. In some embodiments, R 1a is a halogen.

[0113] In some embodiments, R 1a is fluoro. In some embodiments, R 1a is Cl.

[0114] In some embodiments, R 2a is H. In some embodiments, R 2a is C1-C3 alkyl. In some embodiments, R 2a is H or CH. In some embodiments, R 2a is CH3.

[0115] In some embodiments, X 3a is CHR 3a In some embodiments, X 3a is C(O). In some embodiments, X 3a is CH or C(O). In some embodiments, X 3a is CH. In some embodiments, X 3a is CH(CH3)￢.

[0116] In some embodiments, R 3a is H. In some embodiments, R 3a is C1-C3 alkyl. In some embodiments, R 3a is CH3.

[0117] In some embodiments, R 1a is F and X 4a and X 6a are N and R, respectively. 3a and R 5a are CH3, respectively.

[0118] In some embodiments, R 1a is Cl and X 4a and X 6a are N and R, respectively. 3a and R 5a are CH3, respectively.

[0119] In some embodiments, X 4a and X 6aAt least one of X is N. 4a is N. In some embodiments, X 4a is C. In some embodiments, X 6a is N. In some embodiments, X 6a is C.

[0120] In some embodiments, X 4a and X 6a are N and R, respectively. 2a is CH3.

[0121] In some embodiments, R 5a is H. In some embodiments, R 5a is H, CH, or halogen. In some embodiments, R 5a is CH or halogen. In some embodiments, R 5a is H, CH, or F. In some embodiments, R 5a is CH or F. In some embodiments, R 5a is CH3. In some embodiments, R 5a is a halogen. In some embodiments, R 5a is F.

[0122] In one aspect, the present application provides a bifunctional compound of formula (III): [ka] or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or isotopic derivative thereof, wherein L is [ka] and X 6b is CHR 6b or C(O), R 6b is H or C1-C3 alkyl, R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R 3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl, X 1b and X 2b are each independently CH or N, and X 1b and X 2b at least one of is N, In the formula, each of L [ka] indicates a point bond.

[0123] In one aspect, the present application provides a bifunctional compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein: L is [ka] and X 6b is CHR 6b or C(O), R 6b is H or C1-C3 alkyl, R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl, X 1b and X 2b are each independently CH or N, and X 1b and X 2b at least one of is N, In the formula, each of L [ka] indicates a point bond.

[0124] In one aspect, the present application relates to a bifunctional compound of formula (III): [ka] During the ceremony, L is [ka] and X 6b is CHR 6b or C(O), R 6b is H or C1-C3 alkyl, R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R 3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl, X 1b and X 2b are each independently CH or N, and X1b and X 2b at least one of is N, In the formula, each of L [ka] indicates a point bond.

[0125] In some embodiments, R 5b is H. In some embodiments, R 5b is a halogen. In some embodiments, R 5b is F.

[0126] In some embodiments, L is [ka] is.

[0127] In some embodiments, L is [ka] is.

[0128] In some embodiments, L is [ka] is.

[0129] In some embodiments, L is [ka] is.

[0130] In some embodiments, L is [ka] is.

[0131] In some embodiments, L is [ka] is.

[0132] In some embodiments, L is [ka] is.

[0133] In some embodiments, L is [ka] is.

[0134] In some embodiments, L is [ka] is.

[0135] In some embodiments, L is [ka] is.

[0136] In some embodiments, L is [ka] is.

[0137] In some embodiments, X 6b is CHR 3a In some embodiments, X 6a is C(O). In some embodiments, X 6b is CH or C(O). In some embodiments, X 6b is CH. In some embodiments, X 6b is CH(CH3)￢.

[0138] In some embodiments, R 5b is F and X 6b is CH.

[0139] In some embodiments, R1b , R 2b , R 3b , R 4b At least two of R are halogen. 1b , R 2b , R 3b , R 4b Exactly two of R are halogen. 1b , R 2b , R 3b , R 4b At least two of R are halogen. 1b , R 2b , R 3b , R 4b Exactly one of them is a halogen.

[0140] In some embodiments, R 1b , R 2b , R 3b , R 4b At least two of R are F. In some embodiments, R 1b , R 2b , R 3b , R 4b Exactly two of R are F. In some embodiments, R 1b , R 2b , R 3b , R 4b At least two of R are F. In some embodiments, R 1b , R 2b , R 3b , R 4b Exactly one of is F.

[0141] In some embodiments, R 6b is H. In some embodiments, R 6b is C1-C3 alkyl. In some embodiments, R 6b is CH3.

[0142] In some embodiments, X 1b and X 2b At least one of X is N. 1bis N. In some embodiments, X 1b is CH. In some embodiments, X 2b is N. In some embodiments, X 2b is CH.

[0143] In some embodiments, L is [ka] is.

[0144] In some embodiments, L is [ka] is.

[0145] In some embodiments, L is [ka] is.

[0146] In some embodiments, L is [ka] is.

[0147] In some embodiments, L is [ka] is.

[0148] In some embodiments, L is [ka] is.

[0149] In some embodiments, L is [ka] is.

[0150] In some embodiments, L is [ka] is.

[0151] In some embodiments, L is [ka] is.

[0152] In another aspect, the application relates to a compound, wherein the compound is as set forth in Table 1, or a pharmaceutically acceptable salt enantiomer, stereoisomer, solvate, or isotopic derivative thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18]

[0153] In another aspect, the application relates to a compound, wherein the compound is as shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0154] In another aspect, the present application relates to a compound, wherein the compound is a compound as shown in Table 1.

[0155] In another aspect, the application relates to a compound, wherein the compound is as set forth in Table 2, or a pharmaceutically acceptable salt enantiomer, stereoisomer, solvate, or isotopic derivative thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14]

[0156] In another aspect, the application relates to a compound, wherein the compound is as shown in Table 2, or a pharmaceutically acceptable salt thereof.

[0157] In another aspect, the present application relates to a compound, wherein the compound is a compound as shown in Table 2.

[0158] In another aspect, the application relates to a compound, wherein the compound is as set forth in Table 3, or a pharmaceutically acceptable salt enantiomer, stereoisomer, solvate, or isotopic derivative thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0159] In another aspect, the application relates to a compound, wherein the compound is as shown in Table 3, or a pharmaceutically acceptable salt thereof.

[0160] In another aspect, the present application relates to a compound, wherein the compound is a compound as shown in Table 3.

[0161] The compounds of the present disclosure can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules, functional group transformations and manipulations, including the use of protecting groups, as can be obtained in the field of the present disclosure from the relevant scientific literature or from standard reference textbooks in the field. Recognized reference textbooks on organic synthesis, without limitation to any one or several sources, include Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley & Sons: New York, 2001, and Greene, T.W. Wuts, P.G.M. Protective Groups in Organic Synthesis, 3 rd John Wiley & Sons: New York, 1999. The synthetic methods described in International Application Nos. PCT / US2020 / 056145 and PCT / US2022 / 025041 are incorporated herein by reference in their entireties.

[0162] In one embodiment, the compounds of the present disclosure can be prepared according to the procedures and methods disclosed herein. Other bifunctional compounds of the present disclosure can be prepared using similar methods from common intermediates or derivatives thereof. General Synthetic Routes for Preparing Compounds of the Disclosure

[0163] Scheme 1 [ka]

[0164] A compound of Formula I' (commercially available or easily made) can be reacted with a compound of Formula II' (also commercially available or easily made) in a solvent such as DMSO or DMF, reacted with a base such as triethylamine or DIEA, and heated to produce a compound of Formula III'. In this case, X of compound II' can be a leaving group such as a halogen, and Q6 and Q7 are expected to be selectively substituted as shown herein. A non-limiting example is X = Cl, and Q6 and Q7 are both N. A compound of Formula III' can be reacted with a compound of Formula IV' by heating in a solvent such as DMSO in the presence of a base such as DIEA to produce a PROTAC™ of Formula V. A compound of Formula IV' is an advanced building block, where the ULM, linker, and part of the PTM form a complete subunit. In this formula: [ka] represents a 4-8 membered cyclic or spirocyclic amine (any two ring combination selected from 4,4; 4,5; 4,6; 5,4; 5,5; 5,6; 6,4; 6,5; and 6,6), optionally including a second nitrogen atom (N) if there are more than two carbons between them. L' can be a bond, a linker, or part of a linker.

[0165] Scheme 2 [ka]

[0166] Compounds of formula I' in Scheme 1 can be made using procedures found and / or adapted from Kerres et al., 2017, Cell Reports 20, 2860-2875, and are shown in Scheme 2. When G1 is NO2, compounds of formula VI' are dissolved in a solvent such as, for example, DMF, and treated with a base such as, but not limited to, K2CO3 to form R PTM1 -X', where X' can be a leaving group such as, but not limited to, iodo or bromo. PTM1 -X' is commercially available or easily prepared. Alternatively, R PTM1 can be attached to a compound of formula VI' using the Chan-Lam coupling reaction (Chen et al., 2020, Advanced Synthesis and Catalysis 62 (16), 3311-3331), in which the boronic acid and compound of formula VI' are combined with a copper salt, e.g., Cu(OAc)2, and a base, e.g., Na2CO3, in a solvent, e.g., DCE, and heated. In this case, it may be preferable to have G1 = H and perform nitration as shown in the third step of Scheme 2 using KNO3 under acidic conditions. Those skilled in the art will recognize that compounds of formula VIII' can be prepared by combining R PTM1It will be appreciated that the nitration step is skipped if alkylation of 5-nitroisatin (VI' with G1 = NO2) with -X' is carried out directly. Compounds of formula VIII can be reacted with TMS-diazomethane under basic conditions (Duplantier et al., 2009, J. Med. Chem. 52, 3576-3585 and references cited therein) to produce ring-expanded compounds of formula IX'. The hydroxy group of compounds of formula X' can be exposed by treating compounds of formula IX' with BBR3. Compounds of formula I can be obtained in two additional steps by alkylating the hydroxy group of X' with a 2-haloacetamide, followed by reduction of the nitro group. Many methods for achieving nitro reduction are available to those skilled in the art. A method for ubiquitinating and degrading target proteins in cells

[0167] The present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. The method includes administering a bifunctional compound comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety, preferably linked via a linker moiety, as otherwise described herein, wherein the E3 ubiquitin ligase binding moiety is linked to the protein targeting moiety, the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., a ubiquitin ligase, preferably an E3 ubiquitin ligase), and the target protein moiety recognizes the target protein, such that degradation of the target protein occurs when the target protein is placed in proximity to the ubiquitin ligase, resulting in reduced / inhibited action of the target protein and control of protein levels. The control of protein levels provided by the present disclosure provides treatment for a disease state or condition regulated via the target protein by reducing the level of that protein in the patient's cells.

[0168] In one embodiment, the present disclosure is directed to a method of treating a patient in need for a disease state or condition regulated through a protein, wherein degradation of the protein produces a therapeutic effect in the patient, the method comprising administering to a patient in need thereof an effective amount of a compound of any one of Formulas (I-III) or disclosed herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof, optionally in combination with another anti-cancer agent. The disease state or condition may be a disease caused by a microbial organism or other foreign agent, such as, for example, a virus, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by overexpression of a protein resulting in the disease state and / or condition. treatment method

[0169] In one aspect, the present application relates to a method of treating and / or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0170] In one aspect, the present application relates to a method of treating and / or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotopic derivative thereof, in combination with one or more additional anti-cancer agents.

[0171] In one aspect, the cancer to be treated or prevented is breast cancer, ovarian cancer, leukemia, lymphoma, benign lymphoma, malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, synovial sarcoma, meningeal sarcoma, carcinosarcoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B acute lymphoblastic leukemia (PLL), or AML. lymphoma, pre-B-cell lymphoma, B-cell lymphoma, large B-cell lymphoma, diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia (ALL), Philadelphia chromosome positive acute lymphoblastic leukemia (ALL), Philadelphia chromosome positive chronic myeloid leukemia (CML), follicular lymphoma, intravascular large B-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), T-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, non-small cell lung cancer, systemic lupus erythematosus (SLE), brain tumor, or central nervous system cancer.

[0172] In one aspect, the cancer to be treated or prevented is large B-cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, or angioimmunoblastic T-cell lymphoma (AITL).

[0173] The methods of treating cancer described herein result in a reduction in tumor size. Alternatively, or additionally, the cancer is metastatic cancer and the method of treatment comprises inhibiting metastatic cancer cell invasion.

[0174] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., a compound of any of Formulas (I)-(III) or Tables 1-3, as defined herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0175] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., a compound of any of Formulas (I)-(III) or Tables 1-3, as defined herein, or a pharmaceutically acceptable salt thereof.

[0176] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., a compound of any of Formulas (I)-(III) or Tables 1-3, as defined herein.

[0177] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., a compound of any of Formula (I) as defined herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0178] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., any compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0179] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., any compound of formula (I) as defined herein.

[0180] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., a compound of any of Formula (II) as defined herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0181] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., any compound of formula (II) as defined herein, or a pharmaceutically acceptable salt thereof.

[0182] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., any compound of formula (II) as defined herein.

[0183] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., a compound of any of Formula (III) as defined herein, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0184] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., any compound of formula (III) as defined herein, or a pharmaceutically acceptable salt thereof.

[0185] In one aspect, the present application relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of the present disclosure, i.e., any compound of formula (III) as defined herein.

[0186] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from any of Tables 1-3, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0187] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from any of Tables 1-3, or a pharmaceutically acceptable salt thereof.

[0188] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from any of Tables 1-3.

[0189] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 1, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0190] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0191] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 1.

[0192] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 2, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0193] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

[0194] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 2.

[0195] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 3, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or isotopic derivative thereof.

[0196] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 3, or a pharmaceutically acceptable salt thereof.

[0197] In one aspect, the present application relates to a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound selected from Table 3.

[0198] In one aspect, the present application relates to treating cancer with a compound of the present disclosure in combination with another anti-cancer agent. In one embodiment, the cancer treated with a compound of the present disclosure in combination with another anti-cancer agent is lymphoma.

[0199] In one embodiment, the cancer treated with a combination of a compound of the present disclosure and another anticancer agent is multiple myeloma. In one aspect, treating cancer results in a reduction in tumor size. A reduction in tumor size may also be referred to as "tumor regression." Preferably, after treatment, the tumor size is reduced by 5% or more relative to its size before treatment, more preferably, the tumor size is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. Tumor size may be measured by any reproducible means of measurement. In a preferred aspect, tumor size may be measured as the diameter of the tumor.

[0200] In another embodiment, treating cancer results in a reduction in tumor volume. Preferably, after treatment, tumor volume is reduced by 5% or more relative to its volume before treatment, more preferably, tumor volume is reduced by 10% or more, more preferably, by 20% or more, more preferably, by 30% or more, more preferably, by 40% or more, even more preferably, by 50% or more, and most preferably, by 75% or more. Tumor volume may be measured by any reproducible means of measurement.

[0201] In another embodiment, treating cancer results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is reduced by 5% or more compared to the number before treatment, more preferably by 10% or more, more preferably by 20% or more, more preferably by 30% or more, more preferably by 40% or more, even more preferably by 50% or more, and most preferably by more than 75%. The number of tumors may be measured by any reproducible measurement means. In a preferred embodiment, the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0202] In another embodiment, treating cancer results in a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more compared to the number before treatment, more preferably by 10% or more, more preferably by 20% or more, more preferably by 30% or more, more preferably by 40% or more, even more preferably by 50% or more, and most preferably by more than 75%. The number of metastatic lesions may be measured by any reproducible measurement means. In a preferred embodiment, the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0203] In another embodiment, treating cancer results in an increase in the average survival time of a population of treated subjects compared to a population administered with carrier alone. Preferably, the average survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in average survival time of a population can be measured by any reproducible means. In a preferred embodiment, the increase in average survival time of a population can be measured, for example, by calculating the average length of survival for a population after the start of treatment with an active agent or compound of the present disclosure. In another preferred embodiment, the increase in average survival time of a population can be measured, for example, by calculating the average length of survival for a population after the completion of first-line treatment with an active agent or compound of the present disclosure.

[0204] In another embodiment, treating cancer results in an increase in the average survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the average survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the average survival time of a population may be measured by any reproducible means. In a preferred embodiment, the increase in the average survival time of a population may be measured by calculating the average length of survival for the population after the start of treatment with an active agent or compound of the present disclosure. In another preferred embodiment, the increase in the average survival time of a population may be measured by calculating the average length of survival for the population after the completion of first-line treatment with a compound of the present disclosure.

[0205] In another embodiment, treating cancer results in a decrease in tumor growth rate. Preferably, after treatment, tumor growth rate is reduced by at least 5% compared to the growth rate before treatment, more preferably, tumor growth rate is reduced by at least 10%, more preferably, by at least 20%, more preferably, by at least 30%, more preferably, by at least 40%, more preferably, by at least 50%, even more preferably, by at least 50%, and most preferably, by at least 75%. Tumor growth rate may be measured by any reproducible measurement means. In a preferred embodiment, tumor growth rate is measured according to the change in tumor diameter per unit time.

[0206] In another embodiment, treating cancer results in a reduction in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%, more preferably less than 10%, more preferably less than 20%, more preferably less than 30%, more preferably less than 40%, more preferably less than 50%, even more preferably less than 50%, and most preferably less than 75%. Tumor regrowth may be measured by any reproducible means of measurement. In a preferred embodiment, tumor regrowth is measured by measuring the increase in tumor diameter from a previous post-treatment tumor shrinkage. In another preferred embodiment, a reduction in tumor regrowth is indicated by a failure of the tumor to recur after treatment is stopped.

[0207] The dosage of the compounds of the present disclosure for any of the methods and uses described herein will vary according to the agent, the age, weight, and clinical condition of the recipient subject, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors that will influence the selected dosage.

[0208] A therapeutically effective amount of the compound of the present disclosure may be administered one or more times daily for up to 30 days or more, followed by one or more days without administration of the compound. This type of treatment schedule, i.e., administration of the compound of the present disclosure on consecutive days, followed by consecutive days without administration of the compound, may be referred to as a treatment cycle. A treatment cycle may be repeated as many times as necessary to achieve the intended effect.

[0209] In one embodiment, the therapeutically effective amount of a compound of the present disclosure is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 2, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230 , 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 5 45, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 70 0, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855,860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg once, twice, three times, four times, or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30 consecutive days, or once, twice, three, four, or more times daily in single or divided doses for 2, 3, 4, 5, 6, or more months.

[0210] In one embodiment, a therapeutically effective amount of a compound of the present disclosure is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 160 to about 190 mg, about 170 to about 200 mg, about 180 to about 210 mg, about 190 to about 220 mg, about 200 to about 230 mg, About 210 to about 240 mg, about 220 to about 250 mg, about 230 to about 260 mg, about 240 to about 270 mg, about 250 to about 280 mg, about 260 to about 290 mg, about 270 to about 300 mg, about 280 to about 310 mg, about 290 to about 320 mg, about 300 to about 330 mg, about 310 ~340mg, 320~350mg, 330~360mg, 340~370mg, 350~380mg, 360~390mg, 370~400mg, 380~410mg, 390~420mg, 400~430mg, 410~44 0 mg, about 420 to about 450 mg, about 430 to about 460 mg, about 440 to about 470 mg, about 450 to about 480 mg, about 460 to about 490 mg, about 470 to about 500 mg, about 480 to about 510 mg, about 490 to about 520 mg, about 500 to about 530 mg, about 510 to about 540 mg, about 520 to about 550 mg, about 530 to about 560 mg, about 540 to about 570 mg, about 550 to about 580 mg, about 560 to about 590 mg, about 570 to about 600 mg, about 580 to about 610 mg, about 590 to about 620 mg, about 600 to about 630 mg, about 610 to about 640 mg, about 620 ~650mg, 630~660mg, 640~670mg, 650~680mg, 660~690mg, 670~700mg, 680~710mg, 690~720mg, 700~730mg, 710~740mg, 720~75 0 mg, about 730 to about 760 mg, about 740 to about 770 mg, about 750 to about 780 mg, about 760 to about 790 mg, about 770 to about 800 mg, about 780 to about 810 mg, about 790 to about 820 mg, about 800 to about 830 mg, about 810 to about 840 mg, about 820 to about 850 mg,About 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 860 to about 890 mg, about 870 to about 900 mg, about 880 to about 910 mg, about 890 to about 920 mg, about 900 to about 930 mg, about 910 to about 940 mg, about 920 to about 950 mg, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 960 to about 990 mg, or about 970 to about 1,000 mg may be administered in single or divided doses once, twice, three times, four times, or more times daily (this dose is determined based on the patient's weight (kg), body surface area (m), 2 ) and / or may be adjusted for age (years).

[0211] In one embodiment, a therapeutically effective amount of a compound of the present disclosure is about 70 mg to about 1000 mg administered once, twice, three times, four times, or more daily in single or divided doses (this dose is based on the patient's body weight (kg), body surface area (m) 2 ), and / or may be adjusted for age (years).

[0212] A therapeutically effective amount of a compound of the present disclosure may also range from about 0.01 mg / kg per day to about 100 mg / kg per day. In one embodiment, a therapeutically effective amount of a compound of the present disclosure may range from about 0.05 mg / kg per day to about 10 mg / kg per day. In one embodiment, a therapeutically effective amount of a compound of the present disclosure may range from about 0.075 mg / kg per day to about 5 mg / kg per day. In one embodiment, a therapeutically effective amount of a compound of the present disclosure may range from about 0.10 mg / kg per day to about 1 mg / kg per day. In one embodiment, a therapeutically effective amount of a compound of the present disclosure may range from about 0.20 mg / kg per day to about 0.70 mg / kg per day.

[0213] In one embodiment, the therapeutically effective amount of a compound of the present disclosure is about 0.10 mg / kg per day, about 0.15 mg / kg per day, about 0.20 mg / kg per day, about 0.25 mg / kg per day, about 0.30 mg / kg per day, about 0.35 mg / kg per day, about 0.40 mg / kg per day, about 0.45 mg / kg per day, about 0.50 mg / kg per day, about 0.55 mg / kg per day, about 0.60 mg / kg per day, about 0.65 mg / kg per day, about 0.70 mg / kg per day, about 0.75 mg / kg per day, about 0.80 mg / kg per day, about 0.85 mg / kg per day, about 0.90 mg / kg per day, about 0.95 mg / kg per day, or about 1.00 mg / kg per day.

[0214] In one embodiment, the therapeutically effective amount of a compound of the present disclosure is about 1.05 mg / kg per day, about 1.10 mg / kg per day, about 1.15 mg / kg per day, about 1.20 mg / kg per day, about 1.25 mg / kg per day, about 1.30 mg / kg per day, about 1.35 mg / kg per day, about 1.40 mg / kg per day, about 1.45 mg / kg per day, about 1.50 mg / kg per day, about 1.55 mg / kg per day, about 1.60 mg / kg per day, about 1.65 mg / kg per day, about 1.70 mg / kg per day, about 1.75 mg / kg per day, about 1.80 mg / kg per day, about 1.85 mg / kg per day, about 1.90 mg / kg per day, about 1.95 mg / kg per day, or about 2.00 mg / kg per day.

[0215] In one embodiment, the therapeutically effective amount of a compound of the present disclosure is about 2 mg / kg per day, about 2.5 mg / kg per day, about 3 mg / kg per day, about 3.5 mg / kg per day, about 4 mg / kg per day, about 4.5 mg / kg per day, about 5 mg / kg per day, about 5.5 mg / kg per day, about 6 mg / kg per day, about 6.5 mg / kg per day, about 7 mg / kg per day, about 7.5 mg / kg per day, about 8.0 mg / kg per day, about 8.5 mg / kg per day, about 9.0 mg / kg per day, about 9.5 mg / kg per day, or about 10 mg / kg per day.

[0216] In one embodiment, a therapeutically effective amount of a compound of the present disclosure is administered to a subject once daily. In one embodiment, the daily dose of a compound of the present disclosure may be administered to a subject all at once. In one embodiment, the daily dose of a compound of the present disclosure may be administered to a subject in two separate doses (i.e., split doses). In one embodiment, the daily dose of a compound of the present disclosure may be administered to a subject in three separate doses. In one embodiment, the daily dose of a compound of the present disclosure may be administered to a subject in four separate doses. In one embodiment, the daily dose of a compound of the present disclosure may be administered to a subject in five or more separate doses. In one embodiment, these separate doses or split doses are administered to a subject at regular intervals throughout the day, such as, for example, every 12 hours, every 8 hours, every 6 hours, every 5 hours, or every 4 hours.

[0217] The therapeutically effective amount of the compounds of the present disclosure can be estimated initially either in cell culture assays or animal models, usually rats, mice, rabbits, dogs, or pigs.Animal models can also be used to determine the appropriate concentration range and administration route.This information can then be used to determine the useful dose and route for administration in humans.Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (therapeutic effective dose in 50% of the population) and LD 50The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 It can be expressed as a ratio. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0218] Dosage and administration are adjusted to provide a sufficient level of the disclosed compound or to maintain the desired effect.Factors that may be considered include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy.Long-acting pharmaceutical compositions may be administered every 3-4 days, every week, every two weeks, or every month, depending on the half-life and clearance rate of the particular formulation.

[0219] In one embodiment, for methods of treating cancer with a combination of a compound of the present disclosure and an effective amount of at least one additional anti-cancer agent, the therapeutically effective amount of the compound of the present disclosure is as described herein, and the therapeutically effective amount of the at least one additional anti-cancer agent is 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 , 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 7, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130 , 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445 45, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 60 0, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755,760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 mg once, twice, three, four, or more times daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 30 consecutive days, or once, twice, three, four, or more times daily in single or divided doses for 2, 3, 4, 5, 6, or more months.

[0220] In one embodiment, for the method of treating cancer using a combination of a compound of the present disclosure and at least one additional anticancer agent, a therapeutically effective amount of at least one additional anticancer agent is orally administered once daily in a single or divided dose for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30 or more consecutive days. In one embodiment, the combination of a compound of the present disclosure and at least one additional anticancer agent is administered to a subject in need thereof in a fasting state. In one embodiment, the subject has not eaten at least 2 hours before and at least 1 hour after administering the combination of a compound of the present disclosure and at least one additional anticancer agent.

[0221] In one embodiment, the compound of the present disclosure and the at least one additional anti-cancer agent are administered to the subject simultaneously. In one embodiment, the compound of the present disclosure and the at least one additional anti-cancer agent are administered to the subject sequentially.

[0222] In one embodiment, a compound of the present disclosure and at least one additional anti-cancer agent are administered to a subject in close temporal proximity.

[0223] In some embodiments, "temporal proximity" means that the compound of the present disclosure is administered within a period of time before or after the administration of at least one additional anti-cancer agent, such that the therapeutic effect of the compound of the present disclosure overlaps with the therapeutic effect of the at least one additional anti-cancer agent. In some embodiments, the therapeutic effect of the compound of the present disclosure completely overlaps with the therapeutic effect of the at least one additional anti-cancer agent. In some embodiments, "temporal proximity" means that the compound of the present disclosure is administered within a period of time before or after the administration of at least one additional anti-cancer agent, such that there is a synergistic effect between the compound of the present disclosure and the at least one additional anti-cancer agent.

[0224] "Temporal proximity" can vary depending on various factors, including, but not limited to, the age, sex, weight, genetic background, health status, medical history, and treatment history of the subject receiving the therapeutic agent; the disease or condition being treated or alleviated; the therapeutic outcome being achieved; the dose, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks. In some embodiments, multiple administrations of one therapeutic agent may be administered in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may vary during a treatment cycle or within a dosing regimen. Pharmaceutical Composition

[0225] In one embodiment, the compounds of the present disclosure are formulated for oral administration. For example, in one embodiment, the compounds of the present disclosure are formulated as a tablet containing zero, one, two or more of an emulsifier, a surfactant, a binder, a disintegrant, a glidant and a lubricant.

[0226] In one embodiment, the emulsifier is hypromellose.

[0227] In one embodiment, the surfactant is vitamin E polyethylene glycol succinate.

[0228] In one embodiment, the binder (also referred to herein as a filler) is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, glucose, and sorbitol.

[0229] In one embodiment, the disintegrant is croscarmellose sodium.

[0230] In one embodiment, a lubricant refers to a substance used to promote powder flow by reducing interparticle cohesion. In one embodiment, in the dosage form of the present disclosure, the lubricant is selected from the group consisting of silicon dioxide, colloidal anhydrous silica, starch, and talc.

[0231] In one embodiment, a lubricant refers to a substance that prevents ingredients from sticking and / or clumping in machinery used to prepare the dosage forms of the present disclosure. In one embodiment, in the dosage forms of the present disclosure, the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, stearic acid, and vegetable stearin.

[0232] Pharmaceutical compositions containing the compounds of the present disclosure can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants, that facilitate the processing of the compounds of the present disclosure into pharmaceutically usable preparations. Of course, the appropriate formulation depends on the selected route of administration.

[0233] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0234] Sterile injectable solution can be prepared by incorporating the compound of the present disclosure in the appropriate solvent with one or a combination of the above-listed components in the required amount, and then optionally sterilizing by filtration.Generally, dispersion is prepared by incorporating active agent or compound into a sterile vehicle that contains a basic dispersion medium and other components required from the above-listed components.For the preparation of sterile powder for sterile injectable solution, the preparation method is vacuum drying and freeze-drying, and obtains the powder of active ingredient and any additional desired components from the solution that has been previously sterilized and filtered.

[0235] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier.They may be encapsulated in gelatin capsules or compressed into tablets.For oral therapeutic administration, the compounds of the present disclosure can be combined with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the drug or compound in the fluid carrier is orally applied, rinsed in the mouth, expectorated, or swallowed.Pharmaceutically compatible binding agents and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring, or compounds of a similar nature.

[0236] For administration by inhalation, the agents or compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0237] Systemic administration may also be via transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active agent or compound is formulated into an ointment, salve, gel, or cream generally known in the art.

[0238] In one embodiment, the compounds of the present disclosure are prepared in pharmaceutically acceptable carriers that protect the drug or compound from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be clear to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeting infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0239] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions into unit dosage form.As used herein, unit dosage form refers to a physically separate unit that is suitable as a unit dose for the subject to be treated, and each unit contains a predetermined amount of active agent or compound that is calculated to produce desired therapeutic effect in association with required pharmaceutical carrier.The specification of unit dosage form of the present application is determined by and directly depends on the inherent properties of the compound of the present disclosure and the specific therapeutic effect that is achieved.

[0240] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0241] Exemplary modes of administration of the compounds of the present disclosure include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical administration. In one embodiment, the compounds of the present disclosure are administered orally. In one embodiment, the compounds of the present disclosure are administered as tablets, capsules, caplets, solutions, suspensions, syrups, granules, beads, powders, or pellets.

[0242] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising a salt of a compound of the present disclosure and a pharmaceutically acceptable carrier, for example, a) a diluent, for example, purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, such as corn oil, olive oil, sunflower oil, safflower oil, fish oils such as EPA or DHA or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, for example, silica, talcum, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; Also for tablets, c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, wax and / or polyvinylpyrrolidone, and, if necessary, d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures, e) absorbents, colorants, flavors and sweeteners, f) emulsifiers or dispersants, for example, Tween 80, Labrasol, HPMC, DOSS, Caproil 909, Labrac, Labrafil, Peseol, Transcatol, caPmul MCM, caPmul PG-12, Captex 355, Gelucire, vitamin E. TGPS or other acceptable emulsifier, and / or g) an agent that enhances salt absorption such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and / or PEG200.

[0243] For preparing pharmaceutical compositions from the compounds of the present disclosure, or their salts or hydrates, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may contain from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and manufacturing methods for various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0244] Liquid form preparations include solutions, suspensions, and emulsions. For example, water or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0245] Liquid, particularly injectable, compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed salts are dissolved in or mixed with a pharmaceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0246] Parenteral injectable administration is commonly used for subcutaneous, intramuscular, or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid form suitable for dissolution in liquid prior to injection.

[0247] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0248] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0249] Depending on the intended method of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes even in unit doses, consistent with conventional pharmaceutical practice. Similarly, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, intrathecal, subcutaneous, or intramuscular form, all of which can be administered using forms well known to those skilled in the art of pharmaceuticals.

[0250] The pharmaceutical compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume of the free base or salt of the present disclosure.

[0251] Pharmaceutical compositions containing the compounds of the present disclosure may further include one or more additional anti-cancer agents, including any of those disclosed herein.

[0252] All amounts of any component of the oral dosage forms, e.g., tablets, described herein, given on a % w / w basis refer to the total weight of the oral dosage form, unless otherwise indicated. Example

[0253] The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. Of course, the examples are provided to illustrate certain embodiments, and no limitation on the scope of the present disclosure is intended thereby. It should be further understood that various other embodiments, modifications, and equivalents thereof may be made without departing from the spirit of the present disclosure and / or the scope of the appended claims, which may suggest themselves to those skilled in the art.

[0254] Abbreviation: ACN: acetonitrile ADDP: 1,1'-(azodicarbonyl)dipiperidine BAST: N,N-bis(2-methoxyethyl)aminosulfur trifluoride Binap: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc: tert-butoxycarbonyl BPO: Benzoyl peroxide Cbz: carbonylbenzyloxy DAST: Diethylaminosulfur trifluoride DBE: 1,2-dibromoethane DCE: 1,2-dichloroethane DCM: dichloromethane DEAD: Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate DIBAL: dithiobutylaluminum hydride DIEA or DIPEA: Diisopropylethylamine DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMP: Dess-Martin periodinane DMSO: dimethyl sulfoxide dtbpf: 1,1'-bis(di-tert-butylphosphino)ferrocene EA: Ethyl acetate EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc: ethyl acetate HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU: N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate HMDS: Bis(trimethylsilyl)amine HOBt: Hydroxybenzotriazole HPLC: High-performance liquid chromatography HMPA: hexamethylphosphoramide LDA: lithium diisopropylamide LCMS: Liquid chromatography-mass spectrometry MCPBA: meta-chloroperbenzoic acid MeCN: acetonitrile MsCl: methanesulfonyl chloride MW: Microwave NBS: N-bromosuccinimide NMM: N-methylmorpholine NMP: N-methylpyrrolidone Pd-PEPPSI-IPent: Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride PCC: Pyridinium chlorochromate Pd-118 or Pd(dtpf)Cl2: 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium Pd(dba)2: Bis(dibenzylideneacetone)palladium Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium PPTS: Pyridinium p-thulonate PTSA: p-toluenesulfonic acid RuPhos-Pd-G3: XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate RuPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) SEM-Cl: 2-(trimethylsilyl)ethoxymethyl chloride SFC: Supercritical Fluid Chromatography STAB: sodium triacetoxyborohydride t-BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate TEA: Triethylamine THF: tetrahydrofuran TFA: Trifluoroacetic acid TLC: Thin Layer Chromatography TMP: 2,2,6,6-tetramethylpiperidine TEMPO: 2,2,6,6-tetramethylpiperidine-N-oxide TosCl or TsCl: p-toluenesulfonyl chloride TsOH: p-toluenesulfonic acid XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos: 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl XPhos-Pd-G3: [(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate 12354-85-7: Bis(pentamethylcyclopentadienylrhodium dichloride)

[0255] Example 1 – Synthesis of Compounds 30 and 31

[0256] Step 1: 4-Bromo-2-ethyl-3-fluorobenzoic acid [ka]

[0257] A solution of 2,2,6,6-tetramethylpiperidine (13.48 g, 95 mmol) in tetrahydrofuran (100 mL) was treated with n-BuLi (6.11 g, 95 mmol) under a nitrogen atmosphere at −20° C. for 30 minutes, followed by the dropwise addition of 4-bromo-3-fluorobenzoic acid (9.5 g, 43 mmol) at −50° C. The resulting mixture was stirred under a nitrogen atmosphere at −50° C. for 2 hours. To the above mixture, iodoethane (33.83 g, 217 mmol) was added dropwise over 5 minutes at −50° C. The resulting mixture was stirred at room temperature for 2 hours and then acidified to pH 4 with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The resulting mixture was concentrated in vacuo to give 4-bromo-2-ethyl-3-fluorobenzoic acid (10 g, 93%) as a colorless solid. MS (ESI): m / z 244.90 [M+H] + .

[0258] Step 2: methyl 4-bromo-2-ethyl-3-fluorobenzoate [ka]

[0259] To a stirred solution of 4-bromo-2-ethyl-3-fluorobenzoic acid (12 g, 49 mmol) in methanol (100 mL) was added sulfuric acid. (10.0 mL, 187 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere at 60° C. overnight and then concentrated in vacuo. The residue was extracted with ethyl acetate and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (8:1) to give methyl 4-bromo-2-ethyl-3-fluorobenzoate (7.6 g, 60%) as an off-white solid.

[0260] Step 3: 4-bromo-2-(1-bromoethyl)-3-fluorobenzoate methyl [ka]

[0261] To a stirred solution of methyl 4-bromo-2-ethyl-3-fluorobenzoate (7.5 g, 29 mmol) and N-bromosuccinimide (6.14 g, 34 mmol) in dichloroethane (100 mL) was added azobisisobutyronitrile (0.94 g, 6 mmol). The resulting mixture was stirred overnight at 70 °C under a nitrogen atmosphere. It was diluted with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-bromo-2-(1-bromoethyl)-3-fluorobenzoate (9 g, 92%) as a brown oil.

[0262] Step 4: 2-[2,6-bis(benzyloxy)pyridin-3-yl]-5-bromo-4-fluoro-3-methyl-3H-isoindol-1-one [ka]

[0263] To a stirred solution of methyl 4-bromo-2-(1-bromoethyl)-3-fluorobenzoate (5.0 g, 15 mmol) and 2,6-bis(benzyloxy)pyridin-3-amine (5.4 g, 18 mmol) in acetonitrile (100 mL) was added N,N-diisopropylethylamine (5.1 mL, 29 mmol). The resulting mixture was stirred at 70° C. under a nitrogen atmosphere overnight and then concentrated in vacuo. The resulting mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel, mobile phase: acetonitrile / water (10 mmol / L NH4HCO3), 10% to 100% in 30 min) to give 2-[2,6-bis(benzyloxy)pyridin-3-yl]-5-bromo-4-fluoro-3-methyl-3H-isoindol-1-one (7.8 g, 99%) as a brown solid. MS (ESI): m / z 535.15 [M+H] + .

[0264] Step 5: tert-butyl 4-[(1r,3r)-3-[(3R)-4-{2-[2,6-bis(benzyloxy)pyridin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl}-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0265] To a degassed solution of 2-[2,6-bis(benzyloxy)pyridin-3-yl]-5-bromo-4-fluoro-3-methyl-3H-isoindol-1-one (1.2 g, 2 mmol) in dioxane (20 mL) was added tert-butyl 4-[(1r,3r)-3-[(3R)-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (0.95 g, 2.7 mmol), followed by CsCO (2.20 g, 7 mmol) and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (3.15 g, 3.8 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 6 hours. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 70% gradient in 30 min) to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-{2-[2,6-bis(benzyloxy)pyridin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl}-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (1.1 g, 61%) as a brown solid.

[0266] Step 6: tert-butyl 4-((1R,3r)-3-((R)-4-((S)-2-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-3-methyl-1-oxoisoindolin-5-yl)-3-methylpiperazin-1-yl)cyclobutoxy)piperidine-1-carboxylate and tert-butyl 4-((1R,3r)-3-((R)-4-((R)-2-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluoro-3-methyl-1-oxoisoindolin-5-yl)-3-methylpiperazin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0267] The racemic product (1.1 g) was purified by preparative HPLC (column: (S,S) Whelk-O1 4.6 x 50 mm, 3.5 μm, cosolvent: methanol (0.1% diethylamine), 4 mL / min, gradient (B%): 10% to 50% in 2.0 min). The first peak (1.635 min) was collected to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[2,6-bis(benzyloxy)pyridin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (tentatively assigned, 610 mg, 55%) as a brown solid. The second peak (1.999 min) was collected to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3S)-2-[2,6-bis(benzyloxy)pyridin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (tentatively assigned, 450 mg, 41%) as a brown solid.

[0268] Step 7: tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0269] To a solution of tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[2,6-bis(benzyloxy)pyridin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (450 mg, 0.6 mmol) in ethanol (8 mL) was added 10% Pd / C (200 mg, 1.9 mmol) under a nitrogen atmosphere. The mixture was degassed and purged with hydrogen several times, then stirred overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (130 mg, 37%) as a brown solid.

[0270] Step 8: 3-[(3R)-4-fluoro-3-methyl-5-[(2R)-2-methyl-4-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperazin-1-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione [ka]

[0271] To a stirred solution of tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (130 mg, 0.2 mmol) in dioxane (3 mL) was added hydrochloric acid (3 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 3-[(3R)-4-fluoro-3-methyl-5-[(2R)-2-methyl-4-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl] piperazin-1-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (109 mg, 99%) as a white solid. MS (ESI), m / z 528.40 [M+H] + .

[0272] Step 9: 1-Isopropyl-5-nitro-indoline-2,3-dione [ka]

[0273] To a mixture of 5-nitroindoline-2,3-dione (5.00 g, 26 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (7.19 g, 52 mmol) and 2-iodopropane (3.9 mL, 39 mmol). The mixture was stirred at 25° C. for 48 hours. The mixture was poured into water (300 mL) and extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-isopropyl-5-nitro-indoline-2,3-dione (4.00 g, 66%) as a yellow solid, which was used directly in the next step.

[0274] Step 10: 1-Isopropyl-3-methoxy-6-nitro-quinolin-2-one [ka]

[0275] To a stirred solution of 1-isopropyl-5-nitro-indoline-2,3-dione (25.0 g, 107 mmol) in ethanol (400 mL) was added triethylamine (33 mL) followed by a hexane solution of trimethylsilanediazomethane (2 M, 117 mL) at 25 °C. After stirring at 25 °C for 12 hours, the reaction mixture was poured into water (1500 mL) and extracted with dichloromethane (500 mL × 3). The organic layers were combined and concentrated under reduced pressure. The residue was stirred in a mixture of ethyl acetate (50 mL) and petroleum ether (500 mL) at 25 °C for 2 hours and then filtered. The filter cake was dried under reduced pressure to give 1-isopropyl-3-methoxy-6-nitro-quinolin-2-one (45 g, crude) as a yellow solid. MS (ESI) m / z: 263.1 [M+H] + ; 1 H NMR (400MHz, DMSO) δ 8.59 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 9.6, 2.8 Hz, 1H), 7.52 (d, J = 9.6 Hz, 1H), 7.49 (s, 1H), 5.45-5.28 (m, 1H), 3.84 (s, 3H), 1.55 (d, J = 6.8 Hz, 6H).

[0276] Step 11: 3-hydroxy-1-isopropyl-6-nitro-quinolin-2-one [ka]

[0277] A solution of boron tribromide (4.5 mL, 46 mmol) in dichloromethane (40 mL) was added dropwise to a mixture of 1-isopropyl-3-methoxy-6-nitro-quinolin-2-one (11 g, 42 mmol) in dichloromethane (400 mL) at 0 °C. After stirring at 0 °C for 2 hours, the mixture was poured into saturated sodium bicarbonate (1000 mL) and extracted with dichloromethane (500 mL × 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with a mixture of ethyl acetate (50 mL), petroleum ether (500 mL), and acetonitrile (50 mL) at 25 °C for 12 hours and then filtered. The filtrate was concentrated under reduced pressure to give 3-hydroxy-1-isopropyl-6-nitro-quinolin-2-one (28 g, 90%) as a brown solid. MS (ESI) m / z: 280.2 [M+Na] + ; 1 H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.14 (dd, J = 9.2, 2.4 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.33 (s, 1H), 5.58-5.14 (m, 1H), 1.59 (d, J = 6.8 Hz, 6H).

[0278] Step 12: 2-[(1-isopropyl-6-nitro-2-oxo-3-quinolyl)oxy]-N-methyl-acetamide [ka]

[0279] To a solution of 3-hydroxy-1-isopropyl-6-nitroquinolin-2-one (15 g, 60 mmol) and potassium carbonate (16.5 g, 120 mmol) in DMF (500 mL) was added 2-bromo-N-methylacetamide (9.1 g, 60 mmol). The resultant was stirred at room temperature for 2 hours. The mixture was suspended in ice water, filtered, and dried to give 2-[(1-isopropyl-6-nitro-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (13 g, 67%) as a yellow solid. MS (ESI) m / z: 320.1 [M+1] + ; 1 H NMR (400MHz, DMSO) δ 8.60 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 9.6, 2.8 Hz, 1H), 8.01-7.88 (m, 2H), 7.48 (s, 1H), 5.70-5.15 (m, 1H), 4.57 (s, 2H), 2.68 (d, J = 4.8 Hz, 3H), 1.58 (d, J = 7.2 Hz, 6H).

[0280] Step 13: 2-[(6-amino-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide [ka]

[0281] Under a nitrogen atmosphere, 2-[(1-isopropyl-6-nitro-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (13 g) and 10% Pd / C (2 g) were mixed. The mixture was degassed and purged with hydrogen three times, then stirred overnight at room temperature under hydrogen using a hydrogen balloon. The mixture was filtered through a Celite pad and concentrated under reduced pressure to give 2-[(6-amino-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (10 g, 84%) as a brown solid.

[0282] Step 14: 2-[(6-amino-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide [ka]

[0283] To a stirred solution / mixture of 2-[(6-amino-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (10 g, 34 mmol) and 5-chloro-2,4-difluoropyrimidine (5.2 g, 34 mmol) in N,N-dimethylformamide was added N,N-diisopropylethylamine (18.1 mL, 104 mmol) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was suspended in water, filtered, and washed with water (2 x 20 mL). The resulting solid was dried under infrared light to give 2-({6-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (11 g, 76%) as a yellow solid. MS (ESI): m / z 420.05 [M+H] + .

[0284] Step 15: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0285] To a stirred solution of 3-[(3R)-4-fluoro-3-methyl-5-[(2R)-2-methyl-4-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperazin-1-yl]-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (80 mg, 0.2 mmol) and 2-({6-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (58 mg, 0.1 mmol) in dimethyl sulfoxide (5 mL) was added N,N-diisopropylethylamine (0.5 mL). The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 2 hours. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min) to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (100 mg, 78%) as a brown solid. MS (ESI) m / z 927.55 [M+H] + .

[0286] Step 16: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[(3S)-2,6-dioxopiperidin-3-yl]-4-fluoro-3-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy) -N-methylacetamide, and 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[(3R)-2,6-dioxopiperidin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0287] The crude product (50 mg) was purified by preparative HPLC (column: CHIRALPAK ID-3, column size: 4.6 × 50 mm, 3 μm, mobile phase: (hexane: dichloromethane = 1:1, 0.1% diethylamine): ethanol = 60:40, 1.0 mL / min). The first peak (3.421 min) was collected to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[(3S)-2,6-dioxopiperidin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (assumed) (19.5 mg, 18%) as an off-white solid. MS (ESI): m / z 925.65 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.96-7.95 (m, 2H), 7.69 (s, 2H), 7.43-7.41 (m, 1H), 7.20-7.17 (m, 1H), 7.03 (s, 1H), 5.42-5.53 (m, 1H), 4.90-4.88 (m, 1H), 4.67-4.65 (m, 1H), 4.53 (s, 2H), 4.20 - 4.10 (m, 2H), 3.53-3.51 (m, 1H), 3.33-3.32 (m, 1H), 3.27-3.26 (m, 2H), 2.99-2.80 (m, 2H), 2.69-2.67 (m, 2H), 2.59-2.50 (m, 5H), 2.39-2.38 (m, 2H), 2.27-2.22 (m, 3H), 2.21-2.01 (m, 3H), 1.99-1.82 (m, 2H), 1.58-1.56 (m, 6H), 1.48-1.46 (m, 3H), 1.37-1.35 (m, 2H), 1.00-0.98 (m, 3H). The second peak (5.15 min) was collected to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[(3R)-2,6-dioxopiperidin-3-yl]-4-fluoro-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (assumed) (21.5 mg, 43%) as an off-white solid. MS (ESI): m / z 925.65 [M+H] + ; 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.96-7.95 (m, 2H), 7.69 (s, 2H), 7.43-7.41 (m, 1H), 7.20-7.17 (m, 1H), 7.03 (s, 1H), 5.42-5.53 (m, 1H), 4.90-4.88 (m, 1H), 4.67-4.65 (m, 1H), 4.53 (s, 2H), 4.20 - 4.10 (m, 2H), 3.53-3.51 (m, 1H), 3.33-3.32 (m, 1H), 3.27-3.26 (m, 2H), 2.99-2.80 (m, 2H), 2.69-2.67 (m, 2H), 2.59-2.50 (m, 5H), 2.39-2.38 (m, 2H), 2.27-2.22 (m, 3H), 2.21-2.01 (m, 3H), 1.99-1.82 (m, 2H), 1.58-1.56 (m, 6H), 1.48-1.46 (m, 3H), 1.37-1.35 (m, 2H), 1.00-0.98 (m, 3H).

[0288] Example 2 - Synthesis of compound 32 and 33

[0289] Engineering 1: 4-ブロモ-2-エチルbenzoic acid

change

[0290] To a stirred solution of butyllithium (2.5 M, 46 mL, 115 mmol) in tetrahydrofuran (200 mL) was added dropwise 2,2,6,6-tetramethylpiperidine (16.23 g, 115 mmol) under a nitrogen atmosphere at -40 °C. The mixture was stirred at -40 °C for 0.5 h. To the above mixture was added 4-bromobenzoic acid (10.5 g, 52 mmol) in THF (20 mL) dropwise over 0.5 h at -40 °C. The resulting mixture was stirred at -40 °C for an additional 4 h. To the above mixture was added ethyl iodide (32.6 g, 209 mmol) dropwise over 0.5 h at -40 °C, followed by stirring at room temperature for an additional 2 h. Concentrated hydrochloric acid was added until the pH reached 6-7. The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give 4-bromo-2-ethylbenzoic acid (11.5 g, 90%) as a pink solid. MS (ESI): m / z 228.25 [M+H] + .

[0291] Step 2: Methyl 4-bromo-2-ethylbenzoate [ka]

[0292] A solution of 4-bromo-2-ethylbenzoic acid (11.5 g, 50 mmol) in methanol (100 mL) was added dropwise with sulfuric acid (1.5 mL, 28 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 60° C. overnight and then concentrated in vacuo. The residue was suspended in water, filtered, and washed with water (3×10 mL). The resulting solid was dried in vacuo to give methyl 4-bromo-2-ethylbenzoate (12 g) as an off-white solid. MS (ESI): m / z 243.50 [M+H] + .

[0293] Step 3: Methyl 4-bromo-2-(1-bromoethyl)benzoate [ka]

[0294] To a stirred solution of methyl 4-bromo-2-ethylbenzoate (4.1 g, 16 mmol) and N-bromosuccinimide (3.60 g, 20 mmol) in ethyl acetate (50 mL) was added BPO (0.86 g, 3.4 mmol). The resulting mixture was stirred at 70° C. under a nitrogen atmosphere for 5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were concentrated under reduced pressure to give methyl 4-bromo-2-(1-bromoethyl)benzoate (5.4 g) as a white solid. MS (ESI): m / z 321.50 [M+H] + .

[0295] Step 4: 2-[2,6-bis(benzyloxy)pyridin-3-yl]-5-bromo-3-methyl-3H-isoindol-1-one [ka]

[0296] To a stirred solution of methyl 4-bromo-2-(1-bromoethyl)benzoate (5.4 g, 17 mmol) and 2,6-bis(benzyloxy)pyridin-3-amine (7.71 g, 25 mmol) in acetonitrile (50 mL) was added N,N-diisopropylethylamine (6.50 g, 50 mmol). Acetic acid (0.5 mL) was added to the mixture, which was then stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with dichloromethane (50 mL × 3). The combined organic layer was washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: aqueous acetonitrile (10 mmol / L NH4HCO3), gradient: 10% to 80% in 30 min) to give 2-[2,6-bis(benzyloxy)pyridin-3-yl]-5-bromo-3-methyl-3H-isoindol-1-one (6.57 g, 76%) as a yellow solid. MS (ESI): m / z 515.15 [M+H] + .

[0297] Step 5: tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3S)-2-[6-(benzyloxy)-2-oxo-1H-pyridin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate, and tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[6-(benzyloxy)-2-oxo-1H-pyridin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0298] To a stirred solution of 2-[2,6-bis(benzyloxy)pyridin-3-yl]-5-bromo-3-methyl-3H-isoindol-1-one (5.95 g, 11 mmol) and tert-butyl 4-[(1r,3r)-3-[(3R)-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (4.36 g, 10 mmol) in dioxane (100 mL) was added dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (0.81 g, 1 mmol) and sodium tert-butoxide (2.77 g, 29 mmol). The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 80% gradient in 30 min) to afford tert-butyl 4-[(1r,3r)-3-[(3R)-4-{2-[6-(benzyloxy)-2-oxo-1H-pyridin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl}-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (3.1 g, 46%) as a yellow solid. The racemic product was purified by preparative HPLC (CHIRAL ART Cellulose-SB 3.0 × 100 mm, 3 μm column; isopropanol (0.1% diethylamine); 220 nm). The first peak (0.942 min) was collected to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[6-(benzyloxy)-2-oxo-1H-pyridin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (tentatively assigned, 1.2 g, 39%) as a yellow solid.The second peak (0.372 min) was collected to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3S)-2-[6-(benzyloxy)-2-oxo-1H-pyridin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (tentatively assigned, 1.17 g, 38%) as a yellow solid. MS (ES+): m / z 698.65 [M+H]. + .

[0299] Step 6: tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0300] A mixture of tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-[6-(benzyloxy)-2-oxo-1H-pyridin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (1.2 g, 1.7 mmol) and Pd / C (1 g) in ethanol (20 mL) was degassed, purged with hydrogen, and then stirred under a hydrogen atmosphere for 2 days at 30° C. The resulting mixture was filtered through Celite and washed with dichloromethane (10 mL×2). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (820 mg, 78%) as a colorless oil. MS (ESI): m / z 610.35 [M+H] + .

[0301] Step 7: tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-4-chloro-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0302] To a stirred solution of tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (720 mg, 1.2 mmol) and trifluoroacetic acid (296.20 mg, 2.6 mmol) in dichloromethane (1 mL) was added methanol (1 mL) and N-chlorosuccinimide (204.9 mg, 1.5 mmol). The resulting mixture was stirred overnight at 40° C. under a nitrogen atmosphere. The mixture was basified to pH 8 with N,N-diisopropylethylamine. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 80% gradient in 30 min) to give tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3R)-4-chloro-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate (504 mg, 66%) as a white solid. MS (ESI): m / z 644.40 [M+H] + .

[0303] Steps 8 and 9: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-4-chloro-2-[(3S)-2,6-dioxopiperidin-3-yl]-3-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide and and 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-4-chloro-2-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0304] The title compound is prepared analogously to compounds 30 and 31. The two diastereomers of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-4-chloro-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (248 mg) were purified by chiral HPLC (column: CHIRALPAK Separation was performed by IF, 2 × 25 cm, 5 μm, mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol:dichloromethane = 1:1, 12 mL / min, gradient: 40% B to 40% B in 35 min. The first peak (5.658 min) was collected to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-4-chloro-2-[(3S)-2,6-dioxopiperidin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (tentatively assigned, 84 mg) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 8.84 (s, 1H), 8.05 (s, 1H), 7.96 (m, 2H), 7.69 (m, 2H), 7.63 (m, 1H), 7.37 (m, 1H), 7.03 (s, 1H), 4.77-4.69 (m, 2H), 4.55 (s, 2H), 4.20-4.13 (m, 3H), 3.54 (s, 2H), 3.40 (s, 3H), 2.83 (s, 2H), 2.68 (m, 6H), 2.70 (m, 2H), 2.60 (m, 1H), 2.20 (s, 2H), 2.00 (s, 4H), 1.83 (s, 2H), 1.58 (m, 6H), 1.51 (m, 3H), 1.39 (m, 2H), 0.87 (m, 4H); MS (ESI):m / z 945.05 [M+H] + The second peak (7.125 min) was collected to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3R)-4-chloro-2-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (tentatively assigned, 77 mg) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.84 (s, 1H), 8.05 (s, 1H), 7.96 (m, 2H), 7.69 (m, 2H), 7.61 (m, 1H), 7.36 (m, 1H), 7.03 (s, 1H), 4.82 (m, 1H), 4.69 (dm, 1H), 4.55 (s, 2H), 4.21-4.13 (m, 3H), 3.53 (s, 2H), 3.26-3.21 (m, 3H), 2.82 (s, 1H), 2.68 (m, 6H), 2.63-2.53 (m, 3H), 2.20 (s, 1H), 2.16 (s, 2H), 2.01 (s, 4H), 1.83 (s, 2H), 1.55 (m, 6H), 1.45 (m, 3H), 1.39 (m, 2H), 0.87 (m, 4H); MS (ESI):m / z 945.10 [M+H] + .

[0305] Example 3 - Synthesis of compound 34 and 35

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[0306] The title compound is prepared analogously to compounds 32 and 33, starting from tert-butyl 4-[(1r,3r)-3-[(3R)-4-[(3S)-2-[6-(benzyloxy)-2-oxo-1H-pyridin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidine-1-carboxylate. The two diastereomers of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3S)-4-chloro-2-(2,6-dioxopiperidin-3-yl)-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (220 mg) were purified by chiral HPLC (column: CHIRALPAK Separation was performed using IF, 2 × 25 cm, 5 μm, mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: ethanol:dichloromethane = 1:1, flow rate: 12 mL / min, gradient: 40% B to 40% B in 50 min. The first peak (3.676 min) was collected to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3S)-4-chloro-2-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (presumed) (56 mg, 25%) as a white solid. 1H NMR (300 MHz, DMSO) δ 10.94 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.95 (s, 2H), 7.69-7.61 (m, 3H), 7.38 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 5.70-5.05 (m, 1H), 4.71 (d, J = 21.9 Hz, 2H), 4.53 (s, 2H), 4.21-4.06 (m, 3H), 3.55-3.46 (m, 2H), 3.20 (d, J = 10.9 Hz, 3H), 2.85-2.75 (m, 2H), 2.71-2.53 (m, 7H), 2.32 (s, 1H), 2.22-2.02 (m, 7H), 1.82 (d, J = 12.0 Hz, 2H), 1.53 (d, J = 15.0 Hz, 9H), 1.37 (d, J = 9.0 Hz, 2H), 0.87 (d, J = 6.3 Hz, 3H); MS (ESI):m / z 943.55 [M+H] + The second peak (5.243 min) was collected to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R)-4-[(3S)-4-chloro-2-[(3R)-2,6-dioxopiperidin-3-yl]-3-methyl-1-oxo-3H-isoindol-5-yl]-3-methylpiperazin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (56.5 mg, 25%) as a white solid. MS (ESI): m / z 943.55 [M+H] + ; 1H NMR (300 MHz, DMSO) δ 10.92 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.97 (s, 2H), 7.68 (d, J = 1.5 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.01 (s, 1H), 5.50-5.00 (m, 1H), 4.80 (d, J = 6.3 Hz, 1H), 4.66 (d, J = 12.4 Hz, 1H), 4.53 (s, 2H), 4.22-4.06 (m, 3H), 3.60 (s, 2H), 3.28-3.15 (m, 3H), 2.90-2.67 (m, 9H), 2.33 (s, 1H), 2.17 (s, 3H), 1.99 (s, 4H), 1.82 (d, J = 12.0 Hz, 2H), 1.54 (d, J = 9.6 Hz, 9H), 1.37 (d, J = 9.3 Hz, 2H), 0.87 (d, J = 6.0 Hz, 3H).

[0307] Example 4 - Synthesis of Compound 36

[0308] Project 1:5-ブロモ-7-メチル-3H-2-ベンゾフラン-1-オン

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[0309] To a stirred solution of 4-bromo-2,6-dimethylbenzoic acid (10 g, 44 mmol) and N-bromosuccinimide (19.0 g, 109 mmol) in chlorobenzene (100 mL) was added benzoyl peroxide (1.12 g, 4.4 mmol). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The mixture was diluted with 40% w / w aqueous sodium bisulfite (100 mL) and the phases were separated. The organic phase was washed with saturated aqueous sodium bicarbonate (30 mL). The chlorobenzene phase was concentrated by vacuum distillation (30 mL). After the addition of dimethylacetamide (25 mL), this solution was added to a mixture of sodium borohydride (2.5 g, 1.6 mol) in methyl tert-butyl ether (40 mL) and dimethylacetamide (25 mL). The mixture was quenched with 36% w / w hydrochloric acid (25 mL) in water (35 mL). The solvent was removed by vacuum distillation to give 5-bromo-7-methyl-3H-2-benzofuran-1-one (4 g, 40%) as a white crystalline solid. MS (ESI): m / z 227.0 [M+H] + .

[0310] Step 2: 5-Bromo-3-hydroxy-7-methyl-3H-2-benzofuran-1-one [ka]

[0311] To a stirred solution of 5-bromo-7-methyl-3H-2-benzofuran-1-one (4.0 g, 18 mmol) in methanol (100 mL) was added potassium hydroxide (1.48 g, 26 mmol). The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 2 hours. The mixture was acidified to pH 4 with potassium bisulfate (4.80 g, 35 mmol). The aqueous layer was extracted with ethyl acetate and concentrated. The residue was dissolved in dichloromethane (50 mL), manganese dioxide (15.32 g, 176 mmol) was added, and the mixture was stirred at room temperature overnight. The resulting mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. This gave 5-bromo-3-hydroxy-7-methyl-3H-2-benzofuran-1-one (0.8 g, 19%) as an off-white solid. MS (ESI): m / z 242.90 [M+H] + .

[0312] Step 3: Methyl 4-bromo-2-formyl-6-methylbenzoate [ka]

[0313] To a stirred solution of 5-bromo-3-hydroxy-7-methyl-3H-2-benzofuran-1-one (1 g, 4 mmol) and potassium carbonate (1.14 g, 8 mmol) in acetone (20 mL) was added dropwise methyl iodide (0.38 mL, 6 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (30 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel, mobile phase: acetonitrile / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min) to give methyl 4-bromo-2-formyl-6-methylbenzoate (0.7 g, 66%) as a colorless oil.

[0314] Step 4: 3-(5-bromo-7-methyl-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0315] To a stirred solution of methyl 4-bromo-2-formyl-6-methylbenzoate (700 mg, 2.7 mmol) in dichloroethane (10 mL) and methanol (3 mL) was added 3-(chloroamino)piperidine-2,6-dione (668 mg, 4.1 mmol). Then, acetic acid (0.1 mL, 2 mmol) was added to adjust the pH to 8. The resulting mixture was stirred at room temperature overnight. Sodium cyanoborohydride (342 mg, 5.4 mmol) was added to the above mixture. The resulting mixture was stirred at 50° C. for an additional 2 hours. The mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel, mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min) to give 3-(5-bromo-7-methyl-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (420 mg, 46%) as a brown solid.

[0316] Step 4: tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}cyclobutoxy]piperidine-1-carboxylate [ka]

[0317] To a solution of 3-(5-bromo-7-methyl-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (180 mg, 0.5 mmol) and tert-butyl 4-[(1r,3r)-3-(piperazin-1-yl)cyclobutoxy]piperidine-1-carboxylate (181 mg, 0.5 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (522 mg, 1.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44.91 mg, 0.05 mmol). After stirring at 100 °C for 2 hours under a nitrogen atmosphere, the mixture was diluted with ethyl acetate. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The mixture was acidified to pH 6 with saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min) to afford tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}cyclobutoxy]piperidine-1-carboxylate (140 mg, 44%) as a brown solid. MS (ESI): m / z 596.40 [M+H] + .

[0318] Step 5: 3-(7-methyl-1-oxo-5-{4-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperazin-1-yl}-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0319] To a stirred solution of tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}cyclobutoxy]piperidine-1-carboxylate (140 mg, 0.2 mmol) in dioxane (2.0 mL) was added dropwise a solution of hydrochloric acid in dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 3-(7-methyl-1-oxo-5-{4-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperazin-1-yl}-3H-isoindol-2-yl)piperidine-2,6-dione hydrochloride (116 mg, 99%) as a white solid. MS (ESI): m / z 496.45 [M+H] + .

[0320] Step 6: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0321] To a stirred solution of 3-(7-methyl-1-oxo-5-{4-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperazin-1-yl}-3H-isoindol-2-yl)piperidine-2,6-dione (110 mg, 0.2 mmol) and 2-({6-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (71.7 mg, 0.171 mmol) in dimethyl sulfoxide (5 mL) was added dropwise N,N-diisopropylethylamine (1 mL). The resulting mixture was stirred at 50° C. for 2 hours. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min) to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (52.7 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 10.93 (s, 1H), 8.84 (s, 1H), 8.05 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.69 (s, 2H), 7.32 (s, 1H), 7.20 (s, 1H), 7.05 (d, J = 16.9 Hz, 2H), 6.93 (s, 1H), 6.86 (s, 1H), 5.01 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (s, 2H), 4.28 (d, J = 16.9 Hz, 1H), 4.17 (d, J = 17.1 Hz, 2H), 4.11 (s, 1H), 3.56 (s, 1H), 3.24 (t, J = 11.3 Hz, 3H), 2.97 - 2.83 (m, 1H), 2.68 (d, J = 4.6 Hz, 3H), 2.59 (d, J = 16.0 Hz, 1H), 2.55 (s, 3H), 2.44 - 2.32 (m, 1H), 2.20 (s, 2H), 1.95 (d, J = 12.3 Hz, 1H), 1.87 - 1.80 (m, 2H), 1.58 (d, J = 6.8 Hz, 6H), 1.39 (d, J = 9.8 Hz, 3H). MS (ESI): m / z 843.25 [M+H] + .

[0322] Example 5 - Synthesis of Compound 37

[0323] Process 1: (1s,3s)-3-(ベンジルオキシ)シクロブタン-1-オール

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[0324] To a solution of 3-(benzyloxy)cyclobutan-1-one (100 g, 567 mmol) in methanol (500 mL) was added sodium borohydride (13.5 g, 357 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with water at 0 °C and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous sodium sulfate to give (1s,3s)-3-(benzyloxy)cyclobutan-1-ol (99 g, 98%) as a colorless oil.

[0325] Step 2: Trimethyl[(1s,3s)-3-(benzyloxy)cyclobutoxy]silane [ka]

[0326] To a solution of (1s,3s)-3-(benzyloxy)cyclobutan-1-ol (79.0 g, 443 mmol) in dichloromethane (700 mL) was added triethylamine (134.0 g, 1.3 mol) under a nitrogen atmosphere at 0 °C, followed by the dropwise addition of trimethylsilane chloride (53.0 g, 488 mmol) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours, then diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give trimethyl[(1s,3s)-3-(benzyloxy)cyclobutoxy]silane (110 g, 99%) as an off-white oil.

[0327] Step 3: Benzyl 4-[(1s,3s)-3-(benzyloxy)cyclobutoxy]piperidine-1-carboxylate [ka]

[0328] To a solution of trimethyl[(1s,3s)-3-(benzyloxy)cyclobutoxy]silane (67.6 g, 270 mmol) and benzyl 4-oxopiperidine-1-carboxylate (69.3 g, 297 mmol) in dichloromethane (600 mL) was added triethylsilane (34.5 g, 297 mmol) dropwise at −78°C under a nitrogen atmosphere. The resulting mixture was stirred at −78°C for 5 minutes, and then trimethylsilyl trifluoromethanesulfonate (30.0 g, 135 mmol) in dichloromethane (50 mL) was added dropwise. The reaction mixture was stirred at −78°C for 10 minutes, slowly warmed to 0°C, and stirred for an additional 2 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 3). The combined organic layer was washed with brine (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give benzyl 4-[(1s,3s)-3-(benzyloxy)cyclobutoxy]piperidine-1-carboxylate (81 g, 76%) as an oil.

[0329] Step 4: tert-butyl 4-[(1s,3s)-3-hydroxycyclobutoxy]piperidine-1-carboxylate [ka]

[0330] To a solution of benzyl 4-[(1s,3s)-3-(benzyloxy)cyclobutoxy]piperidine-1-carboxylate (20 g, 51 mmol) and di-tert-butyl dicarbonate (16.6 g, 76 mmol) in ethanol (200 mL) and tetrahydrofuran (150 mL) was added Pd / C (10 g) and Pd(OH) / C (10 g) under a nitrogen atmosphere. The mixture was degassed, purged with hydrogen, and then stirred under hydrogen (15 psi) at 55° C. for 48 hours. The reaction mixture was then cooled to room temperature, filtered through Celite, and concentrated. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel, mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), 5% to 40% gradient in 30 min) to give tert-butyl 4-[(1s,3s)-3-hydroxycyclobutoxy]piperidine-1-carboxylate (28 g, 82%) as an off-white solid.

[0331] Step 5: tert-butyl 4-[(1s,3s)-3-(trifluoromethanesulfonyloxy)cyclobutoxy]piperidine-1-carboxylate [ka]

[0332] To a solution of tert-butyl 4-[(1s,3s)-3-hydroxycyclobutoxy]piperidine-1-carboxylate (10.0 g, 37 mmol) in dichloromethane (150 mL) was added triethylamine (11.2 g, 111 mmol) under a nitrogen atmosphere at room temperature, followed by the dropwise addition of triflic anhydride (16.6 g, 59 mmol) at −40° C. over 15 minutes under nitrogen. The mixture was stirred at −40° C. for 2 hours, diluted with dichloromethane (200 mL), washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to afford tert-butyl 4-[(1s,3s)-3-(trifluoromethanesulfonyloxy)cyclobutoxy]piperidine-1-carboxylate (9.6 g, 65%) as a yellow solid.

[0333] Step 6: tert-butyl 4-[(1r,3r)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0334] To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (500 mg, 2.4 mmol) and tert-butyl 4-[(1s,3s)-3-(trifluoromethanesulfonyloxy)cyclobutoxy]piperidine-1-carboxylate (964.6 mg, 2.4 mmol) in acetonitrile (30 mL) was added N,N-diisopropylethylamine (2 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours and then concentrated. The residue was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-[(1r,3r)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]cyclobutoxy]piperidine-1-carboxylate (1 g, 90%) as a yellow oil. MS (ESI): m / z 418.21 [M+H] + .

[0335] Step 7: tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]-3,6-dihydro-2H-pyridin-1-yl}cyclobutoxy]piperidine-1-carboxylate [ka]

[0336] To a solution of tert-butyl 4-[(1r,3r)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]cyclobutoxy]piperidine-1-carboxylate (170 mg, 0.4 mmol) and 3-(5-bromo-7-methyl-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (247 mg, 0.7 mmol) in dioxane (4 mL) and water (0.5 mL) was added cesium fluoride (111 mg, 0.7 mmol) and Pd(dtbpf)Cl (24 mg, 0.04 mmol). After stirring at 90 °C under nitrogen for 2 hours, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]-3,6-dihydro-2H-pyridin-1-yl}cyclobutoxy]piperidine-1-carboxylate (140 mg, 64%) as a brown solid. MS (ESI): m / z 593.35 [M+H] + .

[0337] Step 8: tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidine-1-carboxylate [ka]

[0338] To a solution of tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]-3,6-dihydro-2H-pyridin-1-yl}cyclobutoxy]piperidine-1-carboxylate (140 mg, 0.2 mmol) in tetrahydrofuran (5 mL) and isopropanol (5 mL) was added 10% Pd / C (0.1 g) under a nitrogen atmosphere. The mixture was degassed and purged with hydrogen three times, then stirred overnight at room temperature under a hydrogen atmosphere using a hydrogen balloon. The mixture was filtered through a pad of Celite, washed with tetrahydrofuran, and concentrated under reduced pressure to give tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidine-1-carboxylate (140 mg, 99%) as a brown oil. MS (ESI): m / z 595.35 [M+H] + .

[0339] Step 9: 3-(7-methyl-1-oxo-5-{1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl}-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0340] To a stirred solution of tert-butyl 4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidine-1-carboxylate (140 mg, 0.2 mmol) in dioxane (2 mL) was added HCl gas in 1,4-dioxane (2 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give 3-(7-methyl-1-oxo-5-{1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl}-3H-isoindol-2-yl)piperidine-2,6-dione hydrochloride (100 mg, 85%) as a brown solid. MS (ESI): m / z 495.35 [M+H] + .

[0341] Step 10: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0342] To a stirred solution of 3-(7-methyl-1-oxo-5-{1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl}-3H-isoindol-2-yl)piperidine-2,6-dione (100 mg, 0.2 mmol) and 2-({6-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (65 mg, 0.2 mmol) in DMSO (5 mL) was added dropwise N,N-diisopropylethylamine (2 mL). The resulting mixture was stirred at 50° C. for 2 hours. The crude material was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 50% gradient in 30 min) to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-7-methyl-1-oxo-3H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (45.2 mg, 30%) as an off-white solid. MS (ESI): m / z 894.30 [M+H] + ; 1H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 8.83 (s, 1H), 8.05 (s, 1H), 7.96 (m, 2H), 7.69 (m, 2H), 7.27 (s, 1H), 7.15 (s, 1H), 7.03 (s, 1H), 5.34 (s, 1H), 5.06 (m, 1H), 4.55 (s, 2H), 4.35 (m, 1H), 4.22 (m, 1H), 4.15 (s, 2H), 4.10 (s, 1H), 3.53 (s, 1H), 2.99 (m, 2H), 2.82 (s, 2H), 2.68 (m, 3H), 2.59 (s, 3H), 2.55 (s, 1H), 2.44 - 2.29 (m, 1H), 2.20 - 2.10 (m, 1H), 1.80 (s, 0H), 1.76 (s, 7H), 1.58 (m, 7H), 1.38 (m, 1H).

[0343] Example 6 – Synthesis of Compounds 38 and 39

[0344] Step 1: Methyl 4-bromo-5-fluoro-2-methylbenzoate [ka]

[0345] A solution of 4-bromo-5-fluoro-2-methylbenzoic acid (30.0 g, 128 mmol) and sulfuric acid (30 mL) in methanol (300 mL) was stirred at 50° C. overnight and then concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 4-bromo-5-fluoro-2-methylbenzoate (30 g, 94%) as a yellow oil. MS (ESI): m / z 247.2 [M+H] + .

[0346] Step 2: Methyl 5-fluoro-4-(3-fluoropyridin-4-yl)-2-methylbenzoate [ka]

[0347] To a stirred solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (22 g, 87 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19.5 g, 87 mmol) in dioxane (200 mL) and water (20 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.1 g, 8.7 mmol) and sodium carbonate (18.4 g, 175 mmol). The reaction was stirred overnight at 80 °C, diluted with water, and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) to give methyl 5-fluoro-4-(3-fluoropyridin-4-yl)-2-methylbenzoate (12 g, 54%) as a yellow solid. MS (ESI ): m / z 264.3 [M+H] + .

[0348] Step 3: Methyl 5-fluoro-4-(3-fluoropiperidin-4-yl)-2-methylbenzoate [ka]

[0349] To a stirred solution of methyl 5-fluoro-4-(3-fluoropyridin-4-yl)-2-methylbenzoate (12 g, 46 mmol) and sulfuric acid (10 mL) in methanol (200 mL) was added Pd(OH)2 / C (1 g) at room temperature. The resulting mixture was degassed, purged with hydrogen, and then stirred overnight under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with methanol (3 x 20 mL). The filtrate was concentrated under reduced pressure to give methyl 5-fluoro-4-(3-fluoropiperidin-4-yl)-2-methylbenzoate (11 g, 80%) as a white oil. MS (ESI): m / z 270.30 [M+H] + .

[0350] Step 4: tert-butyl 3-fluoro-4-[2-fluoro-4-(methoxycarbonyl)-5-methylphenyl]piperidine-1-carboxylate [ka]

[0351] To a stirred solution of methyl 5-fluoro-4-(3-fluoropiperidin-4-yl)-2-methylbenzoate (8.0 g, 29 mmol) and sodium carbonate (601 mg, 58 mmol) in tetrahydrofuran (400 mL) and water (400 mL) was added di-tert-butyl dicarbonate (12.6 g, 58 mmol). The resulting mixture was stirred at room temperature for 2 hours, then diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 3-fluoro-4-[2-fluoro-4-(methoxycarbonyl)-5-methylphenyl]piperidine-1-carboxylate (5 g, 50%) as a white solid. MS (ESI): m / z 370.2 [M+H] + .

[0352] Step 5: 4-[1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl]-5-fluoro-2-methylbenzoic acid [ka]

[0353] To a stirred solution of tert-butyl 3-fluoro-4-[2-fluoro-4-(methoxycarbonyl)-5-methylphenyl]piperidine-1-carboxylate (5.0 g, 13 mmol) in tetrahydrofuran (200 mL) and water (200 mL) was added sodium hydroxide (2.71 g, 67 mmol). The resulting mixture was stirred at 50° C. overnight. The mixture was acidified to pH 6 with hydrochloric acid (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-[1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl]-5-fluoro-2-methylbenzoic acid (4.5 g, 94%) as a white solid. MS (ESI): m / z 356.3 [M+H] + .

[0354] Step 6: tert-butyl 3-fluoro-4-(4-fluoro-3-hydroxy-7-methyl-1-oxo-3H-2-benzofuran-5-yl)piperidine-1-carboxylate [ka]

[0355] To a mixture of 4-[1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl]-5-fluoro-2-methylbenzoic acid (4.5 g, 13 mmol) and tetrahydrofuran (200 mL) at −78° C., 1.3 M tert-butyllithium (48 mL, 63 mmol) was added dropwise at −78° C. over 5 minutes. The resulting mixture was stirred at −78° C. for 3 hours. Then, N,N-dimethylformamide (1.8 mL, 25 mmol) was added dropwise at −78° C. over 5 minutes. The resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified to pH 6 with hydrochloric acid (50 mL) at 0° C. and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to give tert-butyl 3-fluoro-4-(4-fluoro-3-hydroxy-7-methyl-1-oxo-3H-2-benzofuran-5-yl)piperidine-1-carboxylate (4.5 g, 92%) as a white solid. MS (ESI): m / z 384.30 [M+H] + .

[0356] Step 7: tert-butyl 3-fluoro-4-[2-fluoro-3-formyl-4-(methoxycarbonyl)-5-methylphenyl]piperidine-1-carboxylate [ka]

[0357] To a stirred solution of tert-butyl 3-fluoro-4-(4-fluoro-3-hydroxy-7-methyl-1-oxo-3H-2-benzofuran-5-yl)piperidine-1-carboxylate (4.5 g, 12 mmol) and methyl iodide (2.50 g, 18 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.87 g, 35 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to give tert-butyl 3-fluoro-4-[2-fluoro-3-formyl-4-(methoxycarbonyl)-5-methylphenyl]piperidine-1-carboxylate (4.3 g, 92%) as a white solid. MS (ESI): m / z 398.2 [M+H] + .

[0358] Step 8: tert-butyl (3R,4S)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidine-1-carboxylate and tert-butyl (3S,4R)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidine-1-carboxylate [ka]

[0359] To a solution of tert-butyl 3-fluoro-4-[2-fluoro-3-formyl-4-(methoxycarbonyl)-5-methylphenyl]piperidine-1-carboxylate (5.8 g, 15 mmol) in dichloroethane (50 mL), tert-butyl (4S)-4-amino-4-carbamoylbutanoate hydrochloride (3.48 g, 14.5 mmol) was added and stirred overnight at 40° C. under a nitrogen atmosphere. Sodium cyanoborohydride (2.75 g, 44 mmol) was then added, and the resulting mixture was stirred overnight at 40° C. The reaction was quenched with water (50 mL) at room temperature, and the resulting mixture was extracted with dichloromethane (100 mL×3). The combined organic layer was washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 silica gel column, mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), 5% to 70% gradient in 50 min) followed by SFC ((S,S)Whelk-O1 4.6 × 50 mm, 3.5 μm column, mobile phase, isopropanol / hexane = 1:2 (0.1% diethylamine), 10% to 50% gradient in 2.0 min). The first peak (2.178 min) was collected to give tert-butyl (3R,4S)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidine-1-carboxylate (1.2 g) as a yellow solid. The second peak (2.308 min) was collected to give tert-butyl (3S,4R)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidine-1-carboxylate (1.3 g) as a yellow solid. MS (ESI): m / z 356.3 [M+H] + .

[0360] Step 9: tert-butyl (4S)-4-carbamoyl-4-{4-fluoro-5-[(3R,4S)-3-fluoropiperidin-4-yl]-7-methyl-1-oxo-3H-isoindol-2-yl}butanoate [ka]

[0361] A solution of tert-butyl (3R,4S)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidine-1-carboxylate (1.2 g, 2.1 mmol) and trimethylsilyl chloride (2.36 g, 22 mmol) in 2-propanol (20 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (4S)-4-carbamoyl-4-{4-fluoro-5-[(3R,4S)-3-fluoropiperidin-4-yl]-7-methyl-1-oxo-3H-isoindol-2-yl}butanoate (860 mg) as a yellow solid. MS (ESI): m / z 451.30 [M+H] + .

[0362] Step 10: tert-butyl 4-[(1r,3r)-3-[(3R,4S)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidin-1-yl]cyclobutoxy]piperidine-1-carboxylate [ka]

[0363] To a stirred solution of tert-butyl (4S)-4-carbamoyl-4-{4-fluoro-5-[(3R,4S)-3-fluoropiperidin-4-yl]-7-methyl-1-oxo-3H-isoindol-2-yl}butanoate (300 mg, 0.7 mmol) and tert-butyl 4-[(1s,3s)-3-(trifluoromethanesulfonyloxy)cyclobutoxy]piperidine-1-carboxylate (670 mg, 1.7 mmol) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (0.5 mL). The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours, then diluted with water and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) to give tert-butyl 4-[(1r,3r)-3-[(3R,4S)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidin-1-yl]cyclobutoxy]piperidine-1-carboxylate (300 mg, 38%) as a yellow solid. MS (ESI): m / z 705.2 [M+H] + .

[0364] Step 11: (3S)-3-{4-fluoro-5-[(3R,4S)-3-fluoro-1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl]-7-methyl-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione [ka]

[0365] To a stirred solution of tert-butyl 4-[(1r,3r)-3-[(3R,4S)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidin-1-yl]cyclobutoxy]piperidine-1-carboxylate (300 mg, 0.4 mmol) in acetonitrile (10 mL) was added (1R)-(-)-10-camphorsulfonic acid (19.7 mg, 1.3 mmol). The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours and then concentrated in vacuo to give (3S)-3-{4-fluoro-5-[(3R,4S)-3-fluoro-1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl]-7-methyl-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (200 mg, 89%) as a white solid. MS (ESI): m / z 428.3 [M+H] + .

[0366] Step 12: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R,4S)-4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0367] To a stirred solution of (3S)-3-{4-fluoro-5-[(3R,4S)-3-fluoro-1-[(1r,3r)-3-(piperidin-4-yloxy)cyclobutyl]piperidin-4-yl]-7-methyl-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (182 mg, 0.3 mmol) and 2-({6-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (120 mg, 0.3 mmol) in dimethyl sulfoxide (4 mL) was added N,N-diisopropylethylamine (0.5 mL). The resulting mixture was stirred at 50 °C for 2 h and then purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min) to give 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3R,4S)-4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (72.0 mg, 27%) as an off-white solid. 1H NMR (300 MHz, DMSO) δ 11.01 (s, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.97 (d, J=9.6 Hz, 2H), 7.70 (s, 2H), 7.28 (d, J=6.1 Hz, 1H), 7.03 (s, 1H), 5.35 (s, 1H), 5.08 (dd, J=13.2, 5.1 Hz, 1H), 4.89 (s, 1H), 4.50 (d, J=30.0 Hz, 3H), 4.31 (d, J=17.2 Hz, 1H), 4.13 (d, J=13.5 Hz, 3H), 3.54 (s, 2H), 3.22 (d, J=10.8 Hz, 4H), 3.04 (d, J=10.4 Hz, 1H), 2.89 (d, J=10.6 Hz, 2H), 2.68 (d, J=4.6 Hz, 3H), 2.62 (s, 1H), 2.58 (s, 3H), 2.55 (s, 2H), 2.24-2.09 (m, 3H), 1.99 (s, 5H), 1.84 (d, J=12.1 Hz, 2H), 1.66 (s, 2H), 1.57 (d, J=6.8 Hz, 5H), 1.38 (d, J=9.4 Hz, 2H), 1.24 (s, 2H), 0.85 (d, J=6.7 Hz, 1H); MS (ESI): m / z 930.39 [M+H] + .

[0368] Step 13: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-[(3S,4R)-4-{2-[(3S)-2,6-dioxopiperidin-3-yl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidin-1-yl]cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0369] The title compound was prepared analogously to steps 9-12 of this example starting from tert-butyl (3S,4R)-4-{2-[(1S)-4-(tert-butoxy)-1-carbamoyl-4-oxobutyl]-4-fluoro-7-methyl-1-oxo-3H-isoindol-5-yl}-3-fluoropiperidine-1-carboxylate. 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.96 (d, J = 4.8 Hz, 2H), 7.69 (d, J = 4.0 Hz, 2H), 7.27 (d, J = 6.0 Hz, 1H), 7.03 (s, 1H), 5.50-5.08 (m, 2H), 4.94-4.72 (m, 1H), 4.53-4.45 (m, 3H), 4.40 (s, 1H), 4.31-4.12 (m, 3H), 3.32 (d, J = 9.4 Hz, 1H), 3.31 (s, 2H), 3.29-3.18 (m, 3H), 3.03 (d, J = 10.4 Hz, 1H), 2.98-2.85 (m, 2H), 2.68 (d, J = 4.6 Hz, 3H), 2.62 (d, J = 3.7 Hz, 4H), 2.58 (s, 1H), 2.47 (s, 1H), 2.24-2.12 (m, 3H), 2.02-1.95 (m, 4H), 1.83 (d, J = 11.6 Hz, 2H), 1.65 (d, J = 12.3 Hz, 1H), 1.57 (d, J = 6.8 Hz, 6H), 1.38 (d, J = 9.2 Hz, 2H); MS (ESI): m / z 930.45 [M+H] + .

[0370] Example 7 – Synthesis of Compound 40

[0371] Step 1: benzyl 4-{2-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]acetyl}piperazine-1-carboxylate [ka]

[0372] To a stirred mixture of [1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]acetic acid (600 mg, 2.3 mmol) and benzylpiperazine-1-carboxylate (509.7 mg, 2.3 mmol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.02 mL, 12 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. Propanephosphonic anhydride (2.94 g, 9.3 mmol) was then added to maintain the pH at 9. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water and extracted with ethyl acetate (2 × 300 mL). The combined organic layer was washed with brine (2 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate=1:1) to give benzyl 4-{2-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]acetyl}piperazine-1-carboxylate (930 mg, 87%) as a pale yellow solid. MS (ESI): m / z 462.25 [M+H] + .

[0373] Step 2: Benzyl 4-[2-(4-hydroxypiperidin-4-yl)acetyl]piperazine-1-carboxylate [ka]

[0374] To a stirred solution of benzyl 4-{2-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]acetyl}piperazine-1-carboxylate (500 mg, 1.1 mmol) in dioxane (4 mL) was added dropwise a solution of hydrochloric acid in 1,4-dioxane (8 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to give benzyl 4-[2-(4-hydroxypiperidin-4-yl)acetyl]piperazine-1-carboxylate hydrochloride (390 mg) as a pale yellow solid. MS (ESI): m / z 362.15 [M+H] + .

[0375] Step 3: benzyl 4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-4-hydroxypiperidin-4-yl}acetyl)piperazine-1-carboxylate [ka]

[0376] To a stirred mixture of benzyl 4-[2-(4-hydroxypiperidin-4-yl)acetyl]piperazine-1-carboxylate (212 mg, 0.6 mmol) and 3-(5-bromo-4-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (200 mg, 0.6 mmol) in N,N-dimethylformamide (10 mL) was added dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (4.93 mg, 0.006 mmol) and cesium carbonate (573 mg, 1.8 mmol) at room temperature. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The reaction was quenched with saturated ammonium chloride solution (300 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3) gradient from 0% to 50% in 40 min) to afford benzyl 4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-4-hydroxypiperidin-4-yl}acetyl)piperazine-1-carboxylate (190 mg, 52%) as a pale yellow solid. MS (ESI): m / z 622.25 [M+H] + .

[0377] Step 4: 3-(4-fluoro-5-{4-hydroxy-4-[2-oxo-2-(piperazin-1-yl)ethyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0378] To benzyl 4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-4-hydroxypiperidin-4-yl}acetyl)piperazine-1-carboxylate (180 mg, 0.3 mmol) was added trifluoroacetic acid (5.0 mL, 67 mmol) at room temperature. The resulting mixture was stirred at 60° C. for 2 hours and then concentrated in vacuo to give 3-(4-fluoro-5-{4-hydroxy-4-[2-oxo-2-(piperazin-1-yl)ethyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (140 mg, 99%) as a tan oil. MS (ESI): m / z 488.25 [M+H] + .

[0379] Step 5: 2-{[6-({5-chloro-2-[4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-4-hydroxypiperidin-4-yl}acetyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0380] To a stirred mixture of 3-(4-fluoro-5-{4-hydroxy-4-[2-oxo-2-(piperazin-1-yl)ethyl]piperidin-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (104.51 mg, 0.2 mmol) and 2-({6-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (60 mg, 0.1 mmol) in dimethyl sulfoxide (4 mL) was added N,N-diisopropylethylamine (2 mL) at room temperature. The reaction was stirred at 50° C. for 6 hours. The crude material was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 0% to 40% gradient in 40 min) to give 2-{[6-({5-chloro-2-[4-(2-{1-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-4-hydroxypiperidin-4-yl}acetyl)piperazin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (53.3 mg, 40%) as an off-white solid. MS (ESI): m / z 887.40 [M+H] + ; 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.90 (s, 1H), 8.09 (s, 1H), 8.01 - 7.90 (m, 2H), 7.72 (d, J = 3.0 Hz, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.08 (s, 1H), 5.32 (s, 1H), 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.96 (s, 1H), 4.56 (s, 2H), 4.48 (d, J = 17.0 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 3.64 (t, J = 13.5 Hz, 8H), 3.13 (t, J = 10.7 Hz, 2H), 3.00 - 2.82 (m, 1H), 2.71 - 2.51 (m, 6H), 2.47 - 2.32 (m, 1H), 1.97 (d, J = 11.9 Hz, 1H), 1.87 - 1.66 (m, 4H), 1.58 (d, J = 6.8 Hz, 6H), 1.23 (s, 1H).

[0381] Example 8 – Synthesis of Compound 41 [ka]

[0382] The title compound can be prepared analogously to compound 40(11) by first removing the Cbz protecting group from the intermediate prepared in step 1. 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.83 (s, 1H), 8.05 (s, 1H), 7.98 (d, J = 4.8 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.02 (s, 1H), 5.34 (s, 1H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 5.00 (s, 1H), 4.51 (d, J = 23.6 Hz, 3H), 4.33 (d, J = 17.0 Hz, 1H), 4.15 (s, 2H), 3.69 (d, J = 16.6 Hz, 4H), 3.34 - 3.26 (m, 1H), 3.12 (d, J = 15.6 Hz, 4H), 2.92 (ddd, J = 17.5, 13.6, 5.4 Hz, 1H), 2.68 (d, J = 4.7 Hz, 3H), 2.61 (d, J = 3.6 Hz, 1H), 2.56 (s, 3H), 2.42 (qd, J = 13.1, 4.5 Hz, 1H), 1.98 (d, J = 12.6 Hz, 1H), 1.63 - 1.53 (m, 9H); MS (ESI): m / z 887.40 [M+H] + .

[0383] Example 9 – Synthesis of Compound 42

[0384] Step 1: benzyl 4-[1-(tert-butoxycarbonyl)-3,3-difluoro-2,6-dihydropyridin-4-yl]piperazine-1-carboxylate [ka]

[0385] A solution of benzyl piperazine-1-carboxylate (1 g, 4.9 mmol) in toluene (1.5 mL) and acetonitrile (15 mL) was treated with sodium acetate (1.0 g, 12 mmol) at room temperature under a nitrogen atmosphere for 15 minutes, followed by the addition of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (1.8 g, 7.5 mmol) in several portions at room temperature. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 16 hours. The mixture was allowed to cool to room temperature and filtered. The filter cake was washed with dichloromethane (3×100 mL), and the filtrate was concentrated under reduced pressure to give benzyl 4-[1-(tert-butoxycarbonyl)-3,3-difluoro-2,6-dihydropyridin-4-yl]piperazine-1-carboxylate (1.1 g, 50%) as a pale yellow oil. MS (ESI): m / z 438.25 [M+H] + .

[0386] Step 2: Benzyl 4-[1-(tert-butoxycarbonyl)-3,3-difluoropiperidin-4-yl]piperazine-1-carboxylate [ka]

[0387] A mixture of benzyl 4-[1-(tert-butoxycarbonyl)-3,3-difluoro-2,6-dihydropyridin-4-yl]piperazine-1-carboxylate (1.1 g, 2.5 mmol), acetic acid (1.5 mL), and sodium cyanoborohydride (0.5 g, 7.4 mmol) in dichloroethane (15 mL) was stirred at room temperature overnight. The mixture was diluted with water and extracted with dichloromethane (3 × 80 mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel, mobile phase: aqueous acetonitrile (10 mmol / L NH4HCO3), 5% to 60% gradient in 30 min) to give benzyl 4-[1-(tert-butoxycarbonyl)-3,3-difluoropiperidin-4-yl]piperazine-1-carboxylate (1.5 g, 71%) as a pale yellow oil. MS (ESI): m / z 440.30 [M+H] + .

[0388] Step 3: tert-butyl 3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate [ka]

[0389] To a solution of benzyl 4-[1-(tert-butoxycarbonyl)-3,3-difluoropiperidin-4-yl]piperazine-1-carboxylate (1.5 g, 3.4 mmol) in isopropanol (30 mL) was added 10% Pd(OH)2 / C (300 mg) under a nitrogen atmosphere. The mixture was then degassed and purged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere at 30°C using a hydrogen balloon for 2 hours, then filtered through a Celite pad and concentrated under reduced pressure to give tert-butyl 3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate (1.05 g, 92%) as a colorless oil.

[0390] Step 4: tert-butyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}-3,3-difluoropiperidine-1-carboxylate [ka]

[0391] To a stirred solution of tert-butyl 3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate (200 mg, 0.7 mmol) and 3-(5-bromo-4-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (223 mg, 0.7 mmol) in N,N-dimethylformamide (5 mL) was added {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloro(2-methyl-1 lambda 4-pyridin-1-yl)palladium (55 mg, 0.1 mmol) and cesium carbonate (640 mg, 2.0 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The residue was diluted with water (400 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), 5% to 65% gradient in 30 min) to afford tert-butyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}-3,3-difluoropiperidine-1-carboxylate (110 mg, 30%) as a brown solid. MS (ESI): m / z 566.40 [M+H] + .

[0392] Step 5: 3-{5-[4-(3,3-difluoropiperidin-4-yl)piperazin-1-yl]-4-fluoro-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione [ka]

[0393] A solution of tert-butyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}-3,3-difluoropiperidine-1-carboxylate (110.0 mg, 0.2 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. The reaction was concentrated to give 3-{5-[4-(3,3-difluoropiperidin-4-yl)piperazin-1-yl]-4-fluoro-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (88.2 mg, 97%) as a brown oil. MS (ESI): m / z 466.25 [M+H] + .

[0394] Step 6: 2-({6-[(5-chloro-2-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}-3,3-difluoropiperidin-1-yl)methyl]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0395] To a mixture of 3-{5-[4-(3,3-difluoropiperidin-4-yl)piperazin-1-yl]-4-fluoro-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (88.2 mg, 0.2 mmol) in dichloroethane (10 mL) and dimethyl sulfoxide (1 mL) was added 2-[(6-{[5-chloro-2-(4-formylpiperidin-1-yl)pyrimidin-4-yl]amino}-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (97.0 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.1 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Sodium triacetoxyborohydride (120.2 mg, 0.6 mmol) was then added and stirred under nitrogen for 2 hours. The reaction was quenched with water (30 mL) and extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel, mobile phase, acetonitrile / water (10 mmol / L NH4HCO3), 5% to 70% gradient in 30 min) to give 2-({6-[(5-chloro-2-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]piperazin-1-yl}-3,3-difluoropiperidin-1-yl)methyl]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (69.3 mg, 36%) as an off-white solid. 1H NMR (300 MHz, DMSO) δ 11.11-10.82 (m, 1H), 8.78 (s, 1H), 8.02-7.93 (m, 3H), 7.77-7.63 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 5.60-5.33 (m, 1H), 5.06 (d, J = 13.2 Hz, 1H), 4.48 (d, J = 22.2 Hz, 5H), 4.30 (d, J = 16.8 Hz, 1H), 3.09 (s, 4H), 2.99-2.79 (m, 10H), 2.66 (d, J = 4.6 Hz, 3H), 2.60 (s, 1H), 2.54 (d, J = 5.9 Hz, 1H), 2.39-1.98 (m, 5H), 1.74 (s, 5H), 1.55 (d, J = 6.9 Hz, 6H), 1.12-0.90 (d, J = 12.3 Hz, 2H); MS (ESI): m / z 962.50 [M+H] + .

[0396] Example 10 – Synthesis of Compound 43

[0397] Step 1: 2-{[6-({5-chloro-2-[4-(dimethoxymethyl)piperidin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0398] To a 100 mL round-bottom flask was added 2-({6-[(5-chloro-2-fluoropyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide (500 mg, 1.2 mmol) and DMSO (5 mL) at room temperature. The resulting mixture was stirred at 50° C. for 4 hours, suspended in water at 0° C., and filtered. The resulting solid was dried under infrared light to give 2-{[6-({5-chloro-2-[4-(dimethoxymethyl)piperidin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (620 mg, 93%) as a brown solid. MS (ESI): m / z 559.05 [M+H] + .

[0399] Step 2: 2-((6-((5-chloro-2-(4-formylpiperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide [ka]

[0400] To a mixture of 2-[[6-([5-chloro-2-[4-(dimethoxymethyl)piperidin-1-yl]pyrimidin-4-yl]amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy]-N-methylacetamide (220 mg) in water (1.0 mL) was added trifluoroacetic acid (2.0 mL) and dichloromethane (4.0 mL). The resulting mixture was stirred in air at 40° C. overnight. The reaction mixture was then concentrated under reduced pressure to give 2-[(6-[[5-chloro-2-(4-formylpiperidin-1-yl)pyrimidin-4-yl]amino]-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (202 mg) as a yellow oil, which was used in the next step without further purification.

[0401] Step 3: 1-[(4E)-1-(tert-butoxycarbonyl)-3,3-difluoropiperidin-4-ylidene]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1lambda 5-pyridin-1-ylium [ka]

[0402] To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (4.0 g, 19 mmol) in acetonitrile / toluene (20 mL / 40 mL) was added sodium acetate (5.6 g, 68 mmol) and acetic acid (4 mL). The resulting mixture was stirred for 15 minutes. Then, tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (5.76 g, 24 mmol) was added and stirred at 100° C. for 4 hours. The mixture was filtered, and the filter cake was washed with dichloromethane (20 mL x 3). The filtrate was concentrated under reduced pressure to give 1-[(4E)-1-(tert-butoxycarbonyl)-3,3-difluoropiperidin-4-ylidene]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1lambda 5-pyridin-1-ylium (1.1 g) as a white solid. MS (ESI): m / z 427.30 [M+H] + .

[0403] Step 4: tert-butyl 3,3-difluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]piperidine-1-carboxylate [ka]

[0404] A solution of 1-[(4E)-1-(tert-butoxycarbonyl)-3,3-difluoropiperidin-4-ylidene]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1lambda 5-pyridin-1-ylium (1.1 g, 2.5 mmol) and sodium triacetoxyborohydride (8.6 g, 40 mmol) in dichloroethane (10 mL) was stirred overnight at room temperature, diluted with water, extracted with dichloromethane (20 mL × 3), mixed, and concentrated. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel, mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 80% gradient in 30 min) to give tert-butyl 3,3-difluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]piperidine-1-carboxylate (1.1 g) as a white solid. MS (ESI): m / z 429.20 [M+H] + .

[0405] Step 5: tert-butyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3,6-dihydro-2H-pyridin-1-yl}-3,3-difluoropiperidine-1-carboxylate [ka]

[0406] To a stirred solution of tert-butyl 3,3-difluoro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]piperidine-1-carboxylate (150 mg, 0.4 mmol) and 3-(5-bromo-4-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (119.5 mg, 0.4 mmol) in dioxane (2 mL) and water (0.2 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (45 mg, 0.07 mmol) and cesium fluoride (159.59 mg, 1.0 mmol). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 3 hours, then diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:3) to give tert-butyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3,6-dihydro-2H-pyridin-1-yl}-3,3-difluoropiperidine-1-carboxylate (118 mg, 59%) as a white solid. MS (ESI): m / z 563.40 [M+H] + .

[0407] Step 6: tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3',3'-difluoro-[1,4'-bipiperidine]-1'-carboxylate [ka]

[0408] A mixture of tert-butyl 4-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3,6-dihydro-2H-pyridin-1-yl}-3,3-difluoropiperidine-1-carboxylate (150 mg, 0.3 mmol) and Pd / C (70 mg) in tetrahydrofuran (1 mL) and isopropanol (5 mL) was degassed, purged with hydrogen, and then stirred under a hydrogen atmosphere overnight at 40° C. The resulting mixture was filtered through Celite and washed with dichloromethane (10 mL×3). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3',3'-difluoro-[1,4'-bipiperidine]-1'-carboxylate (118 mg, 78%) as a white solid. MS (ESI): m / z 565.40 [M+H] + .

[0409] Step 7: 3-(5-{3',3'-difluoro-[1,4'-bipiperidin]-4-yl}-4-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0410] A solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3',3'-difluoro-[1,4'-bipiperidine]-1'-carboxylate (106 mg, 0.2 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (3 mL) was stirred overnight at room temperature. The reaction was concentrated under reduced pressure to give 3-(5-{3',3'-difluoro-[1,4'-bipiperidine]-4-yl}-4-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione trifluoroacetate (87 mg) as a white solid. MS (ESI): m / z 465.25 [M+H] + .

[0411] Step 8: 2-{[6-({5-chloro-2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3',3'-difluoro-[1,4'-bipiperidine]-1'-yl}methyl)piperidin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0412] To a stirred mixture of 3-(5-{3',3'-difluoro-[1,4'-bipiperidin]-4-yl}-4-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (87 mg, 0.2 mmol) in dimethyl sulfoxide (1 mL) and dichloroethane (10 mL) was added 2-[(6-{[5-chloro-2-(4-formylpiperidin-1-yl)pyrimidin-4-yl]amino}-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (96 mg, 0.2 mmol) in dichloroethane (2 mL). The mixture was basified to pH 7-8 with N,N-diisopropylethylamine and stirred at room temperature overnight. To the above mixture was added sodium triacetoxyborohydride (119 mg, 0.6 mmol) and stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 80% gradient in 30 min) to give 2-{[6-({5-chloro-2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3',3'-difluoro-[1,4'-bipiperidine]-1'-yl}methyl)piperidin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (50.9 mg) as a white solid.1 H NMR (300 MHz, DMSO) δ 11.01 (s, 1H), 8.81 (s, 1H), 8.04 (s, 1H), 7.95 m, 2H), 7.69 (m, 2H), 7.54 (s, 2H), 7.15 (s, 1H), 5.11 (m, 1H), 4.61-4.36 (m, 6H), 3.01-2.89 (s, 8H), 2.83 (m, 5H), 2.71 - 2.54 (m, 2H), 2.21-2.02 (s, 6H), 1.73 (s, 9H), 1.57 (m, 7H), 1.02 (s, 2H); MS (ESI): m / z 961.50 [M+H] + .

[0413] Example 11 – Synthesis of Compound 44

[0414] Step 1: tert-butyl 3'-fluoro-3,6-dihydro-2H-[4,4'-bipyridine]-1-carboxylate [ka]

[0415] To a stirred mixture of 4-bromo-3-fluoropyridine (5.0 g, 28 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (8.78 g, 28 mmol) in dioxane (20 mL) and water (2 mL) was added sodium carbonate (9.03 g, 85 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.31 g, 2.8 mmol). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours, then diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10:1) to give tert-butyl 3'-fluoro-3,6-dihydro-2H-[4,4'-bipyridine]-1-carboxylate (7.3 g, 92%) as a yellow oil. MS (ESI): m / z 279.2 [M+H] + .

[0416] Step 2: 1-benzyl-1'-(tert-butoxycarbonyl)-3-fluoro-3',6'-dihydro-2'H-[4,4'-bipyridin]-1-ium tert-butyl [ka]

[0417] To a solution of tert-butyl 3'-fluoro-3,6-dihydro-2H-[4,4'-bipyridine]-1-carboxylate (7.3 g, 26 mmol) and acetone (70 mL) was added benzyl bromide (5.38 g, 31 mmol) dropwise over 3 minutes at 0 °C. The resulting mixture was stirred at 60 °C overnight and then concentrated in vacuo. The residue was triturated with petroleum ether (600 mL) to give 1-benzyl-1'-(tert-butoxycarbonyl)-3-fluoro-3',6'-dihydro-2'H-[4,4'-bipyridine]-1-ium (9 g, 93%) as a brown solid. MS (ESI): m / z 370.3 [M+H] + .

[0418] Step 3: tert-butyl 1'-benzyl-3'-fluoro-2H,2'H,3H,3'H,6H,6'H-[4,4'-bipyridine]-1-carboxylate [ka]

[0419] To a solution of 1-benzyl-1'-(tert-butoxycarbonyl)-3-fluoro-3',6'-dihydro-2'H-[4,4'-bipyridine]-1-ium (9 g) in methanol (200 mL) was added NaBH4 (4.61 g, 122 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 days, then diluted with water and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to afford tert-butyl 1'-benzyl-3'-fluoro-2H,2'H,3H,3'H,6H,6'H-[4,4'-bipyridine]-1-carboxylate (3.5 g, 39%) as a yellow oil. MS (ESI): m / z 373.30 [M+H] + .

[0420] Step 4: tert-Butyl 3'-fluoro-[4,4'-bipiperidine]-1-carboxylate [ka]

[0421] A mixture of tert-butyl 1'-benzyl-3'-fluoro-2H,2'H,3H,3'H,6H,6'H-[4,4'-bipyridine]-1-carboxylate (1.8 g, 4.8 mmol) and Pd(OH)2 / C (0.90 g, 6.4 mmol) in methanol (50 mL) was degassed, purged with hydrogen, and then stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through Celite and washed with dichloromethane (3 × 10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 3'-fluoro-[4,4'-bipiperidine]-1-carboxylate (1.4 g) as a yellow oil. MS (ES) + ): m / z 287.30 [M+H] + .

[0422] Step 5: 1-benzyl 1'-tert-butyl 3-fluoro-[4,4'-bipiperidine]-1,1'-dicarboxylate [ka]

[0423] To a stirred solution of tert-butyl 3'-fluoro-[4,4'-bipiperidine]-1-carboxylate (1.2 g, 4.2 mmol) and triethylamine (848 mg, 8.4 mmol) in dichloromethane was added benzyl chloroformate (857.7 mg, 5 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel, mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), gradient 10% to 50% in 10 min) to give 1'-tert-butyl 1-benzyl 3-fluoro-[4,4'-bipiperidine]-1,1'-dicarboxylate (570 mg, 32%) as a white solid. MS (ESI): m / z 421.30 [M+H] + .

[0424] Step 6: Benzyl 3-fluoro-[4,4'-bipiperidine]-1-carboxylate [ka]

[0425] To a solution of 1-benzyl 1'-tert-butyl 3-fluoro-[4,4'-bipiperidine]-1,1'-dicarboxylate (270 mg, 0.6 mmol) in 1,4-dioxane (5.0 ml) was added HCl (gas) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give benzyl 3-fluoro-[4,4'-bipiperidine]-1-carboxylate (200 mg, 97%) as a white solid. MS (ESI): m / z 321.30 [M+H] + .

[0426] Step 7: Benzyl 1'-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3-fluoro-[4,4'-bipiperidine]-1-carboxylate [ka]

[0427] To a stirred mixture of benzyl 3-fluoro-[4,4'-bipiperidine]-1-carboxylate (400 mg, 1.2 mmol) and 3-(5-bromo-4-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (426 mg, 1.2 mmol) in N,N-dimethylformamide, dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (5.25 mg, 0.006 mmol) and cesium carbonate (814 mg, 2.5 mmol) were added. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, aqueous acetonitrile (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min) to give benzyl 1'-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3-fluoro-[4,4'-bipiperidine]-1-carboxylate (210 mg, 29%) as a white solid. MS (ESI): m / z 581.30 [M+H] + .

[0428] Step 8: 3-(4-fluoro-5-{3'-fluoro-[4,4'-bipiperidin]-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione [ka]

[0429] To benzyl 1'-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3-fluoro-[4,4'-bipiperidine]-1-carboxylate (150 mg, 0.3 mmol) was added trifluoroacetic acid (3 mL, 0.03 mmol). The resulting mixture was stirred at 50 ° C for 3 hours and then concentrated under vacuum to give 3-(4-fluoro-5-{3'-fluoro-[4,4'-bipiperidine]-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (100 mg, 87%) as a brown oil. MS (ESI): m / z 447.30 [M+H] + .

[0430] Step 9: 2-{[6-({5-chloro-2-[4-({1'-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3-fluoro-[4,4'-bipiperidine]-1-yl}methyl)piperidin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide [ka]

[0431] To a stirred mixture of 3-(4-fluoro-5-{3'-fluoro-[4,4'-bipiperidin]-1-yl}-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (70 mg, 0.2 mmol) and 2-[(6-{[5-chloro-2-(4-formylpiperidin-1-yl)pyrimidin-4-yl]amino}-1-isopropyl-2-oxoquinolin-3-yl)oxy]-N-methylacetamide (80.43 mg, 0.2 mmol) in dichloroethane (5 mL), N,N-diisopropylethylamine was added dropwise and the pH was adjusted to 8. The resulting mixture was stirred at 40°C overnight. To the above mixture, sodium triacetoxyborohydride (99.68 mg, 0.5 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The crude material was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 55% gradient in 10 min) to give 2-{[6-({5-chloro-2-[4-({1'-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-3H-isoindol-5-yl]-3-fluoro-[4,4'-bipiperidine]-1-yl}methyl)piperidin-1-yl]pyrimidin-4-yl}amino)-1-isopropyl-2-oxoquinolin-3-yl]oxy}-N-methylacetamide (41 mg, 25%) as an off-white solid. 1H NMR (300 MHz, DMSO) δ 10.97 (s, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.52-7.45 (m, 1H), 7.39 (dd, J=7.9, 1.5 Hz, 1H), 7.32 (d, J=4.4 Hz, 4H), 7.31-7.18 (m, 1H), 5.09 (dd, J=13.2, 5.1 Hz, 1H), 4.41 (d, J=17.2 Hz, 1H), 4.27 (d, J=17.2 Hz, 1H), 3.49 (s, 2H), 2.90 (dq, J=13.5, 6.6, 5.3Hz, 3H), 2.70-2.51 (m, 2H), 2.37 (qd, J=13.1, 4.3 Hz, 1H), 2.02 (dtd, J=17.0, 11.4, 4.1 Hz, 3H), 1.74 (s, 3H), 1.69 (dd, J=12.2, 3.5 Hz, 1H); MS (ESI): m / z 943.39 [M+H] + .

[0432] Example 12: Synthesis of Compound 1

[0433] Step 1: tert-butyl 4-[(1r,3r)-3-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl}cyclobutoxy]piperidine-1-carboxylate [ka]

[0434] tert-Butyl 4-[(1r,3r)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]cyclobutoxy]piperidine-1-carboxylate in 1,4-dioxane and water (Example 5, Step 6; To a stirred solution / mixture of CsF (512.82 mg, 1.109 mmol, 1.5 equiv.) and 3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (WO2019060693, 250 mg, 0.739 mmol, 1.00 equiv.), CsF (336.90 mg, 2.217 mmol, 3 equiv.) and Pd(dtbpf)Cl (48.18 mg, 0.074 mmol, 0.1 equiv.) were added dropwise / portionwise at 90 °C under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (10 × mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector: UV 254 nm. This afforded tert-butyl 4-[(1r,3r)-3-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]-3,6-dihydro-2H-pyridin-1-yl}cyclobutoxy]piperidine-1-carboxylate (230 mg, 52.40%) as a white solid. LC-MS (ES) + ): m / z 594.37 [MH + ], t R =1.119 min (2.0 min run).

[0435] Step 2: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[4-fluoro-1-oxo-2-(2-oxopiperidin-3-yl)-3H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0436] Compound 1 was prepared as 45 mg of an off-white solid (100%) using the procedure of Example 5 / Compound 37, steps 8-10. 1 H NMR (300 MHz, DMSO-d6, ppm):δ 11.08 (s, 1H), 8.84 (s, 1H), 8.05 (s, 1H), 7.97 (d, J=10.4 Hz, 2H), 7.70 (d, J=1.4 Hz, 2H), 7.06-6.89 (m, 4H), 5.37 (dd, J=12.8, 5.3 Hz, 1H), 4.55 (s, 2H), 4.13 (d, J=14.8 Hz, 3H), 3.57 (s, 3H), 3.53 (s, 1H), 3.22 (d, J=10.0 Hz, 3H), 3.00 (d, J=9.9 Hz, 4H), 2.87 (d, J=14.8 Hz, 2H), 2.69 (d, J=4.6 Hz, 3H), 2.22-2.12 (m, 2H), 2.00 (d, J=5.6 Hz, 3H), 1.82 (d, J=11.3 Hz, 8H), 1.72 (d, J=11.4 Hz, 1H), 1.58 (d, J=6.8 Hz, 5H), 1.38 (d, J=8.7 Hz, 3H).

[0437] LC-MS (ES + ): m / z 895.39[MH + ], t R = 1.235 min (3.0 min run).

[0438] Example 13: Synthesis of Compound 5

[0439] Step 1: 3-[(4-bromophenyl)amino]piperidine-2,6-dione [ka]

[0440] To a stirred solution of 4-bromoaniline (2.0 g, 11.6 mmol, 1.0 equiv.) and 3-bromopiperidine-2,6-dione (2.2 g, 11.6 mmol, 1.0 equiv.) in DMF (50 mL) was added DIEA (4.5 g, 34.9 mmol, 3.0 equiv.) at room temperature. The resulting mixture was stirred at 100 °C overnight. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CHCN / water (10 mmol / L FA), 5% to 50% gradient in 45 min; detector, UV 254 nm. This afforded 3-[(4-bromophenyl)amino]piperidine-2,6-dione (260 mg) as a gray-brown solid. LC-MS (ES) + ): m / z 279.00 [MH + ], t R =0.908 min (2.0 min run).

[0441] Step 2: tert-butyl 4-[(1r,3r)-3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperazin-1-yl)cyclobutoxy]piperidine-1-carboxylate [ka]

[0442] Pd-PEPPSI-IPentCl (Khadra A, Mayer S, Organ MG. Pd-PEPPSI-IPent) was prepared by dissolving 3-[(4-bromophenyl)amino]piperidine-2,6-dione (260 mg, 0.8 mmol, 1.0 equiv.), tert-butyl 4-[(1r,3r)-3-(piperazin-1-yl)cyclobutoxy]piperidine-1-carboxylate (WO2022221673, 299.8 mg, 0.8 mmol, 1.0 equiv.), and CsCO (863.10 mg, 2.649 mmol, 3.0 equiv.) in DMF (5.0 mL). Cl : A Useful Catalyst for the Coupling of 2-Aminopyridine Derivatives. Chemistry. 2017 Mar 2;23(13):3206-3212. A mixture of 2-methylpyridine (o-picoline) (67.28 mg, 0.08 mmol, 0.1 equiv.) and 2-methylpyridine (o-picoline) (67.28 mg, 0.08 mmol, 0.1 equiv.) was degassed with nitrogen three times. The mixture was stirred at 110 °C overnight. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with ethyl acetate (300 mL). The resulting mixture was extracted with EtOAc (200 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: MeCN / water (10 mmol / L NH4HCO3), 5% to 50% gradient in 30 min; detector: UV 254 nm). This afforded tert-butyl 4-[(1r,3r)-3-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperazin-1-yl)cyclobutoxy]piperidine-1-carboxylate (136 mg, 28%) as a black solid. LC-MS (ES) + ): m / z 542.40 [MH + ], t R =0.704 min (1.2 min run).

[0443] Step 3: [ka]

[0444] Compound 5 was prepared as 33.8 mg of a white solid using the procedure of Example 5 / Compound 37, steps 9-10. 1 H NMR (300 MHz, DMSO-d6,ppm): δ 8.83 (s, 1H), 8.04 (s, 1H), 7.97 (s, 2H), 7.69 (d, J = 10.2 Hz, 3H), 7.28 (d, J = 8.5 Hz, 2H), 7.16 (s, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 4.54 (d, J = 7.3 Hz, 2H), 4.18-4.10 (m, 3H), 3.52 (s, 1H), 3.20 (d, J = 10.8 Hz, 2H), 3.08 (s, 3H), 2.78 (s, 1H), 2.66 (d, J = 4.5 Hz, 3H), 2.39 (s, 4H), 2.32 (s, 1H), 2.17 (s, 2H), 2.02-1.96 (m, 3H), 1.80 (s, 2H), 1.56 (d, J = 6.8 Hz, 6H), 1.37 (s, 2H), 1.22 (s, 4H), 0.82 (s, 2H). LC-MS (ES + ): m / z 841.30 [MH + ], t R = 7.599 min (13.0 min run).

[0445] Example 14: Synthesis of Compound 17

[0446] Step 1: 3-(5-bromoindol-1-yl)piperidine-2,6-dione [ka]

[0447] To a 30 mL sealed tube, 5-bromoindole (1.02 g, 5.20 mmol, 2.0 equiv) and NaH (156 mg, 3.90 mmol, 1.5 equiv, 60%) in THF (10 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. To the above mixture, 3-bromopiperidine-2,6-dione (0.50 g, 2.60 mmol, 1.0 equiv) in THF (5 mL) was added dropwise at 0 °C. The resulting mixture was further stirred at 60 °C overnight. The resulting mixture was extracted with CHCl / IPA (4:1, 3 × 20 mL). The combined organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give 3-(5-bromoindol-1-yl)piperidine-2,6-dione (420 mg, 52.56%) as a white solid. LC-MS (ES + ): m / z 306 [MH + ], t R = 0.91 min (2.00 min run).

[0448] Step 2: 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[1-(2,6-dioxopiperidin-3-yl)indol-5-yl]piperazin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0449] Compound 17 was prepared similarly to Example 13 / Compound 5 to yield 65.9 mg (46.80%) of a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.83 (s, 1H), 8.05 (s, 1H), 8.00 - 7.92 (m, 2H), 7.70 (m, 2H), 7.35 - 7.24 (m, 2H), 7.06 - 6.99 (m, 2H), 6.91 (m, 1H), 6.36 (m, 1H), 5.53 (m, 1H), 5.33 (s, 1H), 4.55 (s, 2H), 4.25 - 4.02 (m, 3H), 3.54 (s, 1H), 3.24 (m, 2H), 3.06 (s, 4H), 2.95 - 2.80 (m, 2H), 2.69 (m, 4H), 2.60 (s, 1H), 2.45 (s, 4H), 2.40 (s, 3H), 2.15 (m, 2H), 1.83 (m, 2H), 1.58 (m, 6H), 1.39 (m, 2H). LC-MS (ES + ): m / z 864.38 [MH + ], t R = 1.13 min, (2.00 min run).

[0450] Example 15: Synthesis of Compound 21

[0451] Step 1: 3-(5-bromoindazol-1-yl)piperidine-2,6-dione and 3-(5-bromoindazol-2-yl)piperidine-2,6-dione [ka]

[0452] To a 100 mL three-necked round-bottom flask, 5-bromo-1H-indazole (1970.23 mg, 9.999 mmol, 2.00 equiv) and THF (40 mL) were added at room temperature. To the above mixture, NaH (239.97 mg, 10.000 mmol, 2.00 equiv) was added portionwise at 0° C. The resulting mixture was stirred at 60° C. for an additional 30 minutes. To the above mixture, 3-bromopiperidine-2,6-dione (960 mg, 5.000 mmol, 1.00 equiv) in THF was added dropwise at 60° C. The resulting mixture was stirred at 60° C. overnight. The resulting mixture was diluted with ethyl acetate (200 mL). The resulting mixture was added to 200 mL of 20% HCl (aq). The aqueous layer was extracted with EtOAc (2×80 mL). The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (2:3), to isolate the two regioisomers.

[0453] 3-(5-Bromoindazol-1-yl)piperidine-2,6-dione (1 g, 64.91%) was obtained as an off-white solid. LC-MS (ES + ): m / z 309.95 [MH + ], t R =0.721 min (2.0 min run).

[0454] 3-(5-Bromoindazol-2-yl)piperidine-2,6-dione (600 mg, 38.95%) was obtained as an off-white solid.

[0455] LC-MS (ES + ): m / z 307.85[MH + ], t R = 0.687 min (2.0 min run).

[0456] Step 2: Synthesis of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[1-(2,6-dioxopiperidin-3-yl)indazol-5-yl]piperazin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-isopropyl-2-oxoquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0457] Compound 21 was prepared similarly to Example 13 / Compound 5 by replacing 3-[(4-bromophenyl)amino]piperidine-2,6-dione with 3-(5-bromoindazol-1-yl)piperidine-2,6-dione in step 1 to yield 55 mg (35.47%) as a light brown solid. 1 H NMR (300 MHz, DMSO-d6, ppm) δ 11.08 (s, 1H), 8.85 (s, 1H), 8.04-7.91 (m, 4H), 7.69 (m, 2H), 7.49 (m, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 7.02 (s, 1H), 5.76 (m, 1H), 5.32 (s, 1H), 4.55 (s, 2H), 4.25-4.07 (m, 3H), 3.23 (m, 1H), 3.20 (s, 2H), 3.09 (s, 4H), 2.82 (s, 3H), 2.77-2.64 (m, 1H), 2.46 (s, 4H), 2.31-2.19 (m, 3H), 2.19 (s, 3H), 2.00 (m, 2H), 1.83 (m, 2H), 1.57 (m, 6H), 1.38 (m, 2H). LC-MS (ES + ): m / z 866.45 [MH + ], t R = 6.315 min (13.0 min run).

[0458] Example 16: Synthesis of Compound 22 [ka]

[0459] Compound 22 was prepared similarly to Example 13 / Compound 5 by replacing 3-[(4-bromophenyl)amino]piperidine-2,6-dione with 3-(5-bromoindazol-2-yl)piperidine-2,6-dione in step 1 to yield 27 mg (16%) as a pale gray solid. 1 H NMR (300 MHz, DMSO-d6, ppm) δ 8.84 (s, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.97 (m, 2H), 7.70 (s, 2H), 7.47 (m, 1H), 7.17 (m, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 5.64 (m, 1H), 4.55 (s, 2H), 4.11 (m, 3H), 3.54 (s, 1H), 3.26-3.13 (m, 2H), 3.07 (s, 2H), 3.07 (s, 4H), 2.77-2.65 (m, 2H), 2.50 (s, 1H), 2.45 (s, 3H), 2.31 (s, 1H), 2.19 (s, 4H), 1.82 (s, 5H), 1.57 (m, 6H), 1.39 (s, 3H), 1.24 (s, 1H). LC-MS (ES + ): m / z 866.45[MH + ], t R = 5.598 minutes (10.0 minute run).

[0460] Example 17: Synthesis of Compound 23 [ka]

[0461] Compound 23 was prepared similarly to compound 21 by replacing 3-(5-bromoindazol-1-yl)piperidine-2,6-dione with 3-(5-bromo-1,3-benzodiazol-1-yl)piperidine-2,6-dione in the first step to afford the title compound as 42 mg (23%) of an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.86 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.97 (m, 2H), 7.70 (m, 2H), 7.38 (m, 1H), 7.13 (m, 1H), 7.03 (s, 1H), 5.62 (m, 1H), 5.32 (s, 1H), 4.55 (s, 2H), 4.24 - 4.07 (m, 2H), 3.54 (s, 1H), 3.23 (m, 2H), 3.10 (s, 3H), 2.75 (m, 6H), 2.45 (s, 3H), 2.25 - 2.15 (m, 3H), 1.99 (m, 0H), 1.84 (m, 2H), 1.57 (m, 6H), 1.38 (m, 1H). LC-MS (ES + ): m / z 866.55 [MH + ], t R = 2.694 minutes (9 minute run).

[0462] Example 18: Synthesis of Compound 24 [ka]

[0463] Compound 24 was prepared similarly to compound 21 by replacing 3-(5-bromoindazol-1-yl)piperidine-2,6-dione with 3-(6-bromo-1,3-benzodiazol-1-yl)piperidine-2,6-dione in the first step to give 52.6 mg (44%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.86 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.97 (m, 2H), 7.70 (m, 2H), 7.38 (m, 1H), 7.13 (m, 1H), 7.03 (s, 1H), 5.62 (m, 1H), 5.32 (s, 1H), 4.55 (s, 2H), 4.24 - 4.07 (m, 2H), 3.54 (s, 1H), 3.23 (m, 2H), 3.10 (s, 3H), 2.75 (m, 6H), 2.45 (s, 3H), 2.25 - 2.15 (m, 3H), 1.99 (m, 0H), 1.84 (m, 2H), 1.57 (m, 6H), 1.38 (m, 1H). LC-MS (ES + ): m / z 866.55 [MH + ], t R = 2.694 minutes (9 minute run).

[0464] Compound characterization (mass spectrometry)

[0465] Mass spectrometry data for compounds of the present disclosure are provided in Table 4 below.

[0466] Table 4. Mass spectrometry data for compounds of the present disclosure [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14] [Table 4-15] Biological Activity Data for Compounds of the Present Disclosure

[0467] Protein synthesis. BCL6 protein was expressed by transforming Invitrogen One Shot cells with the GS63525 pET24a-His-SUMO-TEV-BCLm-Avitag plasmid according to the manufacturer's instructions. Biotin was added to a final concentration of 50 μM, and IPTG was added to a final concentration of 1 mM. The cultures were then incubated overnight at room temperature with shaking.

[0468] Immunofluorescence Protocol for High-Content Imaging of BCL6

[0469] T47D cells were seeded in 100 μl volume of RPMI1640-10% FBS in 96-well black / clear bottom plates for adherent cells (Corning #3904).

[0470] Day 1. T47D breast cancer epithelial cells were seeded at a density that resulted in approximately 70-90% confluence at the endpoint. Cells were seeded in the morning at 7K / 0.1 mL / well, followed by the addition of an exemplary bifunctional degradation compound.

[0471] Compound treatment

[0472] Day 2: Prepare 11-point 3-fold serial dilutions of exemplary bifunctional compounds in DMSO and dispense appropriate volumes into cell growth medium to produce a 2X final concentration of exemplary bifunctional compounds. Add an equal volume (0.1 ml) of 2X exemplary bifunctional compound / medium mix to the previously seeded cells to achieve a final top concentration of 0.1 or 1 μM in aqueous cell growth medium. Incubate at 37°C, 5% CO2 for 3 days.

[0473] Immunofluorescence on Day 5. Discard the cell culture medium. Wash the wells with 200 μL of room temperature phosphate-buffered saline (PBS). 4% paraformaldehyde (PFA) was prepared from 16% PFA (Electron Microscopy Sciences #15710) using 1X PBS. 50 μL of 4% PFA was added to each well and incubated at room temperature for 15 minutes to fix the cells. The PFA was aspirated, and the cells were washed twice with PBS (200 μL).

[0474] 0.1% Triton X-100 in PBS was prepared using 10% Triton X-100 stock. Cells were permeabilized by adding 100 μL of 0.1% Triton X-100 in PBS to each well and incubating at room temperature for 15 minutes. Cells were washed twice with PBS.

[0475] 3% BSA / PBS (Thermofisher #37515 Blocker BSA in TBS, 10%) was made and 100 μL was added to each well. Cells were incubated at room temperature for at least 1 hour.

[0476] Blocker BSA / PBS was used to make 1% BSA / PBS and 3% BSA / PBS was removed from the wells.

[0477] For no primary antibody controls, 50 μL of 1% BSA / PBS was added.

[0478] The primary antibody (BCL6 Rb Ab, CST-14895, Cell Signaling) was diluted 1:300 in 1% BSA / PBS using the blocker BSA / PBS.

[0479] 50 μl of primary antibody was added to all remaining wells (i.e., all wells except the primary antibody control) and the cells were incubated overnight at 4°C with slow orbital movement.

[0480] Day 6. The contents of the wells were removed and the cells were washed four times with 200 μL of PBS. 1% BSA / PBS was prepared using a solution of the blocker BSA in PBS.

[0481] In the same mix, the secondary antibodies goat anti-Rb IgG Alexa-488 were diluted 1:1000 and CellMask-Alexa-647 1:3000 in 1% BSA / PBS. Add 50 μL to each well and incubate for 1 hour at room temperature in the dark.

[0482] The cells were washed three times with 200 μL of PBS and then incubated with 100 μL of Hoechst dye at 1 μg / mL (20 mM stock) for 10 minutes to stain the cell nuclei. The wells were then washed with 200 μL of PBS, 100 μL of PBS was added to each well, and the plate was covered with a plastic opaque cover. The plate was stored at 4°C and covered with aluminum foil until imaging.

[0483] Plates were equilibrated to room temperature before reading. The bottom of the plate was wiped with 70% isopropanol immediately before imaging.

[0484] Imaging:

[0485] 10X, 4 fields / well includes top hat smoothing in the analysis protocol.

[0486] Supplies / Reagents:

[0487] 16% Paraformaldehyde: Electron Microscopy Sciences #15710

[0488] Hoechst: Thermofisher # 62249

[0489] Blocker: 10% BSA in PBS: Thermofisher #37515

[0490] Blocker: BSA in TBS, 10%: Thermofisher #37520

[0491] Goat anti-rabbit or mouse AlexaFluor-488: Thermofisher #A11008

[0492] Cell Mask Deep Red AlexaFluor-647: Thermofisher #C10046

[0493] Washing buffer, PBS: 20x PBS, Thermofisher

[0494] Table 5. Bioactivity data for compounds of the present disclosure [Table 5-1] [Table 5-2] Enumeration of Embodiments

[0495] Aspects of the present disclosure are further described with reference to the following numbered embodiments.

[0496] 1A. A bifunctional compound of formula (I), formula (II), or formula (III), [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or C1-C6 alkyl; Q is, [ka] and X is N or CH; Y1, Y2, and Y3 are each independently N or CR 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl; Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), Q's [ka] indicates the point of attachment to X or glutarimide, R 1a is H or a halogen, R 2a is H or C1-C3 alkyl; X 3a But CHR 3a or C(O), R 3a is H or C1-C3 alkyl; X 4a and X 6aare each independently CH or N; R 5a is H, C1-C3 alkyl, or halogen; L, [ka] and X 6b But CHR 6b or C(O), R 6b is H or C1-C3 alkyl; R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R 3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl; X 1b and X 2b are each independently CH or N, and X 1b and X 2b at least one of is N, In the formula, each of L [ka] indicates the point of attachment. 1B. Bifunctional compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or C1-C6 alkyl; Q is, [ka] and X is N or CH; Y1, Y2, and Y3 are each independently N or CR 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl; Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), Q's [ka] indicates the point of attachment to X or glutarimide. 1C. Bifunctional compounds of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1a is H or a halogen, R 2a is H or C1-C3 alkyl; X 3a But CHR 3a or C(O), R 3a is H or C1-C3 alkyl; X 4a and X 6a are each independently CH or N; R 5a is H, C1-C3 alkyl, or halogen. 1D. Bifunctional compounds of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein: L, [ka] and X 6b But CHR 6b or C(O), R 6b is H or C1-C3 alkyl; R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R 3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl; X 1b and X 2b are each independently CH or N, and X 1b and X 2b at least one of is N, In the formula, each of L [ka] indicates the point of attachment. 1E. The compound is a compound of formula (II-a): [ka] or a pharmaceutically acceptable salt thereof. 1F. The compound is a compound of formula (II-b), formula (II-c), formula (II-d), formula (II-e), formula (II-f), formula (II-g), formula (II-h), formula (II-i), or formula (II-j), [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 1G. The compound is a compound of formula (III-a), formula (III-c), formula (III-d), formula (III-f), formula (III-g), formula (III-h), or formula (III-i), [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 1H. Bifunctional compounds of formula (IV-b) or formula (IV-e): [ka] [ka] or a pharmaceutically acceptable salt thereof. 2A. Bifunctional compounds of formula (I), formula (II), or formula (III), [ka] [ka] [ka] wherein R 1 is H or C1-C6 alkyl; Q is, [ka] and X is N or CH; Y1, Y2, and Y3 are each independently N or CR 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl; Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), Q's [ka] indicates the point of attachment to X or glutarimide, R 1a is H or a halogen, R 2a is H or C1-C3 alkyl; X 3a But CHR 3a or C(O), R 3a is H or C1-C3 alkyl; X 4a and X 6a are each independently CH or N; R 5a is H, C1-C3 alkyl, or halogen; L, [ka] and X 6b But CHR 6b or C(O), R 6b is H or C1-C3 alkyl; R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R 3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl; X 1b and X 2b are each independently CH or N, and X 1b and X 2b at least one of is N, In the formula, each of L [ka] indicates the point of attachment. 2B. Bifunctional compounds of formula (I): [ka] wherein R 1 is H or C1-C6 alkyl; Q is, [ka] and X is N or CH; Y1, Y2, and Y3 are each independently N or CR 3 and Z1 and Z2 are each independently N or CH; R 2 is H or C1-C6 alkyl; Each R 3 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -O-(C1-C6 haloalkyl), Q's [ka] indicates the point of attachment to X or glutarimide. 2C. Bifunctional compounds of formula (II): [ka] wherein R 1a is H or a halogen, R 2a is H or C1-C3 alkyl; X 3a But CHR 3a or C(O), R 3a is H or C1-C3 alkyl; X 4a and X 6a are each independently CH or N; R5a is H, C1-C3 alkyl, or halogen. 2D. Bifunctional compounds of formula (III): [ka] wherein L, [ka] and X 6b But CHR 6b or C(O), R 6b is H or C1-C3 alkyl; R 1b , R 2b , R 3b , and R 4b are each independently H or halogen, and R 1b , R 2b , R 3b , R 4b at least one of is a halogen; R 5b is H or a halogen, R 6b is H or C1-C3 alkyl; X 1b and X 2b are each independently CH or N, and X 1b and X 2b at least one of is N, In the formula, each of L [ka] indicates the point of attachment. 2E. The bifunctional compound of embodiment 2A or 2C, wherein the compound is a compound of formula (II-a). [ka] 2F. The bifunctional compound of embodiment 2A or 2C, wherein the compound is a compound of Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), or Formula (II-j): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] 2G. The bifunctional compound of embodiment 2A or 2D, wherein the compound is a compound of Formula (III-a), Formula (III-c), Formula (III-d), Formula (III-f), Formula (III-g), Formula (III-h), or Formula (III-i). [ka] [ka] [ka] [ka] [ka] [ka] [ka] 2H. Bifunctional compounds of formula (IV-b) or formula (IV-e): [ka] [ka] 3.Q is [ka] The bifunctional compound of any one of embodiments 1A, 1B, 2A or 2B, which is, or a pharmaceutically acceptable salt thereof. 4. The bifunctional compound according to any one of embodiments 1A, 1B, 2A, or 2B, or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, and Y3 is CH. 5. A bifunctional compound according to any one of embodiments 11A, 1B, 2A, or 2B, or a pharmaceutically acceptable salt thereof, wherein one of Y1, Y2, and Y3 is N, and the other two of Y1, Y2, or Y3 are CH. 6. A bifunctional compound according to any one of embodiments 1A, 1B, 2A, or 2B, or a pharmaceutically acceptable salt thereof, wherein two of Y1, Y2, and Y3 are N and the other of Y1, Y2, or Y3 is CH. 7.R 1 The bifunctional compound according to any one of embodiments 1A, 1B, 2A or 2B, or a pharmaceutically acceptable salt thereof, wherein is H or CH3. 8. The bifunctional compound according to any one of embodiments 1A, 1B, 2A or 2B, or a pharmaceutically acceptable salt thereof, wherein X is N. 9. The bifunctional compound according to any one of embodiments 1A, 1B, 2A or 2B, or a pharmaceutically acceptable salt thereof, wherein X is CH. 10.R 2The bifunctional compound according to any one of embodiments 1A, 1B, 12A, or 2B, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, or isopropyl. 11.Each R 3 The bifunctional compound of any one of embodiments 1A, 1B, 2A, or 2B, or a pharmaceutically acceptable salt thereof, wherein is independently H, methyl, fluoro, or methoxy. 12.R 1a The bifunctional compound according to any one of embodiments 1A, 1C, 1E, 2A, 2C, or 2E, wherein is F, or a pharmaceutically acceptable salt thereof. 13.R 1a The bifunctional compound according to any one of embodiments 1A, 1C, 1E, 2A, 2C, or 2E, or a pharmaceutically acceptable salt thereof, wherein is Cl. 14.R 1a The bifunctional compound of any one of embodiments 1A, 1C, 1E, 2A, 2C, or 2E, wherein is H, or a pharmaceutically acceptable salt thereof. 15.X 4a and X 6a The bifunctional compound according to any one of embodiments 1A, 1C, 1E, 1F, 2A, 2C, 2E, or 2F, or a pharmaceutically acceptable salt thereof, wherein each is N. 16.X 4a and X 6a or a pharmaceutically acceptable salt thereof. 17.R 3a The bifunctional compound of any one of embodiments 1A, 1C, 1E, 2A, 2C, or 2E, or a pharmaceutically acceptable salt thereof, wherein is CH3. 18.R 3a The bifunctional compound of any one of embodiments 1A, 1C, 1E, 2A, 2C, or 2E, wherein is H, or a pharmaceutically acceptable salt thereof. 19.R 5aThe bifunctional compound of any one of embodiments 1A, 1C, 1E, 1F, 2A, 2C, 2E, or 2F, or a pharmaceutically acceptable salt thereof, wherein is CH3. 20.R 5a The bifunctional compound according to any one of embodiments 1A, 1C, 1E, 1F, 2A, 2C, 2E, or 2F, wherein is H, or a pharmaceutically acceptable salt thereof. 21.R 5a The bifunctional compound according to any one of embodiments 1A, 1C, 1E, 1F, 2A, 2C, 2E, or 2F, wherein is F, or a pharmaceutically acceptable salt thereof. 22.R 2a The bifunctional compound of any one of embodiments 1A, 1C, 1E, 2A, 2C, or 2E, or a pharmaceutically acceptable salt thereof, wherein is CH3. 23.R 2a The bifunctional compound of any one of embodiments 1A, 1C, 1E, 2A, 2C, or 2E, wherein is H, or a pharmaceutically acceptable salt thereof. 24.L [ka] or a pharmaceutically acceptable salt thereof. 25.L [ka] or a pharmaceutically acceptable salt thereof. 26.L [ka] or a pharmaceutically acceptable salt thereof. 27.L [ka] or a pharmaceutically acceptable salt thereof. 28.L [ka] 28. The bifunctional compound of any one of embodiments 1A, 1D, 1G, 1E, 2A, 2D, 2G, or 2E or 27, wherein: 29.L [ka] 28. The bifunctional compound of any one of embodiments 1A, 1D, 1G, 1E, 2A, 2D, 2G, or 2E or 27, wherein: 30. A bifunctional compound selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. 31. A bifunctional compound selected from any one of the compounds in Table 1. 32. A pharmaceutical composition comprising a bifunctional compound according to any one of embodiments 1A-1D or 3-31, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 33. A pharmaceutical composition comprising a bifunctional compound according to any one of embodiments 2A-2D or 3-31, and one or more pharmaceutically acceptable excipients. 34A. A pharmaceutical composition comprising a bifunctional compound according to embodiment 1A or 2A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 34B. A pharmaceutical composition comprising a bifunctional compound according to embodiment 1B or 2B, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 34C. A pharmaceutical composition comprising a bifunctional compound according to embodiment 1C or 2C, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 34D. A pharmaceutical composition comprising a bifunctional compound according to embodiment 1D or 2D, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 34E. A pharmaceutical composition comprising a bifunctional compound according to embodiment 2A and one or more pharmaceutically acceptable excipients. 34F. A pharmaceutical composition comprising a bifunctional compound according to embodiment 2B and one or more pharmaceutically acceptable excipients. 34G. A pharmaceutical composition comprising a bifunctional compound according to embodiment 2C and one or more pharmaceutically acceptable excipients. 34H. A pharmaceutical composition comprising a bifunctional compound according to embodiment 2D and one or more pharmaceutically acceptable excipients. 36. The pharmaceutical composition of any one of embodiments 31-34H, wherein the composition further comprises an effective amount of at least one additional anti-cancer agent. 37A. A method for treating a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound described in any one of embodiments 1-31 or a therapeutically effective amount of a pharmaceutical composition described in any one of embodiments 32-36. 37B. A method for treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound described in any one of embodiments 1-31 or a therapeutically effective amount of a pharmaceutical composition described in any one of embodiments 32-36. 38. The method of embodiment 37A or 37B, wherein a therapeutically effective amount of the bifunctional compound or pharmaceutical composition is orally administered to the subject. 39. The method of embodiment 37A, 37B, or 38, wherein a therapeutically effective amount of the bifunctional compound or pharmaceutical composition is administered to the subject once a day, twice a day, three times a day, or four times a day. 40. The method of any one of embodiments 37A, 37B, or 38-39, wherein the therapeutically effective amount of the bifunctional compound or pharmaceutical composition is administered to the subject once daily. 41. The method of any one of embodiments 37A, 37B, or 38-39, wherein the therapeutically effective amount of the bifunctional compound or pharmaceutical composition is administered to the subject in one dose, or in two, three, or four divided doses. 42. The method of any one of embodiments 37A, 37B, or 38-41, wherein the therapeutically effective amount of the bifunctional compound is from about 1 mg to about 1000 mg. 43. The method of any one of embodiments 37A, 37B, or 38-41, wherein the therapeutically effective amount of the bifunctional compound is from about 5 mg to about 750 mg. 44. The method of any one of embodiments 37A, 37B, or 38-41, wherein the therapeutically effective amount of the bifunctional compound is from about 10 mg to about 500 mg. 45. The method of any one of embodiments 37A, 37B, or 38-41, wherein the therapeutically effective amount of the bifunctional compound is from about 20 mg to about 250 mg. 46. ​​The method of any one of embodiments 37A, 37B, or 38-45, wherein the subject is in a fed state at the time of administration. 47. The method of any one of embodiments 37A, 37B, or 38-45, wherein the subject is in a fasted state at the time of administration. 48. The method of any one of embodiments 37A, 37B, or 38-47, further comprising administering to a subject in need thereof an effective amount of at least one additional anti-cancer agent. 49. The method of any one of embodiments 37A, 37B, or 38-48, wherein the disease or disorder is associated with aberrant BCL6 expression and / or activity. 50. The method of any one of embodiments 37A, 37B, or 38-48, wherein the disease or disorder is a cancer associated with aberrant BCL6 expression and / or activity. 51. The disease or disorder is breast cancer, ovarian cancer, leukemia, lymphoma, benign lymphoma, malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, synovial sarcoma, meningeal sarcoma, carcinosarcoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B acute lymphoblastic leukemia, pre-B lymphoma, B-cell lymphoma, large cell type The method of any one of embodiments 37A, 37B, or 38-50, wherein the cancer is B-cell lymphoma, diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive chronic myeloid leukemia (CML), follicular lymphoma, intravascular large B-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), T-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, non-small cell lung cancer, systemic lupus erythematosus (SLE), brain tumor, or central nervous system cancer. 52. The method of any one of embodiments 37A, 37B, or 38-50, wherein the disease or disorder is large B-cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, or angioimmunoblastic T-cell lymphoma (AITL).

Claims

1. a bifunctional compound of formula (I), formula (II), or formula (III), 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 or a pharmaceutically acceptable salt thereof, wherein: R １ is H or C １ -C ６ is alkyl, Q is, 【Chemistry 4】 and X is N or CH; Y １ , Y ２ , and Y ３ are each independently N or CR ３ and Z １ and Z ２ are each independently N or CH; R ２ is H or C １ -C ６ is alkyl, Each R ３ are independently H, halogen, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), -O-(C １ -C ６ haloalkyl), Q's 【Transformation 5】 represents the point of attachment to X or glutarimide, R １ａ is H or a halogen; R ２ａ is H or C １ -C ３ is alkyl, X ３ａ But CHR ３ａ or C(O), R ３ａ is H or C １ -C ３ is alkyl, X ４ａ and X ６ａ are each independently CH or N; R ５ａ But H, C １ -C ３ alkyl, or halogen; L, 【Transformation 6】 and X ６ｂ But CHR ６ｂ or C(O), R ６ｂ is H or C １ -C ３ is alkyl, R １ｂ , R ２ｂ , R ３ｂ , and R ４ｂ are each independently H or halogen, and R １ｂ , R ２ｂ , R ３ｂ , R ４ｂ at least one of is a halogen; R ５ｂ is H or a halogen; R ６ｂ is H or C １ -C ３ is alkyl, X １ｂ and X ２ｂ are each independently CH or N, and X １ｂ and X ２ｂ at least one of is N; In the formula, each of L 【Transformation 7】 indicates the point of attachment.

2. 2. The bifunctional compound of claim 1, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

3. 2. The bifunctional compound of claim 1, wherein the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof:

4. 2. The bifunctional compound of claim 1, wherein the compound is a compound of formula (III) or a pharmaceutically acceptable salt thereof:

5. A bifunctional compound of formula (I), formula (II), or formula (III): 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 During the ceremony, R １ is H or C １ -C ６ is alkyl, Q is, 【Chemistry 11】 and X is N or CH; Y １ , Y ２ , and Y ３ are each independently N or CR ３ and Z １ and Z ２ are each independently N or CH; R ２ is H or C １ -C ６ is alkyl, Each R ３ are independently H, halogen, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, —O—(C １ -C ６ alkyl), or —O—(C １ -C ６ haloalkyl), Q's 【Chemistry 12】 indicates the point of attachment to X or glutaramide, R １ａ is H or a halogen; R ２ａ is H or C １ -C ３ is alkyl, X ３ａ But CHR ３ａ or C(O), R ３ａ is H or C １ -C ３ is alkyl, X ４ａ and X ６ａ are each independently CH or N; R ５ａ But H, C １ -C ３ alkyl, or halogen; L, 【Chemistry 13】 and X ６ｂ But CHR ６ｂ or C(O), R ６ｂ is H or C １ -C ３ is alkyl, R １ｂ , R ２ｂ , R ３ｂ , and R ４ｂ are each independently H or halogen, and R １ｂ , R ２ｂ , R ３ｂ , R ４ｂ at least one of is a halogen; R ５ｂ is H or a halogen; R ６ｂ is H or C １ -C ３ is alkyl, X １ｂ and X ２ｂ are each independently CH or N, and X １ｂ and X ２ｂ at least one of is N; In the formula, each of L 【Chemistry 14】 indicates the point of attachment.

6. 6. The bifunctional compound of claim 1, 3, or 5, wherein the compound is a compound of formula (II-a), or a pharmaceutically acceptable salt thereof. 【Chemistry 15】

7. Q is 【Chemistry 16】 6. The bifunctional compound of claim 1, 2, or 5, wherein:

8. Y １ , Y ２ , and Y ３ 8. The bifunctional compound of claim 1, 2, 5, 6, or 7, or a pharmaceutically acceptable salt thereof, wherein each of is CH.

9. R １ is H or CH ３ 9. The bifunctional compound according to any one of claims 1, 2, 5, or 6 to 8, or a pharmaceutically acceptable salt thereof, wherein:

10. 10. The bifunctional compound of any one of claims 1, 2, 5, or 6-9, or a pharmaceutically acceptable salt thereof, wherein X is N.

11. R ２ 11. The bifunctional compound of any one of claims 1, 2, 5, or 6-10, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, or isopropyl.

12. R ３ 12. The bifunctional compound of any one of claims 1, 2, 5, or 6-11, or a pharmaceutically acceptable salt thereof, wherein each is independently H, methyl, fluoro, or methoxy.

13. R １ａ 10. The bifunctional compound of claim 1, 3, or 5, or a pharmaceutically acceptable salt thereof, wherein:

14. X ４ａ and X ６ａ 10. The bifunctional compound of claim 1, 3, or 5, or a pharmaceutically acceptable salt thereof, wherein each is N.

15. R ５ａ is CH ３ 7. The bifunctional compound of claim 1, 3, 5 or 6, wherein:

16. R ２ａ 7. The bifunctional compound of claim 1, 3, 5 or 6, or a pharmaceutically acceptable salt thereof, wherein

17. L 【Chemistry 17】 6. The bifunctional compound of claim 1, 4, or 5, wherein:

18. L [Chemistry 18] 6. The bifunctional compound of claim 1, 4, or 5, wherein:

19. L 【Chemistry 19】 6. The bifunctional compound of claim 1, 4, or 5, wherein:

20. A bifunctional compound selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

21. A bifunctional compound selected from any one of the compounds in Table 1.

22. A pharmaceutical composition comprising the bifunctional compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

23. 23. The pharmaceutical composition of claim 22, wherein the composition further comprises an effective amount of at least one additional anti-cancer agent.

24. 24. A method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of the bifunctional compound of any one of claims 1 to 21, or the pharmaceutical composition of claim 22 or 23.

25. 25. The method of any one of claims 24, further comprising administering to the subject in need thereof an effective amount of at least one additional anti-cancer agent.

26. The method of claim 24 or 25, wherein the disease or disorder is associated with aberrant BCL6 expression and / or activity.

27. 27. The method of claim 26, wherein the disease or disorder is cancer associated with aberrant BCL6 expression and / or activity.

28. The disease or disorder may be breast cancer, ovarian cancer, leukemia, lymphoma, benign lymphoma, malignant lymphoma, Burkitt's lymphoma, non-Hodgkin's lymphoma, B-cell non-Hodgkin's lymphoma, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, synovial sarcoma, meningeal sarcoma, carcinosarcoma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B acute lymphoblastic leukemia, pre-B lymphoma, B-cell lymphoma, 28. The method of any one of claims 24 to 27, wherein the cancer is selected from the group consisting of bronchial tumors, large B-cell lymphoma, diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive chronic myeloid leukemia (CML), follicular lymphoma, intravascular large B-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), T-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, non-small cell lung cancer, systemic lupus erythematosus (SLE), brain tumor, and central nervous system cancer.

29. 28. The method of any one of claims 24 to 27, wherein the disease or disorder is large B-cell lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, or angioimmunoblastic T-cell lymphoma (AITL).

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