Compounds for modulating RET protein

Abstract

The present disclosure relates to proteolysis-inducing compounds against the proto-oncogene tyrosine-protein kinase receptor (RET), which may be wild-type RET or mutant RET, useful in the treatment of diseases and disorders mediated by the RET protein, e.g., compounds of formula (I): TIFF2025525917000237.tif30160

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 370,307, filed August 3, 2022, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) The present disclosure relates to degrading compounds for the proto-oncogene tyrosine protein kinase receptor (RET) rearranged during transfection. The degrading compounds described herein are useful for treating diseases and disorders associated with the regulation of the RET protein, whether wild-type or mutant RET. In particular, the present invention relates to compounds and pharmaceutical compositions that degrade the proto-oncogene tyrosine protein kinase receptor (RET), whether wild-type or mutant RET, via the ubiquitin proteasome pathway (UPP), methods of using the compounds and pharmaceutical compositions to treat diseases and disorders associated with the RET protein and pathway, and methods for synthesizing the compounds and compositions. [Background technology]

[0003] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Damaged, misfolded, or excess proteins are selectively identified and eliminated via the ubiquitin-proteasome pathway (UPP). The UPP plays a central role in regulating almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neuronal and muscular degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels, and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection. Proteins undergo proteasomal degradation when E3 ubiquitin ligases covalently attach multiple ubiquitin molecules to terminal lysine residues, where they are digested into small peptides and ultimately into amino acids that serve as building blocks for new proteins. Defects in proteasomal degradation are associated with various diseases, including cancer.

[0004] Cereblon forms part of an E3 ubiquitin ligase complex that interacts with damaged DNA-binding protein 1, and together with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1), forms an E3 ubiquitin ligase complex where it functions as a substrate receptor, selecting proteins for ubiquitination. Binding of lenalidomide to cereblon promotes subsequent binding of cereblon to Ikaros and Aiolos, leading to ubiquitination and degradation by the proteasome (see Lu, G. et al. "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins" Science, 2014, 343:305-309; Kroenke, J. et al. "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells" Science, 2014, 343:301-305).

[0005] The cell surface tyrosine kinase receptor RET (rearranged during transfection), a proto-oncogene tyrosine protein kinase receptor, is widely known to play important roles in cell survival, differentiation, cell proliferation, migration, and chemotaxis. Germline missense and somatic mutations in RET cause medullary thyroid carcinoma (MTC) and neuroendocrine tumors, while RET fusion proteins, overexpression, and copy number gains are present in a wide range of cancers, including papillary thyroid carcinoma, pancreatic cancer, melanoma, leukemia, lung adenocarcinoma, and breast cancer (Liu Xuan et al., "RET kinase alterations in targeted cancer therapy," Cancer Drug Resist, 2020; and Mulligan LM., "RET revisited: expanding the oncogenic portfolio," Nat Rev Cancer, 2014, 14(3), 173-186).

[0006] Academic and clinical interest in RET has led to the identification of several clinically relevant RET mutations, such as RET G810R, RET G810S, and RET G810C (Solomon, et al., “RET Solvent Front Mutations Mediated Acquired Resistance to Selective RET Inhibition in RET-driven Malignancies”, J Thoracic Oncolog., 2020). Treatment of patients with non-small cell lung cancer with selpercatinib has been shown to induce resistance-conferring RET mutations (e.g., RET G810R, RET G810S, and RET G810C mutations).

[0007] Other approved tyrosine kinase inhibitors, such as sunitinib, sorafenib, ponatinib, and lenvatinib, have also demonstrated some RET activity in preclinical studies and are currently being investigated in a number of phase II clinical trials for the treatment of RET fusion-positive lung adenocarcinoma (LAD) (Song M., "Progress in Discovery of KIF5B-RET Kinase Inhibitors for Treatment of Non-Small-Cell Lung Cancer", J Med Chem., 2015, 58(9), 3672-3681; Watson AJ., et al., "Identification of Selective Inhibitors of RET and Comparison with Current Clinical Candidates Through Development and Validation of a Robust Screening Cascade", F1000Research 2016, 5:1005).

[0008] Despite these efforts, there remains an unmet need for new RET-modulating agents to treat RET-mediated disorders in hosts in need of treatment, including humans.

[0009] A first aspect of the present disclosure generally relates to compounds of Formula I, as described herein, and pharmaceutically acceptable salts, solvates, isomers, enantiomers, and tautomers thereof, which comprise a targeting ligand that binds to RET, an E3 ligase binding moiety (usually via a cereblon subunit), and a linker that covalently attaches the targeting ligand to the E3 ligase binding moiety.

[0010] A first aspect of the present disclosure is a compound of formula I: [ka] [In the formula, R1 is -OCH2CH3, -OCH3, -OCF3, -OCH2CH2OH, -OCH2CH2F, 1-methylpyrazol-4-yl or halogen; A is independently H, OH, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R2; wherein R2 is independently halogen, OH, C1-C3 alkyl, or C1-C3 alkoxy; B is a group capable of binding an E3 ligase; L1 is independently a bond, -C1-C3 alkylenyl-, -NHCO-, -CONH-, -O-, or -NH-; L2 is independent of -(CH2) p -(4-12-heterocycloalkyl)-Y1-C(O)-Y2-, -(CH2) p -(4-12-heterocycloalkyl)-C(O)-Y1-Y2-, -(CH2) p -(4-12-heterocycloalkyl)-C(O)-Y1-C(O)-Y2-, -(CH2) p -(4-12-heterocycloalkyl)-Y1-Y2-, -(OCH2CH2) p -(4-12-heterocycloalkyl)-Y-, -(CH2OCH2C(O)) p -(4-12-heterocycloalkyl)-Y-, -(CH2OCH2C(O)NH) p -Y2-, -(CH2) p -(4-12-heterocycloalkyl)-Y-(CHCHO) p -C(O)-Y2-, -(CH2) p -(4-12-heterocycloalkyl)-Y-(CHCHO) p -Y2-, -(CH2) p-(4-12-heterocycloalkyl)-Y1-(OCH2CH2) p -Y2-, -(CH2) p -(4-12-heterocycloalkyl)-Y1-(OCH2CH2) p -C(O)-(OCH2CH2) p -Y2-, -(CH2OCH2) p -(heteroaryl)-Y2-, —NHC(O)-(4-12-heterocycloalkyl)-Y1-C(O)-Y2-, -NHC(O)-(CH2) p -(4-12-heterocycloalkyl)-Y1-C(O)-Y2-, -NHC(O)-(CH2) p -(4-12-heterocycloalkyl)-Y-, -C(O)NH-Y1-Y2-; -(CH2) p -NH-Y1-Y2-; -C(O)NH-(CH2CH2O) p -Y2-, -C(O)-(CH2CH2O) p -Y2-, -(CH2OCH2) p -NR3C(O)-(CH2CH2O) p -Y2-, -(CH2) p -NR3C(O)-(CH2CH2O) p -Y2-, -(CH2OCH2CH2) p -(4-12-heterocycloalkyl)-Y-C(O)-(CHCHO) p -Y2- -(CH2OCH2) p -C(O)NH-(CH2CH2O) p -Y2-, where: R3 is -H or -C1-C3 alkyl; Y1 independently represents a bond, -C 1-8 Alkylenyl, 4-12 membered heterocycloalkyl or -C3-C 10is cycloalkyl; Y2 is independently join, -C1-C3 alkyl-, -(CH2) m -O-, -O-(CH2) m -(4- to 6-membered heterocycloalkyl), -(CH2) m -O-(CH2) m -NH-, -(CH2) m -NH-, -(CH2) m -NHC(O)-(CH2) m O-, -(CH2) m -C(O)NH-(CH2) m -, -(CH2) m -C3-C 10 cycloalkyl-, -(CH2) m -aryl, -(CH2) m -heteroaryl-, -(CH2) m -(4- to 6-membered heterocycloalkyl)-, -(CH2) m -(4- to 6-membered heterocycloalkyl)-C(O)-, -(CH2) m -(4-6 membered heterocycloalkyl)-C(O)-(CH2) m -, -(CH2) m -(4-6 membered heterocycloalkyl)-C(O)-(CH2) m -O-, -(CH2) m -C3-C 10 cycloalkyl-C(O)NH-, -(CH2) m -(4-6 membered heterocycloalkyl)-O-; X1 is CH or N; X2 is CH or N; m is independently an integer of 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. and pharmaceutically acceptable salts, solvates, isomers, enantiomers and tautomers thereof.

[0011] Another aspect of the present disclosure is a compound of formula II: [ka] [In the formula, R1 is -OCH2CH3, -OCH3, -OCF3, -OCH2CH2OH, -OCH2CH2F, 1-methylpyrazol-4-yl or halogen; A1 is independently aryl or heteroaryl, said aryl or heteroaryl being optionally substituted with one or more R2; wherein R2 is independently halogen, OH, C1-C3 alkyl, or C1-C3 alkoxy; B is a group capable of binding an E3 ligase; L4 is independent of -(CH2) p -(4-12-heterocycloalkyl)-Y1-C(O)-Y2-, -(CH2) p -(4-12-heterocycloalkyl)-C(O)-Y1-Y2-, -(CH2) p -(4-12-heterocycloalkyl)-Y1-Y2-, where: Y1 independently represents -C 1-8 Alkylenyl, 4-12 membered heterocycloalkyl or -C3-C 10 is cycloalkyl; Y2 is independently -C1-C3 alkyl-, -(CH2) m -O-, -O-(CH2) m -(4- to 6-membered heterocycloalkyl), -(CH2) m -(4- to 6-membered heterocycloalkyl)-, -(CH2) m -(4- to 6-membered heterocycloalkyl)-C(O)- or -(CH2) m -(4- to 6-membered heterocycloalkyl)-O-; L3 is a bond, -C 1-8 Alkylenyl, 4-8 membered heterocycloalkyl, -C3-C 10 Cycloalkyl or -(4-8 membered heterocycloalkyl)-(CH2) m - and; X1 is CH or N; X2 is CH or N; X7 is O, S, NH or a bond; m is independently an integer of 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. and pharmaceutically acceptable salts, solvates, isomers, enantiomers and tautomers thereof.

[0012] Another aspect of the present disclosure relates to a method of treating RET-mediated disorders and diseases in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or Formula II.

[0013] Another aspect of the present disclosure relates to a method for modulating RET protein, the method comprises administering to a patient in need of treatment an effective amount of a compound of formula I or formula II. In some embodiments, the method for treating RET-mediated disorders and diseases in a subject comprises modulating RET protein in the subject.

[0014] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a compound of Formula I or Formula II and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant. The pharmaceutical composition may be effective for treating a disease or disorder associated with RET regulation in a subject in need of treatment. The pharmaceutical composition may comprise a compound of the present invention used to treat the diseases described herein. The composition may comprise at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0015] Another aspect of the present disclosure relates to a compound of Formula I or Formula II, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease associated with RET modulation. The present invention also provides the use of a compound described herein in the manufacture of a medicament for treating a disease associated with RET.

[0016] The present invention also provides methods for treating diseases or disorders by degrading RET using the present compounds of Formula I or Formula II and pharmaceutically acceptable compositions of the compounds of Formula I or Formula II. The present invention also provides compounds of Formula I or Formula II that bind to and inhibit E3 ligase, further degrading the RET protein. These E3 ligase-binding compounds (degrading compounds) are also useful in treating RET-mediated diseases and cancers, including Hirschsprung's disease, medullary thyroid carcinoma (MTC), thyroid cancer, familial medullary thyroid carcinoma, multiple endocrine neoplasia, multiple endocrine neoplasia type 2 (MEN-2, MEN-2A, MEN-2B), neuroendocrine tumors, central nervous system tumors, central hypoventilation syndrome, renal failure, pheochromocytoma, parathyroid hyperplasia, and non-small cell lung cancer.

[0017] The present invention further provides compounds that can degrade RET while bound to E3 ligase. In some embodiments, the efficacy-safety profile of the compounds of the present disclosure can be improved compared to other known RET inhibitors. Compared with conventional treatments using RET-binding ligands, the compounds of the present invention can provide multiple advantages, such as overcoming resistance in certain cases and prolonging the kinetics of drug efficacy by disrupting proteins.

[0018] Furthermore, the present technology has the advantage that it can be used in many different types of diseases, including disorders mediated by fusion proteins, overexpression or copy number gain of RET, such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, acute myeloid leukemia (AML), chronic myelomonocytic leukemia, lung adenocarcinoma, lung cancer, non-small cell lung cancer (NSCLC), non-syndromic paraganglioma, breast cancer, non-hereditary (sporadic) cancer, colon cancer or hematological malignancies. Other features and advantages of the present invention will be apparent to those skilled in the art upon reading the "Detailed Description of the Invention" below. Detailed Description of the Invention

[0019] The present disclosure relates to RET degrading compounds of Formula I or Formula II, as well as pharmaceutically acceptable salts, solvates, hydrates, isomers, and tautomers thereof, which are capable of inhibiting E3 ligase activity and, thereby, are useful in methods of treating the human or animal body. The disclosure also relates to methods for making these compounds, pharmaceutical compositions containing them, and their use in treating disorders and diseases in which RET is implicated, such as inflammation, autoimmune diseases, cancer, infectious diseases, diseases or disorders of the central nervous system, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, psychiatric diseases, graft-versus-host disease, allodynia, or RET-associated diseases in subjects determined to have a germline or somatic mutation in RET.

[0020] definition Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0021] As used herein, the term "alkyl" refers to optionally substituted straight- and branched-chain aliphatic groups having 1 to 30 carbon atoms. "C1, C2, C3, C4, C5, or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include, but are not limited to, groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In certain embodiments, a straight chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in other embodiments, a straight chain or branched alkyl has 4 or fewer carbon atoms. As used herein, the term "heteroalkyl" intends an alkyl having one or more heteroatoms.

[0022] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0023] As used herein, the term "alkenyl" refers to unsaturated aliphatic groups analogous in chain length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, a straight-chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0024] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0025] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in chain length and possible substitution to the alkyls described above, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonyl, decynyl) and branched alkynyl groups. In certain embodiments, a straight-chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0026] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0027] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0028] As used herein, the term "cyano" refers to a nitrile group (eg, --CN).

[0029] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of a polycyclic cycloalkyl, only one of the rings of the cycloalkyl must be non-aromatic.

[0030] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3- to 8-membered monocyclic or bicyclic, 7- to 12-membered bicyclic (fused, bridged, spiro) or 11- to 14-membered tricyclic ring system (fused, bridged, spiro) having one or more heteroatoms (e.g., O, N, S, P, or Se), for example, 1, 1-2, 1-3, 1-4, 1-5, or 1-6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless otherwise specified.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepam, 1,4-di ... nyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuranyl]-yl, 7'H-spiro[cyclohexane -1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3- d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like.In the case of polycyclic heterocycloalkyls, only one of the rings of the heterocycloalkyl must be non-aromatic (eg, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0031] As used herein, the term "optionally substituted heterocycloalkyl" refers to an unsubstituted heterocycloalkyl or a substituted heterocycloalkyl having specified substituents replacing one or more hydrogen atoms on one or more carbon or heteroatoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0032] Unless otherwise specified, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, naphthyl, etc. When two aromatic rings are included (e.g., bicyclic), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). An aryl group can be optionally substituted with one or more substituents, for example, 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). The substituents may themselves be optionally substituted. Furthermore, when containing two or more fused rings, aryl groups as defined herein can have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.

[0033] Unless otherwise specified, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. Heteroaryl, as defined herein, also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl, as defined herein, also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, wherein the aromatic groups are optionally substituted independently with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinium, and the like. nyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indo Linyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolinyl pyrrolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-pyrrolo[2,[1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridinyl thiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when comprising two or more fused rings, a heteroaryl group as defined herein can be one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, such as a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered aromatic heterocycle containing 1 to 3 nitrogen atoms, wherein the saturated or partially unsaturated ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se, or B and is optionally substituted with one or more oxygen atoms. In heteroaryl ring systems comprising two or more fused rings, the saturated or partially unsaturated ring may be further fused to a saturated or partially unsaturated ring as defined herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-11H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl or benzo[c][1,2]oxaborol-1(3H)-olyl.

[0034] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have at one or more ring positions (e.g., a ring-forming carbon or heteroatom such as N) such substituents as those described above, e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aryl The aryl and heteroaryl groups may be substituted with aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0035] When a substituent is shown to have a bond across the bond connecting two atoms in a ring, such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom through which it is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom in the formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0036] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is indicated as substituted with 0 to 2 R, then said group can be optionally substituted with up to two R groups, and each R is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0037] As used herein, the term "hydroxy" or "hydroxyl" includes groups with an --OH or --O-- group.

[0038] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0039] The terms "haloalkyl" or "haloalkoxyl" refer to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0040] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl or a haloalkyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0041] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0042] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a group selected from a given group, provided that the replacement does not exceed the normal valence of the designated atom and that the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents do not occur in aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" refer to a compound that can be isolated from an RM to a useful degree of purity and subsequently formulated into an effective therapeutic agent.

[0043] It is understood that the present disclosure provides methods for synthesizing compounds of any of the formulas described herein. The present disclosure also provides detailed methods for synthesizing various disclosed compounds of the present disclosure according to the following schemes, as well as those shown in the Examples.

[0044] It should be understood that throughout this specification, when a composition is described as having, comprising, or consisting of certain components, it is contemplated that the composition also consists essentially of, or consists of, the recited components. Similarly, when a method or process is described as having, comprising, or consisting of certain process steps, the steps also consist essentially of, or consist of, the recited process steps. Furthermore, it should be understood that the order of steps or order of performing certain operations is immaterial so long as the invention remains operable. Moreover, two or more steps or operations can be conducted simultaneously.

[0045] It will be understood that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups, and thus variously substituted starting materials can be used. The steps generally yield the desired final compound at or near the end of the overall process, although in certain instances it may be desirable to further convert the compound to a pharmaceutically acceptable salt thereof.

[0046] It will be understood that the compounds of the present disclosure may be prepared in a variety of ways from commercially available starting materials, compounds known in the literature, or readily prepared intermediates by employing standard synthetic methods and procedures that are known or will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods or procedures for the preparation of organic molecules or functional group transformations or manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Citations, including but not limited to, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), which are incorporated herein by reference, are useful and well-known references in organic synthesis known to those skilled in the art.

[0047] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups must be protected from reaction conditions using protecting groups. Protecting groups are used to distinguish between similar functional groups within a molecule. A list of protecting groups and methods for their introduction and removal can be found in Greene, TW, Wuts, PGM, Protective Grout in Organic Synthesis, 3rd edition. John Wiley & Sons. New York, 1999.

[0048] Unless otherwise specified, reference to a method of treatment or prevention will be understood to include the use of the compounds to provide treatment or prevention as described herein. Furthermore, unless otherwise specified, reference to a method of treatment or prevention will be understood to include the use of the compounds for the manufacture of a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0049] Unless otherwise specified, it is understood that references to methods of treatment include the use of compounds to provide treatment as described herein. Furthermore, unless otherwise specified, it is understood that references to methods of treatment include the use of compounds to manufacture a medicament for treating such a condition. Treatment also includes the treatment of humans or non-human animals, including rodents and other disease models. As used herein, the term "subject" is interchangeable with the term "subject in need of treatment," and both refer to a subject having a disease or at increased risk of developing a disease. "Subject" also includes mammals. A mammal is, for example, a human or a suitable non-human mammal (e.g., a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig). In one embodiment, the mammal is a human. A subject in need of treatment may be one who has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need of treatment may also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need of treatment may be at increased risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject who has a predisposition to developing such a disorder compared to the population as a whole). The subject may be resistant to treatment at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need of treatment has failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, a subject in need of treatment has undergone at least one prior therapy.

[0050] As used herein, the term "treatment" or "treating" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, characterized by administering a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treating" also includes the treatment of cells in vitro or in animal models. It is understood that "treating" or "treatment" includes the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a disease state, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of an existing disease state, disorder, or condition in a person suffering from or predisposed to suffering from the disease state, disorder, or condition but who has not yet experienced or displayed clinical or subclinical symptoms of the disease state, disorder, or condition; (2) inhibiting the disease state, disorder, or condition, i.e., preventing, reducing, or delaying the disease or its recurrence (in the case of maintenance therapy) or the onset of at least one clinical or subclinical symptom; or (3) palliating or attenuating the disease, i.e., causing regression of the disease state, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0051] It will be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, can also be used to prevent the associated disease, condition or disorder, or to identify suitable candidate substances for that purpose.

[0052] As used herein, the terms "prevention," "preventing," or "protection against" refer to reducing or eliminating the onset of symptoms or complications of such diseases, conditions, or disorders.

[0053] Those skilled in the art will appreciate that they can refer to the general references for detailed descriptions of the known technologies discussed herein or equivalent technologies. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005), Sambrook et al., Molecular Cloning, A Laboratory Manual 3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis in rapeutics (1975), Remington, Inc: Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). Of course, these texts may also be referenced when making or using an embodiment of the present disclosure.

[0054] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0055] As used herein, the term "pharmaceutical composition" refers to a formulation comprising a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk form or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an infusion bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose of composition is an effective amount and will vary depending on the particular treatment involved. Those skilled in the art will appreciate that routine variations in dosage may be necessary depending on the age and condition of the patient. Dosages will also vary depending on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, nasal, and the like. Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and any needed preservatives, buffers, or propellants.

[0056] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0057] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that is generally safe, non-toxic, and useful in preparing pharmaceutical compositions that are biologically and otherwise acceptable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0058] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral administration, e.g., intravenous administration, intradermal administration, subcutaneous administration, oral administration (e.g., ingestion), inhalation administration, transdermal administration (topical administration), transmucosal administration, etc. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can contain the following components: a sterile diluent, e.g., water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent, e.g., benzyl alcohol or methylparaben; an antioxidant, e.g., ascorbic acid or sodium bisulfate; a chelating agent, e.g., ethylenediaminetetraacetic acid; a buffer, e.g., acetate, citrate, or phosphate; and an agent for adjusting tonicity, e.g., sodium chloride or glucose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

[0059] It will be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapy treatment.For example, the compound of the present disclosure can be injected into blood or body cavity, or taken orally, or administered through the skin using a patch.The dosage should be sufficient to provide effective treatment, but not so high as to cause unacceptable side effects.The pathology of the disease state (e.g., the disease or disorder disclosed herein) and the health status of the patient should preferably be carefully monitored during and for a reasonable period after treatment.

[0060] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, health, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents being administered. The therapeutically effective amount for a given situation can be determined by routine testing, within the skill and judgment of the clinician.

[0061] It should be understood that for any compound, the therapeutically effective amount can be estimated initially using cell culture assays (e.g., tumor cells) or animal models (usually in rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can be used to determine useful doses and routes of administration for human administration. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions exhibiting a high therapeutic index are preferred. Dosages can vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0062] Dosage and administration may be adjusted to provide adequate levels of the active substance or to maintain the desired effect, taking into account factors such as the severity of the disease, the patient's general health, age, weight, sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to treatment.

[0063] The pharmaceutical composition containing the active compound of the present disclosure can be prepared by generally known methods, for example, conventional mixing, dissolving, granulating, sugar-coating, powdering, emulsifying, encapsulating, encapsulating or lyophilizing processes.The pharmaceutical composition can be prepared by conventional methods using one or more pharmaceutically acceptable carriers, including excipients and / or auxiliary agents that facilitate the processing of the active compound into pharmaceutical preparations.The appropriate formulation depends on the selected route of administration.

[0064] 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. Carriers suitable for intravenous administration 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. The composition must be stable under the conditions of manufacture and storage and must be 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, polyalcohols (such as sugars, mannitol, and sorbitol), and sodium chloride in the composition. The absorption of injectable compositions can be prolonged by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

[0065] Sterile injectable solution can be prepared by mixing the required amount of active compound in a suitable solvent with one or a combination of the above-listed ingredients as needed, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle containing a basic dispersion medium and the other necessary ingredients from the above-listed ingredients.For the preparation of sterile powder for preparing sterile injectable solution, the preparation method is vacuum drying and freeze-drying, and obtains a powder of active ingredient and any additional desired ingredients from the solution previously sterile-filtered.

[0066] Oral compositions generally contain an inert diluent or edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or compressed into tablets.For oral therapeutic purposes, the active compound can be combined with an excipient and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a liquid carrier for use as a mouthwash, in which case the compound in the liquid carrier is administered to the mouth and rinsed, 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 or compounds of a similar nature: 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 or sterotate; a lubricant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavor.

[0067] For administration by inhalation, the 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.

[0068] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, for example, for transmucosal administration, surfactants, bile salts and fusidic acid derivatives are used.For transmucosal administration, nasal sprays or suppositories can be used.For transdermal administration, active compound is formulated into ointments, salves, gels or creams as is generally known in the art.

[0069] The active compounds can be prepared with pharmaceutically acceptable carriers that prevent rapid elimination of the compound from the body, such as sustained-release formulations, e.g., implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells using 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.

[0070] Oral or parenteral compositions are particularly advantageously formulated in dosage unit form for ease of administration and uniform dosage.Dosage unit form as used herein refers to a physically separate unit suitable as a unitary dosage for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.The dosage form of the present disclosure is determined and directly depends on the inherent properties of active compound and the specific therapeutic effect to be achieved.

[0071] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors that influence the selected dosage. Generally, the dosage should be sufficient to delay, preferably regress, and more preferably cause complete regression of the symptoms of the diseases or disorders disclosed herein. Dosages range from about 0.01 mg / kg to about 5000 mg / kg per day. An effective amount of a pharmaceutical agent is an amount that produces an objectively identifiable improvement, as noted by a clinician or other competent individual. Improvements in survival and growth rates refer to regression. As used herein, the term "effective dosage" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0072] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0073] It is understood that the compounds of the present disclosure may further form salts, and therefore all of these forms are within the scope of the present claimed disclosure.

[0074] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, where the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, the conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, and the like. The salts include, but are not limited to, inorganic or organic salts selected from: acetic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids (e.g., glycine, alanine, phenylalanine, arginine, etc.).

[0075] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonia salt, arginine salt, or lysine salt.

[0076] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced with a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). It is understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1 or any ratio other than 1:1 (eg, 3:1, 2:1, 1:2, or 1:3).

[0077] It should be understood that a reference to a pharmaceutically acceptable salt includes any solvent addition forms (solvates) or crystal forms (polymorphs) of the same salt, all as defined herein.

[0078] The compound or its pharmaceutically acceptable salt can be administered orally, intranasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally and parenterally.In one embodiment, the compound is administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0079] The dosage regimen utilizing the compound is selected according to various factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition to be treated, the route of administration; the patient's renal and hepatic function; and the specific compound or its salt employed.Any ordinary skilled physician or veterinarian can easily determine and prescribe the effective amount of the drug required to prevent, eliminate, or stop the progression of the condition.Any ordinary skilled physician or veterinarian can easily determine and prescribe the effective amount of the drug required to eliminate or stop the progression of the condition.

[0080] Techniques for formulating and administering the compounds of the present disclosure are described in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co, Easton, Pa. (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage in the range described herein.

[0081] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methodologies useful in practicing the present disclosure. The examples do not limit the disclosure of the claims. Based on the present disclosure, one skilled in the art will be able to identify and employ other components and methodologies useful in practicing the present disclosure.

[0082] In the synthetic schemes described herein, for simplicity, compounds may be depicted in one particular configuration. Such a particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers, but it will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0083] All publications and patent documents cited herein are incorporated by reference as if such publications or documents were specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not an admission that any is pertinent prior art, nor is it an admission as to the content or age of any such publication or patent document. While the invention has been described in writing above, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the following foregoing description and examples are illustrative only and do not limit the scope of the claims appended hereto.

[0084] As used herein, the phrases "compounds of the present disclosure," "degradation compounds of the present disclosure," and "degradation compounds" refer both generally and specifically to compounds disclosed herein.

[0085] Compounds of the Disclosure In one aspect, the present disclosure provides a compound of formula (I): [ka] wherein A, B, L1, L2, R1, X1, X2, and n are as described herein as set forth in this disclosure. and pharmaceutically acceptable salts, solvates, hydrates, isomers or tautomers thereof.

[0086] In some embodiments, the present disclosure provides a compound of formula I(a): [ka] (wherein HetA is a 4- to 6-membered heterocycloalkyl) The present invention relates to the compound

[0087] In other embodiments, compounds of the present disclosure have Formula I(b): [ka] (wherein HetA is a 4- to 6-membered heterocycloalkyl) is.

[0088] In other embodiments, compounds of the present disclosure have formula I(c): [ka] (wherein HetA is a 4- to 6-membered heterocycloalkyl) is.

[0089] In other embodiments, compounds of the present disclosure have formula I(d): [ka] (wherein HetA is a 4- to 6-membered heterocycloalkyl) is.

[0090] In other embodiments, compounds of the present disclosure have formula I(e): [ka] (wherein HetA is a 4- to 6-membered heterocycloalkyl) is.

[0091] In yet another embodiment, the compounds of the present disclosure have formula I(f): [ka] (wherein HetA is a 4- to 6-membered heterocycloalkyl) is.

[0092] In other embodiments, compounds of the present disclosure have formula I(g): [ka] is.

[0093] In other embodiments, compounds of the present disclosure have formula I(h): [ka] is.

[0094] In other embodiments, compounds of the present disclosure have Formula II: [ka] is.

[0095] In some embodiments of the compounds of the present disclosure, R1 is halogen, -OCH2CH3, -OCF3, -OCH2CH2OH, or -OCH2CH2F. In some embodiments, R1 can be halogen, -OCH2CH3, -OCF3, or -OCH2CH2OH. In some embodiments, R1 can be halogen, -OCH2CH3, or -OCF3. In some embodiments, R1 can be halogen or -OCH2CH3. In some embodiments, R1 is halogen. In some embodiments, R1 is -OCH2CH3. In some embodiments, R1 is -OCF3. In some embodiments, R1 is -OCH2CH2OH. In some embodiments, R1 is -OCH3. In some embodiments, R1 is 1-methyl-pyrazol-4-yl.

[0096] In certain embodiments of the compounds of the present disclosure, A is H, OH, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heteroaryl. In other embodiments, A is OH, C1-C6 alkyl, C3-C8 cycloalkyl, or aryl. In other embodiments, A is OH, C1-C6 alkyl, or C3-C8 cycloalkyl. In other embodiments, A is OH or C1-C6 alkyl. In other embodiments, A is OH. In other embodiments, A is C1-C6 alkyl. In other embodiments, A is C3-C8 cycloalkyl. In other embodiments, A is aryl. In other embodiments, A is heteroaryl. In other embodiments, A is C1-C6 alkyl optionally substituted with one or more R2. In other embodiments, A is C3-C8 cycloalkyl optionally substituted with one or more R2. In other embodiments, A is aryl optionally substituted with one or more R2. In other embodiments, A is heteroaryl optionally substituted with one or more R2.

[0097] In some embodiments of the compounds of the present disclosure, A is aryl or heteroaryl. In other embodiments, A is aryl optionally substituted with one or more R. In other embodiments, A is heteroaryl optionally substituted with one or more R.

[0098] In some embodiments, R2 is halogen, OH, C1-C3 alkyl, or C1-C3 alkoxy. In other embodiments, R2 is halogen. In other embodiments, R2 is OH. In other embodiments, R2 is C1-C3 alkyl. In other embodiments, R2 is C1-C3 alkoxy. In other embodiments, A is H.

[0099] In some embodiments of the compounds of the present disclosure, L is a bond, -C1-C3 alkylenyl-, -NHCO-, -CONH-, -O-, or -NH-. In further embodiments, L can be -C1-C3 alkylenyl-, -NHCO-, -CONH-, or -O-. In further embodiments, L can be -C1-C3 alkylenyl-, -NHCO-, or -CONH-. In further embodiments, L can be -C1-C3 alkylenyl- or -NHCO-. In further embodiments, L can be -C1-C3 alkylenyl-. In still further embodiments, L can be -NHCO-. In still further embodiments, L can be -CONH-. In still further embodiments, L can be -O-. Yet, in still further embodiments, L can be -NH-. In still further embodiments, L can be a bond.

[0100] In certain embodiments of the compounds of the present disclosure, L2 is independently -(CH2) p -(4-12-heterocycloalkyl)-Y1-C(O)-Y2-.

[0101] In certain embodiments, L2 is -(CH2) p -(4-12-heterocycloalkyl)-C(O)-Y1-Y2-.

[0102] In some embodiments, L2 is -(CH2) p -(4-12-heterocycloalkyl)-C(O)-Y1-C(O)-Y2-.

[0103] In some embodiments, L2 is -(CH2) p -(4-12-heterocycloalkyl)-Y1-Y2-.

[0104] In certain embodiments, L2 is -(OCH2CH2) p -(4-12-heterocycloalkyl)-Y2-.

[0105] In certain embodiments, L2 is -(CH2OCH2C(O)) p -(4-12-heterocycloalkyl)-Y2-.

[0106] In certain embodiments, L2 is -(CH2OCH2C(O)NH) p -Y2-.

[0107] In some embodiments, L2 is -(CH2) p -(4-12-heterocycloalkyl)-Y-(CHCHO) p -C(O)-Y2-.

[0108] In some embodiments, L2 is -(CH2) p -(4-12-heterocycloalkyl)-Y-(CHCHO) p -Y2-.

[0109] In some embodiments, L2 is -(CH2) p -(4-12-heterocycloalkyl)-Y1-(OCH2CH2) p -Y2-.

[0110] In some embodiments, L2 is -(CH2) p -(4-12-heterocycloalkyl)-Y1-(OCH2CH2) p -C(O)-(OCH2CH2) p -Y2-.

[0111] In certain embodiments, L2 is -(CH2OCH2) p -(heteroaryl)-Y2-.

[0112] In certain embodiments, L2 is -NHC(O)-(4-12-heterocycloalkyl)-Y1-C(O)-Y2-.

[0113] In certain embodiments, L2 is -NHC(O)-(CH2) p-(4-12-heterocycloalkyl)-Y1-C(O)-Y2-.

[0114] In some embodiments, L2 is -NHC(O)-(CH2) p -(4-12-heterocycloalkyl)-Y2-.

[0115] In some embodiments, L2 is -C(O)NH-Y1-Y2-.

[0116] In some embodiments, L2 is -(CH2) p -NH-Y1-Y2-.

[0117] In certain embodiments, L2 is -C(O)NH-(CH2CH2O) p -Y2-.

[0118] In certain embodiments, L2 is -(CH2OCH2) p -NR3C(O)-(CH2CH2O) p -Y2-.

[0119] In some embodiments, L2 is -(CH2) p -NR3C(O)-(CH2CH2O) p -Y2-.

[0120] In some embodiments, L2 is -(CH2OCH2CH2) p -(4-12-heterocycloalkyl)-Y-C(O)-(CHCHO) p -Y2-.

[0121] In some embodiments, L2 is -(CH2OCH2) p -C(O)NH-(CH2CH2O) p -Y2-.

[0122] In some embodiments, L3 is a bond, -C 1-8 Alkylenyl, 4-12 membered heterocycloalkyl, -C3-C10 Cycloalkyl or -(4-8 membered heterocycloalkyl)-(CH2) m In some embodiments, L3 is a bond. In some embodiments, L3 is -C 1-8 In some embodiments, L3 is -C3-C alkylenyl. In some embodiments, L3 is 4-8 membered heterocycloalkyl. In some embodiments, L3 is -C3-C 10 In some embodiments, L3 is -(4- to 8-membered heterocycloalkyl)-(CH2). m -It is.

[0123] In certain embodiments of the compounds of the present disclosure, L4 is -(CH2) p -(4-12-heterocycloalkyl)-Y1-C(O)-Y2-.

[0124] In certain embodiments of the compounds of the present disclosure, L4 is -(CH2) p -(4-12-heterocycloalkyl)-C(O)-Y1-Y2-.

[0125] In certain embodiments of the compounds of the present disclosure, L4 is -(CH2) p -(4-12-heterocycloalkyl)-Y1-Y2-.

[0126] In further embodiments of the disclosed compounds, R3 is -H or -C1-C3 alkyl. In yet other embodiments, R3 is -H. In yet other embodiments, R3 is -C1-C3 alkyl.

[0127] In some embodiments of the present disclosure, Y1 is a bond, -C 1-8 Alkylenyl, 4-12 membered heterocycloalkyl or -C3-C 10 In some embodiments, Y is a single bond. In other embodiments, Y is C 1-8 In another embodiment, Y is alkylenyl. In another embodiment, Y is 4-12 membered heterocycloalkyl. In another embodiment, Y is -C10 It is cycloalkyl.

[0128] In further embodiments of the compounds of the present disclosure, Y2 can be a single bond.

[0129] In a further embodiment of the present disclosure, Y2 is -C1-C3 alkyl-.

[0130] In yet another embodiment of the present disclosure, Y2 is -(CH2) m -O-.

[0131] In another embodiment of the present disclosure, Y2 is -O-(CH2) m -(4- to 6-membered heterocycloalkyl)-.

[0132] In another embodiment of the present disclosure, Y2 is -(CH2) m -O-(CH2) m -NH-.

[0133] In another embodiment of the present disclosure, Y2 is -(CH2) m -NH-.

[0134] In another embodiment of the present disclosure, Y2 is -(CH2) m -NHC(O)-(CH2) m It is O-.

[0135] In some embodiments of the present disclosure, Y2 is -(CH2) m -C(O)NH-(CH2) m -It is.

[0136] In some embodiments of the present disclosure, Y2 is -(CH2) m -C3-C 10 It is cycloalkyl-.

[0137] In some embodiments of the present disclosure, Y2 is -(CH2) m -aryl-.

[0138] In some embodiments of the present disclosure, Y2 is -(CH2) m -heteroaryl-.

[0139] In some embodiments of the present disclosure, Y2 is -(CH2) m -(4- to 6-membered heterocycloalkyl)-.

[0140] In some embodiments of the present disclosure, Y2 is -(CH2) m -(4- to 6-membered heterocycloalkyl)-C(O)-.

[0141] In some embodiments of the present disclosure, Y2 is -(CH2) m -(4-6 membered heterocycloalkyl)-C(O)-(CH2) m -It is.

[0142] In another embodiment of the present disclosure, Y2 is -(CH2) m -(4-6 membered heterocycloalkyl)-C(O)-(CH2) m -O-.

[0143] In another embodiment of the present disclosure, Y2 is -(CH2) m -C3-C 10 It is cycloalkyl-C(O)NH-.

[0144] In another embodiment of the present disclosure, Y2 is -(CH2) m -(4- to 6-membered heterocycloalkyl)-O-.

[0145] In another embodiment of the present disclosure, X 1 is CH or N. In some embodiments, X 1 is CH. In some embodiments, X 1 is N.

[0146] In another embodiment of the disclosure, X2 is CH or N. In some embodiments, X2 is CH. In some embodiments, X2 is N.

[0147] In another embodiment of the present disclosure, X7 is O, S, NH, or a bond. In some embodiments, X7 is O. In some embodiments, X7 is S. In some embodiments, X7 is NH. In some embodiments, X7 is a bond.

[0148] In further embodiments of the compounds of the present disclosure, each m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In some embodiments, m is independently 0. In some embodiments, m is independently 1. In some embodiments, m is independently 2. In some embodiments, m is independently 3. In some embodiments, m is independently 4. In some embodiments, m is independently 5. In some embodiments, m is independently 6. In some embodiments, m is independently 7. In some embodiments, m is independently 8. In some embodiments, m is independently 9. In some embodiments, m is independently 10. In some embodiments, m is independently 11. In some embodiments, m is independently 2. In some embodiments, m is independently 13. In some embodiments, m is independently 14. In some embodiments, m is independently 15. In some embodiments, m is independently 16.

[0149] In still other embodiments of the present disclosure, n is, independently at each occurrence, 0, 1, or 2. In yet other embodiments, n is 0 or 1. In yet other embodiments, n is 0 or 2. In yet other embodiments, n is 1 or 2. In yet other embodiments, n is 0. In yet other embodiments, n is 1. In yet other embodiments, n is 2.

[0150] In still other embodiments of the present disclosure, p, at each occurrence, is independently 0, 1, 2, or 3. In yet other embodiments, p is 1 or 2. In yet other embodiments, p is 1 or 3. In yet other embodiments, p is 2 or 3. In yet other embodiments, p is 1. In yet other embodiments, p is 2. In yet other embodiments, p is 3. In still other embodiments, p is 0.

[0151] In yet another embodiment of the present disclosure, B represents a group capable of binding an E3 ligase. In some embodiments, the E3 ligase binding moiety B is of the following structure: [ka]

[0152] In other embodiments, the E3 ligase binding group B has the following structure: [ka]

[0153] In other embodiments, the E3 ligase binding group B is a cereblon subunit. In further embodiments, the cereblon subunit may have the following general structure: [ka] wherein X3, X4, X5 and X6 are independently N or CH.

[0154] In further embodiments, the cereblon subunit may have the following general structure: [ka] wherein X3, X4, X5 and X6 are independently N or CH.

[0155] In other embodiments, suitable compounds of the present disclosure include: N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6 dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}pentanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)heptanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[9-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)nonanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[5-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)pentanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)heptanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[11-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)undecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[13-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)tridecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[15-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)pentadecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]butylamino]-2-oxo-ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]propanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]propanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[5-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pentanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[6-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexylamino]-2-oxo-ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(6-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)hexanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[1-[6-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexyl]triazol-4-yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[1-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]butyl]triazol-4-yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]ethyl]triazol-4-yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperazine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperidine-4-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperazin-1-yl]acetamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-2-[1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]-4-piperidyl]acetamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a-pyridin-4-yl)-2-pyridyl]-4-piperidyl]-4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]methyl]piperidine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-4-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]piperidine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]methyl]-1-piperidyl]acetamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(1-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}azetidin-3-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]azetidin-3-yl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbonyl]azetidin-3-yl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)azetidin-3-yl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[4-benzyl-1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)piperidin-4-yl]-1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperidine-4-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-1-fluorocyclopropane-1-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutane-1-carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)azetidin-3-yl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-N-(2-methylpropyl)piperidine-4-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(3-methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (S)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)spiro[3.3]heptane-2-carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; 6-(4-{[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)piperidin-4-yl]methyl}piperazine-1-carbonyl)-N-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]spiro[3.3]heptane-2-carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propanoyl)-3,9-diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)-3,9-diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[6-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)-2,6-diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{9-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9-diazaspiro[5.5]undecan-3-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{9-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9-diazaspiro[5.5]undecan-3-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-1-carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({9-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]-3,9-diazaspiro[5.5]undecan-3-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[6-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)-2,6-diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(9-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}-3,9-diazaspiro[5.5]undecan-3-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)-3,9-diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3-oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(2-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}ethoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(2-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(2-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}ethoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]piperidin-4-yl}methyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]acetyl}piperidin-4-yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperidin-4-yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperidin-4-yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]methyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}piperidin-1-yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]azetidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}azetidin-1-yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(methylamino)methyl]piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-7-yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-7-yl]amino}decyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(8-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}octyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}decyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)propanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2-yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; (S)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; or N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide.

[0156] In other embodiments, suitable compounds of the present disclosure include: 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}pentanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; or 6-{[1-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}heptanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile.

[0157] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described herein.

[0158] In some embodiments, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0159] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, as well as prodrugs and pharmaceutically acceptable salts thereof.

[0160] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 and pharmaceutically acceptable salts thereof.

[0161] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 1 and pharmaceutically acceptable salts thereof.

[0162] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0163] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting isotopically labeled reagents for non-isotopically labeled reagents by practicing the methods disclosed in the schemes and / or examples described herein.

[0164] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0165] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0166] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., enriched with or labeled with one or more atoms selected from S and S). 2 In some embodiments, the compound is 18 In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 I-labeled compounds, or any combination thereof. In some embodiments, the compounds are 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds or any combination thereof.

[0167] F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36S-labeled compounds can be prepared using any of a variety of techniques recognized by those skilled in the art. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples set forth herein, 18 F, 125 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 The compounds can be prepared by carrying out the procedures disclosed in the embodiments and / or examples described herein using S-labeled reagents in place of non-isotopically labeled reagents.

[0168] A compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and 36 S atom(s) are within the scope of the present invention. Additionally, substitution with isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S) may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage.

[0169] For the avoidance of doubt, where a group is identified herein by "as described herein," that group is to be understood to include the broadest definition first appearing and each and every specific definition associated with that group.

[0170] Suitable pharmaceutically acceptable salts of compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as, for example, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. In addition, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium salts, potassium salts, alkaline earth metal salts, such as calcium salts, magnesium salts, ammonium salts, or salts with organic bases that yield a pharmaceutically acceptable cation (e.g., salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine).

[0171] It will be understood that the compounds of any one of the formulae disclosed herein and their pharmaceutically acceptable salts include stereoisomers, mixtures of stereoisomers, and all isomeric polymorphs of said compounds.

[0172] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers," or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers of opposite chirality is called a "racemic mixture."

[0173] As used herein, the term "chiral center" refers to a carbon atom bonded to four non-identical substituents.

[0174] As used herein, the term "chiral isomer" refers to a compound that has at least one chiral center. Compounds with more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Cahn-Ingold-Prelog precedence rules (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413. Cahn and Ingold, J. Chem Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0175] As used herein, the term "geometric isomer" refers to diastereomers resulting from restricted rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These conformations are distinguished in compound names by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or opposite sides of a double bond in the molecule according to the Cahn-Ingold-Prelog precedence rules.

[0176] It is understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers, and when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomer, and it is understood that not all isomers have the same level of activity.

[0177] It is understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof, and it is also understood that not all atropisomers have the same level of activity.

[0178] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. This conversion involves the formal migration of a hydrogen atom accompanied by the interchange of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solutions where tautomerization is possible, the tautomers reach chemical equilibrium. The exact ratio of tautomers varies depending on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert via tautomerization is called tautomerism. While various types of tautomerism are possible, two are commonly observed: keto-enol tautomerism, in which electron and hydrogen atom shifts occur simultaneously; and ring-chain tautomerism, which occurs when an aldehyde group (-CHO) in a sugar molecule reacts with a hydroxyl group (-OH) in the same molecule, resulting in a cyclic (ring-like) configuration, such as that exhibited by glucose.

[0179] It should be understood that the compounds of the present disclosure may be depicted as different tautomers. Also, if a compound has tautomers, it should be understood that all tautomers are intended to be included within the scope of the present disclosure, and that the name of the compound does not exclude any tautomers. It will be understood that certain tautomers may be more active than others.

[0180] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the Cahn-Ingold-Prelog R- and S-sequencing rules or the way the molecule rotates the plane of polarized light, and are designated as dextrorotatory (dextrorotatory) or levorotatory (levorotatory) (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures of them. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0181] The compounds of the present disclosure may have one or more asymmetric centers, and such compounds can be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to encompass both individual enantiomers and mixtures, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers (e.g., by synthesis from optically active starting materials or by separation of racemates) are well known in the art (see Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some compounds of the present disclosure may have geometric isomer centers (E and Z isomers). It is understood that the present disclosure encompasses all optical isomers, diastereoisomers, geometric isomers, and mixtures thereof that have inflammasome inhibitory activity.

[0182] It should be understood that the compounds of any formula described herein include the compounds themselves, as well as their salts and optionally their solvates.Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on the substituted compounds disclosed herein.Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate and acetate (e.g., trifluoroacetate).

[0183] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on the substituted compounds disclosed herein and a negatively charged group (e.g., carboxylate). Suitable cations include ammonium cations such as sodium, potassium, magnesium, calcium, tetramethylammonium, or diethylamine. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0184] It is understood that compounds of the present disclosure (e.g., salts of compounds) can exist in hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0185] As used herein, the term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to form solvates by retaining a fixed molar ratio of solvent molecules in the crystalline solid state. When the solvent is water, the resulting solvate is a hydrate, and when the solvent is alcohol, the resulting solvate is an alcoholate. Hydrates are formed by combining one or more molecules of water with one molecule of a substance, with the water retaining its molecular state as HO.

[0186] As used herein, the term "analog" refers to a compound that is structurally similar to another but differs slightly in composition (such as the replacement of an atom with an atom of another element, the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but not in structure or origin.

[0187] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0188] It should also be understood that any one particular compound of formula disclosed herein can exist in solvated form, such as hydrate, as well as in unsolvated form.Suitable pharmaceutically acceptable solvate is hydrate, such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all of the above-mentioned solvated forms that have inflammasome inhibitory activity.

[0189] It should also be understood that any particular compound of any formula disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof that have inflammasome inhibitory activity.It is generally known that crystalline materials can be analyzed using conventional techniques, such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be measured by Karl Fischer analysis.

[0190] Compounds of any one of the formulas disclosed herein can exist in a number of different tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other isomers are encompassed by formula (I) regardless of the description. Examples of tautomers include keto, enol, and enolate forms, such as the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, nitro / acinitro, etc. Figure US11319319-20220503-C00141

[0191] The compounds of any one of the formulas disclosed herein may be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs can be formed when the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing alkyl or acyl substituents that can be cleaved in vivo at the ester or amide group in any one of the formulas disclosed herein.

[0192] Thus, the present disclosure includes compounds of any one of the formulas disclosed herein as defined herein when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure includes compounds of any one of the formulas disclosed herein made by organic synthetic means, as well as compounds made in the human or animal body by metabolism of a precursor compound, i.e., compounds of any one of the formulas disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0193] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein are those that are suitable for administration to the human or animal body based on sound medical judgment, without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard (Else). Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, edited by H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N Kakeya, et al., Chem.Pharm Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", ACS Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0194] Suitable pharmaceutically acceptable prodrugs of the compound of any one of the formulas disclosed herein having a hydroxy group are, for example, its ester or ether, which can be cleaved in vivo.The ester or ether of the compound of any one of the formulas disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that can be cleaved in the human or animal body to generate the parent hydroxy compound.Suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include inorganic esters, such as phosphate esters (including phosphoramido cyclic esters).Further suitable pharmaceutically acceptable ester-forming groups for hydroxy groups include C1-C10 alkanoyl groups (e.g., acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups), C1-C10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0195] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein bearing a carboxy group are, for example, in vivo cleavable amides thereof, for example, amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-(C4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids or esters such as glycine.

[0196] Suitable pharmaceutically acceptable prodrugs of any one of the compounds of formula disclosed herein having an amino group are, for example, its in vivo cleavable amide derivatives.Suitable pharmaceutically acceptable amides from amino group include, for example, amides formed with C1-C10 alkanoyl groups, such as acetyl group, benzoyl group, phenylacetyl group, and substituted benzoyl group and phenylacetyl group.Examples of ring substituents on phenylacetyl group and benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0197] The in vivo effect of any one of the compounds of the formulas disclosed herein may be partially exerted by one or more metabolic products formed in the human or animal body after administration of any one of the compounds of the formulas disclosed herein.As mentioned above, the in vivo effect of any one of the compounds of the formulas disclosed herein may also be exerted by the metabolism of precursor compounds (prodrugs).

[0198] How to use The compounds described herein can be used in an effective amount to treat a patient, typically a human, in need of treatment for a disorder mediated by RET, which may be wild-type RET or mutant RET, as generally described herein. In certain embodiments, the compounds of the present invention degrade additional proteins, such as Aurora kinase or VEGFR2. In certain embodiments, the compounds of the present invention degrade RET and Aurora A kinase (AURKA).

[0199] Another aspect of the present invention provides a compound as described herein or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for the treatment or prevention of cancer in a patient in need thereof (wherein there is a need for RET inhibition to treat or prevent cancer).

[0200] In certain embodiments, the methods comprise administering to a patient in need of treatment an effective amount of an active compound described herein, or a salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination with another bioactive agent or drug, in combination or alternation.

[0201] In certain embodiments, the present invention provides a method of treating any of the disorders described herein in a patient in need thereof.

[0202] In other embodiments, the patient is administered an additional therapeutic agent. In other embodiments, the compound described herein and the additional therapeutic agent are administered simultaneously or sequentially.

[0203] In certain embodiments, the present application provides a method of preventing any of the disorders described herein in a patient in need of treatment.

[0204] In certain embodiments, the patient is a human.

[0205] Another aspect of the present invention provides a method for treating or preventing a proliferative disease, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0206] In certain embodiments, the disease is mediated by RET, eg, RET plays a role in the development or progression of the disease.

[0207] In certain embodiments, the RET-mediated disorder is a benign proliferative disorder, metastasis, neoplasia, tumor, solid tumor, rhabdoid tumor, carcinoma, leukemia, cancer, abnormal cell proliferation, amyloid proteinosis, proteinosis, fibrotic disorder, inflammation, arthritis, pulmonary disorder, or immune disorder.

[0208] In certain embodiments, the RET-mediated disorder is cancer that has metastasized, for example, cancer that has metastasized to the brain. In certain embodiments, the RET-mediated disorder is cancer that has metastasized to the brain, lung, bone, liver, peritoneum, adrenal gland, skin or muscle.

[0209] In certain embodiments, the compounds of the invention cross the blood-brain barrier and can be used to treat cancers that involve the central nervous system or that have metastasized to the brain.

[0210] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0211] In certain embodiments, the RET-mediated disorder includes, but is not limited to, abnormal cell proliferation, e.g., a tumor or cancer or a bone marrow or lymphoproliferative disorder (e.g., B-cell or T-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder).

[0212] In certain embodiments, the hematological cancer is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryocytic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLE), and / or mixed lineage leukemia (MCL). LL), erythroid leukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL)2 and / or BCL6 rearrangement / overexpression [double-hit and triple-hit lymphomas], myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma (including bortezomib-resistant mantle cell lymphoma).

[0213] Solid tumors that can be treated using the compounds described herein include lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)), breast cancer (including inflammatory breast cancer), ER-positive breast cancer (including tamoxifen-resistant ER-positive breast cancer and triple-negative breast cancer), colon cancer, midline carcinoma, liver cancer, kidney cancer, prostate cancer (including castration-resistant prostate cancer (CRPC)), brain tumors (including glioma, neuroblastoma, and medulloblastoma, including MYC-amplified medulloblastoma), colorectal cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, and ependymal tumors. These include, but are not limited to, ovarian cancer, head and neck cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer (including pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PanNET)), osteosarcoma, giant cell tumor of bone, thyroid cancer, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland cancer, gastric cancer, maxillary cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), NUT midline carcinoma, testicular cancer, squamous cell carcinoma, hepatocellular carcinoma (HCC), MYCN-driven solid tumors, and NUT midline carcinoma (NMC).

[0214] In a further embodiment, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0215] In a further embodiment, the disease or disorder is soft tissue sarcoma, myeloid sarcoma, or osteosarcoma.

[0216] In further embodiments, the disease or disorder is any of angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Kaposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningeal sarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0217] In a further embodiment, the disease or disorder is multiple myeloma.

[0218] In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neuroinflammation, allergies, pain, neuropathic pain, fever, lung disease, pulmonary inflammation, adult dyspnea chronic pulmonary inflammatory disease and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal disease, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcer disease, gastric ulcer, autoimmune disease, graft versus host reaction and allograft rejection, cancer, leukemia, lymphoma, colorectal cancer, brain tumor, bone cancer, parathyroid neoplasia (epithelial cancer), ), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip, oral cavity, esophageal, small intestine, stomach, colon, liver, bladder, pancreatic, ovarian, cervical, lung, breast, skin, squamous cell and / or basal cell carcinoma, prostate, renal cell carcinoma, and other known cancers affecting epithelial cells throughout the body, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis including neoplasia, metastasis, central nervous system disorders, central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy, or B-cell lymphoma.

[0219] In other embodiments, the pharmaceutical composition comprising a compound described herein and the additional therapeutic agent are administered simultaneously or sequentially.

[0220] In other embodiments, the disease or disorder is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, squamous cell carcinoma of the head and neck, leukemia, lymphoma, myeloma, solid tumor, blood cancer or solid cancer.

[0221] In some embodiments, the method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immunologically mediated diseases, hi other embodiments, the condition is selected from a proliferative disorder.

[0222] In certain embodiments, the RET-mediated disease is an immune disease, such as an autoimmune disease, including, but not limited to, Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type 1 diabetes.

[0223] One aspect of the present application provides compounds useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases. Examples of proliferative or hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer; ovarian cancer; cervical cancer; prostate cancer; testicular cancer, genitourinary cancer; esophageal cancer; laryngeal cancer, glioblastoma; neuroblastoma; gastric cancer; skin cancer, keratoacanthoma; lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone cancer; colon cancer; colorectal cancer; adenoma; pancreatic cancer, pancreatic adenocarcinoma; thyroid, follicular, undifferentiated, papillary carcinoma; seminoma; melanoma; sarcoma; bladder cancer; liver and biliary tract cancer; kidney cancer; myeloid diseases; lymphatic system diseases, Hodgkin's disease, hairy cell; buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer; small intestine cancer; colorectal cancer, colon cancer, rectal cancer, cancer of the brain and central nervous system; chronic myeloid leukemia (CML) and leukemia. The term "cancer" includes, but is not limited to, myeloma, lymphoma, or cancer selected from the following: gastric cancer, renal cancer, and / or head and neck cancer, oral cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma, and lung cancer.

[0224] The term "cancer" refers to any cancer caused by the proliferation of malignant neoplastic cells, e.g., tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc. For example, cancers include, but are not limited to, mesothelioma, leukemia and lymphoma, e.g., cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, human T-cell lymphotropic virus (HTLV)-associated lymphoma such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia-lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors (e.g., brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas), common solid tumors in adults (e.g., head and neck cancers such as oral, laryngeal, nasopharyngeal, and esophageal cancers, genitourinary cancers such as prostate, bladder, kidney, uterine, ovarian, and testicular cancers, lung cancers such as small cell and non-small cell carcinomas, breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin syndrome such as medulloblastoma and meningioma, and liver cancer).

[0225] Additional exemplary forms of cancer include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0226] Additional cancers for which the compounds described herein may be useful for prevention, treatment, and research include, for example, colon cancer, familial adenomatous polyposis coli cancer, hereditary non-polyposis colorectal cancer, or melanoma. Further cancers include labial cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid cancer and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), gallbladder cancer, bronchial cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of the present application, the present application provides the use of one or more compounds described herein in the manufacture of a medicament for the treatment of cancer, including, but not limited to, the various types of cancer disclosed herein. In some embodiments, the compounds described herein are useful for the treatment of cancer, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myelofibrosis-associated myelotransformation disease, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds described herein are useful for the treatment of hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute myeloid leukemia, and acute lymphocytic leukemia (ALL). In one embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts or isotopic derivatives, can be used in an effective amount to treat a host (e.g., a human) with, for example, a lymphoma or a lymphoproliferative or myeloproliferative disorder or disorder. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma.For example, the host may be, but is not limited to, non-Hodgkin's lymphoma: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-necrotic cell lymphoma); diffuse small dividing cell lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenstrom's lymphoma. May have macroglobulinemia lymphoma.

[0227] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, or isotopic derivatives, can be used in an effective amount to treat patients (e.g., humans) suffering from Hodgkin's lymphoma (e.g., but not limited to, nodular sclerosing classical Hodgkin's lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL). This use further encompasses the treatment or prevention of cell proliferation disorders (e.g., hyperplasia, dysplasia, and precancerous lesions). Dysplasia is the earliest precancerous lesion that a pathologist can recognize in a biopsy. The compounds can be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions appear in the skin, esophageal tissue, breast, and intraepithelial tissue of the cervix.

[0228] In certain embodiments, the compounds of the present invention are used to treat abnormal cell growth, such as tumors or cancers, that have a RET protein with a mutation, wherein the mutation is at one of the amino acid positions listed below. The mutation may be selected, for example, from one of the exemplary mutations listed, or may be a different mutation. [Table 1]

[0229] In certain embodiments, the RET protein has two mutations selected from the table above. In other embodiments, the RET protein has three mutations selected from the table above. In other embodiments, the RET protein has four or more mutations, optionally selected from the table above.

[0230] In certain embodiments, the tumor or cancer has a mutation in the RET protein that is a substantial or partial driver of cancer cell proliferation. In another embodiment, the tumor or cancer has a RET modified protein that does not significantly act as a driver of abnormal cell proliferation, but can be therapeutically utilized with selected RET degrading compounds described herein to kill tumor cells.

[0231] In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein V804L mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein V804M mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein M918T mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein S891A mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein L790F mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein E768D mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein C618S mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein C618R mutation. In certain embodiments, compounds of the present invention are used to treat tumors or cancers with a RET protein 634 missense mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a RET protein C634R mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a RET protein C634Y mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a RET protein C634G mutation. In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers with a RET protein with a G810R mutation.

[0232] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with a G810S mutation.

[0233] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with a G810C mutation.

[0234] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the C634W mutation.

[0235] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the M918T mutation.

[0236] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the V804L mutation.

[0237] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the V804M mutation.

[0238] In certain embodiments, compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell growth (e.g., tumor or cancer) having a RET protein fused to another protein, e.g., a fusion selected from CCDC6-RET, NCOA4-RET, KIF5B-RET, PRKAR1A-RET, TRIM24-RET, TRIM33-RET, GOLGA5-RET, HOOK3-RET, KTN1-RET, ERC1-RET, MBD1-RET, TRIM27-RET, BRC-RET, FGFR10P-RET, PCM1-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, CUX1-RET, KIAA1468-RET, and KIAA1217-RET.

[0239] In certain embodiments, compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth (e.g., tumors or cancers) that harbor a CCDC6-RET fusion. In certain embodiments, compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth (e.g., tumors or cancers) that harbor an NCOA4-RET fusion.

[0240] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell growth (eg, tumors or cancers) harboring a KIF5B-RET fusion.

[0241] In accordance with the above, the present application further provides a method for preventing or treating any of the above diseases or disorders in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as described herein or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition being treated and the desired effect.

[0242] Pharmaceutical Compositions and Combination Therapies In some embodiments, the compounds of formula I or pharmaceutically acceptable salts thereof may be used alone or in combination in effective amounts to treat a patient, such as a human, having a disorder described herein or a RET-mediated disorder.

[0243] The disclosed compounds described herein can be used in effective amounts alone or in combination with another compound of the invention or another bioactive or second therapeutic agent to treat a patient, such as a human, having a disorder, including but not limited to those described herein.

[0244] The term "bioactive agent" is used to describe an agent other than the selected compound of the present invention that can be used in combination with or separately from a compound of the present invention to achieve a desired therapeutic outcome. In one embodiment, the compound of the present invention and the bioactive agent are administered so as to be active in vivo during a time window where, for example, their Cmax, Tmax, AUC, or other pharmacokinetic parameters overlap. In another embodiment, the compound of the present invention and the bioactive agent are administered to a patient in need of treatment where their pharmacokinetic parameters do not overlap, but one therapeutically influences the therapeutic effect of the other. In one aspect of this embodiment, the bioactive agent is an immunomodulator, non-limiting examples of which include, but are not limited to, checkpoint inhibitors, including, for example, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig suppressor of T cell activation (VISTA) inhibitors, small peptides, nucleotides, or other inhibitors. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody. PD-1 inhibitors, which inhibit immunosuppression by binding to the PD-1 receptor and thereby inhibiting the interaction between PD-1 and PD-L1, include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.).PD-L1 inhibitors that inhibit the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby suppressing immunosuppression, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and suppress immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics).An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559, PDL2 / lg fusion proteins (e.g., AMP 224) or inhibitors of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.In yet another embodiment, one of the active compounds described herein can be administered in combination with or separately from an effective amount of an estrogen inhibitor (such as, but not limited to, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist) to treat abnormal tissues of the female reproductive system (e.g., breast cancer, ovarian cancer, endometrial cancer, or uterine cancer). Partial antiestrogens such as raloxifene and tamoxifen maintain some estrogenic activity (e.g., estrogenic uterine growth-promoting activity). On the other hand, the complete antiestrogenic drug fulvestrant lacks estrogenic activity on the uterus and is effective against tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are set forth in WO2014 / 19176 assigned to Astra Zeneca, WO2013 / 090921, WO2014 / 203129, WO2014 / 203132 and US2013 / 0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423 and 8,703,810, and US2015 / 0005286, WO2014 / 205136 and WO2014 / 205138. Further non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclophenyl, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrat; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.Other estrogen ligands that can be used in accordance with the present invention are described in U.S. Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117; WO2011 / 156518; U.S. Pat. Nos. 8,455,534 and 8,299,112; U.S. Pat. No. 9,078,871; U.S. Pat. No. 8,853,423; U.S. Pat. No. 8,703,810; US 2015 / 0005286; and WO 2014 / 205138; US2016 / 0175289; US2015 / 0258080; WO2014 / 191726; WO2012 / 084711; WO2002 / 013802; WO 2002 / 004418;WO 2002 / 003992;WO 2002 / 003991;WO 2002 / 003990;WO 2002 / 003989;WO 2002 / 003988;WO 2002 / 003986;WO 2002 / 003977;WO 2002 / 003976;WO 2002 / 003975;WO 2006 / 078834;US 6821989;US 2002 / 0128276;US 6777424;US 2002 / 0016340;US 6326392;US 6756401;US 2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; US 6583170; US 6479535; WO 1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497; US 5880137; WO 2012 / 048058 and WO 2007 / 087684. In another embodiment, the active compounds described herein can be administered in combination with or without an effective amount of an androgen (e.g., testosterone) inhibitor (e.g., but not limited to, a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist) for the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. In one embodiment, the prostate cancer or testicular cancer is androgen-resistant.Non-limiting examples of anti-androgen compounds are described in WO2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Further non-limiting examples of anti-androgen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine. In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113. In one embodiment, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-27 2; PB272), avatinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), trastuzumab, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer). In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, adotrastuzumab emtansine, and pertuzumab. In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab and ocrelizumab. In one embodiment, the bioactive agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and venetoclax (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide). navitoclax (navitoclax), ABT-263 ((R)-4-(4-(((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-(4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trichlorophenyl)-4-pyridyl)-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Ovatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amycin In one embodiment, the bioactive agent is a kinase inhibitor, such as cyclopropyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Oblimersen).In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. Examples of PI3 kinase inhibitors include wortmannin, demethoxyviridine, perifosine, idelalisib, pictilisib, palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine]). -9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanylhydrogen(S)-methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]-oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK21 26458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-lH -benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-l-(4-(2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropan-1-one)), GS-1101 (5-fluoro-3-phenyl-2-([S]-1-[9H-purine-6.-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinazol), AS252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH-indazol-4-yl)-6-[[4-(methylsulfonamide) [S]-1-(4-(2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422), SF11 26 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4 -[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-l-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]-methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-l,4,7-trioxo-2,3,3a,9,10,ll-hexahydride loindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, piralalisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS173, VS-5584 (SB2343), Examples of anti-cancer drugs include, but are not limited to, CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, and apitolisib (GDC-0980; RG7422). Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,dianilinopyrimidine inhibitors such as [N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl]acrylamide) (Avila Therapeutics) (see U.S. Patent Publication No. 2011 / 0117073), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (α-cyano-β-hydroxybenzoates), -β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6.7-tetrahydrobenzo[b]-thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-(4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl )amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyl lysin-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one) and other molecules capable of inhibiting BTK activity (e.g., those BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59), the entire contents of which are incorporated herein by reference. Syk inhibitors include, but are not limited to, celdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate dihydrogen salt), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide hydrochloride), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643; the entire contents of which are incorporated herein by reference), Compound D (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643; the entirety of which is incorporated herein), PRT060318 (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643; the entirety of which is incorporated herein), luteolin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643; the entirety of which is incorporated herein), apigenin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643; the entirety of which is incorporated herein), 3614-3643; incorporated herein in its entirety), quercetin (Singh et al.,Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.Chem.2012, 55, 3614-3643; incorporated herein in its entirety), fisetin (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.Chem.2012, 55, 3614-3643; incorporated herein in its entirety), myricetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med.Chem.2012, 55, 3614-3643; incorporated herein in its entirety), morin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643; the entire contents of which are incorporated herein. In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known, and examples thereof include trametinib / GSK1120212: (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib: (6-(4-bromo- bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369: ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / DC-0973 (l-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEAl 19: (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901: (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733: ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162: (5-[(4-bromo-2-fluorophenyl)amino] amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766: (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655: (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide) or AZD8330: (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy), -1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088. In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known, and examples thereof include vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), Lysine-2-carboxamide; 4-methylbenzenesulfonate), AZ628: (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712: (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidinyl) RAF-265: (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoardisine (2-bromo-6,7-dihydro-1H,5H-pyridin-4-ylamino), chloro[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV: (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib: N-oxide (4-[-4-[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496,Examples of suitable bioactive agents include LY3009120 and GX818 (encorafenib). In one embodiment, the bioactive agent is an AKT inhibitor (for example, but not limited to, MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine), an FLT-3 inhibitor (for example, but not limited to, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandotinib (MLN518), ENMD-2076, and KW-2449), or a combination thereof. In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, deforolimus, and the like. Examples of MEK inhibitors include tametinib / GSKl120212: (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6.7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenyl)acetamide), selmetinib: (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369: ((S)-N-(2,3-dihydro hydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973: (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib), refametinib / BAY869766 / RDEAl19: (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide),PD-0325901: (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733: ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162: (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766: (3-[[3-fluoro-

[0013] In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, leolysin and siG12D LODER. In one embodiment, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol. Additional biologically active compounds include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358,R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, Aurora kinase inhibitor, PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, anti-HGF antibody, focal adhesion kinase (FAK) inhibitor, Map kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, atumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanton, LY317615, Newradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl] L-glutamic acid 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, ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus cul Met-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethrin tamoxifen, 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, floxur dine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, barbicine, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimitidine, trastuzumab,Denileukin diftitox, gefitinib, bortezimib, 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 / ZK222584, VX-745, PD184352, rapamycin, 40- O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2 a, 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, ibrittonomab tiuxetan, androgen, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etoposide Ditronate, 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,These include erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In one embodiment, the bioactive agent is imatinib mesylate (Gleevac, (登録商標) ), dasatinib (Sprycel (登録商標) ), nilotinib (Tasigna (登録商標) ), bosutinib (Bosulif (登録商標) ), trastuzumab (Herceptin (登録商標) ), trastuzumab-DM1, pertuzumab (Perjeta (商標) ), lapatinib (Tykerb (登録商標) ), gefitinib (Iressa (登録商標) ), erlotinib (Tarceva (登録商標) ), cetuximab (Erbitux (登録商標) ), panitumumab (Vectibix (登録商標) ), vandetanib (Caprelsa (登録商標) ), vemurafenib (Zelboraf (登録商標) ), vorinostat (Zolinza (登録商標) ), romidepsin (Istodax (登録商標) ), bexarotene (Tagretin (登録商標) ), Alitretinoin (Panretin (登録商標) ), tretinoin (Vesanoid (登録商標) ), calfilizomib (Kyprolis (商標) ), pralatrexate (Folotyn (登録商標) ), bevacizumab (Avastin (登録商標) ), Zivaflibercept (Zaltrap (登録商標) ), sorafenib (Nexavar (登録商標) ), sunitinib (Sutent (登録商標) ), pazopanib (Votrient (登録商標) ), regorafenib (Stivarga (登録商標) ) and cabozantinib (Cometriq (商標)), but are not limited to. In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant. Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins, also called cytotoxins or cytotoxic agents (including any agent detrimental to cell viability), and liposomes or other vesicles containing chemotherapeutic compounds. Common anti-cancer agents include: vincristine (Oncovin), (登録商標) ) or liposomal vincristine (Marqibo (登録商標) ), Daunorubicin (Daunomycin or Cerubidine (登録商標) ) or doxorubicin (Adriamycin (登録商標) ), cytarabine (cytosine arabinoside, ara-C, or Cytosar (登録商標) ), L-asparaginase (Elspar (登録商標) ) or PEG-L-asparaginase (PEGaspargase or Oncaspar (登録商標) ), etoposide (VP-16), teniposide (Vumon (登録商標) ), 6-mercaptopurine (6-MP or Purinethol (登録商標) ), methotrexate, cyclophosphamide (Cytoxan (登録商標) ), prednisone, dexamethasone (Decadron), imatinib (Gleevec (登録商標) ), dasatinib (Sprycel (登録商標) ), nilotinib (Tasigna (登録商標) ), bosutinib (Bosulif (登録商標) ) and ponatinib (Iclusig (商標)Examples of additional suitable chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimicrobial agents, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), and betamethasone. sodium phosphate, betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCl, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxyanthracin dione, docetaxel, dolasetron mesylate, doxorubicin HCl, dronabinol, Escherichia coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citroram factor, etoposide phosphate, filgrastim, floxuridine, fluconazole zole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon alpha-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoids, mechlorethamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna,These include, but are not limited to, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, primycin, polipheprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepachlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0245] In some embodiments, the compounds of the present invention are administered in combination with chemotherapeutic agents (e.g., cytotoxic agents or other compounds useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopirotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel.Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metuldopa, and urdopa; ethylenimines and methylamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; karystatin; CC-1065 (including synthetic analogs of adozelesin, carzelesin, and bizelesin); cryptophycins (particularly cryptophycin 1, cryptophycin 2, cryptophycin 3, cryptophycin 4, cryptophycin 5, cryptophycin 6, cryptophycin 7, cryptophycin 8, cryptophycin 9, cryptophycin 10, cryptophycin 11, cryptophycin 12, cryptophycin 13, cryptophycin 14, cryptophycin 15, cryptophycin 16, cryptophycin 17, cryptophycin 18, cryptophycin 19, cryptophycin 20, cryptophycin 21, cryptophycin 22, cryptophycin 23, cryptophycin 24, cryptophycin 25, cryptophycin 26, cryptophycin 27, cryptophycin 28, cryptophycin 29, cryptophycin 30, cryptophycin 31, cryptophycin 32, cryptophycin 33, cryptophycin 34, cryptophycin 35, cryptophycin 36, cryptophycin 37, cryptophycin 38, cryptophycin 39, cryptophycin 40, cryptophycin 41, cryptophycin 42, cryptophycin 43, cryptophycin 44, cryptophycin 45, cryptophycin scin 8); dolastatins; duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodistatin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembicin, phenesterine, prednimustine, trofosfamide and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; enediyne antibiotics (e.g., calicheamicins, especially calicheamicingamol and calicheamicin omegal (e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994); dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and the neocarzinostatin chromophore and related chromoprotein-enediyne antibiotic chromophores; aclacinomycin, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, cardinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adrIAMycin. (登録商標)(Doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfilomycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptomycin, antimetabolites such as tozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, and doxifluridine pyrimidine analogues such as enocitabine and floxuridine; androgens such as calucinone, dromostanolone propionate, epitiostanol, mepitiostane and testolactone; antiadrenergics such as aminoglutethimide, mitotane and trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatlaxa acetamide; defofamine; demecolcine; diaziconazole; elfomitine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidynin; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraelin; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK (登録商標)Polysaccharide complexes (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gasetocin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids (e.g., TAXOL (登録商標) (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE (登録商標) , Cremophor-free albumin-genetically modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL, TAXOTERE (登録商標) Doxetaxel (Rhone-Poulenc Rorer, Antony, France); Chlorambucil; GEMZAR (登録商標) Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE (登録商標)The chemotherapeutic agents include vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives thereof. Two or more chemotherapeutic agents can be used in the cocktail administered in combination with the compound of the present invention. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).Additional therapeutic agents that can be administered in combination with the compounds disclosed herein include bevacizumab, sutanib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, and dromexizumab. Vitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukin, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, Indinavir sulfate, belinstat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, pritidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, These include oxaliplatin (Eloxatin), PD032991, ribociclib (LEE011), amevaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B). In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells, triggering their destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment and promoting the expansion of tumor blood vessels. When VEGF binds to bevacizumab, it is unable to interact with its cell receptors, preventing signaling that promotes the growth of new blood vessels.Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors inhibit the targeted receptor from transmitting normal growth-promoting signals. They can also induce apoptosis, activating the immune system and destroying tumor cells. In one embodiment of the present invention, the bioactive agent is an immunosuppressant. Immunosuppressants include calcineurin inhibitors, such as cyclosporine or ascomycin, e.g., cyclosporin A (NEORAL). (登録商標) ), FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, such as rapamycin or its derivatives, such as sirolimus (RAPAMUNE (登録商標) ), everolimus (Certican (登録商標) ), temsirolimus, zotarolimus, Biolimus-7, Biolimus-9, rapalogs such as ridaforolimus, azathioprine, Campath 1H, S1P receptor modulators such as fingolimod or analogs thereof, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, such as the sodium salt, or a prodrug thereof, for example, mycophenolate mofetil (CELLCEPT (登録商標) ), OKT3 (ORTHOCLONE OKT3 (登録商標) ), prednisone, ATGAM (登録商標) , THYMOGLOBULIN (登録商標) , brequinar sodium, OKT4, T10B9.A-3A, 33B.1, 15-deoxyspergualin, tresperimus, leflunomide, ARAVA (登録商標) , CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT (登録商標) ), daclizumab (ZENAPAX (登録商標) ), Mizorubine, Methotrexate, Dexamethasone, ISAtx-247, SDZ ASM 981 (Pimecrolimus, Elidel (登録商標) ), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (Enbrel from Immunex) (登録商標)adalimumab (sold as Humira) (登録商標) ), infliximab (Remicade (登録商標) ), anti-LFA-1 antibody, natalizumab (Antegren (登録商標) ), enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benolylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen In some embodiments, the bioactive agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in the treatment of cancer. In some embodiments, the biologic is an anti-angiogenic agent, e.g., an anti-VEGF agent, e.g., bevacizumab (AVASTIN). (登録商標) In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. Such agents include RITUXAN (登録商標) (rituximab), ZENAPAX (登録商標) (daclizumab), SIMULECT (登録商標) (basiliximab), SYNAGIS (登録商標) (palivizumab), REMICADE (登録商標) (infliximab), HERCEPTIN (登録商標) (trastuzumab), MYLOTARG (登録商標) (gemtuzumab ozogamicin), CAMPATH (登録商標) (alemtuzumab), ZEVALIN (登録商標) (ibritumomab tiuxetan), HUMIRA (登録商標) (adalimumab), XOLAIR (登録商標) (omalizumab), BEXXAR (登録商標) (tositumomab-l-131), RAPTIVA (登録商標) (efalizumab), ERBITUX (登録商標)(cetuximab), AVASTIN (登録商標) (bevacizumab), TYSABRI (登録商標) (natalizumab), ACTEMRA (登録商標) (Tocilizumab); VECTIBIX (登録商標) (panitumumab), LUCENTIS (登録商標) (ranibizumab), SOURIS (登録商標) (eculizumab), CIMZIA (登録商標) (certolizumab pegol), SIMPONI (登録商標) (golimumab), ILARIS (登録商標) (canakinumab), STELARA (登録商標) (ustekinumab), ARZERRA (登録商標) (ofatumumab), PROLIA (登録商標) (denosumab);NUMAX (登録商標) (motavizumab), ABSTRAX (登録商標) (raxibacumab), BENLYSTA (登録商標) (belimumab), YERVOY (登録商標) (ipilimumab), ADCETRIS (登録商標) (brentuximab vedotin), PERJETA (登録商標) (pertuzumab), KADCYLA (登録商標) (ado-trastuzumab emtansine) and GAZYVA (登録商標)(obinutuzumab). Antibody-drug conjugates are also included. Combination therapy may include a non-drug therapeutic agent. For example, the compounds of the present application can be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical resection of tumor tissue. In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially, in any order. The first therapeutic agent can be administered immediately after, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours after the second therapeutic agent, or within 1 to 7, 1 to 14, 1 to 21, or 1 to 30 days before or after the second therapeutic agent. In certain embodiments, the second therapeutic agent is administered on a different dosing schedule than the compounds of the present invention. For example, the second therapeutic agent may have a drug-free period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a drug-free period. For example, the first therapeutic agent may have a drug-free period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In some embodiments, both the first and second therapeutic agents have drug-free periods.

[0246] VII. Pharmaceutical Compositions The compounds of Formula I, II, III, IV, V, VI, or VII described herein, or pharmaceutically acceptable salts thereof, can be administered as solvent-free chemicals, but are more typically administered as pharmaceutical compositions containing an effective amount to a patient, usually a human, in need of such treatment for any of the disorders described herein. Thus, the present disclosure provides pharmaceutical compositions comprising an effective amount of the compound or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain the compound or salt as the only active agent, or in other embodiments, may contain the compound and at least one additional active agent.

[0247] Generally, the composition of the present disclosure is administered in a therapeutically effective amount by any of the accepted administration methods.The range of appropriate dosage varies depending on many factors, such as the severity of the disease to be treated, the age and relative health condition of the subject, the potency of the compound used, the route and form of administration, the indication for the indicated administration, and the choice and experience of the medical professional.Those skilled in the art of treating such diseases can determine the therapeutically effective amount of the composition of the present disclosure for a given disease without undue experimentation, based on their own knowledge and the disclosure of this application.

[0248] In certain embodiments, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples include dosage forms containing at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

[0249] In certain embodiments, patients can be treated with low-dose therapy using the compounds of the present invention. For example, the pharmaceutical composition can be in a dosage form containing about 0.1 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 800 μg, or about 200 μg to about 600 μg of the active compound. For example, the pharmaceutical composition can be in a dosage form containing at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 μg of the active compound or a salt thereof.

[0250] In certain embodiments, the dose is in the range of about 0.01 to 100 mg / kg of the patient's body weight, e.g., at least about 0.01 mg / kg, at least about 0.05 mg / kg, at least about 0.1 mg / kg, at least about 0.5 mg / kg, at least about 1 mg / kg, at least about 1.5 mg / kg, at least about 2 mg / kg, at least about 2.5 mg / kg, at least about 3 mg / kg, at least about 3.5 mg / kg, at least about 4 mg / kg, at least about 4.5 mg / kg, at least about 5 mg / kg, at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, at least about 60 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg or at least about 100 mg / kg.

[0251] A pharmaceutically or therapeutically effective amount of the composition is delivered to the patient. The precise effective amount will vary from patient to patient and will depend on the species, age, size and health of the subject, the nature and extent of the condition being treated, the recommendations of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. Effective amounts for a given situation can be determined by routine experimentation. For purposes of this disclosure, a therapeutic amount may range, for example, from about 0.01 mg / kg to about 250 mg / kg, more typically from about 0.1 mg / kg to about 10 mg / kg, of body weight in at least one administration. A subject can be administered an amount necessary to reduce and / or alleviate the signs, symptoms, or causes of the disorder, or to effect other desired changes in a biological system. Where necessary, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.

[0252] In some embodiments, compounds disclosed herein or used as described are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, a compound disclosed herein or used as described is administered at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or more.

[0253] In certain embodiments, the compounds of the present invention are administered once a day, twice a day, three times a day, or four times a day. In certain embodiments, the compounds of the present invention are administered orally once a day. In certain embodiments, the compounds of the present invention are administered orally twice a day. In certain embodiments, the compounds of the present invention are administered orally three times a day. In certain embodiments, the compounds of the present invention are administered orally four times a day.

[0254] In certain embodiments, the compounds of the present invention are administered intravenously once a day. In certain embodiments, the compounds of the present invention are administered intravenously twice a day. In certain embodiments, the compounds of the present invention are administered intravenously three times a day. In certain embodiments, the compounds of the present invention are administered intravenously four times a day.

[0255] In some embodiments, the compounds of the present invention are administered with a drug holiday between treatment cycles.For example, the drug holiday of the compounds can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days per treatment cycle.

[0256] The pharmaceutical composition can also contain a molar ratio of the active compound to the additional active agent. For example, the pharmaceutical composition can contain an anti-inflammatory or immunosuppressant agent in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.

[0257] These compositions can contain any amount of the active compound that achieves the desired result, for example, 0.1 to 99% by weight (wt.%) of the compound, usually at least about 5% by weight of the compound, and in some embodiments, about 25% to about 50% by weight, or about 5% to about 75% by weight of the compound.

[0258] Pharmaceutical preparations are preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients. The unit dosage form can be a packaged preparation, and the packaged preparation containing a divided amount of the preparation includes packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or any of these may be packaged in an appropriate number.

[0259] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfonate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, dihydrogen phosphate, hydroxybenzoate ... -hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0260] Thus, the compositions of the present disclosure can be administered as pharmaceutical formulations containing conventional pharmaceutically acceptable carriers suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous, and intravenous), injection, inhalation or spray, intraaortic, intracranial, subcutaneous, intraperitoneal, subcutaneous, or other means of administration. Typical administration methods are oral, topical, or intravenous, using convenient daily dosages that can be adjusted according to the severity of the affliction.

[0261] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semi-solid or liquid dosage form, such as a tablet, suppository, pill, capsule, powder, liquid, syrup, suspension, cream, ointment, lotion, paste, gel, spray, aerosol, foam or oil, injection or infusion, transdermal patch, subcutaneous patch, inhalant, medical device, suppository, buccal, sublingual, parenteral or ophthalmic solution, preferably in a unit dosage form suitable for single administration of a precise dose.

[0262] Some dosage forms, such as tablets and capsules, are divided into suitably sized unit doses containing an appropriate amount of the active ingredient (e.g., an amount effective to achieve a desired purpose). The composition contains an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may further include other pharmaceutical agents, adjuvants, diluents, buffers, etc. Carriers include excipients and diluents and must be of sufficient purity and sufficiently low toxicity to be suitable for administration to the patient being treated. Carriers may be inert or may themselves have pharmaceutical properties. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of the compound for administration per unit dose. Types of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, fillers, emulsifiers, flavorings, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tablet fillers, wetting agents, or solidifying materials. Some carriers may be listed in more than one category; for example, vegetable oils may be used as lubricants in some formulations and as diluents in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, petrolatum, lanolin, polyethylene glycol, alcohol, transdermal enhancers, and vegetable oils. Any active agent that does not substantially inhibit the activity of the compounds of the present invention can be included in the pharmaceutical composition. Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, and ethanol. Depending on the purpose of treatment, the compounds can be provided in the form of, for example, solids, liquids, spray-dried products, microparticles, nanoparticles, controlled-release systems, etc. Excipients suitable for non-liquid formulations are also known to those skilled in the art. A comprehensive discussion of pharmaceutically acceptable excipients and salts can be found in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).Additionally, auxiliary substances, such as wetting or emulsifying agents, biological buffers, surfactants, and the like, can be present in such vehicles. A biological buffer can be any solution that is pharmacologically acceptable and that provides the formulation with the desired pH (i.e., a pH within the physiologically acceptable range). Examples of buffers include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, and the like. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, or the like, the active compounds described herein and any pharmaceutical adjuvants in excipients (e.g., water, saline, aqueous dextrose, glycerol, ethanol, and the like) to form a solution or suspension. If desired, the administered pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances, such as wetting agents, emulsifying agents, or pH buffering agents (e.g., sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.). Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, cited above. In yet another embodiment, provided is the use of excipients that are penetration enhancers, including polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethylchitosan, polyacrylic acid); and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). The pharmaceutical composition / formulation may be formulated for oral administration. For oral administration, the compositions will generally take the form of a tablet, capsule, softgel capsule, or may take the form of an aqueous or non-aqueous solution, suspension, or syrup.Tablets and capsules are typical oral dosage forms. Oral tablets and capsules can contain one or more commonly used carriers, such as lactose and cornstarch. Lubricants, such as magnesium stearate, are also commonly added. Typically, the compositions of the present disclosure can be combined with oral non-toxic, pharmaceutically acceptable inert carriers, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. When using liquid suspensions, the active agent can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water) and an emulsifier and suspending agent. If necessary, flavoring agents, coloring agents, and / or sweeteners can also be added. Other optional ingredients for incorporation into oral formulations herein include, but are not limited to, preservatives, suspending agents, thickeners, etc.

[0263] For ocular delivery, the compounds may be administered, as desired, for example, via intravitreal, intrastromal, intracavitary, subtenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular injection, transscleral, retrobulbar, posterior cruciate, corneal fornix, or lacrimal injection, or through a mucus, mucin, or mucosal barrier, in immediate or controlled release form, or via an ophthalmic device.

[0264] Parenteral preparations can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or emulsions. Usually, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersants or wetting agents, and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty esters, or polyols are conventionally used as solvents or suspending media. In addition, for parenteral administration, sustained-release or sustained-release systems can be used to maintain a constant dosage.

[0265] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injections, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the recipient's blood. Aqueous and non-aqueous sterile suspensions may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Certain parenteral routes of administration include introducing the formulations of the present disclosure into the patient's body through a needle or catheter injected with a sterile syringe or other mechanical device, such as a continuous infusion system. The formulations provided by the present disclosure can be administered using a syringe, infuser, pump, or any other device recognized in the art for parenteral administration. Formulations according to the present disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. They can also be prepared using sterile water or other sterile injectable solvents just before use.

[0266] Sterile injectable solutions are prepared by blending one or more compounds of the present disclosure in the required amount in an appropriate solvent, optionally incorporating various other ingredients as listed above, followed by filtered sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other required ingredients from those listed above. In the case of sterile powders for preparing sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution. Thus, for example, a parenteral composition suitable for administration by injection is prepared by mixing 1.5% by weight of the active ingredient with 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0267] Alternatively, the pharmaceutical composition of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0268] The pharmaceutical compositions of the present disclosure can also be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and / or other conventional solubilizing or dispersing agents. Formulations for oral administration include tablets, lozenges, gels, and the like. Alternatively, oral administration can be achieved using transmucosal administration systems known to those skilled in the art. The compounds of the present disclosure can also be delivered through the skin or muscle tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches," in which the drug is typically contained within a laminated structure that functions as a drug delivery device that is applied to the body surface. In such structures, the drug composition is typically contained in a layer, or "reservoir," beneath an upper backing layer. The laminated device can contain a single reservoir or multiple reservoirs. In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material, which serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, etc.

[0269] Alternatively, the drug-containing reservoir and skin-contact adhesive may be present as separate layers, with the adhesive underlying the reservoir, which may be a polymer matrix as described above, a liquid or gel-like reservoir, or other form. The backing layer of these laminates serves as the top surface of the device and serves as the primary structural element of the laminate structure, providing much of the flexibility for the device. The material selected for the backing layer should be substantially impermeable to the active agent and other materials present.

[0270] The compositions of the present disclosure can be formulated for aerosol administration, particularly respiratory and intranasal administration. The compounds can have a small particle size, typically less than 5 microns. Such particle sizes can be obtained by means known in the art, for example, by micronization. The active ingredient is provided in a pressurized pack together with a suitable propellant (e.g., a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide, or other suitable gas. The aerosol can also contain a surfactant, such as lecithin. The dosage of the drug can be controlled by a metered valve.

[0271] Alternatively, the active ingredient can be provided in dry powder form, for example, by mixing the compound with a suitable powder base (e.g., lactose, starch, or starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP)). The powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dose form, for example, in capsules or cartridges of gelatin or blister packs, from which the powder can be administered using an inhaler.

[0272] Formulations suitable for rectal administration are usually presented as unit-dose suppositories, which may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and shaping the resulting mixture.

[0273] In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the modes of administration defined above.

[0274] In certain embodiments, pharmaceutical compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6):318 (1986)), and typically take the form of a suitably buffered solution of the active compound.

[0275] In one embodiment, a microneedle patch or device is provided for delivering a drug to biological tissue, particularly the skin, which can deliver a drug through or into the skin or other tissue barrier at a clinically relevant rate with minimal or no tissue damage, pain, or irritation.

[0276] Formulations suitable for pulmonary administration can be delivered by a wide range of passive, breath-driven, and active-powered single- and multi-dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of an appropriate pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and pulmonary pathophysiology.

[0277] Synthesis Method The compounds of the present disclosure can be prepared in many ways known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, or variations thereon that will be appreciated by those skilled in the art, together with synthetic methods known in the art of organic chemical synthesis. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature and standard reference books in the field. Classic reference works such as, but not limited to, sources such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), which are incorporated herein by reference, are useful and recognized reference texts on organic synthesis known to those skilled in the art.

[0278] The order of certain steps, such as the introduction and removal of protecting groups, may be varied within the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups must be protected from reaction conditions using protecting groups. Protecting groups are also used to distinguish between similar functional groups within a molecule. A list of protecting groups and methods for their introduction and removal can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999.

[0279] It will be appreciated that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups, and thus variously substituted starting materials can be used. While this method generally provides the desired final compound at the end or later in the overall process, in certain instances it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0280] In the synthetic schemes described herein, for simplicity, compounds may be depicted in one particular configuration. Such a particular configuration should not be construed as limiting the disclosure to any one isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers, but it will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0281] Methods include, but are not limited to, those described below. Compounds of the present disclosure can be synthesized by following the steps outlined in general Schemes 1, 2, and 3, which include various orders for combining intermediates or compounds. Starting materials are either commercially available, prepared by known procedures reported in the literature, or prepared as shown below. [ka]

[0282] General Scheme 1: Compound i1 is coupled with compound i2 under basic conditions (e.g., DIPEA) to give compound i3. Compound i3 is deprotected (e.g., under acidic conditions using HCl) and reacted with a carboxylic acid bearing a group A under amide coupling conditions (e.g., HATU followed by DIEA) to give compound i4 (wherein L1 is —NHC(O)).

[0283] General Scheme 2: Compound i5 is reacted with a reducing agent (e.g., LiBH) to give compound i6. Compound i6 is oxidized (e.g., Dess-Martin oxidation) to give compound i7. Compound i7 is coupled with a Boc-protected piperazine using a reductive amination reagent (e.g., sodium triacetoxyborohydride) to give compound i8, which is deprotected (e.g., with TFA) to give compound i9.

[0284] General Scheme 3: Compound i10 is coupled with an amide coupling reagent (e.g., benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate "BOP") to give compound i12, a compound of Formula I, where L2 is -(CH2) p -(4-12-heterocycloalkyl)-C(O)-Y1-Y2-.

[0285] The various examples presented herein are synthesized according to the general procedure shown in Scheme 1, or via similar synthetic routes. [Example]

[0286] The compounds described herein can be prepared using conventional organic synthesis methods and commercially available starting materials or the methods provided herein. The examples and compounds of formula I (including but not limited to) can be prepared as outlined in the examples described herein. It should be noted that a person skilled in the art would know how to modify the procedures shown in the examples to obtain the desired product.

[0287] Analysis method NMR The following conditions were used for acquisition of proton nuclear magnetic resonance (NMR) spectra: NMR spectra were acquired on a 400 MHz or 500 MHz Bruker instrument using either DMSO-d or CDCl as the solvent and internal standard. NMR spectra were measured on a Bruker instrument using either DMSO-d or CDCl as the solvent and internal standard. Raw NMR data were analyzed using either ADC Labs' ACD Spectrus version 2015-01 or MestReNova software.

[0288] Chemical shifts are reported in parts per million (ppm) downfield from the internal tetramethylsilane (TMS) or TMS position inferred from the deuterated NMR solvent. Apparent multiplicities are reported as singlet (s), doublet (d), triplet (t), quadruple (q), or multiplet (m). Peaks that exhibit broadening are denoted as br. Integrals are approximate. It should be noted that integrated intensities, peak shapes, chemical shifts, and coupling constants may vary with solvent, concentration, temperature, pH, and other factors. Furthermore, peaks that overlap or exchange with water or solvent peaks in NMR spectra may not have reliable integrated intensities. In some cases, NMR spectra are obtained with water peak suppression, which can result in overlapping peaks disappearing or changing their shape or integral.

[0289] Liquid chromatography The following preparative and / or analytical (LC / MS) liquid chromatography methods were used. Method A: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size; Mobile Phase A: ACN / HO (5:95) (containing 10 mM AA); Mobile Phase B: ACN / HO (95:5) (containing 10 mM AA); Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow Rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Method B: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particle size; Mobile Phase A: ACN / H2O (5:95) (containing 0.05% TFA); Mobile Phase B: ACN / H2O (95:5) (containing 0.05% TFA); Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow Rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Method Column 6: Column: Waters Acquity BEH C18 2.1 x 50 mm, 1.7 μm particle size; Mobile Phase A: 95:5 acetonitrile:water (with 0.05% TFA); Mobile Phase B: 95:5 acetonitrile:water (with 0.05% TFA); Temperature: 50 °C; Gradient: 0% B to 100% B over 1.00 min, then hold at 100% B for 0.50 min; Flow Rate: 1.0 mL / min; Detection: MS and UV (254 nm). Column: Waters Acquity BEH C18 2.1 x 50 mm 1.7 μm particles; Mobile phase A: 95:5 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50 °C; Gradient: 0% B to 100% B in 1.00 min, then hold at 100% B for 0.50 min; Flow rate: 1.0 mL / min; Detection: MS and UV (254 nm). UHPLC Method D: Column: Waters Acquity BEH C18 2.1 x 50 mm, 1.7 μm particle size; Mobile Phase A: 95:5 acetonitrile:water (with 0.05% TFA); Mobile Phase B: 95:5 acetonitrile:water (with 0.05% TFA); Temperature: 50 °C; Gradient: 0% B to 100% B over 3.00 min, then hold at 100% B for 0.50 min; Flow Rate: 1.0 mL / min; Detection: MS and UV (254 nm). Method P: Mode: Binary Gradient, Pump A: LC-20ADXR, Pump B: LC-20ADXR, Total Flow Rate: 1.5000 mL / min, B Concentration: 30.0%, Oven Temperature: 40°C, PDA Model: SPD-M20A, Lamp: D2, Start Wavelength: 190 nm, End Wavelength: 400 nm, Column Name: XBridge BEH Shield RP18, Length: 30 mm, Inner Diameter: 4.6 mm, Specifications: 2.5 μm particle size, Mobile Phase A: Water / 5 mM NH4HCO3, Mobile Phase B: Acetonitrile; Acquisition Mode: Scan, Polarity: Positive. Method Q: Mode: Binary Gradient, Pump A: LC-40D XR, Pump B: LC-40D XR; Oven Temperature: 40°C; PDA Model: SPD-M20A, Lamp: D2, Start Wavelength: 190 nm, End Wavelength: 400 nm; Column Compound Name: ACE Excel 2C18, Length: 30 mm, Inner Diameter: 3.0 mm, Column Particle Size: 2.0 um, Mobile Phase A: Water + 0.05% TFA, Mobile Phase B: Acetonitrile + 0.05% TFA, Start Time: 0.00 min, End Time: 3.00 min, Acquisition Mode: Scan, Polarity: Positive; LCMS5: Waters Acquity BEH C18 2.1 x 50 mm 1.7 μm particle size; Mobile phase A: 95:5 water:acetonitrile (containing 0.05% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.05% TFA); Temperature: 50 °C; Gradient: 0% B to 100% B over 2.00 min, then hold at 100% B for 0.50 min; Flow rate: 1.0 mL / min; Detection: MS and UV (254 nm)

[0290] Acronyms and Abbreviations Table 1 provides a list of acronyms and abbreviations used herein, along with their meanings. [Table 2-1] [Table 2-2]

[0291] Example 1 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka] A. Methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate To a sealable reaction vial containing 6-ethoxy-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (1.55 g, 5.49 mmol) and methyl 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (2.00 g, 7.36 mmol) in anhydrous DMSO (11 ml) was added diisopropylethylamine (3.00 ml, 17.18 mmol). The vial was sealed, and the mixture was stirred at 90° C. for 16 hours. After the mixture was cooled to room temperature, methyl 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (1.00 g, 3.68 mmol) and diisopropylethylamine (1.50 mL, 8.59 mmol) were added, and the mixture was stirred at 90° C. for an additional 24 hours. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhydrous Na2SO4), filtered, and concentrated in vacuo to give the crude product as an oil. Purification by flash chromatography on silica gel gave the desired product as a pale yellow solid (2.63 g, 90% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.35 - 8.30 (m, 1H), 8.18 (s, 1H), 8.10 (d, J=2.1 Hz, 1H), 7.71 (dd, J=8.8, 2.5 Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 6.79 (dd, J=8.9, 0.7 Hz, 1H), 4.82 (br s, 1H), 4.13 - 4.03 (m, 4H), 3.76 (s, 3H), 3.38 (ddd, J=13.6, 10.6, 3.2 Hz, 2H), 2.27 - 2.16 (m, 2H), 2.14 - 2.02 (m, 2H), 1.50 (t, J=7.0 Hz, 3H), 1.45 (s, 9H). MS:m / z 521.2 [M+H] + (Methods Column 6).

[0292] B. Methyl 4-amino-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-piperidine-4-carboxylate To a solution of methyl 4-((tert-butoxycarbonyl)amino)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate (2.63 g, 5.05 mmol) in DCM (30 ml) was added HCl (4N in dioxane, 30 ml, 120 mmol) dropwise via syringe at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at ambient temperature for 5 hours and then concentrated in vacuo to remove volatiles. The residue was treated with MeCN, then frozen and lyophilized overnight to give the desired product as a trisHCl salt as an off-white solid (2.83 g, 100% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J=2.1 Hz, 1H), 8.58 (s, 1H), 8.35 (d, J=2.5 Hz, 1H), 7.89 (dd, J=8.9, 2.4 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.11 (br d, J=9.1 Hz, 1H), 4.16 (br q, J=7.0 Hz, 2H), 4.06 - 3.97 (m, 2H), 3.81 (s, 3H), 3.76 - 3.64 (m, 3H), 3.53 - 3.44 (m, 1H), 2.18 (ddd, J=13.6, 6.9, 3.8 Hz, 2H), 2.00 - 1.89 (m, 2H), 1.38 (t, J=7.0 Hz, 3H). MS:m / z 421.1 [M+H] + (Methods column 6)

[0293] C. Methyl 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(2,5-difluoro-benzamido)piperidine-4-carboxylate To a solution of methyl 4-amino-1-(5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperidine-4-carboxylate, 3HCl (2.25 g, 4.25 mmol) in DCM (40 mL) was added 2,5-difluorobenzoic acid (1.01 g, 6.38 mmol) and HATU (2.42 g, 6.38 mmol) at room temperature under nitrogen, followed by DIEA (4.71 mL, 27.00 mmol). The resulting mixture was stirred at ambient temperature for 19 hours, then concentrated to half its original volume and directly purified by flash chromatography on silica gel to give the desired product as a yellow solid (1.67 g, 70% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.38 - 8.31 (m, 1H), 8.19 (s, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.77 (ddd, J=8.8, 5.9, 3.2 Hz, 1H), 7.72 (dd, J=8.9, 2.5 Hz, 1H), 7.23 - 7.03 (m, 4H), 6.82 (d, J=8.9 Hz, 1H), 4.22 - 4.13 (m, 2H), 4.09 (q, J=7.0 Hz, 2H), 3.79 (s, 3H), 3.39 (ddd, J=13.8, 10.4, 3.3 Hz, 2H), 2.40 - 2.30 (m, 2H), 2.29 - 2.20 (m, 2H), 1.50 (t, J=7.0 Hz, 3H). Analysis LCMS: m / z 561.3 [M+H] + , RT=1.601 min (UHPLC method D).

[0294] D. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)-piperidin-4-yl)-2,5-difluorobenzamide To a solution of methyl 1-(5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(2,5-difluorobenzamido)piperidine-4-carboxylate (1.55 g, 2.76 mmol) in THF (55 mL) was added lithium borohydride (0.27 g, 11.05 mmol) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred and allowed to warm slowly to room temperature overnight. After 22 h, the reaction mixture was diluted with EtOAc, transferred to a separatory funnel, and carefully washed with 10% aqueous citric acid (ca. 10 mL). The organic layer was washed with water followed by brine, then dried (anhydrous NaSO), filtered, and concentrated in vacuo to give a pale yellow solid (1.15 g, 78%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=2.1 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.96 (s, 1H), 7.75 (dd, J=8.9, 2.5 Hz, 1H), 7.42 - 7.30 (m, 3H), 7.28 (d, J=2.1 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 4.83 (t, J=5.9 Hz, 1H), 4.23 - 4.12 (m, 4H), 3.62 (d, J=6.0 Hz, 2H), 3.25 - 3.13 (m, 2H), 2.26 (br d, J=13.4 Hz, 2H), 1.67 - 1.54 (m, 2H), 1.38 (t, J=7.0 Hz, 3H). Analysis LCMS: m / z 533.4 [M+H] + , RT=1.266 min (UHPLC method D).

[0295] E. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-2,5-difluorobenzamide To a solution of N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-2,5-difluorobenzamide (1.59 g, 2.99 mmol) in DCM (20 ml) was added Dess-Martin periodinane (1.33 g, 3.14 mmol) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred and allowed to warm to room temperature. After 21 h, Dess-Martin periodinane (1.33 g, 3.14 mmol) was added and stirring was continued for an additional 5.5 h. The reaction was quenched with water and extracted with DCM. The organic layer was washed with water and then concentrated in vacuo to give an orange solid. After trituration with DCM, the solid by-product was removed by vacuum filtration to give a filtrate that was purified by flash chromatography on silica gel to give the desired product as a cream-colored solid (711.2 mg, 45% yield). MS: m / z 531.2 [M+H] + (Methods column 6)

[0296] F. Tert-butyl 4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(2,5-difluorobenzamido)piperidin-4-yl)methyl)piperazine-1-carboxylate To a solution of N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-2,5-difluorobenzamide (0.71 g, 1.34 mmol) in DCM (7.5 mL) in a sealable reaction vial at room temperature was added tert-butyl piperazine-1-carboxylate (0.75 g, 4.02 mmol). The mixture was stirred for 1 h, and then sodium triacetoxyborohydride (0.43 g, 2.01 mmol) was added in one portion. The resulting mixture was stirred for 15 h and then directly purified by flash chromatography on silica gel to give the desired product as an off-white solid (732.8 mg, 78% yield). MS: m / z 701.4 [M+H] + (Methods column 6)

[0297] G. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)-2,5-difluorobenzamide To a solution of tert-butyl 4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(2,5-difluorobenzamido)-piperidin-4-yl)methyl)piperazine-1-carboxylate (1.70 g, 2.42 mmol) in DCM (25 ml) was added TFA (3.70 ml, 48.0 mmol) dropwise via syringe at 0° C. under a nitrogen atmosphere. The ice bath was removed, and the reaction solution was stirred at ambient temperature for 5 hours before being concentrated in vacuo to give the crude product as an orange residue. Purification by RP Prep-HPLC gave the desired product as a white solid bis-TFA salt (777.8 mg, 39% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.56 - 8.42 (m, 2H), 8.33 (d, J=2.5 Hz, 1H), 8.20 - 8.08 (m, 1H), 7.80 (dd, J=8.9, 2.6 Hz, 1H), 7.42 - 7.32 (m, 3H), 7.28 (d, J=2.1 Hz, 1H), 7.04 (d, J=8.9 Hz, 1H), 4.24 - 4.13 (m, 4H), 3.24 - 3.14 (m, 2H), 3.12 - 3.01 (m, 4H), 2.88 - 2.70 (m, 5H), 2.36 - 2.27 (m, 2H), 1.70 - 1.58 (m, 2H), 1.38 (t, J=7.0 Hz, 3H). MS:m / z 601.3 [M+H] + (Methods column 6)

[0298] H. Tert-butyl 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoate To a mixture of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, HCl (320.0 mg, 0.88 mmol) in MeCN (12 mL) in a sealable reaction vial at room temperature, tert-butyl 7-bromoheptanoate (256.0 mg, 0.97 mmol) was added, followed by sodium iodide (32.9 mg, 0.22 mmol) and DIEA (0.23 mL, 1.32 mmol). The vial was sealed, and the mixture was stirred at 80 °C. After 15 h, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel to give the desired product as an off-white solid (310.4 mg, 69% yield). MS: m / z 513.3 [M+H] + (Methods column 6)

[0299] I. 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid To a mixture of tert-butyl 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoate (310.4 mg, 0.61 mmol) in DCM (15 mL) was added TFA (1.0 mL, 12.98 mmol) at room temperature under nitrogen. The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated in vacuo to remove volatiles. The resulting residue was treated with MeCN, frozen, and lyophilized overnight to afford the desired product as a TFA salt solid (279.0 mg, 81% yield), which was used without further purification. MS: m / z 457.2 [M+H] (Method column 6).

[0300] J. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide To a sealed vial containing 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid (191.0 mg, 0.34 mmol) in TFA / DMF (3.4 mL) was added BOP (201.0 mg, 0.45 mmol). To the resulting mixture was added the bis-TFA salt of N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)-2,5-difluorobenzamide (198.0 mg, 0.24 mmol) in DMF (3.4 mL), followed by DIEA (0.34 mL, 1.95 mmol). The reaction vial was capped and the reaction mixture was stirred at room temperature. After 90 h, the reaction mixture was diluted with DMF and purified by RP Prep-HPLC to give the title compound (124.9 mg, 50% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) d 10.94 (br s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.6 Hz, 1H), 8.12 (s, 1H), 7.75 (dd, J=8.8, 2.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.38 - 7.31 (m, 3H), 7.28 - 7.23 (m, 2H), 7.15 (d, J=2.3 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 5.09 (dd, J=13.3, 5.0Hz, 1H), 4.38 - 4.29 (m, 1H), 4.26 - 4.12 (m, 5H), 3.41 (br d, J=2.0 Hz, 4H), 3.22 - 3.09 (m, 6H), 2.97 - 2.84 (m, 1H), 2.72 (s, 2H), 2.64 - 2.55 (m, 1H), 2.48 - 2.23 (m, 11H), 2.03 - 1.94 (m, 1H), 1.67 - 1.55 (m, 2H), 1.53 - 1.41 (m, 4H), 1.38 (t, J=7.0 Hz, 3H), 1.33 - 1.25 (m, 4H) - Low integration due to overlap with suppressed water and obscuration by DMSO signal. Analytical LCMS: m / z 1039.3 [M+H] + RT = 1.273 min (UHPLC Method D). Prep-HPLC purification conditions: Column: Phen Axia C18 5μ 30x100 mm; Flow rate: 40 mL / min; Mobile phase A: 95% H2O / 5% MeCN (containing 0.01M NH4OAc). Mobile phase B: 5% H2O / 95% MeCN (containing 0.01M NH4OAc); Gradient: 20–100% B (40 min); Elution: 19.9–21.7 min; Runs: 5.

[0301] Example 2 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide [ka] A. Tert-butyl oct-7-enoate To a stirred solution of oct-7-enoic acid (1000 mg, 7.03 mmol) in DCM (20 mL) and tert-butanol (20 mL) was added DCC (1740 mg, 8.44 mmol) and DMAP (85 mg, 0.70 mmol), and the mixture was stirred at rt overnight. The precipitate was filtered, the filtrate was concentrated, the residue was washed with EtO, and the filtrate was concentrated to give the product (1.3 g, 93% yield) as a colorless oil, which was used directly in the next step without further purification.

[0302] B. Tert-butyl 7-oxoheptanoate To a mixture of tert-butyl oct-7-enoate (100 mg, 0.50 mmol) in tert-butanol (10 mL) and water (10 mL), potassium citrate (15 mg, 0.05 mmol), NMO (120 mg, 1.01 mmol), and citric acid (195 mg, 1.01 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then cooled to 0 °C, sodium periodate (220 mg, 1.01 mmol) was added, and the mixture was stirred for 0.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep TLC to give tert-butyl 7-oxoheptanoate (80 mg, 79% yield) as a colorless oil. 1H NMR (300 MHz, chloroform-d) δ 9.77 (t, J=1.8 Hz, 1H), 2.44 (td, J=7.4, 1.8 Hz, 2H), 2.22 (t, J=7.4 Hz, 2H), 1.63 (ddt, J=15.1, 13.0, 7.4 Hz, 4H), 1.44 (s, 9H), 1.42 - 1.32 (m, 1H), 1.37 - 1.16 (m, 1H).

[0303] C. Tert-butyl 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoate To a stirred solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.15 mmol) in DCM (5 mL) was added tert-butyl 7-oxoheptanoate (60 mg, 0.30 mmol) and DIEA (0.02 mL, 0.30 mmol). The mixture was stirred at rt for 5 min, followed by addition of AcOH (0.02 mL, 0.30 mmol), and the mixture was stirred at rt for 0.5 h. The reaction was cooled to 0 °C, and NaBH(OAc)3 (65 mg, 0.30 mmol) was added. The mixture was stirred at rt for 2 h. The resulting residue was purified by prep-HPLC to afford the desired product (50 mg, 64% yield) as an off-white semi-solid. MS: m / z 513.2 [M+H]+..

[0304] D. 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid To a stirred solution of tert-butyl 7-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]heptanoate (150 mg, 0.29 mmol) in DCM (10 mL) was added TFA (2 mL) and the mixture was stirred at rt for 3 h. Upon completion, the reaction was concentrated to afford the desired product (120 mg, 86% yield) as an off-white semi-solid. MS: m / z 457.3 [M+H] + .

[0305] E. Methyl 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(3-fluoropicolinamido)piperidine-4-carboxylate To a mixture of methyl 4-amino-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]piperidine-4-carboxylate (1200 mg, 2.85 mmol) and 3-fluoropyridine-2-carboxylic acid (485 mg, 3.42 mmol) in DMF (20 mL) was added HATU (1300 mg, 3.42 mmol) and DIEA (0.66 mL, 8.55 mmol), and the resulting mixture was stirred at rt for 2 h. The reaction was quenched with ice-water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over NaSO, and filtered. After concentration under reduced pressure, flash chromatography on silica gel afforded the desired product (1240 mg, 80% yield) as an off-white solid. MS: m / z 544 [M+H].

[0306] F. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(hydroxymethyl)piperidin-4-yl)-3-fluoropicolinamide To a solution of methyl 1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[(3-fluoropyridine-2-carbonyl)amino]piperidine-4-carboxylate (1200 mg, 2.21 mmol) in THF (30 mL) and ethanol (30 mL) was added CaCl (490 mg, 4.42 mmol) at rt. The resulting mixture was stirred at rt for 3 h, then cooled to 0 °C and NaBH (167 mg, 4.42 mmol) was added. The mixture was stirred at ambient temperature (~15 °C) overnight. Another batch of NaBH (167 mg, 4.42 mmol) was added at 0 °C, and the mixture was stirred at ambient temperature for an additional 8 h. A third batch of NaBH4 (83.0 mg, 2.21 mmol) was added at 0 °C, and the mixture was stirred for an additional 18 h. It was cooled to 0 °C in an ice / HO bath and quenched by the dropwise addition of 10% citric acid. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified on a reverse-phase column (eluted with 0.5% TFA in water / MeCN) to give the desired product (550 mg, 48.3% yield) as an off-white semi-solid. MS: m / z 515.2 [M+H] + .

[0307] G. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-formylpiperidin-4-yl)-3-fluoropicolinamide To a solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(hydroxymethyl)-4-piperidyl]-3-fluoro-pyridine-2-carboxamide (400 mg, 0.78 mmol) in DCM (20 mL) was added Dess-Martin periodinane (410 mg, 1.16 mmol) at 0 °C. The reaction solution was stirred at rt for 3 h and then purified by prep-TLC (eluted with EA:DCM = 2:1) to give the desired product (220 mg, 55% yield) as an off-white solid. MS: m / z 514.1 [M+H]+ .

[0308] H. Tert-butyl 4-((1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(3-fluoropicolinamido)piperidin-4-yl)methyl)piperazine-1-carboxylate To a stirred solution of N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-formyl-4-piperidyl]-3-fluoro-pyridine-2-carboxamide (120 mg, 0.23 mmol) and tert-butyl piperazine-1-carboxylate (130 mg, 0.70 mmol) in DCM (10 mL) was added Ti(OiPr) (133 mg, 0.47 mmol), and the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated, and the residue was purified by prep-TLC (EA:DCM=2:1) to give the desired product (130 mg, 81% yield) as an off-white solid. MS: m / z 684.5 [M+H].

[0309] I. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)-3-fluoropicolinamide [ka] To a mixture of tert-butyl 4-[[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[(3-fluoropyridine-2-carbonyl)amino]-4-piperidyl]methyl]piperazine-1-carboxylate (30 mg, 0.04 mmol) in DCM (5 mL), TFA (1 mL) was added, and the mixture was stirred at rt for 3 hours. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to obtain the desired product (11.8 mg, 0.02 mmol, 46.08% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=2.1 Hz, 1H), 8.58 (s, 1H), 8.52 - 8.41 (m, 2H), 8.33 (d, J=2.5 Hz, 1H), 8.24 (brs, 1H), 7.89 - 7.79 (m, 2H), 7.67 - 7.62 (m, 1H), 7.65 (dt, J=8.5, 4.3 Hz, 1H), 7.04 -7.02 (m, 1H), 4.21 - 4.13 (m, 4H), 3.19 - 3.07 (m, 6H), 2.84 - 2.75 (m 6), 2.39 - 2.35 (m, 2H), 1.71 - 1.64 (M, 2H), 1.38 (t, J=7.0 Hz, 3H);Analysis LCMS ESI-MS(+) m / z 584.5 [M+H] + , RT = 1.31 min, Purity: 97% (Method Q). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 38% B, 38% B in 10 min; RT = 7.62 min.

[0310] J. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide To a stirred solution of 7-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]heptanoic acid (20 mg, 0.04 mmol) in DMF (1 mL) was added N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)-3-fluoropicolinamide (23.16 mg, 0.04 mmol), TCFH (24.99 mg, 0.07 mmol), and NMI (0.01 mL, 0.13 mmol). The mixture was stirred at rt for 2 hours. The reaction mixture was subjected to prep-HPLC purification to afford the title compound (21 mg, 48% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.88 (s, 1H), 8.70 - 8.57 (m, 2H), 8.53 - 8.50 (m, 1H), 8.36 (d, J=2.6 Hz, 1H), 7.94 - 7.87 (m, 1H), 7.83 (dd, J=8.8, 2.6 Hz, 1H), 7.73 - 7.67 (m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.21 - 7.12 (m, 2H), 7.08 (d, J=8.8 Hz, 1H), 5.07 (dd, J=13.3, 5.1 Hz, 1H), 4.39 - 4.20 (m, 6H), 4.19 - 4.14 (m, 3H), 3.80 - 3.47 (m, 6H), 3.25 - 3.07 (m, 10H), 2.98 - 2.84 (m, 1H), 2.64 - 2.52 (m, 5H), 2.46 - 2.39(m, 1H), 2.38 - 2.30 (m, 3H), 2.03 - 1.92 (m, 1H), 1.82 - 1.64 (m, 4H), 1.57 - 1.45 (m, 2H), 1.43 - 1.27 (m, 7H);Analytical LCMS ESI-MS(+) m / z 1022.6 [M+H] +, RT = 1.32 min, Purity: 97% (Method Q). Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 22% B, 22% B in 12 min; RT = 17.05 min.

[0311] Example 3 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide [ka]

[0312] The title compound was prepared as a white solid in 61% yield by following the procedure of Example 2 using N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)-3-methylbutanamide in Step E. 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.86 (s, 1H), 8.67 (d, J=2.1 Hz, 1H), 8.58 (s, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.02 (s, 1H), 7.83 (dd, J=9.0, 2.5 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.06 (d, J=9.0 Hz, 1H), 5.10 - 5.01 (m, 1H), 4.44 - 4.32 (m, 2H), 4.30 - 4.10 (m, 6H), 4.08 - 3.96 (m, 3H), 3.65 - 3.41 (m, 7H), 3.21 - 3.06 (m, 12H), 2.65 - 2.55 (m, 1H), 2.40 - 2.27(m, 4H), 2.18 - 2.10 (m, 2H), 2.06 - 1.94 (m, 2H), 1.74 - 1.60 (m, 4H), 1.56 - 1.45 (m, 2H), 1.43 - 1.27 (m, 7H),0.91 (d, J=6.4 Hz, 6H);Analysis LCMS ESI-MS(+) m / z 983.5 [M+H] + , RT=1.71 min, Purity: 99% (Method P); Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B~30% B, 30% in 13 min B;RT=12.65 min.

[0313] Example 4 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6 dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide [ka]

[0314] A. Tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoate To a stirred solution of 3-[1-oxo-6-(4-piperidyl)isoindolin-2-yl]piperidine-2,6-dione (50 mg, 0.15 mmol) in CHCN (5 mL) was added tert-butyl prop-2-enoate (40 mg, 0.31 mmol) and DBU (0.05 mL, 0.31 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was purified by reverse-phase column chromatography to give the desired product (60 mg, 86% yield) as an off-white semi-solid. MS: m / z 456.4 [M+H] + .

[0315] B. 3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoic acid To a stirred solution of tert-butyl 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoate (60 mg, 0.13 mmol) in DCM (10 mL) was added TFA (0.02 mL) and the mixture was stirred at rt for 3 h. The reaction mixture was concentrated to give the desired product (50 mg, 91% yield) as an off-white semi-solid. MS: m / z 400.3 [M+H] + .

[0316] C. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide To a stirred solution of 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoic acid (30 mg, 0.08 mmol) in DMF (3 mL), N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(piperazin-1-ylmethyl)-4-piperidyl]-3-fluoro-pyridine-2-carboxamide (44 mg, 0.08 mmol), HATU (60 mg, 0.15 mmol), and DIEA (0.04 mL, 0.23 mmol) were added, and the mixture was stirred at 0° C. for 2 hours. The reaction solution was purified by reverse-phase column chromatography to give a crude product, which was further purified by Prep-HPLC to give the title compound (25.8 mg, 35% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.80 (brs, 1H), 8.68 - 8.58 (m, 2H), 8.52 - 8.50 (m, 1H), 8.46 (s, 1H), 8.36 (d, J=2.6 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.73 - 7.67 (m, 1H), 7.62 - 7.56 (m, 2H), 7.55 - 7.51 (m, 1H), 7.31 - 7.24 (m, 1H), 7.13 - 7.00 (m, 1H), 5.13 - 5.07 (m, 1H), 4.49 - 4.40 (m, 2H), 4.35 - 4.24 (m, 4H), 4.16 - 4.12 (m, 2H), 3.70 - 3.51 (m, 6H), 3.43 - 3.26 (m, 4H), 3.23 - 3.05 (m, 5H), 3.01 - 3.83 (m, 5H), 2.65 - 2.57 (m, 2H), 2.48 - 2.33 (m, 2H), 2.10 - 1.89 (m, 5H), 1.84 - 1.70 (m, 2H), 1.39 (t, J = 7.0 Hz, 3H) ESI-MS(+) m / z 965.6 [M+H] +, RT = 1.33 min, Purity: 98% (Method Q); Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30 x 150 mm 5 μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 22% B, 22% B in 12 min; RT = 17.05 min.

[0317] Example 5 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka]

[0318] A. Tert-butyl 5-(methoxy(methyl)amino)-5-oxopentanoate To a stirred solution of 5-tert-butoxy-5-oxo-pentanoic acid (1.0 g, 5.31 mmol) in DCM (20 mL) at -5 °C, N-methoxymethanamine hydrogen hydrochloride (1.0 g, 10.63 mmol), HATU (3.0 g, 7.97 mmol), and DIEA (1.63 mL, 21.25 mmol) were added. The reaction mixture was stirred at rt for 3 h, concentrated, and purified by silica gel column chromatography (eluted with PE:EA = 10:1) to give the desired product (1.1 g, 89.5% yield) as a colorless oil. MS: m / z 232 [M+H] + .

[0319] B. Tert-butyl 5-oxopentanoate To a stirred solution of tert-butyl 5-[methoxy(methyl)amino]-5-oxo-pentanoate (800 mg, 3.46 mmol) in THF (10 mL) was added dropwise a solution of LiAlH (1 mol / L in THF, 6 mL, 6 mmol) at 0 °C, and the mixture was stirred for 3 min. A saturated aqueous solution of sodium sulfate was slowly added dropwise to quench the reaction, and the resulting mixture was filtered through Celite, and the filter cake was thoroughly washed with ethyl acetate. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (eluted with PE:EA = 3:1) afforded tert-butyl 5-oxopentanoate (300 mg, 50.4% yield) as a colorless oil. 1 H NMR (300 MHz, chloroform-d) δ 9.78 (t, J=1.5 Hz, 1H), 2.63–2.43 (m, 2H), 2.30–2.25 (m, 2H), 1.96–1.86 (m, 2H), 1.45 (s, 9H).

[0320] C. tert-Butyl 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoindolin-5-yl)piperazin-1-yl)pentanoate To a stirred solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (100 mg, 0.30 mmol) in DCM (1 mL) was added tert-butyl 5-oxopentanoate (52.45 mg, 0.30 mmol). The mixture was stirred at room temperature for 1 hour. NaBH(OAc)3 (129.09 mg, 0.61 mmol) was added at 0 °C and stirred for 2 hours. The reaction mixture was concentrated, and the resulting crude product was purified by reverse-phase column chromatography to give the desired product (110 mg, 74.5% yield) as a white solid. MS: m / z 485 [M+H] + .

[0321] D. 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoic acid To a stirred solution of tert-butyl 5-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pentanoate (100 mg, 0.21 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 2 hours and then concentrated to give the crude product, which was used directly in the next step without purification. MS: [M+H] + m / z 429.

[0322] E. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide To a stirred solution of 5-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pentanoic acid (30 mg, 0.07 mmol) in DMF (3 mL) was added N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(piperazin-1-ylmethyl)-4-piperidyl]-2,5-difluoro-benzamide (43 mg, 0.07 mmol), HATU (40 mg, 0.11 mmol), and DIEA (24 mg, 0.22 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by reverse-phase column chromatography to give the crude product, which was further purified by Prep-HPLC to give the title compound (27.8 mg, 38.1% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.67 (brs, 1H), 8.68 (d, J=2.1 Hz, 1H), 8.59 (s, 1H), 8.36 - 8.35(m, 1H), 7.83 -7.80 (m, 1H), 7.62 - 7.59 (m, 1H), 7.53 -7.37 (m, 3H),7.28 (d, J=2.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.09 - 7.03 (m, 1H), 5.10 - 5.04 (m, 1H), 4.42 - 4.10 (m, 11H), 4.09 - 3.99 (m, 3H), 3.64 - 3.46 (m, 5H), 3.28 - 3.07 (m, 9H), 3.01 - 2.83 (m, 2H), 2.65 - 2.56 (m, 2H), 2.46 - 2.35 (s, 4H), 2.02 - 1.92 (m, 1H), 1.76 - 1.64 (m, 3H), 1.60 - 1.51 (m, 2H), 1.39 (t, J=6.9 Hz, 3H);Analysis LCMS ESI-MS(+) m / z 1011.6 [M+H] + , RT = 1.43 min, Purity: 97% (Method Q); Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 33% B, 33% B in 10 min; RT = 10.8 min.

[0323] Example 6 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka] A. Tert-butyl 2-oxoacetate To a stirred solution of tert-butyl prop-2-enoate (1000 mg, 7.8 mmol) in water (30 mL) and tert-butanol (30 mL) was added potassium citrate (240 mg, 0.78 mmol), citric acid (3000 mg, 0.78 mmol), and NMO (1830 mg, 15.6 mmol). The mixture was stirred at rt for 1 h, then sodium periodate (2503 mg, 11.7 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was diluted with ethyl acetate, and the biphasic mixture was separated in a separatory funnel. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, and filtered. After concentration under reduced pressure, Prep-TLC gave tert-butyl 2-oxoacetate (340 mg, 33.5% yield) as a pale yellow oil.

[0324] B. Tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)acetate To a stirred solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (70 mg, 0.21 mmol) in DCM (5 mL) was added tert-butyl 2-oxoacetate (55 mg, 0.43 mmol) and DIEA (0.04 mL, 0.43 mmol). This was stirred at rt for 5 minutes, and acetic acid (0.02 mL, 0.43 mmol) was added. The reaction mixture was stirred at rt for 0.5 hours, and NaBH(OAc)3 (90 mg, 0.43 mmol) was added at 0 °C. This mixture was stirred at rt for 4 hours, concentrated, and purified by flash chromatography to give the desired product (80 mg, 81.5% yield) as an off-white semi-solid. MS: [M+H] + m / z 443.7.

[0325] C. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)acetic acid To a stirred solution of tert-butyl 2-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]acetate (80 mg, 0.18 mmol) in DCM (10 mL) was added TFA (0.03 mL). The reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated to give 2-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]acetic acid (65 mg, 89.4% yield), which was used in the next step without purification. MS: m / z [M+H] + 387.3.

[0326] D. N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide To a stirred solution of 2-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]acetic acid (30 mg, 0.08 mmol) in DMF (3 mL), N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(piperazin-1-ylmethyl)-4-piperidyl]-2,5-difluorobenzamide (48 mg, 0.08 mmol) and HATU (45 mg, 0.12 mmol) were added. After cooling to 0 °C, DIEA (0.02 mL, 0.23 mmol) was added and the mixture was stirred at 0 °C for 2 h. The reaction solution was purified by pre-HPLC to obtain the desired product (11.9 mg, 15.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.18 (brs, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J=2.6 Hz, 1H), 7.84 (dd, J=8.9, 2.6 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.51 - 7.33 (m, 3H), 7.29 (d, J=2.0 Hz, 1H), 7.20 - 7.11 (m, 2H), 7.08 (d, J=8.9 Hz, 1H), 5.07 (dd, J=13.3, 5.1 Hz, 1H), 4.46 - 4.33 (m, 3H), 4.30 - 4.13 (m, 5H), 4.02 - 3.89 (m, 2H), 3.67 - 3.06 (m, 15H), 2.98 - 2.85 (m, 2H), 2.64 - 2.55 (m, 3H), 2.40 - 2.35 (m, 3H), 2.41 (s, 1H), 1.79 - 1.64 (m, 2H), 1.39 (t, J=6.9 Hz, 3H);Analysis LCMS ESI-MS(+) m / z 969.3 [M+H] + , RT = 1.63 min, Purity: 99% (Method Q); Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 33% B, 33% B in 10 min; RT = 10.25 min.

[0327] Example 7 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)cyclopropanecarboxamide [ka] To a stirred solution of 7-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]heptanoic acid (20 mg, 0.04 mmol) in DMF (1 mL) was added N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(piperazin-1-ylmethyl)-4-piperidyl]cyclopropanecarboxamide (23.16 mg, 0.04 mmol), TCFH (24.99 mg, 0.07 mmol), and NMI (0.01 mL, 0.13 mmol). The mixture was stirred at rt for 2 h, and the reaction solution was directly subjected to Prep-HPLC purification to give the title compound (10.5 mg, 0.01 mmol, 24% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.73 - 8.53 (m, 2H), 8.35 - 8.14 (m, 1H), 7.83 - 7.70 (m, 2H), 7.56 - 7.53 (m, 1H), 7.28 - 7.26 (m, 1H), 7.11 - 7.08 (m, 2H), 6.97 - 6.94 (m, 1H), 5.06 (dd, J=13.4, 5.3 Hz, 1H), 4.40 - 4.08 (m, 6H), 3.54 - 3.28 (m, 10H), 3.13 - 3.06 (m, 2H), 2.95 - 2.86 (m, 2H), 2.68 - 2.60 (m, 5H), 2.47 - 2.40 (m, 5H), 2.32 - 2.16 (m, 4H), 2.02 - 1.70 (m, 3H), 1.64 - 1.46 (m, 6H), 1.40 - 1.29 (m, 7H), 0.64 - 0.59 (m, 4H); Analysis LCMS ESI-MS(+) m / z 968 [M+H] +, RT = 1.18 min, Purity: 99.8% (Method Q); Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 27% B, 27% B in 10 min; RT = 9.85 min.

[0328] Example 8 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide [ka] The title compound was prepared as a white solid in 18% yield according to the preparation of Example 4 using N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)-3-methylbutanamide in Step C. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.64 (d, J=2.1 Hz, 1H), 8.57 (s, 1H), 8.31 (d, J=2.6 Hz, 1H), 8.18 (s, 1H), 7.74 (dd, J=8.9, 2.6 Hz, 1H), 7.56 - 7.52 (m, 3H), 7.40 (s, 1H), 7.26 (d, J=2.1 Hz, 1H), 6.95 (d, J=8.9 Hz, 1H), 5.13 - 5.08 (m, 1H), 4.43 - 4.39 (m, 1H), 4.30 - 4.26 (m, 1H), 4.20 - 4.10 (m, 4H), 3.45 - 3.41(m, 7H), 3.11 - 2.98 (m, 5H), 2.98 - 2.85 (m, 1H), 2.71 - 2.56 (m, 6H), 2.44 - 2.34(m, 3H), 2.28 - 2.06 (m, 4H), 2.05 - 1.92 (m, 4H), 1.84 - 1.76 (m, 2H), 1.73 - 1.61 (m, 2H), 1.59 - 1.49 (m, 2H), 1.38 (t, J=6.9 Hz, 3H), 0.89 (d, J=6.1 Hz, 6H); Analytical LCMS ESI-MS(+) m / z 926.6 [M+H] + , RT=1.41 min, Purity: 96.9% (Method Q); Prep-HPLC purification conditions: カラム: mL / min;グラジエント:10 minで2% B~27% B, 27% B;RT=9.87 min.

[0329] Example 9 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)cyclopropanecarboxamide [ka] The title compound was prepared as a white solid in 15% yield according to the preparation of Example 4 using N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(piperazin-1-ylmethyl)piperidin-4-yl)cyclopropanecarboxamide in Step C. 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.61 (m, 1H), 8.57 - 8.55 (m, 1H), 8.31 (d, J=2.5 Hz, 1H), 8.23 (s, 2H), 7.75 (dd, J=8.8, 2.5 Hz, 1H), 7.60 - 7.58 (m, 1H), 7.56 - 7.53 (m, 1H), 7.26 - 7.24 (m, 1H), 6.96 (d, J=8.8 Hz, 1H), 5.09 (dd, J=13.3, 5.1 Hz, 1H), 4.46 - 4.41 (m, 1H), 4.33 - 4.28 (m, 1H), 4.17 - 4.10 (m, 4H), 3.62 - 3.59 (m, 2H), 3.51 - 3.45 (m, 4H), 3.29 - 3.26 (m, 2H), 3.13 - 3.06 (m, 2H), 2.95 - 2.86 (m, 3H), 2.84 - 2.75 (m, 1H), 2.71 - 2.58 (m, 6H), 2.47 - 2.36 (m, 4H), 2.25 - 2.22 (m, 2H), 2.09 - 1.95 (m, 1H), 1.93 - 1.69 (m, 4H), 1.60 - 1.53 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H), 0.83 - 0.32 (m, 4H); analytical LCMS ESI-MS (+) m / z 910 [M+H] + , RT=1.15 min, Purity: 99.3% (Method Q); Prep-HPLC purification conditions: カラム: mL / min;グラジエント:10 minで2% B~25% B, 25% B;RT=10.15 min.

[0330] Example 10 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka] The title compound was prepared as a white solid in 30% overall yield according to the preparation of Example 5 using 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione in Step C. 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=2.0 Hz, 1H), 8.59 - 8.58 (m, 1H), 8.37 (d, J=2.5 Hz, 1H), 7.85 (dd, J=8.9, 2.5 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.57 - 7.34 (m, 5H), 7.29 (d, J=2.0 Hz, 1H), 7.09 (d, J=8.9 Hz, 1H), 5.12 (dd, J=13.2, 5.1 Hz, 1H), 4.49 - 4.43 (m, 1H), 4.38 - 4.23 (m, 3H), 4.16 - 4.12 (m, 2H), 3.69 - 3.55 (m, 4H), 3.51 - 3.49 (m, 4H), 3.38 - 2.84 (m, 13H), 2.67 - 2.55 (m, 1H), 2.48 - 2.32 (m, 4H), 2.13 - 1.84 (m, 5H), 1.81 - 1.48 (m, 6H), 1.39 (t, J=6.9 Hz, 3H). MS:m / z:[M+H] +1010.6. Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 6% B to 36% B, 36% B in 10 min; RT = 9.67 min.

[0331] Example 11 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka] The title compound was prepared as a white solid in 17% overall yield according to the preparation of Example 5 using tert-butyl 7-oxoheptanoate and 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione in Step C. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (d, J=2.1 Hz, 1H), 8.59 - 8.56 (m, 1H), 8.36 (d, J=2.5 Hz, 1H), 7.85 (dd, J=8.9, 2.5 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.56 - 7.37 (m, 5H), 7.29 (d, J=2.1 Hz, 1H), 7.09 (d, J=8.9 Hz, 1H), 5.14 - 5.09 (m, 1H), 4.49 -4.27 (m, 3H), 4.16 - 4.12 (m, 3H), 3.69 - 3.61 (m, 4H), 3.59 - 3.54 (m, 7H), 3.30 - 2.84 (m, 10H), 2.67 - 2.57 (m, 1H), 2.48 - 2.31 (m, 4H), 2.12 - 2.85 (m, 5H), 1.81 - 1.64 (m, 4H), 1.59 - 1.47 (m, 2H), 1.41 - 1.33 (m, 7H);MS:m / z [M+H] + 1038.7, 98% purity. Prep-HPLC purification conditions: Column: Xselect CSH C18 OBD Column 30x150mm 5μm; Mobile phase A: Water (0.5% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 32% B, 32% B in 10 min; RT = 12.63 min.

[0332] Example 12 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka] To a solution of 3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]propanoic acid (38 mg, 0.09 mmol), N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-(piperazin-1-ylmethyl)-4-piperidyl]-2,5-difluorobenzamide (57 mg, 0.09 mmol) in DMA (2 mL) was added T3P (45.27 mg, 0.14 mmol) and DIEA (0.02 mL, 0.28 mmol). The mixture was stirred at rt for 2 h. Upon completion, the resulting solution was purified by Prep-HPLC to afford the desired product (19.1 mg, 20.15% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (d, J=2.3 Hz, 1H), 8.56 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 7.91 - 7.79 (m, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.39 - 7.31 (m, 3H), 7.31 - 7.23 (m, 2H), 7.17 (d, J=2.3 Hz, 1H), 6.98 (d, J=8.9 Hz,1H), 5.19 - 4.98 (m, 1H), 4.38 - 4.32 (m, 1H), 4.28 - 4.09 (m, 5H), 3.49 - 3.45 (m, 5H), 3.22 - 3.09 (m, 6H), 2.98 - 2.81 (m, 1H), 2.74 - 2.72 (m, 2H), 2.66 - 2.53 (m, 8H), 2.46 - 2.42 (m, 4H), 2.42 - 2.28 (m, 3H), 2.07 - 1.95 (m, 1H), 1.62 - 1.58 (m, 2H), 1.39 (t, J=6.9 Hz, 3H). Analysis LCMS ESI-MS(+) m / z 984 [M+H] +, RT=1.60 min, Purity: 95% (Method Q); Prep-HPLC purification conditions: XBridge Prep OBD C18 Column, 30x150 mm, 5μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.1%NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 42% B to 52% B, 52% B in 8 min; RT = 7.85 min.

[0333] Example 13 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka] The title compound was prepared as a white solid in 11.82% overall yield according to the preparation of Example 5 using 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione in Step C. 1H NMR (400 MHz, DMSO-d6) δ 8.55 - 8.47 (m, 2H), 8.27 (d, J=2.6 Hz, 1H), 8.24 (s, 1H), 7.73 (dd, J=8.8, 2.6 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.34 -7.24 (m, 4H), 7.22 - 7.20 (m, 2H), 6.95 (d, J=9.0 Hz, 1H), 5.01 (dd, J=13.3, 5.1 Hz, 1H), 4.35 (d, J=17.1 Hz, 1H), 4.22 (d, J=17.1Hz, 1H), 4.14 - 4.08 (m, 4H), 3.43 -3.36 (m, 4H), 3.30 - 3.24 (m, 4H), 3.11 (t, J=12.4 Hz, 2H), 2.87 -2.80 (m, 5H), 2.73 -2.58 (m, 6H), 2.48 -2.43 (m, Analysis LCMS ESI-MS(+) m / z 1011.6 [M+H] + , RT = 1.43 min, Purity: 95.6% (Method Q); Prep-HPLC purification conditions: Column: Xselect CSH F-Phenyl OBD Column 19 x 150 mm 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 10% B to 32% B, 32% B in 8 min; RT = 7.67 min.

[0334] Example 14 N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide [ka] The title compound was prepared as a white solid in 12.2% overall yield following the preparation of Example 6 using tert-butyl 4-oxobutanoate in Step B. 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (d, J=2.5 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.81 - 7.72 (m, 1H), 7.52 (d, J=9.1 Hz, 1H), 7.43 - 7.31 (m, 3H), 7.27 (d, J=2.5 Hz, 1H), 7.05 - 7.03 (m, 2H), 6.97 (d, J=9.0 Hz, 1H), 5.04 (dd, J=13.2, 5.1 Hz, 1H), 4.33 - 4.30 (m, 1H), 4.25 - 4.05 (m, 5H), 3.38 (d, J=2.5 Hz, 8H), 3.26 (d, J=5.8 Hz, 4H), 3.15 (t, J=12.4 Hz, 2H), 2.98 - 2.79 (m, 1H), 2.73 - 2.71 (m, 2H), 2.61 - 2.58 (m, 1H), 2.47 (s, 3H), 2.41 - 2.24 (m, 8H), 2.09 - 1.92 (m, 1H), 1.78 - 1.57 (m, 4H), 1.38 (t, J=6.9 Hz, 3H);LCMS ESI-MS(+) m / z 998 [M+H] + , RT=1.44 min, Purity: 97.2% (Method Q); Prep-HPLC conditions: Column: XSelect CSH Prep C18 OBD Column, 19x250 mm, 5μm; Mobile phase A: Water (10 mmol / L NH4HCO3+0.1%NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 47% B to 50% B, 50% B in 12 min; RT = 10.5 min. Using methods similar to those described in Examples 1-14, the following titled Examples 15-30 were obtained.

[0335] Example 15 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka] The title compound was prepared as a white solid according to the preparation of Example 1 using in Step H 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione, HCl and tert-butyl 3-bromopropanoate. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.19 - 8.08 (m, 1H), 7.75 (dd, J=8.8, 2.6 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.42 - 7.29 (m, 4H), 7.27 (d, J=2.1 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 5.14 - 5.05 (m, 1H), 4.46 - 4.25 (m, 2H), 4.24 - 4.12 (m, 4H), 3.43 (br d, J=1.1 Hz, 4H), 3.22 - 3.11 (m, 2H), 3.03 - 2.84 (m, 3H), 2.74 (s, 2H), 2.69 - 2.52 (m, Analysis LCMS: m / z 982.3 [M+H] +RT = 1.238 min (UHPLC Method D). Prep-HPLC purification conditions: Column: Phen Axia C18 5μ 30 x 100 mm; Flow rate: 40 mL / min; Mobile phase A: 95% H2O / 5% MeCN (containing 0.01 M NH4OAc). Mobile phase B: 5% H2O / 95% MeCN (containing 0.01 M NH4OAc); Gradient: 20–80% B (40 min); Elution: 20.8–22.8 min; Run number: 2.

[0336] Example 16 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka] The title compound was prepared as a white solid according to the preparation of Example 1 using in Step H 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione, HCl. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.12 (s, 1H), 7.75 (dd, J=8.8, 2.6 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.34 (ddq, J=7.8, 5.1, 2.6 Hz, 3H), 7.27 (d, J=2.0 Hz, 1H), 7.08 - 7.02 (m, 2H), 6.97 (d, J=8.8 Hz, 1H), 5.09 - 5.00 (m, 1H), 4.36 - 4.28 (m, 1H), 4.24 - 4.12 (m, 5H), 3.45 - 3.35 (m, 4H), 3.29 - 3.24 (m, 4H), 3.22 - 3.10 (m, 2H), 2.96 - 2.83 (m, 1H), 2.72 (s, 2H), 2.62 - 2.54 (m, 1H), 2.41 - 2.23 (m, 8H), 2.01 - 1.92 (m, 1H), 1.68 - 1.56 (m, 2H), 1.54 - 1.42 (m, 4H), 1.38 (t, J=6.9 Hz, 3H), 1.33 - 1.25 (m, 4H) - Some product peaks were obscured by DMSO signals; analytical LCMS: m / z 1039.5 [M+H] + RT = 1.254 min (UHPLC Method D). Prep-HPLC purification conditions: Column: Phen Axia C18 5μ 30 x 100 mm; Flow rate: 40 mL / min; Mobile phase A: 95% H2O / 5% MeCN (containing 0.01 M NH4OAc). Mobile phase B: 5% H2O / 95% MeCN (containing 0.01 M NH4OAc); Gradient: 10–100% B (40 min); Elution: 25.5–27.1 min; Run number: 3.

[0337] Example 17 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka] The title compound was prepared as a white solid according to the preparation of Example 1 using in Step H 3-(1-oxo-6-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione, HCl and tert-butyl 3-bromopropanoate. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (br s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.9 Hz, 1H), 8.13 (s, 1H), 7.75 (dd, J=8.9, 2.6 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.39 - 7.30 (m, 3H), 7.27 (d, J=2.1 Hz, 1H), 6.97 (d, J=9.1 Hz, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H), 4.45 - 4.36 (m, 1H), 4.34 - 4.24 (m, 1H), 4.23 - 4.11 (m, 4H), 3.50 - 3.36 (m, 4H), 3.22 - 3.11 (m, 2H), 3.02 - 2.84 (m, 3H), 2.74 (s, 2H), 2.68 - 2.53 (m, 6H), 2.49 - 2.29 (m, 7H), 2.12 - 1.94 (m, 3H), 1.82 - 1.74 (m, 2H), 1.71 - 1.55 (m, 4H), 1.38 (t, J=6.9 Hz, 3H); Analysis LCMS: m / z 982.3 [M+H] +RT=1.309 min (UHPLC Method D). Prep-HPLC purification conditions: Column: Phen Axia C18 5μ 30x100mm; Flow rate: 40mL / min; Mobile phase A: 95% H2O / 5% MeCN (containing 0.01M NH4OAc). Mobile phase B: 5% H2O / 95% MeCN (containing 0.01M NH4OAc); Gradient: 10–100% B (40 min); Elution: 20.1–24.5 min; Runs: 5.

[0338] Example 18 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}pentanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0339] Example 19 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0340] Example 20 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0341] Example 21 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0342] Example 22 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)heptanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0343] Example 23 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[9-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)nonanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0344] Example 24 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka] The title compound was prepared as a solid according to the preparation of Example 1 using in Step H 1-(6-amino-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione and tert-butyl 9-bromononanoate. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (br d, J=0.8 Hz, 1H), 8.65 (d, J=2.1 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=2.8 Hz, 1H), 8.12 (s, 1H), 7.75 (dd, J=8.9, 2.6 Hz, 1H), 7.37 - 7.31 (m, 3H), 7.28 - 7.24 (m, 2H), 6.97 (d, J=8.9 Hz, 1H), 6.51 (dd, J=8.9, 1.8 Hz, 1H), 6.29 (d, J=1.7 Hz, 1H), 5.90 (t, J=5.4 Hz, 1H), 4.23 - 4.12 (m, 4H), 3.85 (t, J=6.7 Hz, 2H), 3.80 (s, 3H), 3.45 - 3.36 (m, 4H), 3.21 - 3.11 (m, 2H), 3.09 - 3.01 (m, 2H), 2.74 - 2.66 (m, 4H), 2.48 - 2.43 (m, 3H), 2.37 - 2.29 (m, 2H), 2.26 (br t, J=7.5 Hz, 2H), 1.66 - 1.56 (m, 4H), 1.52 - 1.44 (m, 2H), 1.42 - 1.22 (m, 12H); Analytical LCMS: m / z 998.7 [M+H] + , RT=1.459 min (UHPLC method D). Prep-HPLC purification conditions: カラム: Phen Axia C18 5μ 30x100mm; flow rate: 40mL / min flow rate; mobile phase A: 95% H2O / 5% MeCN (0.01M NH4OAc). Mobile phase B: 5% H2O / 95% MeCN (0.01M NH4OAc); グラジエント: 20~100%B (40 min); dissolution: 23.7~25.5 minutes; number of application times: 5.

[0345] Example 25 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0346] Example 26 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[5-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)pentanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0347] Example 27 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)heptanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0348] Example 28 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[11-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)undecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0349] Example 29 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[13-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)tridecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide [ka]

[0350] Example 30 N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[15-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)pentadecanoyl]piperazin-1-yl}methyl)...

Claims

1. Formula I: 【Chemical 1】 [In the formula, R 1 -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 F, halogen or 1-methyl-pyrazol-4-yl; A is independently H, OH, C 1 -C 6 Alkyl, C 3 -C 8 cycloalkyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, aryl or heteroaryl optionally comprises one or more R 2 where R 2 are independently halogens, OH, C 1 -C 3 Alkyl or C 1 -C 3 is alkoxy; B is a group capable of binding an E3 ligase; L 1 are independently bonded, -C 1 -C 3 alkylenyl-, -NHCO-, -CONH-, -O-, or -NH-; L 2 are independently -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -C(O)-Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-C(O)-Y 1 -Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-C(O)-Y 1 -C(O)-Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -Y 2 -, -(OCH 2 CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 2 -, -(CH 2 OCH 2 C(O)) p -(4- to 12-heterocycloalkyl)-Y 2 -, -(CH 2 OCH 2 C(O)NH) p -Y 2 - -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -(CH 2 CH 2 O) p -C(O)-Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -(CH 2 CH 2 O) p -Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -(OCH 2 CH 2 ) p -Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -(OCH 2 CH 2 ) p -C(O)-(OCH 2 CH 2 ) p -Y 2 -, -(CH 2 OCH 2 ) p -(heteroaryl)-Y 2 -, —NHC(O)-(4- to 12-heterocycloalkyl)-Y 1 -C(O)-Y 2 -, -NHC(O)-(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -C(O)-Y 2 -, -NHC(O)-(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 2 -, -C(O)NH-Y 1 -Y 2 -; -(CH 2 ) p -NH-Y 1 -Y 2 -; -C(O)NH-(CH 2 CH 2 O) p -Y 2 - -C(O)-(CH 2 CH 2 O) p -Y 2 -、 -(CH 2 AND 2 ) p -NR 3 C(O)-(CH 2 CH 2 O) p -Y 2 -、 -(CH 2 ) p -NR 3 C(O)-(CH 2 CH 2 O) p -Y 2 -、 -(CH 2 OCH 2 CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -C(O)-(CH 2 CH 2 O) p -Y 2 -or -(CH 2 OCH 2 ) p -C(O)NH-(CH 2 CH 2 O) p -Y 2 -wherein where: R 3 is -H or -C 1 -C 3 is alkyl; Y 1 are independently bond, -C 1-8 Alkylenyl, 4- to 12-membered heterocycloalkyl or -C 3 -C 10 is cycloalkyl; Y 2 is, independently, join, -C 1 -C 3 Alkyl-, -(CH 2 ) m -O-、 -O-(CH 2 ) m -(4- to 6-membered heterocycloalkyl), -(CH 2 ) m -O-(CH 2 ) m -NH- -(CH 2 ) m -NH- -(CH 2 ) m -NHC(O)-(CH 2 ) m O- -(CH 2 ) m -C(O)NH-(CH 2 ) m - -(CH 2 ) m -C 3 -C 10 cycloalkyl-, -(CH 2 ) m -aryl, -(CH 2 ) m -heteroaryl-, -(CH 2 ) m -(4 to 6-membered heterocycloalkyl)-, -(CH 2 ) m -(4 to 6-membered heterocycloalkyl)-C(O)-, -(CH 2 ) m -(4- to 6-membered heterocycloalkyl)-C(O)-(CH 2 ) m -, -(CH 2 ) m -(4- to 6-membered heterocycloalkyl)-C(O)-(CH 2 ) m -O-, -(CH 2 ) m -C 3 -C 10 cycloalkyl-C(O)NH- or -(CH 2 ) m -(4- to 6-membered heterocycloalkyl)-O-; X 1 is CH or N; X 2 is CH or N; each m is independently an integer from 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. or a pharmaceutically acceptable salt, solvate, isomer, enantiomer or tautomer thereof.

2. The compound has the formula I(a): 【Chemistry 2】 wherein HetA is a 4-6 membered heterocycloalkyl.

2. The compound of claim 1, having the formula:

3. The compound has formula I(b): 【Chemistry 3】 wherein HetA is a 4-6 membered heterocycloalkyl.

2. The compound of claim 1, having the formula:

4. The compound has formula I(c): 【Chemistry 4】 wherein HetA is a 4-6 membered heterocycloalkyl.

2. The compound of claim 1, having the formula:

5. The compound has formula I(d): 【Chemistry 5】 wherein HetA is a 4-6 membered heterocycloalkyl.

2. The compound of claim 1, having the formula:

6. The compound has the formula I(e): 【Chemistry 6】 wherein HetA is a 4-6 membered heterocycloalkyl.

2. The compound of claim 1, having the formula:

7. The compound has the formula I(f): 【Chemistry 7】 wherein HetA is a 4-6 membered heterocycloalkyl.

2. The compound of claim 1, having the formula:

8. 3. The compound of formula I(g): 【Chemistry 8】 2. The compound of claim 1, having the formula:

9. The compound has formula I(h): 【Chemistry 9】 2. The compound of claim 1, having the formula:

10. The group B capable of binding to an E3 ligase has the following structure: 【Chemistry 10】 The compound according to any one of claims 1 to 9, wherein

11. The group B capable of binding to an E3 ligase has the following structure: 【Chemistry 11】 The compound according to any one of claims 1 to 9, wherein

12. A is of the following structure: 【Chemistry 12】 The compound according to any one of claims 1 to 11, wherein

13. The compound is: N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6 dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-fluoropicolinamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-3-methylbutanamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)cyclopropanecarboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}pentanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)heptanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[9-({3-[(2,6-dioxopiperidin-3-yl)amino]phenyl}amino)nonanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(9-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]amino}nonanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[5-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)pentanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[7-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)heptanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[11-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)undecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[13-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)tridecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[15-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]oxy}acetamido)pentadecanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]butylamino]-2-oxo-ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]piperazin-1-yl]propanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]propanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[5-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]pentanoyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]-2-oxo-ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propyl]piperazin-1-yl]ethoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[2-[6-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexylamino]-2-oxo-ethoxy]methyl]-4-piperidyl]-2,5-difluoro-benzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(5-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)pentanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(6-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)hexanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperazin-1-yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)butanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[1-[6-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]hexyl]triazol-4-yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[1-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]butyl]triazol-4-yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-[1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-[[1-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]ethyl]triazol-4-yl]methoxymethyl]-4-piperidyl]-2,5-difluoro-benzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(((1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperazine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperidine-4-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]piperazin-1-yl]acetamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-2-[1-[3-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]propanoyl]-4-piperidyl]acetamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]methyl]piperidine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-4-[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]piperidine-1-carboxamide; N-[4-benzyl-1-[5-(3-cyano-6-ethoxy-pyrazolo[1,5-a]pyridin-4-yl)-2-pyridyl]-4-piperidyl]-2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-1-piperidyl]methyl]-1-piperidyl]acetamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(3-(2,6-dioxopiperidin-3-yl)phenyl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(1-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}azetidin-3-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]azetidin-3-yl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazole-6-carbonyl]azetidin-3-yl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)azetidin-3-yl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[4-benzyl-1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)piperidin-4-yl]-1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperidine-4-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidine-1-carbonyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidin-1-yl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-1-fluorocyclopropane-1-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutane-1-carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)azetidin-3-yl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperazin-1-yl)methyl)-N-isopropylpiperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-N-(2-methylpropyl)piperidine-4-carboxamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(3-methyl-2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (S)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)propanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)spiro[3.3]heptane-2-carbonyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; 6-(4-{[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)piperidin-4-yl]methyl}piperazine-1-carbonyl)-N-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]spiro[3.3]heptane-2-carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propanoyl)-3,9-diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)-3,9-diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[6-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)-2,6-diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{9-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9-diazaspiro[5.5]undecan-3-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{9-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-3,9-diazaspiro[5.5]undecan-3-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}spiro[3.3]heptane-2-carbonyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-1-carbonyl}spiro[3.3]heptan-2-yl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({9-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]-3,9-diazaspiro[5.5]undecan-3-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[6-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)-2,6-diazaspiro[3.3]heptan-2-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(9-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}-3,9-diazaspiro[5.5]undecan-3-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)-3,9-diazaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3-oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(2-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}ethoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropoxy)ethyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(2-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}ethoxy)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(2-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]carbamoyl}ethoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{2-[2-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropoxy)ethoxy]ethyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]piperidin-4-yl}methyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]acetyl}piperidin-4-yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperidin-4-yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[(1-{2-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]acetyl}piperidin-4-yl)methyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(4-{[1-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperidin-4-yl]methyl}piperazin-1-yl)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-3-oxopropyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}piperidin-1-yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(3-{3-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]azetidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-({4-[3-(3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}azetidin-1-yl)propanoyl]piperazin-1-yl}methyl)piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecan-3-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}piperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(methylamino)methyl]piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 4-[6-(4-{[4-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]oxy}acetyl)piperazin-1-yl]methyl}-4-ethylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)piperidin-4-yl)-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-{[4-(7-{4-[2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperazin-1-yl]methyl}piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpropanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylpentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-methylheptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; 4-[6-(4-{[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperazin-1-yl]methyl}-4-methylpiperidin-1-yl)pyridin-3-yl]-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-7-yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-7-yl]amino}decyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(8-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}octyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(10-{[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]amino}decyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)piperidine-4-carboxamide; 1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-(2,5-difluorobenzamido)-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)piperidine-4-carboxamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)propanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(5-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2-yl)pentanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[9-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carbonyl]piperidin-4-yl]-2,5-difluorobenzamide; (S)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; (R)—N-(1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-((4-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperazin-1-yl)methyl)piperidin-4-yl)-2,5-difluorobenzamide; or N-[1-(5-{3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl}pyridin-2-yl)-4-[(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}-N-(propan-2-yl)heptanamido)methyl]piperidin-4-yl]-2,5-difluorobenzamide, The compound according to any one of claims 1 to 12, selected from:

14. Formula II: 【Chemistry 13】 [In the formula, R 1 -OCH 2 CH 3 , -OCH 3 , -OCF 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 F, 1-methylpyrazol-4-yl or halogen; A 1 is independently aryl or heteroaryl, and said aryl or heteroaryl optionally contains one or more R 2 where R 2 are independently halogens, OH, C 1 -C 3 Alkyl or C 1 -C 3 is alkoxy; B is a group capable of binding an E3 ligase; L 4 are independently -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -C(O)-Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-C(O)-Y 1 -Y 2 -, -(CH 2 ) p -(4- to 12-heterocycloalkyl)-Y 1 -Y 2 - and where: Y 1 independently, -C 1-8 Alkylenyl, 4- to 12-membered heterocycloalkyl or -C 3 -C 10 is cycloalkyl; Y 2 is, independently, -C 1 -C 3 Alkyl-, -(CH 2 ) m -O- -O-(CH 2 ) m -(4- to 6-membered heterocycloalkyl), -(CH 2 ) m -(4 to 6-membered heterocycloalkyl)-, -(CH 2 ) m -(4- to 6-membered heterocycloalkyl)-C(O)- or -(CH 2 ) m -(4- to 6-membered heterocycloalkyl)-O-; L 3 is a bond, -C 1-8 Alkylenyl, 4-8 membered heterocycloalkyl, -C 3 -C 10 Cycloalkyl or -(4- to 8-membered heterocycloalkyl)-(CH 2 ) m - and; X 1 is CH or N; X 2 is CH or N; X 7 is O, S, NH or a bond; each m is independently an integer from 0 to 16; n is an integer from 0 to 2; and p is an integer from 0 to 3. or a pharmaceutically acceptable salt, solvate, isomer, enantiomer or tautomer thereof.

15. The compound is: 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(5-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}pentanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; 6-{[1-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}propanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile; or 6-{[1-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}heptanoyl)piperidin-4-yl]methoxy}-4-{6-[(1R,5S)-6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl]pyridin-3-yl}pyrazolo[1,5-a]pyridine-3-carbonitrile, 15. The compound of claim 14, selected from:

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A method for treating a RET-mediated disorder, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

18. 16. An effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof (optionally in a pharmaceutical composition), for use in the treatment of a RET mediated disorder.

19. 20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a RET-mediated disorder.

20. 20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof (optionally in a pharmaceutical composition), in the manufacture of a medicament for the treatment of a RET mediated disorder.

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