Isoindolinone glutarimide and phenylglutarimide analogues as degraders of RET kinase

Abstract

The present disclosure provides compounds of formula (I): which induce proteolysis of the proto-oncogene tyrosine protein kinase receptor (RET), which may be either wild-type or mutant RET (useful in the treatment of diseases and disorders mediated by said protein): This relates to the compound represented by TIFF2026506696000135.tif42150.

Description

[Technical Field]

[0001] (cross reference) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 446,097, filed February 16, 2023, the entire contents of which are incorporated herein by reference.

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

[0003] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved 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 are targeted for proteasomal degradation upon covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases, which digest the protein into small peptides and ultimately their constituent amino acids that serve as building blocks for new proteins. Malfunctioning of proteasomal degradation is associated with various disorders, including cancer.

[0004] Cereblon forms part of an E3 ubiquitin ligase complex that interacts with damaged DNA-binding protein 1, and forms an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1), where the complex functions as a substrate receptor and selects proteins for ubiquitination. Lenalidomide binds to cereblon, which subsequently promotes its binding to Ikaros and Aiolos, leading to their ubiquitination and degradation by the proteasome (Lu, G. et al., "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins," Science, 2014, 343:305-309; Kronke, 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 rearranged upon transfection (RET), a proto-oncogene tyrosine protein kinase receptor, is widely known for its essential roles in cell survival, differentiation, proliferation, migration, and chemotaxis. Germline missense and somatic mutations in RET cause medullary thyroid cancer (MTC) and neuroendocrine tumors, whereas RET fusion proteins, overexpression, and copy number gains are observed in a wide range of additional cancers, including papillary thyroid cancer, 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] Increasing academic and clinical interest in RET has led to the identification of several clinically relevant RET mutations, including 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 was found to induce resistance-conferring RET mutations, including 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 the 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 in the art for novel RET-modulating agents for treating RET-mediated disorders in hosts in need thereof, including humans. Summary of the Invention

[0009] A first aspect of the present disclosure generally relates to a compound of Formula I: [ka] [In formula: Ring B is a 4-12 membered heterocycloalkyl or C3-C8 cycloalkyl; Ring D is the cereblon binding moiety; L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; L 2 is -C(O)-(CH2) p-(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4 to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, -(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, or -C(O)NH-(CH2) p -NH-; p is an integer from 1 to 12. and pharmaceutically acceptable salts, solvates, isomers, enantiomers and tautomers thereof.

[0010] Another aspect of the present disclosure relates to a method for 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.

[0011] Another aspect of the present disclosure is directed to a method for modulating RET protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula I. In some embodiments, a method for treating RET-mediated disorders and diseases in a subject comprises modulating RET protein in the subject.

[0012] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant. The pharmaceutical composition may be effective in treating a disease or disorder associated with RET modulation in a subject in need of such treatment. The pharmaceutical composition may comprise a compound of the present invention for use in treating a disease described herein. The composition may comprise at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0013] Another aspect of the present disclosure relates to a compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease associated with RET modulation. Another aspect of 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.

[0014] The present invention also provides methods of treating diseases or disorders by degrading RET using the compounds of Formula I and pharmaceutically acceptable compositions of the compounds of Formula I.

[0015] The present invention also provides compounds of Formula I that bind to and inhibit E3 ligase and degrade the RET protein. These E3 ligase-binding compounds (degraders) may also be useful in the treatment of RET-mediated diseases and cancers, including Hirschsprung's disease, medullary thyroid cancer (MTC), thyroid cancer, familial medullary thyroid cancer, multiple endocrine neoplasia, multiple endocrine neoplasia type 2 (MEN-2, MEN-2A, MEN-2B), neuroendocrine tumors, central nervous system tumors, central hypoventilation syndrome, renal aplasia, pheochromocytoma, and parathyroid hyperplasia.

[0016] The present invention further provides compounds that can degrade RET while binding 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. In addition, the present technology also has the advantage of being able to be used for many different types of diseases, including disorders mediated by RET fusion proteins, overexpression, or increased copy number, 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 hematopoietic malignancies. Additional features and advantages of the present technology will be apparent to those skilled in the art upon reading the following detailed description of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present disclosure relates to RET-degrading compounds of Formula I, and pharmaceutically acceptable salts thereof, which may inhibit E3 ligase activity and are therefore useful in methods of treating the human or animal body. The disclosure also relates to methods of making these compounds, pharmaceutical compositions containing the compounds, and their use in treating disorders and diseases in which RET is involved, such as inflammation, autoimmune disease, cancer, infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychiatric disease, a graft-versus-host disease, allodynia, or a RET-associated disease, in a subject determined to have a germline or somatic mutation in RET.

[0018] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings set forth below.

[0019] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to encompass 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 encompass C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include, but are not limited to, moieties 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 some 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.

[0020] As used herein, the term "(optionally) substituted alkyl" refers to an unsubstituted alkyl or an alkyl in which one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone have been replaced with specified substituents. 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.

[0021] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in chain length and substitution to the alkyls described above, but which contain 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.

[0022] As used herein, the term "(optionally) substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl in which one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone have been replaced with specified substituents. 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.

[0023] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in chain length and substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, 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.

[0024] As used herein, the term "(optionally) substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl in which one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone have been replaced with specified substituents. 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.

[0025] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties with one or more specified substituents. For example, substituted heterocycloalkyls include 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.

[0026] As used herein, the term "cyano" refers to a nitrile group (eg, --CN).

[0027] As used herein, the term "cycloalkyl" refers to a cycloalkyl group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C 10 , or C3-C8), a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system. 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 polycyclic cycloalkyl, only one of the rings of the cycloalkyl need be non-aromatic.

[0028] The term "heterocycloalkyl," as used herein, unless otherwise specified, refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, 7-12 membered bicyclic (fused, bridged, or spiro) or 11-14 membered tricyclic ring system (fused, bridged, or spiro) having one or more heteroatoms (such as O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups include, but are not limited to, 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-Oxazepanyl, 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'-isobenzofuran]-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- Examples include 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, etc. In the case of polycyclic heterocycloalkyls, only one ring of the heterocycloalkyl need be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0029] As used herein, the term "(optionally) substituted heterocycloalkyl" refers to a heterocycloalkyl that is unsubstituted or in which one or more hydrogen atoms on one or more carbon or heteroatoms have been replaced with specified substituents. Such substituents can 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.

[0030] 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, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, for example, with one to five 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 themselves may be optionally substituted. Additionally, when containing two or more fused rings, aryl groups as defined herein may 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.

[0031] Unless otherwise specified, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group having 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 bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl, as defined herein, also means tricyclic heteroaromatic groups containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. Aromatic groups may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, 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, Triazinyl, 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, Indolinyl, 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, tetrahydrobenzothiazine ... Triazolo[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]pyridazinyl, 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. Additionally, when containing two or more fused rings, heteroaryl groups as defined herein may have one or more saturated or partially unsaturated rings, such as a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, fused to a fully unsaturated aromatic ring, 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 oxo. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to a saturated or partially unsaturated ring as described herein. Illustrative ring systems of these aryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-11H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxaindolyl, 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.

[0032] A 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 described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, The aryl and heteroaryl groups can 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 an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic to form polycyclic ring systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0033] 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 the indicated group, provided that the substitution results in a stable compound without exceeding the normal valence of the designated atom. If the substituent is oxo or keto (i.e., =0), then 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" are intended to refer to a compound that can be isolated from an RM to a useful degree of purity and is sufficiently robust to be formulated into an effective therapeutic agent.

[0034] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom to which such substituent is bonded to the remainder of a compound represented by a given formula, then such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0035] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 2 R moieties, then such group may be optionally substituted with up to 2 R moieties, and R at each occurrence is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0036] As used herein, the term "hydroxy" or "hydroxyl" includes groups with an --OH or --O-- group.

[0037] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0038] The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl that is substituted with one or more halogen atoms.

[0039] As used herein, the term "(optionally) substituted haloalkyl" refers to a haloalkyl that is unsubstituted or that has one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms replaced with specified substituents. 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.

[0040] 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 alkoxyl 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.

[0041] It should be 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 schemes below as well as those shown in the Examples.

[0042] It should be understood that throughout the specification, when a composition is described as having, comprising, or consisting of certain components, it is also intended that the composition consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, comprising, or consisting of certain process steps, the process also consists essentially of or consists 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 may be performed simultaneously.

[0043] It should 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. Although the processes generally provide the desired final compound at the completion or end of the overall process, in certain cases it may be desirable to further convert the compound to a pharmaceutically acceptable salt thereof.

[0044] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, literature-described compounds, or readily prepared intermediates, and utilizing any standard synthetic methods and procedures that are known to those of ordinary skill in the art or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and preparations can be obtained from the relevant scientific literature or from standard reference works in the field. Classic texts, incorporated herein by reference, such as, but not limited to, one or several sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; 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), are useful and recognized references in organic synthesis known to those skilled in the art.

[0045] 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 may require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups in a molecule. A list of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999.

[0046] Unless otherwise specified, any reference to a method of treatment or prevention should be understood to include the use of a compound to provide such treatment or prevention as described herein. Unless otherwise specified, any reference to a method of treatment or prevention should be further understood to include the use of a compound to manufacture a medicament for treating or preventing such conditions. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0047] Unless otherwise specified, any reference to a method of treatment should be understood to include providing such treatment using the compounds as described herein. Unless otherwise specified, any reference to a method of treatment should further be understood to include the manufacture of a medicament for treating such a condition using the compounds. Treatment 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 thereof," and both refer to a subject having a disease or at risk of developing a disease. "Subject" includes mammals. A mammal can be, for example, a human or a suitable non-human mammal, such as 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 thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, the subject in need may be a subject at increased risk for developing such a disease or disorder compared to the general population (i.e., a subject who is more susceptible to developing such a disorder compared to the general population). The subject in need may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has never responded to treatment). The subject may be resistant at the start of treatment, or may become resistant during treatment. In some embodiments, the subject in need has undergone all known effective treatments for the disease or disorder disclosed herein to no avail. In some embodiments, the subject in need has undergone at least one conventional treatment.

[0048] As used herein, the terms "RET kinase inhibitor" and "RET kinase inhibitor" can be used interchangeably and refer to a compound that inhibits the rearranged (RET) kinase protein or fragments of the RET kinase protein upon transfection.The term "RET kinase inhibitor" also refers to a series of compounds that are used to treat non-small cell lung cancer and / or thyroid cancer in subjects whose tumors have one or more alterations or mutations in the RET gene.The term "RET kinase inhibitor" can also refer to known RET kinase inhibitors, such as alectinib, cabozantinib, lenvatinib, pralsetinib, sorafenib, sunitinib, vandetanib, bepafestinib, and their analogs.

[0049] As used herein, the term "treating" or "treatment" refers to the management and care of a patient for the purpose of eradicating a disease, condition, or disorder, and includes 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 "treatment" may also include treatment of cells in vitro or in animal models. It should be understood that reference to "treating" or "treatment" includes the alleviation of established symptoms of the condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the onset of clinical signs of the condition, disorder, or condition occurring in a human who may be affected by or susceptible to the condition, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical signs of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, alleviating, or delaying the progression of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical sign thereof; or (3) palliating or alleviating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical sign thereof.

[0050] The compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, can be or may be used to prevent the associated disease, condition or disorder, or to identify suitable candidates for such purposes.

[0051] As used herein, the terms "preventing," "prevent" or "protecting from" describe reducing or eliminating the onset of symptoms or complications of such disease, condition or disorder.

[0052] Those skilled in the art will recognize that for detailed descriptions of known techniques discussed herein or equivalent techniques, general references may be referred to, including 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 of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). These references may, of course, also be referred to in making or using embodiments of the present disclosure.

[0053] 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.

[0054] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of a disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a unit dose composition is an effective amount and will vary depending on the particular treatment involved. Those skilled in the art will recognize that routine variations in dosage may sometimes be necessary depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intraspinal, intranasal, etc. Dosage forms suitable for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and, if necessary, with preservatives, buffers, or propellants.

[0055] As used herein, the term "pharmaceutically acceptable" refers to those 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 undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0056] As used herein, the term "pharmaceutically acceptable excipient" generally refers to an excipient that is safe, non-toxic, and not biologically or otherwise undesirable, and that is useful in preparing pharmaceutical compositions, 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 such excipients.

[0057] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral administration, e.g., intravenous administration, intradermal administration, subcutaneous administration, oral (e.g., oral ingestion), inhalation administration, transdermal (topical) administration, and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous administration may contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate; and a tonicity adjuster such as sodium chloride or dextrose. The pH may be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

[0058] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject in many well-known ways currently used in chemotherapy treatment. For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, or taken orally, or applied to the skin using a patch. The selected dose should be sufficient to constitute effective treatment, but not so high as to cause unacceptable side effects. The patient's disease condition (e.g., a disease or disorder disclosed herein) and the patient's health condition should preferably be closely monitored during and after treatment for a reasonable period of time.

[0059] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The 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, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected to be administered. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0060] It should be understood that for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, for example, of neoplastic cells, or in animal studies, usually in rats, mice, rabbits, dogs, or pigs. Animal studies may also be used to determine appropriate dosage ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as 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, and can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions exhibiting large therapeutic indices are preferred. Dosages may vary within this range depending on the dosage form utilized, the patient's sensitivity, and the route of administration.

[0061] Dosage is adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors to consider include the severity of the condition, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to therapy.

[0062] The pharmaceutical composition containing the active compound of the present disclosure can be prepared by generally known methods, for example, by conventional mixing, dissolving, granulating, dragee making, liquefying, emulsifying, encapsulating, encapsulating or lyophilizing processes.The pharmaceutical composition can be formulated by conventional methods using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants, which facilitate the processing of the active compound into pharmaceutical preparations that can be used.Of course, the appropriate formulation depends on the selected route of administration.

[0063] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, sterile water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and 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 the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining 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 will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0064] Sterile injectable solution can be prepared by incorporating the active compound in the required amount in a suitable solvent, optionally with one or a combination of the above-listed ingredients, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating the active compound into a sterile vehicle that contains the base dispersion medium and the other ingredients required from the above-listed ingredients.For the sterile powder used to prepare sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which produces a powder containing the active ingredient and any other desired ingredients from the previously sterile-filtered solution.

[0065] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or compressed into tablets.For the purpose of oral therapeutic administration, the active compound can be compounded with excipients and used in the form of tablets, lozenges or capsules.Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound is orally applied in the fluid carrier, and then rinsed and 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 with similar properties: 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 Sterothes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate or orange flavoring.

[0066] 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.

[0067] Systemic administration can also be by transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for permeating the barrier is used in the formulation.Such penetrants are generally known in the art, and for example, for transmucosal administration, include surfactants, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved through the use of nasal sprays or suppositories.For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as is generally known in the art.

[0068] The active compound can be prepared using a pharmaceutically acceptable carrier, such as a controlled-release formulation, including implants and microencapsulated delivery systems, which will protect the compound from rapid elimination from the body.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 clear to those skilled in the art.Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc.Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0069] For ease of administration and uniform dosage, it is particularly advantageous to formulate oral or parenteral compositions in unit dosage form.As used herein, unit dosage form refers to a physically separate unit suitable as a unit dosage for the subject to be treated, and each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect in combination with required pharmaceutical carrier.The specification of unit dosage form of the present disclosure is determined by and directly depends on the unique properties of active compound and the specific therapeutic effect to be achieved.

[0070] In therapeutic applications, the dosage 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 will influence the selected dosage. Generally, the dosage should be sufficient to cause a delay, preferably regression, of symptoms of the diseases or disorders disclosed herein, and preferably complete regression of the disease or disorder. Dosages may range from about 0.01 mg / kg / day to about 5000 mg / kg / day. An effective amount of a pharmaceutical agent is one that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improvements in survival and growth indicate regression. As used herein, the term "dosage effective manner" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0071] It should be appreciated that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0072] Furthermore, for compounds of the present disclosure that are capable of forming salts, it should be understood that all of these forms are also encompassed within the scope of the claimed disclosure.

[0073] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 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, glucopeptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isopropyl alcohol, methyl methyl ester ... Included are those derived from inorganic and organic acids selected from sethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, acetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0074] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0075] Other examples of pharmaceutically acceptable salts include salts of 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 either replaced by a metal ion, e.g., an alkali metal ion, alkaline earth metal ion, or aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that in forming a salt, the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0076] It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0077] The compound or its pharmaceutically acceptable salt can be administered orally, intranasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intraspinal and parenterally.In one embodiment, the compound is administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0078] 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 and its salt utilized.A physician or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to prevent, inhibit, or arrest the progression of the condition.A physician or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to inhibit or arrest the progression of the condition.

[0079] Techniques for formulating and administering the compounds disclosed in this disclosure can be found in Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing Co, Easton, Pa. (1995). In embodiments, 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, and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0080] All percentages and proportions used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will be apparent from the various examples. The examples provided illustrate various components and methodologies useful in implementing the present disclosure. The examples do not limit the disclosure of the claims. Based on this disclosure, one skilled in the art will be able to identify and utilize other components and methodologies useful in implementing the present disclosure.

[0081] In the synthetic schemes described herein, compounds may be depicted in one particular configuration for simplicity. Such particular configuration should not 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; however, 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.

[0082] All publications and patent documents cited herein are incorporated by reference as if each such publication or document was 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 does it constitute any admission as to their contents or date. While the invention has now been described by way of specification, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative and not limiting of the scope of the claims that follow.

[0083] As used herein, the terms "disclosed compounds," "disclosed degraders," and "degraders" refer both generically and specifically to those compounds disclosed herein.

[0084] Disclosed Compounds In one aspect, the present disclosure provides, inter alia, a compound of formula (I): [ka] [In the formula, ring B, ring D, L 1 , L 2 and inhibitors of RET kinase are as defined herein. and pharmaceutically acceptable salts, solvates, isomers, enantiomers, and tautomers thereof.

[0085] In some embodiments, ring D is independently: [ka] and; L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4 to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, -(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, or -C(O)NH-(CH2) p -NH-; R 5 is H, halogen, CF3, OH, CN, NO2 or C1-C4 alkyl; R 6 or R 6 ' are each independently H, or R 6 can be taken together to form an oxo group, or R 6 Two examples of ' can be taken together to form an oxo group; R 7is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two geminal or vicinal R's 7 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; and p is an integer from 1 to 12.

[0086] In some embodiments of the compounds of the present disclosure, the compound has Formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0087] In a further embodiment, X 1 are independently N or CR 1 is.

[0088] In a further embodiment, R 1 are independently H or halogen, or C1-C3 alkyl; R 3 but: [ka] If so, then R 2 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 aryl, or 4-12 membered heteroaryl; R 3 is C3-C8 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 aryl, or 4- to 12-membered heteroaryl, then R2 teeth [ka] and; Ring B is independently heterocycloalkyl or C3-C8 cycloalkyl; Ring D is independently [ka] and; L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4 to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, -(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, or -C(O)NH-(CH2) p -NH-; R 5 is H, halogen, CF3, OH, CN, NO2 or C1-C4 alkyl; R 6 or R 6 ' are each independently H, or R 6 can be taken together to form an oxo group, or R6 Two examples of ' can be taken together to form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two geminal or vicinal R's 7 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; and p is an integer from 1 to 12.

[0089] In one embodiment of the disclosure, the compounds of the disclosure have the formula Ia-1: [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ia-2: [ka] or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ia-3: [ka] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ia-4: [ka] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ia-5: [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments of the present disclosure, the compounds of the disclosure have Formula Ib: [ka] or a pharmaceutically acceptable salt thereof. 1 and R 2 are each independently H, halogen, or NR 10 R 11 or C1-C4 alkyl; R 4 but [ka] If so, then R 3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 4 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then R 3 teeth [ka] and; Ring D is [ka] is a group selected from L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or heteroaryl; L 2 is -C(O)NH-(CH2) p -, -NHC(O)-(CH2) p -, -C(O)NH-(CH2) p -NH-, -NHC(O)-(CH2) p -NH-, -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4-12 membered heterocycloalkyl)-NH-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4 to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2) p -(4 to 12-membered heterocycloalkyl)-C(O)-, or -(CH2) p -(4 to 12-membered heterocycloalkyl)-C(O)-; R 5 is H, halogen, OH, CN, NO2, or C1-C4 alkyl; R 6 or R 6 Each instance of ' is independently H, or R 6 can be taken together to form an oxo group, or R 6 Two examples of ' can be taken together to form an oxo group; R 7is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Two geminal or vicinal R's 7 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; m is an integer from 0 to 2; and p is an integer from 1 to 12.

[0095] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ib-1: [ka] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ib-2: [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ib-3: [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ib-4: [ka] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ib-5: [ka] or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments of the present disclosure, compounds of the disclosure have the formula Ib-6: [ka] or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments of the present disclosure, the disclosed compound is [ka] [ka] or a pharmaceutically acceptable salt, solvate, isomer, enantiomer or tautomer thereof.

[0102] In some embodiments of the present disclosure, the disclosed compound is [ka] or a pharmaceutically acceptable salt, solvate, isomer, enantiomer or tautomer thereof.

[0103] In some embodiments of the present disclosure, the disclosed compound is [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments of the present disclosure, the disclosed compound is [ka] or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments of the compounds of the present disclosure, R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, or aryl. In other embodiments, R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, or heterocycloalkyl. 1 is C1-C6 alkyl or C3-C8 cycloalkyl. In other embodiments, R 1 is C1-C6 alkyl. In other embodiments, R 1 is C-C cycloalkyl. In other embodiments, R 1 is heterocycloalkyl. In other embodiments, R 1 is aryl. In other embodiments, R 1 is heteroaryl. In a further embodiment, R 1 is one or more R 8 In another embodiment, R 1 is one or more R 8 In a further embodiment, R 1 is one or more R 8 In a further embodiment, R is a heterocycloalkyl optionally substituted with 1 is one or more R 8 In a further embodiment, R is an aryl optionally substituted with 1 is one or more R8 is heteroaryl, optionally substituted with

[0106] In some embodiments, R 8 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 8 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, or aryl. 8 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or heterocycloalkyl. 8 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C cycloalkyl. 8 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, or C-C alkynyl. 8 is H, halogen, CN, NO, OH, NH, C-C alkyl, or C-C alkenyl. 8 is H, halogen, CN, NO, OH, NH, or C-C alkyl. 8 is H, halogen, CN, NO, OH, or NH. In other embodiments, R 8 is H, halogen, CN, NO, or OH. In other embodiments, R 8 is H, halogen, CN, or NO. In other embodiments, R 8 is H, halogen, or CN. In other embodiments, R 8 is H or halogen. In a further embodiment, R 8is H. In a further embodiment, R 8 is halogen. In a further embodiment, R 8 is CN. In a further embodiment, R 8 is NO. In a further embodiment, R 8 is OH. In a further embodiment, R 8 is NH. In a further embodiment, R 8 is C1-C6 alkyl. In a further embodiment, R 8 is C-C alkenyl. In a further embodiment, R 8 is C2-C6 alkynyl. In a further embodiment, R 8 is C3-C8 cycloalkyl. In a further embodiment, R 8 is heterocycloalkyl. In a further embodiment, R 8 is aryl. In a further embodiment, R 8 is heteroaryl.

[0107] In some embodiments of the compounds of the present disclosure, B is aryl or heteroaryl. In other embodiments, B is aryl. In other embodiments, B is heteroaryl. In other embodiments, B is selected from one or more R 9 In other embodiments, B is aryl, optionally substituted with one or more R 9 In some embodiments of the compounds of the present disclosure, D is aryl or heteroaryl. In other embodiments, D is aryl. In other embodiments, D is heteroaryl. In other embodiments, D is one or more R 9 In other embodiments, D is aryl optionally substituted with one or more R 9 is heteroaryl, optionally substituted with

[0108] In some embodiments, R 9is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 9 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, or aryl. 9 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or heterocycloalkyl. 9 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C cycloalkyl. 9 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, or C-C alkynyl. 9 is H, halogen, CN, NO, OH, NH, C-C alkyl, or C-C alkenyl. 9 is H, halogen, CN, NO, OH, NH, or C-C alkyl. 9 is H, halogen, CN, NO, OH, or NH. In other embodiments, R 9 is H, halogen, CN, NO, or OH. In other embodiments, R 9 is H, halogen, CN, or NO. In other embodiments, R 9 is H, halogen, or CN. In other embodiments, R 9 is H or halogen. In a further embodiment, R 9 is H. In a further embodiment, R 9 is halogen. In a further embodiment, R 9 is CN. In a further embodiment, R 9is NO. In a further embodiment, R 9 is OH. In a further embodiment, R 9 is NH. In a further embodiment, R 9 is C1-C6 alkyl. In a further embodiment, R 9 is C-C alkenyl. In a further embodiment, R 9 is C2-C6 alkynyl. In a further embodiment, R 9 is C3-C8 cycloalkyl. In a further embodiment, R 9 is heterocycloalkyl. In a further embodiment, R 9 is aryl. In a further embodiment, R 9 is heteroaryl.

[0109] In certain embodiments of the compounds of the disclosure, B is heterocycloalkyl or C3-C8 cycloalkyl. In further embodiments, B is heterocycloalkyl. In further embodiments, B is C3-C8 cycloalkyl. In certain embodiments of the compounds of the disclosure, D is heterocycloalkyl or C3-C8 cycloalkyl. In further embodiments, D is heterocycloalkyl. In further embodiments, D is C3-C8 cycloalkyl.

[0110] In some embodiments of the compounds of the present disclosure, L 1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. 1 is C1-C6 alkyl or C2-C6 alkenyl. 1 is C1-C6 alkyl. In other embodiments, L 1 is C2-C6 alkenyl. In other embodiments, L 1 is C2-C6 alkynyl.

[0111] In some embodiments of the compounds of the present disclosure, L 2 is -C(O)-(CH2)p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4 to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2) p -(4 to 12-membered heterocycloalkyl)-C(O)-, or -(CH2) p In a further embodiment, L is -(4- to 12-membered heterocycloalkyl)-C(O)-. 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4 to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, or -C(O)-(CH2) p In a further embodiment, L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p-(4 to 12 membered heterocycloalkyl)-, or -(OCH2CH2) p In a further embodiment, L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, or -C(O)-(CH2CH2O) p In a further embodiment, L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, or -C(O)NH-(CH2CH2O) p In a further embodiment, L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, or -C(O)NH-(CH2) p In a further embodiment, L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)- or -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-. Furthermore, in a further embodiment, L 2 is -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-. Furthermore, in a further embodiment, L2 is -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-. Furthermore, in a further embodiment, L 2 is -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-. Furthermore, in a further embodiment, L 2 is -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-. Furthermore, in a further embodiment, L 2 is -C(O)-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-. Furthermore, in a further embodiment, L 2 Ha-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-. Furthermore, in a further embodiment, L 2 is -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)-. Furthermore, in a further embodiment, L 2 Ha-(CH2) p It may be -(4- to 12-membered heterocycloalkyl)-C(O)-.

[0112] In certain embodiments of the compounds of the present disclosure, R 2 is independently, NR 10 R 11 In a further embodiment of the compounds of the present disclosure, R 2 are independently H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0113] In some embodiments of the compounds of the present disclosure, R 10 is independently H or C1-C4 alkyl. In other embodiments, R 10 is H. In other embodiments, R 10is C1-C4 alkyl.

[0114] In some embodiments of the compounds of the present disclosure, R 11 is independently H or C1-C4 alkyl. In other embodiments, R 11 is H. In other embodiments, R 11 is C1-C4 alkyl.

[0115] In certain embodiments of the compounds of the present disclosure, R 3 is H, halogen, NH, C-C alkyl, C-C alkyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 3 is H, halogen, or NH. In a further embodiment, R 3 is H or halogen. Moreover, in a further embodiment, R 3 is H. Moreover, in a further embodiment, R 3 is halogen. Moreover, in a further embodiment, R 3 is NH. Moreover, in a further embodiment, R 3 is C1-C4 alkyl.

[0116] In some embodiments of the compounds of the present disclosure, R 4 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. 4 is C1-C6 alkyl or C2-C6 alkenyl. 4 is C1-C6 alkyl. In other embodiments, R 4 is C2-C6 alkenyl. In other embodiments, R 4 is C2-C6 alkynyl.

[0117] In a further embodiment, R 4is C-C alkyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, NH, —NH(C-C alkyl), or —N(C-C alkyl)(C-C alkyl). 4 is C-C alkyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, NH, or —NH(C-C alkyl). 4 is C-C alkyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, or NH. 4 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy or C1-C6 thioalkyl. 4 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy. 4 is C1-C6 alkyl optionally substituted with one or more C1-C6 thioalkyl. 4 is C1-C6 alkyl optionally substituted with one or more NH2. Moreover, in a further embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more -NH(C1-C6 alkyl). 4 is C1-C6 alkyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0118] In a further embodiment, R 4 is a C-C alkenyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, NH, —NH(C-C alkyl), or —N(C-C alkyl)(C-C alkyl). 4is a C-C alkenyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, NH, or —NH(C-C alkyl). 4 is a C-C alkenyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, or NH. 4 is a C2-C6 alkenyl optionally substituted with one or more C1-C6 alkoxy or C1-C6 thioalkyl. 4 is C-C alkenyl optionally substituted with one or more C-C alkoxy. 4 is a C2-C6 alkenyl optionally substituted with one or more C1-C6 thioalkyl. 4 is a C2-C6 alkenyl optionally substituted with one or more NH2. 4 is a C2-C6 alkenyl optionally substituted with one or more -NH(C1-C6 alkyl). 4 is a C2-C6 alkenyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0119] In a further embodiment, R 4 is C-C alkynyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, NH, —NH(C-C alkyl), or —N(C-C alkyl)(C-C alkyl). 4 is a C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, or —NH(C1-C6 alkyl). 4is a C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, or NH2. In a further embodiment, R 4 is a C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy or C1-C6 thioalkyl. 4 is a C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy. 4 is a C2-C6 alkynyl optionally substituted with one or more C1-C6 thioalkyl. 4 is a C2-C6 alkynyl optionally substituted with one or more NH2. 4 is a C2-C6 alkynyl optionally substituted with one or more -NH(C1-C6 alkyl). 4 is a C2-C6 alkynyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0120] In further embodiments of the compounds of the present disclosure, two R 4 may join together to form a C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In other embodiments, two R on adjacent carbons may 4 can join together to form a C-C cycloalkyl, heterocycloalkyl, or aryl. In other embodiments, two R on adjacent carbons 4 can join together to form a C-C cycloalkyl or heterocycloalkyl. In other embodiments, two R on adjacent carbons 4 can join together to form a C-C cycloalkyl. In other embodiments, two R on adjacent carbons 4can be joined together to form a heterocycloalkyl. In other embodiments, two R on adjacent carbons 4 can be joined together to form an aryl. In other embodiments, two R on adjacent carbons can be 4 may be taken together to form a heteroaryl.

[0121] In certain embodiments of the compounds of the present disclosure, R 5 is independently H, OH, CN, NO, or C-C alkyl. 5 is H, OH, CN or NO. In a further embodiment, R 5 is H, OH or CN. In a further embodiment, R 5 is H or OH. In another further embodiment, R 5 is H. In another further embodiment, R 5 is OH. In another further embodiment, R 5 is CN. In another further embodiment, R 5 is NO. In another further embodiment, R 5 is C1-C4 alkyl.

[0122] In certain embodiments of the compounds of the present disclosure, R 6 are independently H.

[0123] In some embodiments of the compounds of the present disclosure, R 6 ' is independently H.

[0124] In certain embodiments of the compounds of the present disclosure, two R 6 can combine to form an oxo group.

[0125] In some embodiments of the compounds of the present disclosure, two R 6 ' may combine to form an oxo group.

[0126] In some embodiments of the compounds of the present disclosure, R7 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. 7 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, or aryl. 7 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or heterocycloalkyl. 7 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, or C-C cycloalkyl. 7 is H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, or C-C alkynyl. 7 is H, halogen, CN, NO, OH, NH, C-C alkyl, or C-C alkenyl. 7 is H, halogen, CN, NO, OH, NH, or C-C alkyl. 7 is H, halogen, CN, NO, OH, or NH. In other embodiments, R 7 is H, halogen, CN, NO, or OH. In other embodiments, R 7 is H, halogen, CN, or NO. In other embodiments, R 7 is H, halogen, or CN. In other embodiments, R 7 is H or halogen. In a further embodiment, R 7 is H. In other embodiments, R 7 is halogen. In a further embodiment, R 7 is CN. In a further embodiment, R7 is NO. In a further embodiment, R 7 is OH. In a further embodiment, R 7 is NH. In a further embodiment, R 7 is C1-C6 alkyl. In a further embodiment, R 7 is C-C alkenyl. In a further embodiment, R 7 is C2-C6 alkynyl. In a further embodiment, R 7 is C3-C8 cycloalkyl. In a further embodiment, R 7 is heterocycloalkyl. In a further embodiment, R 7 is aryl. In a further embodiment, R 7 is heteroaryl.

[0127] In another further embodiment of the compounds of the present disclosure, two R 7 may combine together to form a C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In other embodiments, two R on adjacent carbons may 7 may combine together to form a C-C cycloalkyl, heterocycloalkyl, or aryl. In other embodiments, two R on adjacent carbons may 7 may combine together to form a C-C cycloalkyl or heterocycloalkyl. In other embodiments, two R on adjacent carbons may 7 can join together to form a C-C cycloalkyl. In other embodiments, two R on adjacent carbons can 7 can join together to form a heterocycloalkyl. In other embodiments, two R on adjacent carbons can 7 can combine together to form an aryl. In other embodiments, two R on adjacent carbons can 7 may combine together to form a heteroaryl.

[0128] In further embodiments of the compounds of the present disclosure, m, at each occurrence, is 0, 1, or 2. In other embodiments, m is 0 or 1. In other embodiments, m is 0 or 2. In other embodiments, m is 1 or 2. In other embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2.

[0129] In yet another embodiment of the present disclosure, n is, independently at each occurrence, 0, 1, 2, 3, or 4. In yet another embodiment, n is 1 or 2. In yet another embodiment, n is 1 or 3. In yet another embodiment, n is 1 or 4. In yet another embodiment, n is 2 or 3. In yet another embodiment, n is 2 or 4. In yet another embodiment, n is 3 or 4. In yet another embodiment, n is 1. In yet another embodiment, n is 2. In yet another embodiment, n is 3. In yet another embodiment, n is 4. In yet another embodiment, n is 0.

[0130] In yet another embodiment of the present disclosure, p is, independently at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In yet another embodiment of the present disclosure, p is 1 or 2. In yet another embodiment of the present disclosure, p is 1 or 3. In yet another embodiment of the present disclosure, p is 1 or 4. In yet another embodiment of the present disclosure, p is 1 or 5. In yet another embodiment of the present disclosure, p is 1 or 6. In yet another embodiment of the present disclosure, p is 1 or 7. In yet another embodiment of the present disclosure, p is 1 or 8. In yet another embodiment of the present disclosure, p is 1 or 9. In yet another embodiment of the present disclosure, p is 1 or 10. In yet another embodiment of the present disclosure, p is 1 or 11. In yet another embodiment of the present disclosure, p is 1 or 12. In yet another embodiment of the present disclosure, p is 2 or 3. In yet another embodiment of the present disclosure, p is 2 or 4. In yet another embodiment of the present disclosure, p is 2 or 5. In yet another embodiment of the present disclosure, p is 2 or 6. In yet another embodiment of the present disclosure, p is 2 or 7. In yet another embodiment of the present disclosure, p is 2 or 8. In yet another embodiment of the present disclosure, p is 2 or 9. In yet another embodiment of the present disclosure, p is 2 or 10. In yet another embodiment of the present disclosure, p is 2 or 11. In yet another embodiment of the present disclosure, p is 2 or 12. In yet another embodiment of the present disclosure, p is 3 or 4. In yet another embodiment of the present disclosure, p is 3 or 5. In yet another embodiment of the present disclosure, p is 3 or 6. In yet another embodiment of the present disclosure, p is 3 or 7. In yet another embodiment of the present disclosure, p is 3 or 8. In yet another embodiment of the present disclosure, p is 3 or 9. In yet another embodiment of the present disclosure, p is 3 or 10. In yet another embodiment of the present disclosure, p is 3 or 11. In yet another embodiment of the present disclosure, p is 3 or 12. In yet another embodiment of the present disclosure, p is 4 or 5. In yet another embodiment of the present disclosure, p is 4 or 6.In yet another embodiment of the present disclosure, p is 4 or 7. In yet another embodiment of the present disclosure, p is 4 or 8. In yet another embodiment of the present disclosure, p is 4 or 9. In yet another embodiment of the present disclosure, p is 4 or 10. In yet another embodiment of the present disclosure, p is 4 or 11. In yet another embodiment of the present disclosure, p is 4 or 12. In yet another embodiment of the present disclosure, p is 5 or 6. In yet another embodiment of the present disclosure, p is 5 or 7. In yet another embodiment of the present disclosure, p is 5 or 8. In yet another embodiment of the present disclosure, p is 5 or 9. In yet another embodiment of the present disclosure, p is 5 or 10. In yet another embodiment of the present disclosure, p is 5 or 11. In yet another embodiment of the present disclosure, p is 5 or 12. In yet another embodiment of the present disclosure, p is 6 or 7. In yet another embodiment of the present disclosure, p is 6 or 8. In yet another embodiment of the present disclosure, p is 6 or 9. In yet another embodiment of the present disclosure, p is 6 or 10. In yet another embodiment of the present disclosure, p is 6 or 11. In yet another embodiment of the present disclosure, p is 6 or 12. In yet another embodiment of the present disclosure, p is 7 or 8. In yet another embodiment of the present disclosure, p is 7 or 9. In yet another embodiment of the present disclosure, p is 7 or 10. In yet another embodiment of the present disclosure, p is 7 or 11. In yet another embodiment of the present disclosure, p is 7 or 12. In yet another embodiment of the present disclosure, p is 8 or 9. In yet another embodiment of the present disclosure, p is 8 or 10. In yet another embodiment of the present disclosure, p is 8 or 11. In yet another embodiment of the present disclosure, p is 8 or 12. In yet another embodiment of the present disclosure, p is 9 or 10. In yet another embodiment of the present disclosure, p is 9 or 11. In yet another embodiment of the present disclosure, p is 9 or 12. In yet another embodiment of the present disclosure, p is 10 or 11. In yet another embodiment of the present disclosure, p is 10 or 12.In yet another embodiment of the present disclosure, p is 11 or 12. In yet another embodiment of the present disclosure, p is 12. In yet another embodiment of the present disclosure, p is 11. In yet another embodiment of the present disclosure, p is 10. In yet another embodiment of the present disclosure, p is 9. In yet another embodiment of the present disclosure, p is 8. In yet another embodiment of the present disclosure, p is 7. In yet another embodiment of the present disclosure, p is 6. In yet another embodiment of the present disclosure, p is 5. In yet another embodiment of the present disclosure, p is 4. In yet another embodiment of the present disclosure, p is 3. In yet another embodiment of the present disclosure, p is 2. In yet another embodiment of the present disclosure, p is 1. In yet another embodiment of the present disclosure, p is 0.

[0131] In some embodiments, suitable compounds of the present disclosure include: (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(10-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}decyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}butyl)cyclobutane-1-carboxamide; 3-[5-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[5-(4-{5-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-5-oxopentyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[5-(1-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(4-{5-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-5-oxopentyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(1-{5-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-5-oxopentyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(1-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-(6-{4-[7-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}piperidin-1-yl)-7-oxoheptyl]piperazin-1-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione; 1-{4-[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(8-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}octyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-{4-[4-(7-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}heptanamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-{4-[4-(9-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}nonanamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(10-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}decyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(6-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}hexyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(10-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}decyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 9-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]nonanamide; 11-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]undecanamide; 13-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]tridecanamide; 7-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]heptanamide; 13-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]tridecanamide; 7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]heptanamide Examples include:

[0132] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described herein.

[0133] In some embodiments, the present disclosure provides compounds that are isotopic derivatives (e.g., isotopically labeled compounds) of any one of the compounds having the formulas disclosed herein.

[0134] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 7, and prodrugs and pharmaceutically acceptable salts thereof.

[0135] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 7, and pharmaceutically acceptable salts thereof.

[0136] In some embodiments, the compound is an isotopic derivative of a prodrug of any one of the compounds listed in Table 7, and pharmaceutically acceptable salts thereof.

[0137] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 7.

[0138] 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 in the schemes described herein and / or by practicing the procedures disclosed in the Examples.

[0139] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0140] In some embodiments, an isotopic derivative is a deuterium-labeled compound of a compound of any one of the formulas disclosed herein.

[0141] 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 derivatives are deuterium-labeled compounds (i.e., enriched or labeled with respect to one or more atoms selected from S). 2 In some embodiments, the compound is 18 In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds,131 I-labeled compounds, 135 I-labeled compounds, or any combination thereof. In some embodiments, the compound 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds, or any combination thereof.

[0142] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can be prepared by carrying out the procedures disclosed in the schemes and / or examples herein, instead of isotopically labeled reagents. 18 F, 125 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 It can be produced by using a 3S-labeled reagent.

[0143] One or more of the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and 36 Compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof, containing S atoms are within the scope of the present invention. 18 F, 123 I,124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 S) substitution may confer certain therapeutic advantages due to increased metabolic stability, for example, increased in vivo half-life or reduced required dosage.

[0144] For the avoidance of doubt, when a group is defined herein by the phrase "as described herein," it is to be understood that the group encompasses the broadest definition appearing first, as well as any and all specific definitions for that group.

[0145] 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, 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, by way of example only. Additionally, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, or salts with organic bases that provide a pharmaceutically acceptable cation, for example, salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tosyl-(2-hydroxyethyl)amine.

[0146] It will be understood that the compounds of any one of the formulae disclosed herein, as well as any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0147] As used herein, the term "isomers" refers to 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 termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers," or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0148] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0149] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with more than one chiral center can exist either as individual diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer may be 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 (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) rules.

[0150] As used herein, the term "geometric isomer" refers to diastereomers whose existence results from hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0151] It should be understood that the compounds of the present disclosure may be represented as different chiral or geometric isomers. It should also be understood that when a compound is in chiral or geometric isomeric form, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form; it should be recognized that not all isomers have the same activity level.

[0152] It is understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also understood that not all atropic isomers have the same activity levels.

[0153] 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 isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as mixtures of pairs of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerism is called tautomerism. Of the various types of tautomerism possible, two types are commonly observed. In keto-enol tautomerism, the simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, thereby imparting a cyclic (ring-shaped) conformation, as shown in glucose.

[0154] It is understood that the compounds of the present disclosure may be described as different tautomers. It should also be understood that if a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than other tautomers.

[0155] Compounds that have the same molecular formula but differ in the bonding characteristics or sequence of their molecules or 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, e.g., a center of attachment to four different groups, a pair of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomer, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0156] The compounds of the present disclosure may have one or more asymmetric centers, and therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to encompass both individual enantiomers and mixtures thereof (racemic or other mixtures). Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), and are achieved, for example, by synthesis from optically active starting materials or by resolution of racemates. Some of the compounds of the present disclosure may have geometric isomeric centers (E- and Z-isomers). It is understood that the present disclosure encompasses all optical, diastereomeric, and geometric isomers, and mixtures thereof, that possess inflammasome inhibitory activity.

[0157] Any compound of any formula described herein should be understood to include the compound itself, as well as its salts and solvates, if applicable. For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) in 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).

[0158] 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 and a negatively charged group (e.g., carboxylate) in the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0159] It will be understood that compounds of the present disclosure, such as salts of the 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.

[0160] As used herein, the term "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by combining one or more molecules of water with one molecule of a substance, where the water maintains its molecular state as HO.

[0161] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but differs slightly in composition (such as the replacement of an atom with an atom of a different 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 comparable to the reference compound in function and appearance, but dissimilar or comparable in structure or origin.

[0162] As used herein, the term "derivative" refers to compounds that share a common core structure and are substituted with various groups as described herein.

[0163] It should also be understood that a particular compound of any one of the formulae disclosed herein can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0164] It is also understood that a particular compound represented by any one of the formulas disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms, or mixtures thereof, that possess 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, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be measured by Karl Fischer analysis.

[0165] Compounds of any one formula disclosed herein may exist in many different tautomeric forms, and reference to a compound of formula (I) encompasses all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms, and only one of these is specifically described or shown, all other tautomeric forms are also included in formula (I). Examples of tautomeric forms include the keto-, enol-, and enolate-forms of keto / enol (shown below), imine / enamine, amide / aminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro tautomeric pairs, for example:

[0166] The compounds of any one of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the human or animal body to release a compound of the present disclosure. Prodrugs may 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 in vivo cleavable alkyl or acyl substituents at the ester or amide groups in any one of the formulas disclosed herein.

[0167] Thus, the present disclosure encompasses those compounds of any one of the formulae disclosed herein, as described above, when made available by organic synthesis, when made available in the human or animal body by cleavage of the prodrug. Thus, the present disclosure encompasses those compounds of any one of the formulae disclosed herein produced by organic synthetic means, as well as compounds of any one of the formulae disclosed herein produced in the human or animal body by metabolism of a precursor compound, which may be a synthetically produced compound or a metabolically produced compound.

[0168] Suitable pharmaceutically acceptable prodrugs of compounds of any one of the formulas disclosed herein are those that, based on sound medical judgment, are free from undesired pharmacological activity, are free from undue toxicity, and are suitable for administration to the human or animal body. Various forms of prodrugs are described, for example, in the following references: 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 et al. (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and 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.

[0169] Suitable pharmaceutically acceptable prodrugs of the compounds of any one of the formulae disclosed herein, which have a hydroxy group, are, for example, in vivo cleavable esters or ethers thereof. In vivo cleavable esters or ethers of the compounds of any one of the formulae disclosed herein, which contain a hydroxy group, are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups in the case of hydroxy include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups in the case of hydroxy include C1-C2 esters such as acetyl, benzoyl, phenylacetyl, substituted benzoyl, and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 10 and alkoxycarbonyl. 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. In the case of hydroxy, suitable pharmaceutically acceptable ether-forming groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0170] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group include, for example, amines such as ammonia, C methylamine, and the like. 1-4 alkylamines, (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 in vivo cleavable amides thereof such as amides formed with amino acids such as glycine, or esters thereof.

[0171] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein that has an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C6 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 and amides formed with alkanoyl 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.

[0172] The in vivo effects of a compound of any one of the formulas disclosed herein may be exerted in part by one or more metabolic products formed in the human or animal body after administration of a compound of any one of the formulas disclosed herein. As noted above, the in vivo effects of a compound of any one of the formulas disclosed herein may also be exerted by metabolism of a precursor compound (prodrug).

[0173] How to use The compounds described herein may be used in an amount effective to treat a patient, typically a human, in need thereof, having 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 invention inhibit the activity of additional proteins, such as Aurora kinase or VEGFR. 2 In certain embodiments, the compounds of the invention degrade RET and Aurora A kinase (AURKA).

[0174] Another aspect of the present invention provides a compound as described herein, an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for the treatment or prevention of cancer in a patient in need thereof; wherein the treatment or prevention of cancer requires RET inhibition.

[0175] In certain embodiments, the methods of the present invention comprise administering to a patient in need thereof an effective amount of an active compound described herein, or a salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or drug combination.

[0176] In certain embodiments, the present invention provides a method of treating any of the disorders described herein in a patient in need thereof.

[0177] 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.

[0178] In certain embodiments, the present application provides a method of preventing any of the disorders described herein in a patient in need thereof.

[0179] In certain embodiments, the patient is a human.

[0180] 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.

[0181] In some embodiments, the disease is mediated by RET, eg, RET plays a role in the development or progression of the disease.

[0182] In certain embodiments, the RET-mediated disorder is a benign tumor, metastasis, tumorigenesis, tumor, solid tumor, rhabdoid tumor, carcinoma, leukemia, cancer, abnormal cell proliferation, amyloid-based proteinopathy, proteinopathy, fibrotic disorder, inflammation, arthritis, pulmonary disorder, or immune disorder.

[0183] In certain embodiments, the RET-mediated disorder is a cancer that has metastasized, e.g., a cancer that has metastasized to the brain. In certain embodiments, the RET-mediated disorder is a cancer that has metastasized to the brain, lung, bone, liver, peritoneum, adrenal gland, skin, or muscle.

[0184] In certain embodiments, compounds of the invention cross the blood-brain barrier and can be used to treat cancers that involve the CNS or that have metastasized to the brain.

[0185] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0186] In certain embodiments, the RET-mediated disorder is abnormal cell proliferation, including, but not limited to, a tumor or cancer, or a bone marrow or lymphoproliferative disorder such as B- or T-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder.

[0187] 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, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLE), and / or mixed lineage leukemia (MCL). LL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL)2 and / or BCL6 rearrangements / overexpression [double- and triple-hit lymphomas], myelodysplastic / myeloproliferative neoplasms, and mantle cell lymphomas, including bortezomib-resistant mantle cell lymphoma.

[0188] Solid tumors that may be treated with the compounds described herein include, but are not limited to, lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); breast cancer, including inflammatory breast cancer, ER-positive breast cancer (including tamoxifen-resistant ER-positive breast cancer), and triple-negative breast cancer; colon cancer, midline carcinoma, liver cancer, kidney cancer; prostate cancer, including castration-resistant prostate cancer (CRPC); brain cancer, including glioma, glioblastoma, neuroblastoma, and medulloblastoma (including MYC-amplified medulloblastoma); colorectal cancer; Wilms' tumor; Ewing's tumor; These include rhabdomyosarcoma, ependymoma, 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, mesothelial cancer, esophageal cancer, salivary gland cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), neutrophil thyroid cancer, testicular cancer, squamous cell carcinoma, hepatocellular carcinoma (HCC), MYCN-induced solid tumor, and neutrophil thyroid cancer (NMC).

[0189] In a further embodiment, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0190] In further embodiments, the disease or disorder is soft tissue sarcoma, osteosarcoma, or osteosarcoma.

[0191] In further embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Kaposi's sarcoma, osteosarcoma, gastrointestinal stromal sarcoma, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningeal sarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0192] In a further embodiment, the disease or disorder is multiple myeloma.

[0193] In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthropathy, osteoarthritis, juvenile arthritis, and other arthritic conditions, neuroinflammation, allergies, pain, neuropathic pain, fever, lung disorders, pneumonia, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcer disease, gastric ulcer, autoimmune diseases, graft-versus-host reaction and allograft rejection, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, epithelial cell-derived tumors (epithelial cell glandular tumors), and / or inflammatory bowel disease (IGD). cancer), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cavity cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell carcinoma, prostate cancer, renal cell carcinoma, and other known cancers affecting epithelial cells throughout the body, chronic myeloid leukemia (CML), acute promyelocytic leukemia (AML) and acute promyelocytic leukemia (APL), as well as angiogenesis including tumorigenesis, metastasis, central nervous system disorders, central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy, or B-cell lymphoma.

[0194] In other embodiments, the pharmaceutical composition comprising a compound described herein and the additional therapeutic agent are administered simultaneously or sequentially.

[0195] In other embodiments, the disease or disorder is cancer, hi further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastrointestinal cancer, breast cancer, pancreatic cell carcinoma, 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.

[0196] In some embodiments, the method is used to treat or prevent a condition selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases, hi other embodiments, the condition is selected from a proliferative disorder.

[0197] In certain embodiments, the RET-mediated disorder is an immune disorder, 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.

[0198] One aspect of the present application provides compounds that are useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer; ovarian cancer; cervical cancer; prostate cancer; testicular cancer, genitourinary 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, adenocarcinoma; thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminiferous carcinoma; melanoma; sarcoma; bladder cancer; liver cancer and biliary tract cancer; kidney cancer; bone marrow disorders; lymphatic disorders, Hodgkin's lymphoma, hairy cell disorders; buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, oral cancer, pharyngeal cancer; small intestine cancer; colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer; chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma, or gastric cancer, pancreatic cancer, or a cancer selected from the following cancers: head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin's lymphoma, and lung cancer.

[0199] The term "cancer" refers to any cancer caused by the proliferation of malignant tumor cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas (e.g., cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, human T-cell lymphotropic virus (HTLV)-associated lymphomas such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid 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 myeloid leukemia (CML), etc.), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, childhood solid tumors (such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas), head and neck cancers (such as those of the oral cavity, larynx, nasopharynx, and esophagus), common solid tumors of the adult genitourinary tract (such as cancer of the prostate, bladder, kidney, uterus, ovary, and testis), lung cancer (such as small cell and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin syndrome such as medulloblastoma or meningioma, and liver cancer.

[0200] Further 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.

[0201] Additional cancers for which the compounds described herein may be useful in the prevention, treatment and research are, for example, colon cancer, familial adenomatous polyposis adenocarcinoma, and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, parenchymal kidney cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, ovarian cancer, urinary tract cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor), gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, 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 invention provides the use of one or more compounds described herein in the manufacture of a medicament for treating cancer, including, but not limited to, the various types of cancer disclosed herein. In some embodiments, the compounds described herein are useful for treating cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mast cell disease. In some embodiments, the compounds described herein are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic 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, suffering from lymphoma or a lymphocytic or myeloid proliferation disorder or abnormality. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma.For example, the host may be afflicted with a non-Hodgkin's lymphoma, such as AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); diffuse small cleaved cell lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic 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 giant cell disease.

[0202] In another embodiment, the compounds described herein or their corresponding pharmaceutically acceptable salts or isotopic derivatives may be used in an effective amount to treat patients, e.g., humans, with Hodgkin's lymphoma, including, but not limited to, tuberous sclerosis, classical Hodgkin's lymphoma (CHL); mixed cellularity CHL; lymphopenic CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL. The present application further encompasses the treatment or prevention of cell proliferative disorders, such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that can be recognized by a pathologist upon biopsy. The compounds may be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions may occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0203] 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.

[0204] In certain embodiments, the compounds of the present invention are used to treat abnormal cell growth, such as tumors or cancers, that have a mutated RET protein, where 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 in Table 1 below, or may be a different mutation.

[0205] Table 1. Exemplary RET protein mutations [Table 1]

[0206] In certain embodiments, the RET protein has two mutations selected from Table 1 above. In other embodiments, the RET protein has three mutations selected from Table 1 above. In other embodiments, the RET protein has four or more mutations, optionally selected from Table 1 above.

[0207] In certain embodiments, the tumor or cancer has a mutation in the RET protein that is a substantial or partial driver of tumor or cancer cell growth. In another embodiment, the tumor or cancer has a RET modified protein that does not significantly act as a driver of abnormal cell growth, but can be used therapeutically to kill tumor cells using selected RET degraders described herein.

[0208] 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. 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 growth, such as tumors or cancers with a RET protein G810R mutation.

[0209] 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, that have a G810S mutation in the RET protein.

[0210] 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, that have a G810C mutation in the RET protein.

[0211] 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, that have a C634W mutation in the RET protein.

[0212] 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, that have an M918T mutation in the RET protein.

[0213] 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, that have a V804L mutation in the RET protein.

[0214] 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, that have a V804M mutation in the RET protein.

[0215] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell growth, such as a 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.

[0216] In certain embodiments, compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as 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, such as tumors or cancers, that harbor an NCOA4-RET fusion.

[0217] 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, that harbor a KIF5B-RET fusion.

[0218] In accordance with the above, the present application further provides a method for preventing or treating any of the above-mentioned diseases or disorders in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In 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.

[0219] Pharmaceutical Compositions and Combination Therapies In some embodiments, the compounds of Formula I described herein, or pharmaceutically acceptable salts thereof, can be administered as the neat chemical, but are more typically administered as pharmaceutical compositions containing an effective amount to a patient, typically a human, in need of such treatment for any of the disorders described herein. Accordingly, 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 use in any of the applications 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.

[0220] In some embodiments, the compounds of formula I, or pharmaceutically acceptable salts thereof, can be used, either 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.

[0221] The disclosed compounds described herein can be used in effective amounts alone or in combination with another compound of the invention or with another bioactive agent or another therapeutic agent to treat a patient, such as a human, suffering from a disorder, including but not limited to, the disorders described herein.

[0222] The term "bioactive agent" is used to describe an agent, other than a compound selected in accordance with the present invention, that can be used in combination or alternation with a compound of the present invention to achieve a desired therapeutic result. In one embodiment, the compound of the present invention and the bioactive agent are administered such that they are active in vivo for an overlapping period of time, e.g., have overlapping periods of C, T, AUC, or other pharmacokinetic parameters. In another embodiment, the compound of the present invention and the bioactive agent do not have overlapping pharmacokinetic parameters, but are administered to a patient in need thereof such that one therapeutically impacts the therapeutic efficacy of the other. In one aspect of this embodiment, the bioactive agent is an immunomodulatory agent, including, but not limited to, checkpoint inhibitors (including, but not limited to, 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 molecules, peptides, nucleotides, or other inhibitors). In certain embodiments, the immunomodulatory agent is an antibody, such as a monoclonal antibody. PD-1 inhibitors that bind to the PD-1 receptor, thereby blocking the interaction between PD-1 and PD-L1 and subsequently inhibiting immunosuppression, include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.).PD-L1 inhibitors that bind to the PD-L1 receptor, thereby blocking the interaction between PD-1 and PD-L1 and subsequently inhibiting immunosuppression include, for example, aterolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS936559, PDL2 / Ig fusion proteins such as AMP224, 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 may be administered in combination or alternation with an effective amount of an estrogen inhibitor (including, 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) in an amount effective to treat abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. Partial antiestrogen drugs such as raloxifene and tamoxifen retain some estrogenic effects, including estrogenic stimulation of uterine growth, and in some cases, estrogenic effects actually stimulate tumor growth during breast cancer progression. In contrast, the complete antiestrogen fulvestrant has no estrogenic effects on the uterus and is effective against tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are described in WO 2014 / 19176 (assigned to Astra Zeneca), WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US 2013 / 0178445 (assigned to Olema Pharmaceuticals), and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, and US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138.Additional non-limiting examples of anti-estrogen compounds include SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclophenyl, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.Other estrogen ligands that may be used in accordance with the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO 2011 / 156518, U.S. Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015 / 0005286; and WO 2014 / 205138, US 2016 / 0175289, US 2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418;WO 2002 / 003992;WO 2002 / 003991;WO 2002 / 003990;WO 2002 / 003989;WO 2002 / 003988;WO 2002 / 003986;WO 2002 / 003977;WO 2002 / 003976;WO 2002 / 003975;WO 2006 / 078834;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 may be administered in an amount effective to treat abnormal tissue of the male reproductive system, such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor, including, but not limited to, a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, the prostate or testicular cancer is androgen-resistant.Non-limiting examples of antiandrogen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen 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), and neratinib. Examples of suitable bioactive agents include nib (HKI-272; PB272); avitinib (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. Examples of JAK3 inhibitors include 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-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT -263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)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]thiazolinone). In one embodiment, the bioactive agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. Examples of PI3 kinase inhibitors include, but are not limited to, wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelsib, GS-9820, BKM120, GDC-0032 (taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen (S)-methyl 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), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyridin[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2- (2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-((S)-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furin-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-molybdenum)-methylbenzamide] [4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-0521238 4(N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatricisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydrazin-2-yl}phenyl) 4-(4-pyridinyl)- 6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, piralalisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-60524 0, BGT226 (NVP-BGT226), AZD6482, voxitalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY80-6946), XL147, 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[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics, Inc. (see U.S. Patent Application Publication No. 2011 / 0117073, incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy-beta-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)-4,5,67-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]quinoline) xalin-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-083 7((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6: 59, which is incorporated herein by reference in its entirety. 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 dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide·HCl), RO9021 (6-[(1R,2S)-2-amino-ci, 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), (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 (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643),3614-3643 (incorporated herein in its entirety), Compound D (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein in its entirety)), PRT060318 (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein in its entirety)), luteolin (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein in its entirety)), 3614-3643 (incorporated herein in its entirety)), apigenin (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein 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)), 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, which is incorporated herein in its entirety), and morin (Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein in its entirety). In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroaniline)). (S)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[( 2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), 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[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxyc romen-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, BIX02188, binimetinib, SL-327, TAK-733, PD318088. In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are well known and include, for example, vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoardisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib). In one embodiment, the bioactive agent comprises an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honoquinol, PF-04691502, and miltefosine; an FLT-3 inhibitor, including but not limited to P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof. In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include, but are not limited to, tametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyridino[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selmetinob (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]isonicotinamide), dophenyl)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]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) )amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfonyl) amoylamino)-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). In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Examples of suitable bioactive agents include 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 bioactive compounds include, for example, everolimus, trabectedin, Abraxane, TLK286, AV-299, DN-101, pazopanib, GSK690693, RTA744, ON0910·Na, AZD6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, Aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, panitumumab, amrubicin, olevomomab, Lep-etu, nolatrexed, azd2171, batavirin, atumumab, zanolimumab, edotecarin, tetrand Phosphorus, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO140, CC8490, syringitide, gimatecan, IL13-PE38QQR, INO1001, IPdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta744, Sdx102, talampanel, atrasentan, Xr311, romidepsin, ADS-100 380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,Disodium Salt, Heptahydrate, Camptothecin, PEG-Labeled Irinotecan, Tamoxifen, Toremifene Citrate, Anastarazole, 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 Palmate, 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 Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin,Vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimatidine, trastuzumab, denileukin Diftitox, gefitinib, bordesinib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, aldoxifene, 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, LY2 93684, 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 alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard,methylprednisolone, ibritogomab tiuxetan, androgens, dextabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, edwina asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In one embodiment, the bioactive agent is selected from the group consisting of, but not limited to, imatinib mesylate (Gleevac®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), trastuzumab (Herceptin®), trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), panitumumab (Vectibix®), vandetanib (Caprelsa®), vemurafenib (Ze lboraf®), vorinostat (Zolinza®), romidepsin (Istodax®), bexarotene (Tagretin®), alitretinoin (Panretin®), tretinoin (Vesanoid®), carfilizomib (Kyprolis™), pralatrexate (Folotyn®), bevacizumab (Avastin®), diflubenzaflibercept (Zaltrap®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), regorafenib (Stivarga®),and cabozantinib (Cometriq™). In certain embodiments, 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 referred to as cytotoxins or cytotoxic agents) (including any agent detrimental to cell viability), and liposomes or other vehicles containing chemotherapeutic compounds. Common anti-cancer medications include vincristine (Oncovin®) or liposomal vincristine (Marqibo®), daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®). , etoposide (VP-16), teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), methotrexate, cyclophosphamide (Cytoxan®), prednisone, dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of suitable additional chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamineplatinum(II) (DDP) cisplatin, diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium,Calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclotosphamide, cytarabine, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCl, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxyanthracene dione, docetaxel, dolasetron mesylate, doxorubicin HCl, dronabinol, E. coli L-asparaginase, emetamine, , epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrol factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifostamide, interferon α-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoids, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, These include mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCl, primycin, poriflosan 20+ 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.

[0223] 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 include 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, 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, metuledopa, and uredopa; ethyleneimines and methylameramines (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine); acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; calistatin; CC-1065 (including its adozelesin, carzelesin, and bilephrine derivatives); including synthetic analogs of zelesin; cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictine; spongistatin; chlorambucil, chlornaphazine, clofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembrine, phenesterine, prednimustine, trofosfamide, nitrogen mustards such as uracil mustard; carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and nitrosoureas such as ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin gamma 1l and calicheamicin omega 1l (e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994); dynemycins (including dynemycin A); bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin (including morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin, and deoxydoxorubicin)), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mitomycins, mitrom ... tophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; aminoglutethimide, mitotane,Antiadrenal agents such as trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole; elfomitin; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidynin; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxatrone; mopidammol; nitraelin; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE®, a cremophor-free albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; Xeloda; ibandronate; irinotecan (e.g.,Also included are CPT-11); the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoid acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail that can be administered in combination with the compounds of the present invention. Suitable administration regimens for combined chemotherapeutic agents are known in the art. For example, combined administration 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 may 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, trametinib, and the like. Stuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukin, atlizumab, tocilizumab, temosirolimus, everolimus, lucalmumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir Viral, nelfinavir mesylate, indinavir sulfate, belinstat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib , bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amevaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab,These may include pemetrexed (Alimta) and ramucirumab (IMC-1121B). In one embodiment, the additional therapeutic agent 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 may "coat" the surface of cancer cells, potentially 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 that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from transmitting their normal growth-promoting signals. They may also induce apoptosis and activate the immune system to destroy tumor cells. In one embodiment of the present invention, the bioactive agent is an immunosuppressant. Immunosuppressants include calcineurin inhibitors, such as cyclosporine, or ascomycins, such as cyclosporine A (NEORAL®), FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, such as rapamycin or derivatives thereof, such as sirolimus (RAPAMUNE®), everolimus (Certican®), 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, such as mycophenolate mofetil (CELLCEPT®), OKT3 (ORTHOCLONE®), OKT3 (registered trademark), prednisone (ATGAM (registered trademark), THYMOGLOBULIN (registered trademark), brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus,Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT®), daclizumab (ZENAPAX®), mizorubin, methotrexate, dexamethasone, ISAtx-247, SDZ ASM981 (pimecrolimus, Elidel®), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (sold by Immunex as Enbrel®), adalimumab (Humira®), infliximab (Remicade®), anti-LFA-1 antibody, natalizumab (Antegren®), enlimomab, gavilimomab, anti-thymocyte immunoglobulin, siplizumab, alefacept The bioactive agent may be efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, 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., interferon or interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, bioactive agents are biologics. The biologic is an anti-angiogenic agent such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonize an antigen important to cancer.Such agents include RITUXAN® (rituximab); ZENAPAX® (daclizumab); SIMULECT® (basiliximab); SYNAGIS® (palivizumab); REMICADE® (infliximab); HERCEPTIN® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH® (alemtuzumab); ZEVALIN® (ibritumomab tiuxetan); HUMIRA® (adalimumab); XOLAIR® (omalizumab); BEXXAR® (tositumomab-1-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); AVASTIN® (bevacizumab); TYSABRI® (natalizumab); ACTEMRA® (tositumomab) elizumab); VECTIBIX® (panitumumab); LUCENTIS® (ranibizumab); SOURIS® (eculizumab); CIMZIA® (certolizumab pegol); SIMPONI® (golimumab); ILARIS® (canakinumab); STELARA® (ustekinumab); ARZERRA® (ofatumumab); PROLIA® (denosumab) NUMAX® (motavizumab); ABTHRAX® (raxibacumab); BENLYSTA® (belimumab); YERVOY® (ipilimumab); ADCETRIS® (brensuximab vedotin); PERJETA® (pertuzumab); KADCYLA® (adotrastuzumab emtansine); and GAZYVA® (obinutuzumab). Also included are antibody-drug conjugates. Combination therapy may include a therapeutic agent that is a non-drug therapy. For example, a compound may 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 may be administered immediately before or after the second therapeutic agent, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, up to 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7 days, up to 1-14 days, up to 1-21 days, or up to 1-30 days. In certain embodiments, the second therapeutic agent is administered on a different dosing schedule than the compounds of the invention. For example, the second therapeutic agent may have a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 8-day, 9-day, 10-day, 11-day, 12-day, 13-day, or 14-day treatment rest period per treatment cycle. In another embodiment, the first therapeutic agent can have a treatment-free period. For example, the first therapeutic agent can have a treatment-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 certain embodiments, both the first therapeutic agent and the second therapeutic agent have a treatment-free period.

[0224] Generally, the compositions of the present disclosure will be administered in a therapeutically effective amount by any acceptable administration method.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 indications intended by administration, and the preferences and experience of the medical personnel involved.Those skilled in the art of treating such diseases will be able to determine the therapeutically effective amount of the compositions of the disclosure for a given disease without undue experimentation, relying on their own knowledge and the disclosure of this application.

[0225] In certain embodiments, the pharmaceutical composition is in the form of a unit 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. 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 salt thereof.

[0226] In certain embodiments, patients may be treated with low-dose therapy using the compounds of the present invention. For example, pharmaceutical compositions may be in dosage forms 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 active compound. 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 μg of the active compound or a salt thereof.

[0227] In certain embodiments, the dosage is in the range of about 0.01-100 mg / kg of patient 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, / 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.

[0228] A pharmaceutically or therapeutically effective amount of the composition will be delivered to the patient. The precise amount that is effective 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 treating physician's recommendations, and the therapeutic agent or combination of therapeutic agents selected for administration. The effective amount in a given situation can be determined by routine experimentation. For purposes of the present disclosure, a therapeutic amount may be, for example, in the range of about 0.01 mg / kg to about 250 mg / kg of body weight, more typically about 0.1 mg / kg to about 10 mg / kg, in at least one dose. A subject may be administered the same dose as needed to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or to effect any other desired change in a biological system. If desired, formulations may be prepared with enteric coatings suitable for sustained- or controlled-release administration of the active ingredient.

[0229] In some embodiments, a compound disclosed herein or used as described is 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 longer.

[0230] In certain embodiments, compounds of the present invention are administered once daily, twice daily, three times daily, or four times daily. In certain embodiments, compounds of the present invention are administered orally once daily. In certain embodiments, compounds of the present invention are administered orally twice daily. In certain embodiments, compounds of the present invention are administered orally three times daily. In certain embodiments, compounds of the present invention are administered orally four times daily.

[0231] In certain embodiments, compounds of the present invention are administered intravenously once daily. In certain embodiments, compounds of the present invention are administered intravenously twice daily. In certain embodiments, compounds of the present invention are administered intravenously three times daily. In certain embodiments, compounds of the present invention are administered intravenously four times daily.

[0232] In some embodiments, the compounds of the invention are administered with treatment rest periods between treatment cycles, for example, the compounds may have a treatment rest 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.

[0233] The pharmaceutical composition may also contain a molar ratio of the active compound to the additional active compound, for example, the pharmaceutical composition may 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.

[0234] These compositions can contain any amount of the active compound that achieves the desired result, e.g., 0.1 to 99% by weight (wt%) of the compound, usually at least about 5% by weight of the compound, with some embodiments containing from about 25% to about 50% by weight, or from about 5% to about 75% by weight of the compound.

[0235] 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 package contains individual amounts of preparations, such as packaged tablets, capsules, and powders in vials or ampoules.The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these dosage forms in packaged form.

[0236] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-hydroxyethanesulfone. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0237] Thus, the compositions of the present disclosure may be administered as pharmaceutical formulations, including those 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 aerosol, intra-aortic, intracranial, subdermal, intraperitoneal, or subcutaneous administration, or by other means of administration containing conventional pharmaceutically acceptable carriers. Typical methods of administration are buccal, topical, or intravenous, using a convenient daily dosage regimen that can be adjusted according to the degree of affliction.

[0238] Depending on the intended method of administration, the pharmaceutical composition may be in the form of a solid, semi-solid or liquid dosage form such as, for example, a tablet, suppository, pill, capsule, powder, liquid, syrup, suspension, cream, ointment, lotion, paste, gel, spray, aerosol, foam, or oil, a solution for injection or infusion in a medical device, a transdermal patch, a subcutaneous patch, an inhalation formulation, a suppository, preferably in a unit dosage form suitable for precise single administration of a dosage, a buccal or sublingual formulation, a parenteral formulation, or eye drops, etc.

[0239] Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, for example, an effective amount to achieve the desired purpose. The composition may contain an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may also contain other agents, adjuvants, diluents, buffers, etc. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to patients being treated. Carriers can be inert, or the carrier itself may have pharmaceutical benefits. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Types of carriers include, but are not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, excipients, emulsifiers, flavorings, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizers, tableting, 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, starch, cellulose, 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 compound of the present invention may be included in the pharmaceutical composition. Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, etc. The compound may be provided in solid form, such as solids, liquids, spray-dried materials, microparticles, nanoparticles, controlled-release systems, etc., depending on the therapeutic purpose, if necessary. Suitable excipients for non-liquid formulations are also known to those skilled in the art. A detailed discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).In addition, auxiliary substances, such as wetting or emulsifying agents, biological buffers, surfactants, etc., may be present in such vehicles. The biological buffer can be any solution that is pharmacologically acceptable and provides the formulation with a desired pH, i.e., a pH within the physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, Hank's-buffered saline, etc. 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, etc. Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, etc., the active compounds described herein and any pharmaceutical adjuvants in excipients such as water, saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming a solution or suspension. If necessary, the administered pharmaceutical composition may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, etc., e.g., sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc. Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, cited above. In yet another embodiment, the use of penetration enhancer excipients is provided, 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 / combination may be formulated for oral administration. For oral administration, the compositions will generally take the form of a tablet, capsule, soft gelatin solution, or may be an aqueous or non-aqueous solution, suspension, or syrup.Tablets and capsules are typical oral dosage forms. Oral tablets and capsules can contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. Typically, the compositions of the present disclosure can be combined with orally administrable, non-toxic, pharmaceutically acceptable inert carriers, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, calcium 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 beta-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, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. When liquid suspensions are used, the active agent can be combined with any orally administrable, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like, and emulsifying and suspending agents. If desired, flavoring agents, coloring agents, and / or sweetening agents can likewise be added. Other optional ingredients that may be incorporated into the oral formulations described herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

[0240] For intraocular delivery, the compounds may be administered, for example, via intravitreal, intrastromal, intracameral, subtenon, subretinal, retrobulbar, periocular, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, periconeal, or lacrimal injection, or across a mucus, mucin, or mucosal barrier, in an immediate or controlled release manner, or via an ophthalmic device, as appropriate.

[0241] Parenteral preparations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid before injection, or as emulsions. Typically, sterile injectable suspensions are formulated according to techniques known in the art using appropriate carriers, dispersing or wetting agents, and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in acceptable non-toxic parenterally acceptable diluents or solvents. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile fixed oils, fatty esters, or polyols are commonly used as solvents or suspending media. Furthermore, parenteral administration can be associated with the use of delayed-release or sustained-release systems to maintain a constant level of dosage.

[0242] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and encompasses aqueous and non-aqueous isotonic injection solutions (which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient) and aqueous and non-aqueous sterile suspensions (which may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives). Administration via certain parenteral routes may involve introducing the formulations of the present disclosure into the patient's body through a needle or catheter and propelling them with a sterile syringe or some other mechanical device, such as a continuous infusion system. The formulations provided by the present disclosure may be administered using a syringe, injector, 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 are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may 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 medium immediately before use.

[0243] Sterile injectable solutions are prepared by blending one or more compounds of the present disclosure in the required amount in a suitable solvent containing various other ingredients listed above, followed by sterile filtration as needed. Generally, dispersions are prepared by blending various sterilized active ingredients into a sterile vehicle containing the basic dispersion medium and other required ingredients from those listed above. In the case of sterile powders for preparing sterile injectable solutions, typical preparation methods are vacuum drying and freeze-drying techniques, which produce powders containing the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and subjected to sterilization.

[0244] Alternatively, the pharmaceutical compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and will melt in the rectum and release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0245] The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, utilizing 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 buccal administration include tablets, lozenges, gels, and the like. Alternatively, buccal administration can be achieved using transmucosal delivery systems known to those skilled in the art. The compounds of the present disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches," in which the agent is typically contained in a laminated structure that serves as a drug delivery device and is applied to the body surface. In such structures, the drug composition is typically contained in a layer, or "reservoir," underlying a backing layer. The laminated device may contain a single reservoir or multiple reservoirs. In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to secure the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like.

[0246] Alternatively, the drug-containing reservoir and skin contact adhesive may be present as separate, distinct layers, with the adhesive underlying the reservoir, which may be a polymer matrix as described above, or may be a liquid or gel reservoir, or may take other forms. The backing layer of these laminate structures, which serves as the top surface of the device, functions as the primary structural component of the laminate structure and provides the device with much of its flexibility. The material selected for the backing layer should be substantially impermeable to the active agent and any other materials incorporated therein.

[0247] The compositions of the present disclosure can be formulated for aerosol administration, including intranasal administration, particularly to the respiratory tract. The compound may have a small particle size, for example, generally less than 5 microns. Such particle size can be obtained by means known in the art, for example, by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol can also conveniently contain a surfactant, such as lecithin. The drug dosage can be controlled by a metered valve.

[0248] Alternatively, the active ingredient can be provided in dry powder form, for example, in the form of a powder mixture of the compound in a suitable powder base, such as lactose, starch, hydroxypropylmethylcellulose, and starch derivatives such as polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition can be provided in unit dosage form, for example, in gelatin capsules or cartridges, or in blister packs from which the powder can be administered by means of an inhaler.

[0249] Formulations suitable for rectal administration are typically presented as unit-dose suppositories, which may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0250] In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the modes of administration defined above.

[0251] In certain embodiments, pharmaceutical compositions suitable for transdermal administration may be provided 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 an optionally buffered aqueous solution of the active compound.

[0252] In one embodiment, a microneedle patch or device is provided for delivering drugs across or into biological tissue, particularly skin. The microneedle patch or device allows for the delivery of drugs across or into the skin or other tissue barrier at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0253] Formulations suitable for pulmonary administration can be delivered by a variety of passive breath-driven and active power-driven single / multiple dose dry powder inhalers (DPIs).The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers.Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers.The selection of an appropriate pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0254] Example The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. By way of example, and not limitation, compounds of Formula I can be prepared as outlined in the examples described herein. It should be noted that those skilled in the art will know how to modify the procedures shown in the examples to arrive at the desired product.

[0255] Analysis methods and operations NMR The following conditions were used to obtain proton nuclear magnetic resonance (NMR) signals: NMR spectra were measured using either a 400 MHz or 500 MHz Bruker instrument with either DMSO-d or CDCl as the solvent and internal standard. The raw NMR data were analyzed using either ACD Spectrus version 2015-01 by ADC Labs or MestReNova software.

[0256] Chemical shifts are reported in parts per million (ppm) downfield from internal tetramethylsilane (TMS) or from the TMS position estimated by deuterated NMR solvents. Apparent multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), or multiplet (m). Peaks that exhibit broadening are additionally denoted as br. Integrations are approximate. Note that integrated intensities, peak shapes, chemical shifts, and coupling constants may depend on solvent, concentration, temperature, pH, and other factors. Furthermore, peaks that overlap or exchange with water or solvent peaks in NMR spectra may not provide reliable integrated intensities. In some cases, NMR spectra may have been obtained using water peak suppression, resulting in peaks that appear overlapping or have altered shape and / or intensity.

[0257] Liquid chromatography The following preparative and / or analytical (LC / MS) liquid chromatography methods were used.

[0258] Method A: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: ACN / H2O (5:95) + 10 mM AA; Mobile phase B: ACN / H2O (95:5) + 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+).

[0259] Method B: Column: Xbridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: ACN / H2O (5:95) + 0.05% TFA; Mobile phase B: ACN / H2O (95:5) + 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+).

[0260] Method Column 6: Column: Waters Acquity BEH C18 2.1 x 50 mm 1.7 μm particles; Mobile Phase A: 95:5 acetonitrile:water + 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water + 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)

[0261] UHPLC Method D: Column: Waters Acquity BEHC 18 2.1x50mm 1.7µm particles; Mobile Phase A: 95:5 acetonitrile:water + 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water + 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)

[0262] 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, Description: 2.5 μm particles, Mobile Phase A: Water / 5 mM NH4HCO3, Mobile Phase B: Acetonitrile; Acquisition Mode: Scan, Polarity: Positive

[0263] Method Q: Format: 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 Name: ACE Excel 2C18, Length: 30 mm, Inner Diameter: 3.0 mm, Column Particle Size: 2.0 μm, 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;

[0264] LCMS5: Waters Acquity BEHC18 2.1x50mm 1.7µm particles; Mobile phase A: 95:5 water:acetonitrile + 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water + 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)

[0265] Acronyms and Abbreviations Table 2 provides a list of acronyms and abbreviations used herein, along with their meanings. Table 2 [Table 2] [Table 3]

[0266] Synthesis method A suitable general route for preparing the compounds of the present application can be seen in Scheme 1 herein. [ka]

[0267] Unless otherwise noted, the examples presented herein were synthesized according to the general procedures shown in Schemes 2-9. [ka] [ka] [ka] [ka]

[0268] Example A1. Synthesis of (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide [ka] Step A. 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) at room temperature in a sealable reaction vial, 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 then 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)

[0269] Step B. 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) at room temperature under nitrogen was added TFA (1.0 mL, 12.98 mmol). The reaction 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 then lyophilized overnight to afford the desired product as the FTA salt (279.0 mg, 81% yield) as a solid, which was used without further purification. MS: m / z 457.2 [M+H] + (Methods column 6)

[0270] Alternatively, the compound of Step B was obtained as follows (Steps A'-D'):

[0271] Step 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 room temperature overnight. The precipitate was filtered, and the filtrate was concentrated. The residue was then 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.

[0272] Step 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 organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC to give tert-butyl 7-oxoheptanoate (80 mg, 79% yield) as a colorless oil. 1 H NMR (300MHz, chloroform-d) δ 9.77(t,J=1.8Hz,1H), 2.44(td,J=7.4, 1.8Hz,2H), 2.22(t,J=7.4Hz,2H), 1.63( ddt,J=15.1, 13.0, 7.4Hz,4H), 1.44(s,9H), 1.42-1.32(m,1H), 1.37-1.16(m,1H)

[0273] Step 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 room temperature for 5 minutes, then AcOH (0.02 mL, 0.30 mmol) was added and the mixture was stirred at room temperature for 0.5 hours. The reaction was cooled to 0°C, after which NaBH(OAc)3 (65 mg, 0.30 mmol) was added and the mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was concentrated. The resulting residue was purified by preparative HPLC to give the desired product (50 mg, 64% yield) as an off-white solid. MS: m / z 513.2 [M+H] +

[0274] Step 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 room temperature for 3 hours. Upon completion, the reaction was concentrated to give the desired product (120 mg, 86% yield) as an off-white semi-solid. MS: m / z 457.3 [M+H] +

[0275] Step C. tert-Butyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate [ka] In a 250 mL round-bottom flask, 3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 5.43 mmol), tert-butyl 3-hydroxycyclobutanecarboxylate (1403.47 mg, 8.15 mmol), PPh3 (5700 mg, 21.73 mmol), and DTBAD (5004 mg, 21.73 mmol) were suspended in toluene (100 mL). The reaction was placed under vacuum, sonicated, and backfilled with nitrogen. The mixture was stirred at 100 °C for 2 hours. It was concentrated and the crude product was purified by reverse phase column chromatography to give the product tert-butyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (2 g, 57.8% yield) as an off-white solid. Analytical LCMS: m / z 411.2 [M+H] + , RT=1.00 min (Method Q); Analytical LCMS: m / z 523.3[M+H] + , RT=1.15 minutes (Method Q)

[0276] Step D. 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid [ka] To a solution of tert-butyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (500 mg, 0.96 mmol) in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the crude product was used directly in the next step without further purification. MS: m / z 467.1 [M+H] +

[0277] Step E. Methyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate [ka] To a solution of 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid (1 g, 2.14 mmol) in DMF (10 mL) was added MeOH (0.87 mL, 21.45 mmol), HATU (1223.31 mg, 3.22 mmol), and DIEA (0.49 mL, 6.43 mmol). The mixture was stirred at room temperature for 2 hours. The crude product was purified by reverse-phase column chromatography to obtain the product methyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (800 mg, 77.7% yield) as a yellow solid. Analytical LCMS: m / z 481.1[M+H] + , RT=0.98 min (Method Q)

[0278] Step F. Methyl 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate [ka] In a 5 mL microwave vial, methyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (300 mg, 0.62 mmol), tributyl(2-pyridyl)stannane (344.94 mg, 0.94 mmol), PdCl2[P(cy)3]2 (46.11 mg, 0.06 mmol), and CsF (237.37 mg, 1.56 mmol) were suspended in toluene (20 mL). The reaction was placed under vacuum, sonicated, and purged with nitrogen. The resulting mixture was stirred at 100 °C for 48 h. The reaction was filtered, concentrated, and the residue was purified by preparative TLC (DCM:MeOH=20:1) to give methyl 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (100 mg, 37.1% yield) as a yellow solid. MS: m / z 432.2 [M+H] +

[0279] Step G. 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid [ka] To a solution of methyl 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (1.21 g, 2.8 mmol) in methanol (30 mL) and THF (10 mL) was added LiOH (2 M, 1 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was purified by reverse-phase column chromatography (0.5% TFA / MeCN in water) to obtain the product 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid (1.03 g, 85.1% yield) as an off-white solid. Analytical LCMS: m / z 418.1 [M+H] + , RT=1.14 min (Method Q); 1 H NMR (400MHz, DMSO-d6) δ 8.70-8.64(m,1H), 8.21(s,1H), 8.06(s,1H), 7.96-7.83(m,2H), 7.69-7.61(m,1H), 7.45 -7.41(m,1H), 5.41-5.34(m,1H), 2.48-2.30(m,4H), 2.28-2.19(m,2H), 1.28-0.99(m,4H)

[0280] Step H. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide (1r,3r)-3-(4-amino-3-(5-cyclopropyl-4-(pyridin-2-yl)isoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclobutane-1-carboxylic acid·2TFA (315 mg) was dissolved in DMF (4.5 mL), and BOP (260 mg) was dissolved in DMF (4.5 mL). To each reaction vial containing the acid component, (1r,3r)-3-(4-amino-3-(5-cyclopropyl-4-(pyridin-2-yl)isoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclobutane-1-carboxylic acid·2TFA (0.100 mL, 10.84 μmol), BOP (0.099 mL, 0.013 mmol), and DIEA (0.011 mL, 0.065 mmol) were added. The mixture was then placed in a Bohdan Miniblock XT and stirred at 400 rpm at room temperature overnight. The crude material was diluted with 1.5 mL of DMF and a drop of AcOH and subjected to final purification by RP preparative HPLC to give the title compound. The product yield was 2.9 mg, and its estimated purity by reverse-phase analysis was 96.1%. The crude material was purified via preparative reverse-phase chromatography under the following conditions: Column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by UV (220 nm) and MS (ESI+). Fractions containing the desired product were combined and dried via centrifugal evaporation. HPLC conditions: Mobile phase A (ACN / H2O (5:95) + 10 mM AA), Mobile phase B (ACN / H2O (95:5) + 10 mM AA): 85% A and 15% B at 0 min to 45% A and 55% B at 20 min, then hold at 100% B for 4 min. Analytical LCMS: m / z 827.4 [M+H] + , RT=1.54 min, purity: 97.7% (method A); m / z 827.3[M+H] + , RT=1.1 min, purity: 96.1% (method B); 1H NMR (500MHz, DMSO-d6) δ 8.68(brd,J=4.6Hz,1H), 8.22(s,1H), 8.04(brd,J=6.3Hz,1H), 7.99-7.85(m,2H), 7.81(brt,J=5.8Hz,1H), 7.65(d,J=7.9Hz,1H), 7 .52(d,J=9.3Hz,1H), 7.42(t,J=6.4Hz,1H), 7.10-7.01(m,2H), 5.38(brt,J=7.8Hz,1H), 5.03(brdd,J=13.3, 5.1Hz,1H), 4.32(brd,J =17.1Hz,1H), 4.20(d,J=16.6Hz,1H), 3.26(brd,J=4.3Hz,2H), 3.17-3.03(m,2H), 2.96-2.82(m,1H), 2.74(ddd,J=13.0, 9.2, 3.6Hz, 1H), 2.64-2.56(m,2H), 2.55(DMSO), 2.49-2.28(m,10H), 2.11-1.92(m,1H), 1.82(brs,1H), 1.50-1.27(m,8H), 1.20-1.06(m,4H)ppm

[0281] The following examples shown in Table 3 were prepared according to the preparation of Example A1. Table 3. Characterization of Examples A2-A11 [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0282] Following the same synthetic procedures as shown in Steps C-G of Example A1, the following targeted binding moieties (TBMs) containing either an amino acid or a carboxylic acid group, or their corresponding ethyl amides, were synthesized.

[0283] Example B1. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclobutane-1-carboxylic acid;

[0284] Example B2. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethylcyclobutane-1-carboxamide;

[0285] Example B3. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethyl-N-methylcyclobutane-1-carboxamide;

[0286] Example B4. 3-{[(1R,3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}propanoic acid;

[0287] Example B5. 3-{[(1R,3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}propanoic acid;

[0288] Example B6. 1-[(1S,3R)-3-(2-aminoethoxy)cyclopentyl]-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0289] Example B7. 1-[(1R,3R)-3-(2-aminoethoxy)cyclopentyl]-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0290] Example B8. N-(2-{[(1R,3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}ethyl)propanamide;

[0291] Example B9. N-(2-{[(1R,3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}ethyl)propanamide;

[0292] Example B10. 3-{[(1R,3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}-N-ethylpropanamide;

[0293] Example B11. 3-{[(1R,3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}-N-ethylpropanamide;

[0294] Example B12. 3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0295] Example B13. 3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1-[(3S)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0296] Example B14. 1-[(3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}piperidin-1-yl]propan-1-one;

[0297] Example B15. 1-[(3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}piperidin-1-yl]propan-1-one;

[0298] Example B16. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethylcyclobutane-1-carboxamide;

[0299] Example B17. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethyl-N-methylcyclobutane-1-carboxamide;

[0300] Example B18. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethyl-N-methylcyclobutane-1-carboxamide;

[0301] Example B19. (1r,3r)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-N-ethylcyclobutane-1-carboxamide;

[0302] Example B20. (1r,3r)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutane-1-carboxylic acid;

[0303] Example B21. (1s,3s)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-N-ethylcyclobutane-1-carboxamide;

[0304] Example B22. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[2-(2-aminoethoxy)ethyl]cyclobutane-1-carboxamide;

[0305] Example B23. 1-[(1R,3R)-3-(2-aminoethoxy)cyclopentyl]-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0306] Example B24. 1-[(1S,3R)-3-(2-aminoethoxy)cyclopentyl]-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0307] Example B25. N-(2-{[(1R,3R)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclopentyl]oxy}ethyl)propanamide;

[0308] Example B26. N-(2-{[(1R,3S)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclopentyl]oxy}ethyl)propanamide;

[0309] Example A12. Synthesis of 3-[5-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione [ka] Step A. 3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine [ka] To a mixture of 3-(5-cyclopropylisoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5 g, 20.64 mmol) and 2-bromopropane (2.79 g, 22.7 mmol) in DMF (60 mL) was added KCO (26.83 g, 82.56 mmol). The resulting mixture was stirred at 80 °C for 2 h. Upon completion, the resulting solution was quenched with ice water, extracted with EtOAc, and washed with brine. The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (5.5 g, 93.7% yield) as a light yellow solid. Analytical LCMS: m / z 285.2 [M+H] + , RT=0.91 min (Method Q)

[0310] Step B. 3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine [ka] To a mixture of 3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (5 g, 17.59 mmol) and N-iodosuccinimide (5.93 g, 26.38 mmol) in MeCN (50 mL) was added TFA (10 mL, 130.59 mmol). The resulting mixture was stirred at RT overnight. Upon completion, the resulting solution was concentrated. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give 3-(5-cyclopropyl-4-iodoisoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (5.5 g, 76.2% yield) as an off-white solid. Analytical LCMS: m / z 411.2 [M+H] + , RT=1.00 min (Method Q)

[0311] Step C. tert-Butyl 4-(4-iodoimidazol-1-yl)piperidine-1-carboxylate [ka] To a mixture of tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (10 g, 35.8 mmol) and 4-iodo-1H-imidazole (10.42 g, 53.7 mmol) in MeCN (250 mL) was added CsCO (34.9 g, 107.39 mmol), and the resulting mixture was stirred at 80 °C for 3 h. Upon completion, the mixture was cooled to room temperature. The resulting mixture was filtered, the filter cake was washed with ACN (10 mL × 2), and the filtrate was concentrated. The crude product was first purified by reversed-phase flash and then by PREP_SFC (column: DAICEL DCpak P4VP, 3*25 cm, 5 μm; mobile phase A: CO, mobile phase B: MeOH (0.5% 2M NH-MeOH); flow rate: 100 mL / min; gradient: isocratic 15% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 2.18; RT2 (min): 2.85; sample solvent: MEOH (0.1% 2M NH-MEOH); injection volume: 2 mL; number of runs: 75) to give tert-butyl 4-(4-iodoimidazol-1-yl)piperidine-1-carboxylate (3.8 g, 28.1% yield) as a white solid. Analytical LCMS: m / z 378.2 [M+H] + , RT=0.97 min (Method Q). The structure of the desired compound was confirmed by the NOE correlation observed between the proton at the C-5 position of the imidazole ring and the proton at the C-3'(5') position of the piperidine ring.

[0312] Step D. tert-Butyl 4-(4-tributylstannylimidazol-1-yl)piperidine-1-carboxylate [ka] To a mixture of tert-butyl 4-(4-iodoimidazol-1-yl)piperidine-1-carboxylate (1000 mg, 2.65 mmol) in THF (20 mL) was added i-PrMgCl in THF (2 M, 2 mL, 4 mmol) dropwise at −20° C. Then, tributyl(chloro)stannane (949.21 mg, 2.92 mmol) was added sequentially to the above reaction mixture. After stirring at −20° C. for 1 h, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give tert-butyl 4-(4-tributylstannylimidazol-1-yl)piperidine-1-carboxylate (600 mg, 41.9% yield) as a light yellow oil. MS: m / z: 542.3 [M+H] +

[0313] Step E. tert-Butyl 4-[4-[3-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-5-cyclopropyl-isoxazol-4-yl]imidazol-1-yl]piperidine-1-carboxylate [ka] A 20 mL microwave vial was charged with tert-butyl 4-(4-tributylstannylimidazol-1-yl)piperidine-1-carboxylate (1053.84 mg, 1.95 mmol), 3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 0.98 mmol), PdCl2[P(cy)3]2 (73.82 mg, 0.10 mmol), and CsF (370.54 mg, 2.44 mmol) suspended in toluene (9 mL). The mixture was stirred at 100 °C under N2 for 60 h. It was filtered, concentrated and purified by preparative TLC and then by preparative HPLC to give tert-butyl 4-[4-[3-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-5-cyclopropyl-isoxazol-4-yl]imidazol-1-yl]piperidine-1-carboxylate (560 mg, 70% yield) as a white solid. Preparative LCMS: m / z 534.3 [M+H] + , RT=1.17 min (Method Q)

[0314] Step F. 3-[5-cyclopropyl-4-[1-(4-piperidyl)imidazol-4-yl]isoxazol-3-yl]-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine [ka] To a solution of tert-butyl 4-[4-[3-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-5-cyclopropyl-isoxazol-4-yl]imidazol-1-yl]piperidine-1-carboxylate (1800 mg, 3.37 mmol) in DCM (30 mL) was added TFA (10.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated, and the crude product was purified by reverse-phase flash column chromatography (0.5% TFA / ACN in water) to give 3-[5-cyclopropyl-4-[1-(4-piperidyl)imidazol-4-yl]isoxazol-3-yl]-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (990.1 mg, 66% yield) as an off-white solid. Analytical LCMS: m / z 434.3[M+H] + , RT=1.03 min (Method Q); 1 H NMR (300MHz, DMSO-d6) δ 9.41(s,1H), 8.36(s,1H), 8.14(d,J=1.6Hz,1H), 5.10-4.90(m,1H), 4.81-4.65(m,1H), 3.58-3.47(m, 2H), 3.19-3.06(m,2H), 2.47-2.28(m,3H), 2.22-2.02(m,2H), 1.30(d,J=6.6Hz,6H), 1.28-1.13(m,4H)

[0315] Step G. 3-[5-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione 3-(5-Cyclopropyl-4-(1-(piperidin-4-yl)-1H-imidazol-4-yl)isoxazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine·2TFA (308 mg) was dissolved in DMF (4.5 mL), and BOP (247 mg) was dissolved in DMF (4.5 mL). To each reaction vial containing the acid component, 3-(5-cyclopropyl-4-(1-(piperidin-4-yl)-1H-imidazol-4-yl)isoxazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine·2TFA (0.100 mL, 10.84 μmol), BOP (0.099 mL, 0.013 mmol), and DIEA (0.011 mL, 0.065 mmol) were added. The mixture was then placed in a Bohdan Miniblock XT and agitated overnight at 400 rpm. The crude material was diluted with DMF (1.5 mL) and 1 drop of AcOH and subjected to final purification by RP preparative HPLC to give the title compound. The product yield was 4.2 mg, and its estimated purity by reverse-phase analysis was 97.1%. The crude material was purified via preparative reverse-phase chromatography using the following conditions: Column: Xbridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by UV (220 nm) and MS (ESI+). Fractions containing the desired product were combined and dried via centrifugal evaporation. HPLC conditions: Mobile phase A (ACN / H2O (5:95) + 10 mM AA), Mobile phase B (ACN / H2O (95:5) + 10 mM AA): 75% A and 25% B at 0 min to 55% A and 45% B at 20 min, then hold at 100% B for 4 min. Analytical LCMS: m / z 872.3 [M+H] + , RT=1.55 min, purity: 97.1% (method A); m / z 872.3[M+H] + , RT=1.08 min, purity: 97.9% (method B); 1H NMR (500MHz, DMSO-d6) δ 8.23(s,1H), 7.95-7.82(m,3H), 7.80(s,1H), 7.52(d,J=8.6Hz,1H), 7.07-7.00(m,2H), 5.13-5.00(m,2H), 4.59-4.50(m,1H), 4.43-4 .37(m,1H), 4.35-4.28(m,1H), 4.25-4.17(m,1H), 4.06-3.97(m,1H), 3.49(brs,1H), 3.25(brs,2H), 3.22-3.10(m,1H), 3.06-2.97(m ,1H), 2.93-2.84(m,1H), 2.67(brd,J=15.1Hz,1H), 2.59(brdd,J=17.4, 2.3Hz,1H), 2.49-2.27(m,9H), 2.13-2.00(m,2H), 2.00-1.94 (m,1H), 1.91(s,1H), 1.83-1.63(m,2H), 1.55-1.49(m,2H), 1.45(brd,J=6.1Hz,8H), 1.31(brs,4H), 1.27(brs,1H), 1.20-1.07(m,4H)

[0316] The examples shown in Table 4 below were prepared in a manner similar to the preparation of Example A12. Table 4. Characterization of Examples A13-A19 [Table 14] [Table 15] [Table 16] [Table 17]

[0317] Following the same synthetic procedures as shown in Steps A-F of Example A12, the following targeted binding moieties (TBMs) containing either an amino acid or a carboxylic acid group, or their corresponding ethyl amides, were synthesized.

[0318] Example B27. 3-[4-(4-aminocyclohexyl)-5-cyclopropyl-1,2-oxazol-3-yl]-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0319] Example B28. 3-{4-[1-(4-aminobutyl)-1H-imidazol-4-yl]-5-cyclopropyl-1,2-oxazol-3-yl}-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0320] Example B29. N-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}cyclohexyl)propanamide;

[0321] Example B30. N-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)butyl]propanamide;

[0322] Example B31. 1-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]propan-1-one;

[0323] Example B32. 3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazole-4-carboxylic acid;

[0324] Example B33. 3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N-(2-aminoethyl)-5-cyclopropyl-1,2-oxazole-4-carboxamide;

[0325] Example B34. 4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-N-(2-aminoethyl)cyclohexane-1-carboxamide;

[0326] Example B35. (1s,4s)-4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}cyclohexane-1-carboxylic acid;

[0327] Example B36. (1r,4r)-4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}cyclohexane-1-carboxylic acid;

[0328] Example A20. Synthesis of 1-{4-[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide [ka] Step A. (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (A2DF5-107) [ka] A 500 mL round-bottom flask was charged with 2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (4.38 g, 17.96 mmol), (S)—N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (5.20 g, 14.97 mmol), and DIPEA (20.92 mL, 120 mmol) in butan-1-ol (50 mL) to give a solution. The reaction mixture was heated to 70° C. overnight with stirring. 2,6-Dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.644 g, 6.74 mmol) was added. After 2 hours, the reaction was cooled, evaporated under reduced pressure, and dried under high vacuum. The crude product was dissolved in a small amount of DCM and loaded onto a 220 g silica gel cartridge, which was eluted with a 15 column volume gradient of 0% to 100% Hex / EtOAc to give (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (4.2 g, 50.6%). Analytical LCMS: m / z 555.1 [M+H] + , RT=1.33 min (UHPLC method D)

[0329] Step B. tert-Butyl (S)-(4-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)butyl)carbamate [ka] A 5 mL screw-top vial was charged with tert-butyl but-3-yn-1-ylcarbamate (1.375 mL, 7.93 mmol), (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (1100 mg, 1.982 mmol), TEA (1.381 mL, 9.91 mmol), and copper(I) iodide (151 mg, 0.793 mmol) in MeOH (50 mL) to give a suspension. Nitrogen was bubbled through the solution between subsequent additions. Bis(triphenylphosphine)palladium(II) dichloride (278 mg, 0.396 mmol) was added. The reaction mixture was heated to 110 °C with stirring. After 3 h, the reaction was partitioned between ethyl acetate (200 mL) and 10% aqueous LiCl (100 mL). The organic phases were combined and washed with saturated NH4Cl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was dissolved in a small amount of DCM and loaded onto an 80 g silica gel cartridge, which was eluted with a 15-column volume gradient of 0% to 5% CHCl2 / MeOH. The desired fractions were combined, and the resulting solid was diluted with MeOH (50 mL). Pd-C (5% wet C) (500 mg, 0.235 mmol) was added. The reaction was purged three times with vacuum, three times with nitrogen, and three times with vacuum and hydrogen. It was then stirred overnight at 60 °C under hydrogen. The reaction mixture was filtered through Celite. Pd-C (5% wet C) (500 mg, 0.235 mmol) was added to the filtrate, which was heated to 60 °C under H for 6 h. The reaction mixture was filtered through Celite and evaporated under reduced pressure.The crude product was dissolved in a small amount of DCM and loaded onto an 80 g silica gel cartridge, which was eluted with a 15 column volume gradient of 0% to 5% CHCl / MeOH to give (S)-(4-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)butyl)tert-butylcarbamate (1.3 g, 95%) as an off-white solid. Analytical LCMS: m / z 692.3 [M+H]. + , RT=1.71 min, purity: 100% (method B); m / z 692.4[M+H] + , RT=2.13 min, purity: 100% (method A); 1 H NMR (500MHz, DMSO-d6) δ 9.26-9.13(m,1H), 8.73-8.65(m,1H), 8.55-8.48(m,1H), 8.46-8.41(m,1H), 8.04-7.97(m,1 H), 7.95-7.85(m,2H), 6.84-6.70(m,1H), 5.15-5.00(m,1H), 4.42-4.26(m,2H), 3.23-3.10( m, 3H), 2.98-2.87(m, 2H), 2.41-2.31(m, 2H), 2.26-2.17(m, 3H), 1.95-1.88(m, 1H), 1.88-1.67(m, 4H), 1.63-1.53(m, 2H), 1.52-1.46(m, 3H), 1.46-1.33(m, 12H); one CH3 was lost due to water inhibition.

[0330] Step C. (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide [ka] A 100 ml round-bottom flask was charged with tert-butyl (S)-(4-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)butyl)carbamate (240 mg, 0.347 mmol) in MeOH (1 mL) and DCM (10 mL) to give a solution. HCl (4N in dioxane) (2 mL, 8.00 mmol) was added. The reaction was stirred at room temperature for 1 hour. It was evaporated under reduced pressure and dried under high vacuum.

[0331] The reaction mixture was diluted three times with MeOH (1 mL) and evaporated under reduced pressure to give crude (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide diHCl (225 mg, 98%), which was used directly without further purification. Analytical LCMS: m / z 592.4 [M+H] + , RT=1.05 min (UHPLC method D)

[0332] Step D. 1-{4-[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptanamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide dihydrochloride (308.0 mg) was dissolved in DMF (8.8 mL). BOP (266.5 mg) was dissolved in DMF (4.4 mL). To each reaction vial containing the amine component, the above (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide dihydrochloride (0.199 mL, 10.53 μmol), BOP (0.099 mL, 0.014 mmol), and DIEA (0.011 mL, 0.063 mmol) were added. The mixture was then placed in a Bohdan Miniblock XT and stirred at 400 rpm overnight at room temperature. The crude material was diluted with DMF / MeOH (2:1) (1.5 mL) and subjected to final purification. The crude material was purified by preparative LC / MS using the following conditions: Column: Xbridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.05% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.05% trifluoroacetic acid; Gradient: 13% B hold at 0 min, 13-53% B over 20 min, then 100% B hold at 0 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried via centrifugal evaporation. Product yield was 3.0 mg. Analytical LCMS: m / z 1030.40 [M+H] + , RT=1.38 min, purity: 93.3% (method B); m / z 1030.30[M+H] + , RT=1.62 min, purity: 86.6% (method A); 1H NMR (500MHz, DMSO-d6) δ 10.96(s,1H), 8.66(d,J=4.3Hz,1H), 8.57(brd,J=7.9Hz,1H), 8.50-8.35(m,2H), 7.99(dd,J=8.5, 1.8Hz,1H), 7.91(d,J=4.0Hz, 1H), 7.88(d,J=8.5Hz,1H), 7.84-7.72(m,1H), 7.60(d,J=8.5Hz,1H), 7.29(s,1H), 7.22-7.11(m,2H), 5.17-5.01(m,2H), 4.45-4 .30(m,1H), 4.30-4.15(m,2H), 3.22-3.03(m,5H), 3.00(s,2H), 2.98-2.79(m,3H), 2.69(s,1H), 2.65-2.57(m,2H), 2.55(DMSO), 2.49-2.30(m,2H), 2.24(s,3H), 2.06(brt,J=7.5Hz,2H), 2.02-1.80(m,4H), 1.66(brs,2H), 1.64-1.42(m,9H), 1.34-1.15(m,9H)

[0333] Example A21. Synthesis of 1-(4-{4-[(8-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}octyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide [ka] Step A. (S)-5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoate ethyl [ka] A 5 mL screw-top vial was charged with ethyl pent-4-ynoate (1.055 mL, 8.36 mmol), (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (1160 mg, 2.09 mmol), TEA (1.457 mL, 10.45 mmol), and copper(I) iodide (159 mg, 0.836 mmol) in MeOH (50 mL) to give a suspension. Nitrogen was bubbled through the solution between subsequent additions. Bis(triphenylphosphine)palladium(II) dichloride (293 mg, 0.418 mmol) was added. The reaction mixture was heated to 110° C. with stirring. After 3 h, the reaction was partitioned between ethyl acetate (200 mL) and 10% aqueous LiCl (100 mL). The organic phases were combined and washed with saturated NH4Cl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was dissolved in a small amount of DCM and loaded onto an 80 g silica gel cartridge, which was eluted with a 15-column volume gradient of 0% to 5% CH2Cl2 / MeOH.

[0334] The desired fractions were combined, and the resulting solid was diluted with MeOH (50 mL). Pd-C (5% wet C) (500 mg, 0.235 mmol) was added. The reaction was purged three times with vacuum, three times with nitrogen, and then three times with vacuum and hydrogen. It was then stirred at 60 °C under hydrogen overnight. The reaction mixture was filtered through Celite. Pd-C (5% wet C) (500 mg, 0.235 mmol) was added to the filtrate. It was heated to 60 °C under H2 overnight. The reaction mixture was filtered through Celite and evaporated under reduced pressure. The crude product was dissolved in a small amount of DCM and loaded onto an 80 g silica gel cartridge, which was eluted with a 15 column volume gradient of 0% to 5% CHCl / MeOH to give ethyl (S)-5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoate (600 mg, 46.1%). Analytical LCMS: m / z 649.20 [M+H] + , RT=1.69 min, Purity: 97.6% (Method B); m / z 649.20[M+H] + , RT=2.14 min, purity: 98.2% (method A); 1 H NMR (500MHz, DMSO-d6) δ 9.16(brs,1H), 8.66(d,J=4.3Hz,1H), 8.49(brd,J=8.2Hz,1H), 8.45-8.39(m,1H), 7.97(dd,J=8.4, 2.0Hz, 1H), 7.93-7.84(m,2H), 6.31-6.14(m,1H), 6.10(brs,1H), 5.04(brt,J=7.3Hz,1H), 4.32(brdd,J=17.5, 13. 9Hz,2H), 4.03(q,J=7.1Hz,2H), 3.23-3.08(m,4H), 2.55(s,5H), 2.41-2.25(m,4H), 2.19(s,3H), 1.92(s,1 H), 1.85-1.74(m,3H), 1.74-1.65(m,1H), 1.62-1.51(m,4H), 1.47(brd,J=7.0Hz,3H), 1.15(t,J=7.0Hz,3H)

[0335] Step B. (S)-5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoic acid [ka] A 100 mL round-bottom flask was charged with (S)-ethyl 5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoate (600 mg, 0.925 mmol) and NaOH (2.5 N) (3.70 mL, 9.25 mmol) in THF (15 mL) to give a solution. The mixture was heated at 50° C. overnight. The reaction was partitioned with DCM (10% MeOH) (100 mL) and brine (50 mL), and the aqueous phase was extracted with DCM (10% MeOH) (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give crude (S)-5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoic acid (485 mg, 84%), which was used directly without further purification. Analytical LCMS: m / z 621.20 [M+H] + , RT=1.36 min (method B); 1H NMR (500 MHz, DMSO-d) δ 8.66(d,J=4.6Hz,1H), 8.50(brd,J=7.9Hz,1H), 8.46-8.38(m,1H), 7.98(dd,J=8.5, 2.1Hz,1H), 7.93-7.85(m,2H), 5.05(brd,J=7.3Hz,1H), 4.4 0-4.18(m,2H), 3.16(s,2H), 3.00(s,1H), 2.55(s,5H), 2.49-2.32(m,2H) ), 2.31-2.11(m,5H), 1.92(s,1H), 1.88-1.67(m,4H), 1.62-1.43(m,7H)

[0336] Step C. 1-(4-{4-[(8-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}octyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide Following a procedure similar to that described in Step D of Example A20, the title compound was obtained. Analytical LCMS: m / z 934.4 [M+H] + , RT=1.99 min, purity: 100% (method A); 1H NMR (500 MHz, DMSO-d) δ 10.90-10.71(m,2H), 8.66(brs,1H), 8.63-8.52(m,1H), 8.45-8.26(m,2 H), 8.05-7.84(m,3H), 7.83-7.68(m,1H), 7.44-7.26(m,2H), 7.26-7.16( m,2H), 7.15-7.02(m,2H), 6.92(brd,J=6.7Hz,2H), 6.67-6.49(m,2H), 5. 19-4.99(m,1H), 4.35-4.14(m,2H), 3.77-3.59(m,1H), 3.57-3.34(m,2H) , 3.22(brs,1H), 3.17(brs,2H), 3.07-2.88(m,5H), 2.64(brd,J=1.8Hz,1H), 2.59(brs,1H), 2.57-2.54(DMSO), 2.48-2.34(m,2H), 2.31-2.18(m, 3H), 2.12-2.04(m,3H), 2.02-1.84(m,4H), 1.60(brs,1H), 1.55(brs,3H) , 1.52-1.41(m,5H), 1.39-1.28(m,4H), 1.24(brs,5H), 1.21-0.99(m,5H)

[0337] The following examples listed in Table 5 were prepared according to the preparation of Example A20 and Example A21. Table 5. Characterization of Examples A22-A28 [Table 18] [Table 19] [Table 20] [Table 21]

[0338] Example A29. Synthesis of 9-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]nonanamide [ka] Step A. tert-Butyl (4-(6-bromopyridin-3-yl)-4-oxobutyl)carbamate [ka] n-BuLi in THF (1.6 M, 23.74 mL, 38.0 mmol) was added dropwise to a stirred solution of 2,5-dibromopyridine (7.5 g, 31.7 mmol) in diethyl ether (105 mL) and tetrahydrofuran (45 mL) at −78° C. The resulting mixture was stirred at −78° C. for 45 minutes. Then, a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (5.86 g, 31.7 mmol) in tetrahydrofuran (50 mL) was added at −78° C. and stirred at −78° C. for 30 minutes. The reaction was monitored by TLC. The reaction mixture was quenched with saturated NH4Cl solution (50 mL), diluted with water (100 mL), and extracted with ethyl acetate (2×150 mL). The organic layers were combined, washed with saturated brine solution (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product from two separate batches was combined and purified by column chromatography (Biotage Isolera, 120 g + 50 g snaps, dry pack) eluting with 30-40% ethyl acetate in petroleum ether. The desired fractions were pooled together and concentrated under reduced pressure. The resulting product was triturated with 10% ethyl acetate to give tert-butyl (4-(6-bromopyridin-3-yl)-4-oxobutyl)carbamate (9 g, 61.1% yield) as a light brown solid. LCMS: RT = 2.078 min (ACN / HO + 5 mM ammonium formate, Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm, 5 min gradient, wavelength = 220 nm); MS (ES): m / z = 288.8 [M+H] + (mass of the tert-butyl fragment).

[0339] Step B. tert-Butyl (4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-oxobutyl)carbamate [ka] tert-Butyl (4-(6-bromopyridin-3-yl)-4-oxobutyl)carbamate (9 g, 26.2 mmol) was added to a stirred suspension of 4-fluoro-1H-pyrazole (2.48 g, 28.8 mmol) and K2CO3 (9.06 g, 65.6 mmol) in N,N-dimethylformamide (150 mL) at ambient temperature. The resulting mixture was heated to 100 °C and stirred there for 16 h. The reaction was monitored by UPLC. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layers were combined, washed with saturated brine solution (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400 mesh) (Biotage Isolella, 100 g + 50 g Snaps, dry pack) eluting with 40-50% ethyl acetate in petroleum ether. The desired fractions were pooled together and concentrated under reduced pressure. The residue was triturated with 10% ethyl acetate in petroleum ether to give tert-butyl (4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-oxobutyl)carbamate (4.85 g, 46.9% yield) as a light brown solid. LCMS: RT = 2.46 min (ACN / HO + 5 mM ammonium formate, Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm, 5 min gradient, wavelength = 220 nm); MS (ES): m / z = 292.9 [M+H]. + (mass of tertiary butyl fragment)

[0340] Step C. tert-Butyl ((S)-4-(((R)-tert-butylsulfinyl)amino)-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate [ka] Titanium(IV) ethoxide (1.350 mL, 5.74 mmol) was added to a stirred solution of tert-butyl (4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-oxobutyl)carbamate (1 g, 2.87 mmol) and (R)-2-methylpropane-2-sulfinamide (0.348 g, 2.87 mmol) in tetrahydrofuran (20 mL) at ambient temperature. The resulting mixture was heated to 75° C. and stirred there for 16 hours. The reaction was monitored by TLC. The reaction mixture was cooled to −78° C., and then 1 M L-Selectride in THF (8.61 mL, 8.61 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to reach 0° C. and stirred there for 10 minutes. The reaction mixture was cooled to -50°C, quenched with methanol (5 mL), poured into water (60 mL), and stirred for 15 minutes. It was filtered through a pad of Celite and washed with ethyl acetate (200 mL). The organic layer was separated from the filtrate, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400 mesh) (Biotage Isolella, 50 g snap, dry pack) eluting with 90-100% ethyl acetate in petroleum ether. The desired fractions were pooled together and concentrated under reduced pressure to give tert-butyl ((S)-4-(((R)-tert-butylsulfinyl)amino)-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate (730 mg, 54.6% yield) as a light brown solid. LCMS: RT = 2.35 min (ACN / HO + 5 mM ammonium formate, Kinetex XB-C18 (75x3.0) mm, 2.6 μm, 5 min gradient, wavelength = 220 nm); MS (ES): m / z = 452.4 [M−H] -

[0341] Step D. (S)-(4-amino-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate tert-Butyl [ka] 1.25 M HCl in MeOH (1.29 mL, 1.61 mmol) was added to a stirred solution of tert-butyl ((S)-4-(((R)-tert-butylsulfinyl)amino)-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate (730 mg, 1.609 mmol) in methanol (15 mL) at 0 °C. The resulting mixture was allowed to reach ambient temperature over 1 h and stirred there for 1 h. The reaction was monitored by TLC to observe the consumption of starting material. The reaction mixture was diluted with water (80 mL), basified with 10% NaHCO3 solution, and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with saturated brine solution (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl (S)-(4-amino-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate (550 mg, 82% yield) as a light brown gum. LCMS: RT = 1.11 min (ACN / HO + 5 mM ammonium formate, Kinetex XB-C18 (75x3.0) mm, 2.6 μm, 5 min gradient, wavelength = 220 nm); MS (ES): m / z = 350.1 [M+H] +

[0342] Step E. (S)-(4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-(4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamido)butyl)carbamate tert-Butyl [ka] TBTU (4.04 g, 12.59 mmol) was added to a stirred solution of (S)-(4-amino-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate (2.2 g, 6.30 mmol), 4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid lithium salt (2.67 g, 7.56 mmol), and triethylamine (3.51 mL, 25.2 mmol) in N,N-dimethylformamide (30 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixtures from the two separate batches were combined, diluted with water (150 mL), and extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with water (150 mL), saturated brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (Biotage Isolella, 120 g snap) eluting with 80-100% ethyl acetate in petroleum ether. The desired fractions were pooled together and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage Isolella, 120 g snap) eluting with 4-5% methanol in dichloromethane. The desired fractions were pooled together and concentrated under reduced pressure as two fractions (4 g). This was further purified by reverse-phase column chromatography (Combiflash) using ammonium formate in water and ACN as the eluent. The desired fraction was collected as three fractions. Acetonitrile was removed under reduced pressure; the remaining aqueous layer was basified with 10% NaHCO3 solution and extracted with 5% methanol in dichloromethane (2x). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired product (S)-(4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-(4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamido)butyl)tert-butylcarbamate (2.99 g). MS: m / z 678.2 [M+H] +

[0343] Step F. (S)—N-(4-amino-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)-4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamide·HCl 4 M HCl in dioxane (1.881 mL, 7.52 mmol) was added to a stirred solution of tert-butyl (S)-(4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-(4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamido)butyl)carbamate (1.02 g, 1.505 mmol) in dichloromethane (20 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then lyophilized to give (S)—N-(4-amino-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)-4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamide HCl as a pale yellow solid. LCMS: RT=1.65 min (ACN / HO+TFA, Xbridge C8 (50×4.6 mm) 5 μm, 6 min gradient, wavelength=220 nm); MS (ES): m / z=578.2 [M+H] +HPLC purity: 90 / 10 to 10 / 90 H2O / ACN / 0.05% TFA, flow rate = 1 mL / min, gradient 15 min, Kinetex EVO C18 (100x4.6) mm, 2.6 μm, RT = 7.09 min, purity: 97.0%, Kinetex Biphenyl (100x4.6) mm, 2.6 μm, RT = 4.34 min, purity: 96.9%; 1H-NMR: 400 MHz (DMSO-d6): δ 12.19(brs,1H), 11.05(brs, 1H), 8.68(d,J=4.80Hz,2H), 8.46(d,J=2.00Hz,2H),8. 18-8.05(m,2H), 8.04-8.01(m,1H), 7.95-7.86(m,2H), 6.34(s,1H), 6.17(s,1H), 4.9 8-4.89(m,1H), 4.43-4.28(m,2H), 3.48-3.32(m,2H), 3.18(s,3H), 2.83-2.78(m,2H) ), 2.37(s,3H), 2.25(s,3H), 2.03-1.79(m,6H), 1.73-1.68(m,1H), 1.61-1.51(m,1H)

[0344] Step G. 9-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]nonanamide Following a similar procedure as described in Step D of Example A20, the title compound was obtained. Analytical LCMS: m / z 920.4 [M+H] + , RT=1.95 min, purity: 100% (method A); 1H NMR (500MHz, DMSO-d6) δ 10.77(s,1H), 9.31-9.12(m,1H), 8.67-8.64(m,1H), 8.52(brd,J=8.7Hz,1H), 8.42(s,1H), 7.98(brd,J=8.5Hz,1H), 7.91-7.85(m,2H), 7 .76(brs,1H), 7.00(t,J=7.7Hz,1H), 6.42(brd,J=8.2Hz,1H), 6.39-6.32(m,2H), 6.27-6.05(m,2H), 4.93-4.87(m,1H), 4.35-4.25(m,2H) ), 3.90(d,J=2.1Hz,1H), 3.67(brdd,J=9.5, 4.8Hz,1H), 3.43-3.36(m,2H), 3.22-3.00(m,5H), 2.92(brs,2H), 2.66-2.56(m,2H), 2.55(D MSO), 2.49-2.33(m,2H), 2.20-1.98(m,10H), 1.92-1.74(m,4H), 1.74-1.64(m,2H), 1.54-1.45(m,5H), 1.45-1.27(m,4H), 1.23(brs,6H)

[0345] Following the preparation of Example A29, the following examples shown in Table 6 were prepared. Table 6. Characterization of Examples A30-A34 [Table 22] [Table 23] [Table 24] [Table 25] [Table 26]

[0346] Following the same synthetic procedures as shown in Steps A-F of Example A29, the following targeted binding moieties (TBMs) containing either an amino or its corresponding ethyl amide were synthesized.

[0347] Example B37. N-[(S)-(Azetidin-3-yl)[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]methyl]-4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidine-4-carboxamide

[0348] Example B38. N-[(S)-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl](1-propanoylazetidin-3-yl)methyl]-4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidine-4-carboxamide

[0349] Example B39. N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]propanamide

[0350] Intracellular RET degradation assay The potency of intracellular RET-degrading compounds was measured using a bead-based luminescence amplification assay—AlphaLISA Surefire Ultra Detection Kit (Perkin-Elmer). To screen potential degraders, we selected a papillary thyroid carcinoma (TPC-1) cell line expressing the CCDC6-RET fusion gene: the parental line (TPC-1 / CCDC6-RET). Cells were seeded at 10,000 cells / well in 50 μl / well of DMEM (Fisher Scientific) containing 2% FBS serum (Gibco) in a 384-well culture plate (Greiner Bio-One). After cell attachment (4 hours), cells were treated with compounds by directly dispensing serially diluted compounds (25 nL, 1:3 dilutions: 11 points) into the cell culture wells using an Echo-655 acoustic liquid dispenser (Beckman). Low-normalized wells were treated with medium alone, and high-normalized wells were treated with DMSO alone. The treated cell plates were placed in a 37°C, 5% CO2 incubator for 24 hours. After 24 hours, the cell culture medium was removed using a FELIX automated liquid handler (Analytik Jena), and cell lysis buffer (25 μL, provided with the AlphaLisa kit) was added to each well. The cell lysate (5 μL) was transferred to a 384-well microplate (Perkin Elmer), followed by the addition of AlphaLISA Acceptor Bead Mix (2.5 μL). The plate was sealed and kept at room temperature for 1 hour, after which the donor bead mixture was added. The donor bead addition was performed in the dark, and after >1 hour of incubation, AlphaLISA fluorescence was measured at room temperature (excitation 680 nm, emission 615 nm) using an Envision plate reader equipped with an Alphascreen aperture. The amount of RET protein (and therefore the amount of degradation) directly correlates with fluorescence intensity.

[0351] Intensity was normalized to the mean value of 16 wells containing medium alone (blank - low) and 16 wells containing cells + DMSO (high). The % degradation for each well was calculated using the standard formula:

number

number

number

[0352] biological activity Each of the compounds shown in Table 7 was tested in one or more degradation assays described above, for example, the tRET AlphaLISA Degradation Assay using the parental RET TPC-1 cell line, and was found to be active. 50 ) are shown in Table 7. Table 7. Bioactivity data [Table 27]

[0353] Numbered Embodiments Numbered Embodiment 1. Formula (I): [ka] [In formula: The inhibitor of RET kinase is a RET kinase inhibitor moiety; Ring B is a 4-12 membered heterocycloalkyl, C3-C8 cycloalkyl, or omitted; Ring D is the cereblon binding moiety; L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or heteroaryl; L 2 is -C(O)NH-(CH2) p -, -NHC(O)-(CH2) p -, -C(O)NH-(CH2) p -NH-, -NHC(O)-(CH2) p -NH-, -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4-12 membered heterocycloalkyl)-NH-, -C(O)NH-(CH2) p -(4-12 membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4 to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4-12 membered heterocycloalkyl)-, -C(O)-(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, -(CH2) p -(4-12 membered heterocycloalkyl)-C(O)-, or -C(O)NH-(CH2) p -NH-; and p is an integer between 1 and 12. or a pharmaceutically acceptable salt thereof.

[0354] Numbered Embodiment 2. Formula Ia-1 or Formula Ia-2: [ka] [In formula: X 1 is N or CR 1 and; R 1 is H, halogen, or C1-C3 alkyl; R 2 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 aryl, or 4-12 membered heteroaryl; R 3 is C3-C8 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 aryl, or 4-12 membered heteroaryl; Ring D is independently [ka] and; R 5 is H, halogen, CF3, OH, CN, NO2 or C1-C4 alkyl; R 6 or R 6 ' are each independently H, or R 6 can be taken together to form an oxo group, or R 6 Two examples of ' can be taken together to form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two geminal or vicinal R's 7the carbons, taken together, may form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and m is an integer between 0 and 2. or a pharmaceutically acceptable salt thereof.

[0355] Numbered Embodiment 3. Formula Ia-3: [ka] The compound of embodiment 2, numbered as follows:

[0356] Numbered Embodiment 4. Formula Ia-4: [ka] The compound of embodiment 2, numbered as follows:

[0357] Numbered Embodiment 5. Formula Ia-5: [ka] The compound of embodiment 2, numbered as follows:

[0358] Numbered Embodiment 6. Formula Ia-6: [ka] The compound of embodiment 2, numbered as follows:

[0359] Numbered Embodiment 7. Formula Ia-7: [ka] The compound of embodiment 2, numbered as follows:

[0360] Numbered Embodiment 8. Formula Ib-1 or Formula Ib-2: [ka] [ka] [In formula: R 1 and R 2 are each independently H, halogen, or NR 10 R 11 or C1-C4 alkyl; R 3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 4 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring D is [ka] is a group selected from the group consisting of: R 5 is H, halogen, OH, CN, NO2 or C1-C4 alkyl; R 6 or R 6 Each instance of ' is independently H, or R 6 can be taken together to form an oxo group, or R 6 Two examples of ' can be taken together to form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Two geminal or vicinal R's 7 may be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and m is an integer between 0 and 2. or a pharmaceutically acceptable salt thereof.

[0361] Numbered Embodiment 9. Formula Ib-1, Formula Ib-2, Formula Ib-3, or Formula Ib-4: [ka] [ka] [ka] or [ka] The compound of numbered embodiment 8, shown as

[0362] Numbered embodiment 10. [ka] [ka] The compound of numbered embodiment 1 selected from the group consisting of:

[0363] Numbered embodiment 11. [ka] [ka] [ka] The compound of numbered embodiment 1 selected from the group consisting of:

[0364] Numbered embodiment 12. [ka] [ka] The compound of numbered embodiment 1 selected from the group consisting of:

[0365] Numbered embodiment 13. [ka] [ka] The compound of numbered embodiment 1 selected from the group consisting of:

[0366] Numbered Embodiment 14. A pharmaceutical composition comprising a compound of any one of numbered embodiments 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Numbered Embodiment 15. A method for treating a RET-mediated disorder, comprising administering to a patient in need thereof an effective amount of a compound of any one of numbered embodiments 1-13, or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutical composition.

[0367] Numbered Embodiment 16. The method of numbered embodiment 15, wherein the patient is a human. Numbered Embodiment 17 The method of any one of numbered embodiments 15-16, wherein the RET-mediated disorder is cancer. Numbered Embodiment 18. The method of numbered embodiment 17, wherein the cancer is non-small cell lung cancer. Numbered Embodiment 19. The method of embodiment 17, wherein the cancer has metastasized to the brain. Numbered Embodiment 20 The method of any one of numbered embodiments 15-19, wherein the RET-mediated disorder is mediated by mutant RET.

[0368] Numbered Embodiment 21 The method of any one of numbered embodiments 15-19, wherein the RET-mediated disorder is relapsed or refractory cancer. Numbered Embodiment 22. A compound according to any one of numbered embodiments 1-17, or a pharmaceutically acceptable salt thereof, optionally included in a pharmaceutical composition, for use in treating a RET-mediated disorder. Numbered Embodiment 23 The compound of numbered embodiment 22, wherein the RET-mediated disorder is cancer. Numbered Embodiment 24. The compound of numbered embodiment 23, wherein the cancer is non-small cell lung cancer. Numbered Embodiment 25. The compound of numbered embodiment 24, wherein the cancer has metastasized to the brain.

[0369] Numbered Embodiment 26 The compound of any one of numbered embodiments 22-25, wherein the RET-mediated disorder is mediated by mutant RET. Numbered Embodiment 27 The compound of any one of numbered embodiments 22-26, wherein the RET-mediated disorder is relapsed or refractory cancer. Numbered Embodiment 28. Use of a compound according to any one of numbered embodiments 1-17, or a pharmaceutically acceptable salt thereof, optionally included in a pharmaceutical composition, in the treatment of a RET-mediated disorder. Numbered Embodiment 29. The use of numbered embodiment 28, wherein the RET-mediated disorder is cancer. Numbered Embodiment 30. The use of numbered embodiment 29, wherein the cancer is non-small cell lung cancer.

[0370] Numbered Embodiment 31. The use of numbered embodiment 29, wherein the cancer has metastasized to the brain. Numbered Embodiment 32 The use according to any one of numbered embodiments 28-30, wherein the RET-mediated disorder is mediated by mutant RET. Numbered Embodiment 33 The use of any one of numbered embodiments 28-30, wherein the RET-mediated disorder is relapsed or refractory cancer. Numbered Embodiment 34. Use of a compound according to any one of numbered embodiments 1-17, or a pharmaceutically acceptable salt thereof, optionally included in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET-mediated disorder. Numbered Embodiment 35. The use of numbered embodiment 34, wherein the RET-mediated disorder is cancer.

[0371] Numbered Embodiment 36. The use of numbered embodiment 34, wherein the cancer is non-small cell lung cancer. Numbered Embodiment 37. The use of numbered embodiment 34, wherein the cancer has metastasized to the brain. Numbered Embodiment 38 The use according to any one of numbered embodiments 34-37, wherein the RET-mediated disorder is mediated by mutant RET. Numbered Embodiment 39 The use of any one of numbered embodiments 34-37, wherein the RET-mediated disorder is relapsed or refractory cancer.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: The inhibitor of RET kinase is a RET kinase inhibitor moiety; Ring B is a 4- to 12-membered heterocycloalkyl, C ３ -C ８ cycloalkyl or omitted; Ring D is the cereblon binding moiety; L １ is a bond, C １ -C ８ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, or heteroaryl; L ２ is -C(O)NH-(CH ２ ) ｐ -, -NHC(O)-(CH ２ ) ｐ -, -C(O)NH-(CH ２ ) ｐ -NH-, -NHC(O)-(CH ２ ) ｐ -NH-, -C(O)-(CH ２ ) ｐ -(4 to 12-membered heterocycloalkyl)-, -C(O)-(OCH ２ CH ２ ) ｐ -(4 to 12-membered heterocycloalkyl)-, -NHC(O)-(CH ２ ) ｐ -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH ２ ) ｐ -(4 to 12-membered heterocycloalkyl)-, -NHC(O)-(CH ２ ) ｐ -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH ２ ) ｐ -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH ２ CH ２ O) ｐ -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH ２ CH ２ O) ｐ -(4 to 12-membered heterocycloalkyl)-, -(OCH ２ CH ２ ) ｐ -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH ２ ) ｐ -(4- to 12-membered heterocycloalkyl)-C(O)-, -(CH ２ ) ｐ -(4 to 12-membered heterocycloalkyl)-C(O)-, or -C(O)NH-(CH ２ ) ｐ -NH-; and and p is an integer from 1 to 12. or a pharmaceutically acceptable salt thereof.

2. Formula Ia-1 or Formula Ia-2: 【Chemistry 2】 [In the formula: X １ is N or CR １ and R １ is H, halogen, or C １ -C ３ is alkyl; R ２ is H, halogen, CN, NO ２ , OH, NH ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 4- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, or 4-12 membered heteroaryl; R ３ is C ３ -C ８ Alkyl, C ３ -C ８ cycloalkyl, 4- to 12-membered heterocycloalkyl, C ６ -C １０ aryl, or 4-12 membered heteroaryl; Ring D is independently 【Transformation 3】 and R ５ is H, halogen, CF ３ , OH, CN, NO ２ or C １ -C ４ is alkyl; R ６ or R ６ ' are each independently H, or R ６ may be taken together to form an oxo group, or R ６ Two instances of ' can be taken together to form an oxo group; R ７ is H, halogen, CN, NO ２ , OH, NH ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two geminal or vicinal R's ７ Carbons together form C ３ -C ８ may form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and and m is an integer from 0 to 2.

2. The compound of claim 1, wherein: or a pharmaceutically acceptable salt thereof.

3. Formula Ia-3: 【Chemistry 4】 The compound according to claim 2, wherein

4. Formula Ia-4: 【Transformation 5】 The compound according to claim 2, wherein

5. Formula Ia-5: 【Transformation 6】 The compound according to claim 2, wherein

6. Formula Ia-6: 【Transformation 7】 The compound according to claim 2, wherein

7. Formula Ia-7: 【Transformation 8】 The compound according to claim 2, wherein

8. Formula Ib-1 or Formula Ib-2: 【Chemistry 9】 【Chemistry 10】 [In the formula: R １ and R ２ are each independently H, halogen, or NR １０ R １１ , or C １ -C ４ is alkyl; R ３ is H, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ４ is C １ -C ６ Alkyl, C ３ -C ８ is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Ring D is 【Chemistry 11】 is a group selected from the group consisting of: R ５ is H, halogen, OH, CN, NO ２ or C １ -C ４ is alkyl; R ６ or R ６ Each instance of ' is independently H, or R ６ may be taken together to form an oxo group, or R ６ Two instances of ' can be taken together to form an oxo group; R ７ is H, halogen, CN, NO ２ , OH, NH ２ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two geminal or vicinal R's ７ Together, C ３ -C ８ may form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and and m is an integer from 0 to 2. or a pharmaceutically acceptable salt thereof.

9. Formula Ib-1, Formula Ib-2, Formula Ib-3, or Formula Ib-4: 【Chemistry 12】 The compound according to claim 8, wherein 【Request Item 10】 【Chemistry 13】 【Chemistry 14】 2. The compound of claim 1 selected from the group consisting of: 【Request Item 11】 【Chemistry 15】 【Chemistry 16】 and 【Chemistry 17】 2. The compound of claim 1 selected from the group consisting of: 【Request Item 12】 【Chemistry 18】 【Chemistry 19】 2. The compound of claim 1 selected from the group consisting of: 【Request Item 13】 【Chemistry 20】 2. The compound of claim 1 selected from the group consisting of:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method for treating an 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 13, or a pharmaceutically acceptable salt thereof, optionally in the form of a pharmaceutical composition.

16. The method according to any one of claims 14 to 15, wherein the RET-mediated disorder is cancer.

17. 17. The method of claim 16, wherein the cancer is non-small cell lung cancer.

18. 18. The method of claim 17, wherein the cancer has metastasized to the brain.

19. The method according to any one of claims 14 to 18, wherein the RET-mediated disorder is mediated by mutant RET.

20. The method according to any one of claims 14 to 18, wherein the RET-mediated disorder is recurrent or refractory cancer.

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