RET-LDD protein degradation inducer

Abstract

The present disclosure relates to proteolysis-inducing compounds against the proto-oncogene tyrosine-protein kinase receptor (RET), which may be either wild-type RET or a mutant form of RET, which are useful in the treatment of diseases and disorders mediated by said protein, and have formula (I): TIFF2025540907000060.tif43113

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to U.S. Provisional Application No. 63 / 422,741, filed November 4, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to compounds that degrade the proto-oncogene tyrosine protein kinase receptor rearranged during transfection (RET). The degradation inducers 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 proto-oncogene tyrosine protein kinase receptor (RET) via the ubiquitin proteasome pathway (UPP), methods for treating diseases and disorders associated with the RET protein and its pathway using the compounds or pharmaceutical compositions, and methods for 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 occurs 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 modulators, ribosome biogenesis, and viral infection. Proteins undergo proteasomal degradation when E3 ubiquitin ligases covalently attach multiple ubiquitin molecules to their terminal lysine residues, resulting in their degradation into small peptides and ultimately amino acids that serve as building blocks for new proteins. Aberrant proteasomal degradation is associated with various disorders, including cancer and other diseases.

[0004] Cereblon forms part of an E3 ubiquitin ligase complex that interacts with damaged DNA-binding protein 1 and, together with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1), functions as a substrate receptor, selecting proteins for ubiquitination. Binding of lenalidomide to cereblon promotes its binding to Ikaros and Ikaros proteins, followed by ubiquitination and proteasomal degradation (see 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 during 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 carcinoma (MTC) and neuroendocrine tumors, while RET fusion proteins, overexpression, and copy number gains are found in a wide range of additional cancers (e.g., papillary thyroid carcinoma, pancreatic cancer, melanoma, leukemia, lung adenocarcinoma, and breast cancer). (Liu Xuan et al., "RET kinase alterations in targeted cancer therapy," Cancer Drug Resist, 2020; and Mulligan LM., "RET revisited: expanding the oncogenic portfolio," Nat Rev Cancer., 2014, 14(3), 173-186).

[0006] Academic and clinical interest in RET has led to the identification of several clinically relevant RET mutations, 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 has been shown 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 tested in numerous 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). Despite these efforts, there remains an unmet need in the art for new RET modulators to treat RET-mediated disorders in hosts in need thereof, including humans. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Lu, G. et al. “The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins” Science, 2014, 343:305-309 [Non-patent document 2] Kronke, J. et al. “lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells” Science, 2014, 343:301-305 [Non-patent document 3] Liu Xuan et al., “RET kinase alterations in targeted cancer therapy”, Cancer Drug Resist, 2020 [Non-patent document 4] Mulligan LM., “RET revisited: expanding the oncogenic portfolio”, Nat Rev Cancer., 2014, 14(3), 173-186 [Non-Patent Document 5] Solomon, et al., “RET Solvent Front Mutations Mediated Acquired Resistance to Selective RET Inhibition in RET-driven malignancies”, J Thoracic Oncolog., 2020 [Non-patent document 6] 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 [Non-Patent Document 7] 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 Summary of the Invention

[0009] A first aspect of the present disclosure is a compound of formula I: [ka] [In the formula, R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R 8 may be substituted with; A is an aryl or heteroaryl, and the aryl or heteroaryl is one or more R 9 may be substituted with; B is heterocycloalkyl or C3-C8 cycloalkyl; L1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -(OCH2CH2) p-(4- to 12-heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-, or -(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-; R 2 is NR 10 R 11 and; R 3 is H, halogen, NH2, or C1-C4 alkyl; Each R 4 are independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)(C1-C6 alkyl); or Two Rs attached to adjacent carbons 4 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 5 is H, OH, CN, NO2, or C1-C4 alkyl; Each R 6 or R 6’ is H; or The Two R's 6 can be taken together to form an oxo group; or The Two R's 6’ can be taken together to form an oxo group; R 7 , R 8 and R 9 are each independently H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two Rs attached to adjacent carbons 7can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 10 and R 11 are independently H or C1-C4 alkyl; m is an integer from 0 to 2; n is an integer from 0 to 4; and p is an integer from 1 to 8. or a pharmaceutically acceptable salt 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, or a pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present disclosure is directed to a method for modulating RET protein, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof. 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 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant. The pharmaceutical composition may be effective for treating a disease or disorder associated with RET modulation in a subject in need thereof. 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 thereof for use in the treatment or prevention of a disease associated with RET modulation. The present invention also provides the use of a compound described herein in the manufacture of a medicament for the treatment of a disease associated with RET.

[0014] The present invention also provides methods for treating diseases or disorders associated with RET degradation 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 (degradation inducers) may also be useful in the treatment of RET-mediated diseases and cancers, including Hirschsprung's disease, medullary thyroid carcinoma (MTC), thyroid cancer, familial medullary thyroid carcinoma, multiple endocrine neoplasia, multiple endocrine neoplasia type 2 (MEN-2, MEN-2A, MEN-2B), neuroendocrine tumors, central nervous system tumors, central hypoventilation syndrome, renal 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 may be improved compared to other known RET degradation inducers. Moreover, the present technology also has the advantage of being applicable to a wide variety of diseases, including disorders mediated by RET fusion proteins, overexpression, or increased copy number (e.g., papillary thyroid cancer, pancreatic cancer, malignant melanoma, leukemia, acute myeloid leukemia (AML), chronic myelomonocytic leukemia, lung adenocarcinoma, lung cancer, non-small cell lung cancer (NSCLC), asymptomatic paraganglioma, breast cancer, non-hereditary (sporadic) cancer, colorectal cancer, or malignant hematological diseases). Further 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 compounds of Formula I, or pharmaceutically acceptable salts thereof, that degrade RET and are capable of inhibiting E3 ligase activity and are therefore useful in methods of treatment of the human or animal body. The disclosure also relates to methods for preparing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in treating disorders and diseases in which RET is involved (e.g., inflammation, autoimmune disease, cancer, infection, a disease or disorder of the central nervous system, a metabolic disorder, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychiatric disorder, graft-versus-host disease, allodynia, or a RET-mediated 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 meanings set forth below.

[0019] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched-chain saturated fatty acid hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include, but are not limited to, moieties containing 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 chain 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 chain alkyl has 4 or fewer carbon atoms.

[0020] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more (e.g., one, two, or three) hydrogen atoms on one or more (e.g., one, two, three, four, or more) carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, 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 similar in length and possible substitution to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, dekenyl) and branched-chain alkenyl groups. In certain embodiments, straight-chain or branched-chain alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight-chain, C3-C6 for branched-chain). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

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

[0023] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkenyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In certain embodiments, straight-chain or branched-chain alkenyl groups have six or fewer carbon atoms in their backbone (e.g., C2-C6 for straight-chain, C3-C6 for branched-chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, the terms "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" are intended to include C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. 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 having specified substituents replacing one or more (e.g., one, two, or three) hydrogen atoms on one or more (e.g., one, two, three, four, or more) hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0025] Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl includes heterocycloalkyl substituted with one or more (e.g., 1, 2, 3, 4, or more) alkyl groups (e.g., 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 (e.g., --CN).

[0027] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (fused, bridged, or spiro) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one ring in the cycloalkyl must be non-aromatic.

[0028] The term "heterocycloalkyl," as used herein, refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic ring system, a 7-12 membered bicyclic ring system (fused, bridged, or spiro ring), or an 11-14 membered tricyclic ring system (fused, bridged, or spiro ring) having one or more heteroatoms (e.g., O, N, S, P, or Se), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5, or 1-6 heteroatoms, or unless otherwise specified, 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.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, and the like. 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 in the heterocycloalkyl must 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 having specified substituents replacing one or more (e.g., one, two, or three) hydrogen atoms on one or more (e.g., one, two, three, four, or more) unsubstituted carbon or heteroatoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diaryl amino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0030] Unless otherwise specifically defined, the term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups (e.g., phenyl, biphenyl, or naphthyl). When having two aromatic rings (such as bicyclic rings), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point with one or more substituents (e.g., one to five substituents). Examples of 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). Substituents may themselves be optionally substituted. Additionally, when containing two or more fused rings, aryl groups as defined herein can also have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Examples of these aryl group ring systems 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 defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. Heteroaryl, as defined herein, also includes bicyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl, as defined herein, also includes tricyclic heteroaromatic groups in which the heteroatoms are selected from N, O, S, P, Se, or B. Aromatic groups are 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, and the like. Allyl, 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, indole benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrahydrobenzo[4,3-b]pyrazinyl, quinazolinyl, tetrahydrobenzo[4,3-b]phenyl, 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, tetrahydrobenzo[4,3-b]phenyl, tetrahydrobenzo[4 ... 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 comprising two or more fused rings, heteroaryl groups as defined herein may comprise one or more saturated or partially unsaturated rings (e.g., 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 nitrogen atoms) fused to a fully unsaturated aromatic ring, said saturated or partially unsaturated ring containing 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and optionally substituted with one or more oxo. In heteroaryl ring systems comprising two or more fused rings, the saturated or partially unsaturated rings may be further fused to a saturated or partially unsaturated ring as described herein. Examples of ring systems of these heteroaryl groups include, but are not limited to, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-11H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl.

[0032] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can have a substituent as described above (e.g., alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxy, aryloxycarbonyloxy, carboxylate, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxy, aryloxycarbonyl ... The aryl and heteroaryl groups may be substituted with carbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings, which form polycyclic systems but are not aromatic (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 have been replaced with a group selected from the intended group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. When the substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents do not occur in aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" refer to a compound that is sufficiently robust to be isolated from the RM to a useful degree of purity and formulated into an effective therapeutic agent.

[0034] When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is depicted without indicating the atom through which it is attached to the remainder of the compound depicted in a given formula, then the substituent may be bonded through any atom in that formula. Combinations of substituents and / or variables are permissible 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 zero to two R moieties, that group may also be substituted with up to two R moieties, and each occurrence of R is independently selected from the definitions of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

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

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

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

[0039] As used herein, the term "optionally substituted haloalkyl" refers to a haloalkyl having specified substituents replacing one or more (e.g., 1, 2, or 3) hydrogen atoms on one or more (e.g., 1, 2, 3, 4, or more) unsubstituted hydrocarbon backbone carbon atoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, 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, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, 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 following schemes, as well as those shown in the Examples.

[0042] Throughout this specification, when a composition is described as having, comprising, or characterized by particular components, it is to be understood that the composition also contemplates consisting essentially of, or consisting of, the recited components. Similarly, when a method or process is described as having, comprising, or characterized by particular manufacturing steps, it is to be understood that the process also contemplates consisting essentially of, or consisting of, the recited manufacturing steps. Furthermore, it is to be understood that the order of steps or order in which certain actions are performed is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be performed simultaneously.

[0043] It should be understood that the synthetic processes of the present disclosure can tolerate a variety of functional groups and thus can employ a variety of substituted starting materials. The processes generally provide the desired final compound at or near the end of the overall process, although in some 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 from commercially available starting materials, compounds known in the literature, or readily prepared intermediates using standard synthetic methods and procedures known to those skilled 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 manipulations can be obtained from the relevant chemical literature or from standard textbooks in the field. Without being limited to any one or several sources, the classic textbooks incorporated herein by reference (e.g., 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 & Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons (1995)) are recognized as useful and reference textbooks in the field of 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 need to be protected from reaction conditions by the use of protecting groups. Protecting groups may also be used to distinguish between similar functional groups within a molecule. A list of protecting groups and methods for introducing and removing protecting 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 treatment or prevention as described herein. Furthermore, unless otherwise specified, any reference to a method of treatment or prevention should be understood to include the use of a compound for the manufacture of a medicament to treat or prevent a condition as described herein. Treatment or prevention includes treatment or prevention in humans or non-human animals (including rodents and other disease models).

[0047] Unless otherwise specified, any description of a method of treatment should be understood to include the use of a compound to provide treatment as described herein. Furthermore, unless otherwise specified, any description of a method of treatment should be understood to include the use of a compound for the manufacture of a medicament to treat a condition as described herein. 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 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 some embodiments, the mammal is a human. A subject in need thereof can be one who has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, the subject in need thereof may be at a higher risk of developing such a disease or disorder compared to the population as a whole (i.e., more susceptible to such a disorder compared to the population as a whole). The subject in need thereof may be one who has a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant from the start of treatment, or may become resistant during treatment. In some embodiments, the subject in need thereof has undergone all known effective treatments for the disease or disorder disclosed herein without success. In some embodiments, the subject in need thereof has undergone at least one prior treatment.

[0048] As used herein, the term "treatment" or "treating" refers to the management and care of a patient to combat a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eradicate the disease, condition, or disorder. The term "treating" also includes treatment of an in vitro cell or animal model. It should be understood that the term "treating" or "treatment" includes the alleviation of established symptoms of a condition. "Treating" or "treatment" of a condition, disorder, or condition means: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition as it progresses in a person who may be suffering from or susceptible to the condition, disorder, or condition but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (2) suppressing the condition, disorder, or condition, i.e., arresting, alleviating, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment), or at least one clinical or subclinical symptom thereof; or (3) palliating or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0049] It is to be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can also be or may be used to prevent the associated disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0050] As used herein, the terms "prevention," "preventing," or "prevention" refer to reducing or eliminating the manifestations of symptoms or complications of such disease, condition, or disorder.

[0051] Those skilled in the art should understand that for detailed descriptions of the known techniques discussed herein or equivalent techniques, general references can 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 can, of course, also be referenced when making or using embodiments of the present disclosure.

[0052] 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.

[0053] 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 some embodiments, the pharmaceutical composition is present in bulk or in a unit dosage form. The unit dosage form may be any of a variety of dosage forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that routine variations in dosage may be necessary depending on the age and condition of the patient. Dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, nasal, etc. Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In certain embodiments, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that are required.

[0054] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, substances, 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 or animals without excessive toxicity, irritation, allergic response, or other problem or complication, and for which a reasonable benefit / risk ratio is present.

[0055] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and useful in preparing pharmaceutical compositions that are biologically and otherwise desirable, and includes excipients that are acceptable for veterinary as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0056] 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 (e.g., intravenous, intradermal, subcutaneous), oral (e.g., oral ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzoyl 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 an isotonic agent such as sodium chloride or dextrose. 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.

[0057] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to patients by many well-known methods currently used in chemotherapy.For example, the compound of the present disclosure can be injected into blood 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.During and after treatment, it is advisable to carefully observe the condition of the disease (e.g., the disease or disorder disclosed herein) and the health condition of the patient for an appropriate period of time.

[0058] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent for treating, alleviating, or preventing a particular disease or disorder, or for exhibiting 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 for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation, within the skill and judgment of the clinician.

[0059] It should be understood that the therapeutically effective amount of any compound can be estimated initially using cell culture assays (e.g., tumor cells) or animal models, most often rats, mice, rabbits, or pigs. Animal models may also be used to determine appropriate concentration 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 may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., determining the ED50 (the dose therapeutically effective in 50% of the population) and the LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic efficacy is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions exhibiting large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0060] Dosage and administration are adjusted to provide a sufficient concentration of the active agent or to maintain the desired effect.Factors that can be considered include the severity of the disease state, the subject's general health, age, weight, and sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to treatment.

[0061] Pharmaceutical compositions containing the active compounds of the present disclosure may be prepared by commonly known methods (for example, by conventional mixing, dissolving, granulating, dragee-coating, pulverizing, emulsifying, encapsulating, encapsulating, or lyophilizing processes). Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate the processing of the active compounds into pharmaceutically usable preparations. Naturally, the appropriate formulation depends on the selected route of administration.

[0062] 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 are saline, sterile water, Cremophor EL (商標) (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Protection against the action of microorganisms is achieved by various antibacterial or antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0063] Non-toxic injection solution can be prepared by incorporating the active compound in the required amount in a suitable solvent with one or a combination of the above-listed ingredients as needed, and then sterilize by filtration.Generally, dispersion solution is prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and other necessary ingredients as listed above.For the sterile powder used to prepare sterile injection solution, the preparation method is vacuum drying and freeze-drying, and obtains the powder of active ingredient and any desired additional ingredients from the solution that has been previously sterilized by filtration.

[0064] Oral compositions generally contain an inert diluent or edible pharmaceutically acceptable carrier.They can be enclosed in gelatin capsules or pressed into tablets.For oral therapeutic administration, active compounds can be incorporated 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, and the compound in the fluid carrier is applied to the oral cavity, shaken, and expectorated or swallowed.Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0065] 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.

[0066] Systemic administration can be carried out via transmucosal or transdermal routes. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be carried out by using nasal sprays or suppositories. For transdermal administration, the active compound is generally formulated into ointments, salves, gels, or creams, as known in the art.

[0067] The active compounds may be prepared with pharmaceutically acceptable carriers that protect the compound against rapid elimination from the body, such as a controlled-release formulation (including implants and microencapsulated delivery systems). Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art. Materials may also be purchased from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) may also be used as pharmaceutically acceptable carriers. These formulations may be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent No. 4,522,811.

[0068] Oral or parenteral compositions are particularly advantageously formulated in dosage unit form, because they are easy to administer and have uniform dosage.Dosage unit form as used herein refers to a physically separate unit that is suitable as a unit dose for treatment subject, and each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect together with necessary pharmaceutical carrier.The specification of dosage unit form of the present disclosure is determined by and directly depends on the specific characteristics of active compound and the specific therapeutic effect to be achieved.

[0069] 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 patient being treated, and the experience and judgment of the treating physician or practitioner, among other factors that influence the selected dosage. Generally, the dosage should be sufficient to slow, preferably reverse, and preferably cause complete regression of the symptoms of the diseases or disorders disclosed herein. Dosages can range from about 0.01 mg / kg to about 5000 mg / kg per day. An effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improvement in survival and growth means regression. As used herein, the term "dosage-effective" refers to an amount of an active compound that produces a desired biological effect in a subject or cell.

[0070] It should be understood that the pharmaceutical compositions can be included in a container, box, or dispenser together with instructions for administration.

[0071] Additionally, for compounds of the present disclosure that may further form salts, it should be understood that all of these forms are contemplated as being within the scope of the present disclosure.

[0072] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include 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, carboxylic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxybenzo ... These include salts derived from inorganic and organic acids selected from the group consisting of hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids (e.g., glycine, alanine, phenylalanine, arginine, etc.).

[0073] 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.

[0074] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced with a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or is coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1 or any ratio other than 1:1 (e.g., 3:1, 2:1, 1:2, or 1:3).

[0075] Compound or its pharmaceutically acceptable salt can be administered orally, intranasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathoracically, intrathecally and parenterally.In some embodiments, compound is administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0076] The dosing regimen utilizing the compound is selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated, the route of administration; the patient's renal and hepatic function; and the particular compound or salt thereof being used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to counter or arrest the progression of the condition.

[0077] Techniques for formulating and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co, Easton, Pa. (1995). In some 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 is present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0078] Unless otherwise specified, all percentages and ratios used herein are by weight. 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 practicing the present disclosure. The examples do not limit the scope of the claims. Based on this disclosure, one skilled in the art will be able to identify and use other components and methodologies useful in practicing the present disclosure.

[0079] In the synthetic schemes described herein, compounds may be depicted in one specific configuration for simplicity. Such specific configurations are not intended to limit the present disclosure to one or other isomers, tautomers, positional isomers, or stereoisomers, nor do they 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 activity level than another isomer, tautomer, positional isomer, or stereoisomer.

[0080] All publications and patent documents cited herein are incorporated by reference as if each individual publication or document were specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not an admission that any is pertinent prior art, nor is it an admission as to the contents or date thereof. Having thus described the invention in writing, those skilled in the art will recognize that the invention may be practiced in various embodiments, and that the foregoing description and following examples are illustrative only and do not limit the scope of the claims which follow.

[0081] As used herein, the phrases "compounds of the present disclosure," "degradation inducers of the present disclosure," and "degradation inducers" refer both generically and specifically to the compounds disclosed herein.

[0082] Compounds of the Disclosure In some embodiments, the present disclosure provides, inter alia, compounds of formula (I): [ka] [In the formula, R 1 is a C1-C6 alkyl, a C3-C8 cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more (e.g., one, two, three, four, or more) R 8 may be substituted with; A is an aryl or heteroaryl, and the aryl or heteroaryl is selected from one or more (e.g., one, two, three, four, or more) R 9 may be substituted with; B is heterocycloalkyl or C3-C8 cycloalkyl; L1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; L2 is -C(O)-(CH2) p-(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-, or -(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-; R 2 is NR 10 R 11 and; R 3 is H, halogen, NH2, or C1-C4 alkyl; Each R 4 is independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or more) C1-C6 alkoxy, C1-C6 thioalkyl, NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)(C1-C6 alkyl); or Two Rs attached to adjacent carbons 4 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 5 is H, OH, CN, NO2, or C1-C4 alkyl; Each R 6 or R 6’ is H; or The Two R's 6 can be taken together to form an oxo group; or The Two R's 6’can be taken together to form an oxo group; R 7 , R 8 and R 9 are each independently H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two Rs attached to adjacent carbons 7 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 10 and R 11 are independently H or C1-C4 alkyl; m is an integer from 0 to 2; n is an integer from 0 to 4; and p is an integer from 1 to 8. or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, A, B, L1, L2, R1, R2, R3, R4, R5, R6, R 6’ , R7, m, and n are as described herein as set forth in the present disclosure.

[0084] In some embodiments, the present disclosure provides a compound of formula I(a): [ka] or a pharmaceutically acceptable salt thereof.

[0085] In another embodiment, the compounds of the present disclosure have formula I(b): [ka] or a pharmaceutically acceptable salt thereof.

[0086] In some other embodiments, compounds of the present disclosure have formula I(c): [ka] or a pharmaceutically acceptable salt thereof.

[0087] In some other embodiments, compounds of the present disclosure have formula I(d): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0088] In some other embodiments, compounds of the present disclosure have formula I(e): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0089] In still other embodiments, compounds of the present disclosure have formula I(f): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0090] In some other embodiments, compounds of the present disclosure have formula I(g): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0091] In some other embodiments, compounds of the present disclosure have formula I(h): [ka] [In the formula, s1, s2, s3, and s4 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0092] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, 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 another embodiment, R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, or heterocycloalkyl. 1 is C1-C6 alkyl or C3-C8 cycloalkyl. In another embodiment, R 1 is C1-C6 alkyl. In another embodiment, R 1 is C3-C8 cycloalkyl. In another embodiment, R 1 is heterocycloalkyl. In another embodiment, R 1 is aryl. In another embodiment, 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 1 is one or more R 8 In a further embodiment, R 1 is one or more R 8 is heteroaryl optionally substituted with

[0093] 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 another embodiment, R 8 is H, halogen, CN, NO, or OH. In another embodiment, R 8 is H, halogen, CN, or NO. In another embodiment, R 8 is H, halogen, or CN. In another embodiment, R 8 is H or halogen. In a further embodiment, R 8 is H. In a further embodiment, R 8 is halogen. In a further embodiment, R 8is 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 C2-C6 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.

[0094] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, A is aryl or heteroaryl. In other embodiments, A is aryl. In other embodiments, A is heteroaryl. In other embodiments, A is one or more R 9 In another embodiment, A is aryl optionally substituted with one or more R 9 is heteroaryl optionally substituted with

[0095] In some embodiments, R 9 is 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. 9is 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 another embodiment, R 9 is H, halogen, CN, NO, or OH. In another embodiment, R 9 is H, halogen, CN, or NO. In another embodiment, R 9 is H, halogen, or CN. In another embodiment, 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 9 is NO. In yet another embodiment, R 9 is OH. In yet another embodiment, R 9 is NH. In a further embodiment, R 9 is C1-C6 alkyl. In a further embodiment, R 9 is C2-C6 alkenyl. In a further embodiment, R 9 is C2-C6 alkynyl. In a further embodiment, R 9is 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.

[0096] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, B is heterocycloalkyl or C3-C8 cycloalkyl. In further embodiments, B is heterocycloalkyl. In further embodiments, B is C3-C8 cycloalkyl.

[0097] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, L1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In another embodiment, L1 is C1-C6 alkyl or C2-C6 alkenyl. In another embodiment, L1 is C1-C6 alkyl. In another embodiment, L1 is C2-C6 alkenyl. In another embodiment, L1 is C2-C6 alkynyl.

[0098] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-, or -(CH2) pIn a further embodiment, L2 is -(4- to 12-heterocycloalkyl)-C(O)-. In a further embodiment, L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, or -C(O)-(CH2) p In a further embodiment, L2 is -C(O)-(CH2). p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)- or -(OCH2CH2) p In a further embodiment, L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, or -C(O)-(CH2CH2O) p In a further embodiment, L2 is -C(O)-(CH2)p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, or -C(O)NH-(CH2CH2O) p In a further embodiment, L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, or -C(O)NH-(CH2) p In a further embodiment, L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)- or -C(O)-(OCH2CH2) p In a further embodiment, L2 is -C(O)-(CH2). p In a further embodiment, L2 is -C(O)-(OCH2CH2). p In a further embodiment, L2 is -C(O)NH-(CH2). p In a further embodiment, L2 is -C(O)NH-(CH2CH2O) p In a further embodiment, L2 is -C(O)-(CH2CH2O) p In a further embodiment, L2 may be -(4- to 12-heterocycloalkyl)-. p In a further embodiment, L2 is -C(O)-(CH2). pIn a further embodiment, L2 may be -(4- to 12-heterocycloalkyl)-C(O)-. p It may be -(4- to 12-heterocycloalkyl)-C(O)-.

[0099] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, R 2 is independently NR 10 R 11 is.

[0100] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 10 is independently H or C1-C4 alkyl. In another embodiment, R 10 is H. In another embodiment, R 10 is C1-C4 alkyl.

[0101] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 11 is independently H or C1-C4 alkyl. In another embodiment, R 11 is H. In another embodiment, R 11 is C1-C4 alkyl.

[0102] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, R 3 is H, halogen, NH, or C-C alkyl. In a further embodiment, R 3 is H, halogen, or NH. In a further embodiment, R 3 is H or halogen. In yet a further embodiment, R 3 is H. In yet a further embodiment, R 3 is halogen. In yet a further embodiment, R 3 is NH2. In yet a further embodiment, R 3 is C1-C4 alkyl.

[0103] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, 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 another embodiment, R 4 is C2-C6 alkenyl. In another embodiment, R 4 is C2-C6 alkynyl.

[0104] In a further embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)(C1-C6 alkyl). In a further embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, or -NH(C1-C6 alkyl). 4 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, or NH2. In a further embodiment, R 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. In yet a further embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more NH2. In yet a further embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more -NH(C1-C6 alkyl). In yet a further embodiment, R 4is C1-C6 alkyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0105] In a further embodiment, R 4 is 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). 4 is C-C alkenyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, NH, or -NH(C-C alkyl). 4 is C-C alkenyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, or NH. In a further embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkoxy or C1-C6 thioalkyl. 4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkoxy. 4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 thioalkyl. 4 is C2-C6 alkenyl optionally substituted with one or more NH2. In yet a further embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more -NH(C1-C6 alkyl). In yet a further embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0106] In a further embodiment, R 4is C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)(C1-C6 alkyl). In further embodiments, R 4 is C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, or -NH(C1-C6 alkyl). 4 is C-C alkynyl optionally substituted with one or more C-C alkoxy, C-C thioalkyl, or —NH. 4 is C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy or -C1-C6 thioalkyl. 4 is C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy. 4 is C2-C6 alkynyl optionally substituted with one or more C1-C6 thioalkyl. 4 is C2-C6 alkynyl optionally substituted with one or more NH2. In yet a further embodiment, R 4 is C2-C6 alkynyl optionally substituted with one or more -NH(C1-C6 alkyl). In yet a further embodiment, R 4 is C2-C6 alkynyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0107] In still further embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, two R 4 can be joined together to form a C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In another embodiment, two R attached to adjacent carbons can be 4 can be joined together to form a C-C cycloalkyl, heterocycloalkyl, or aryl. In another embodiment, two R attached to adjacent carbons can be4 can be joined together to form a C-C cycloalkyl or heterocycloalkyl. In another embodiment, two R attached to adjacent carbons can be 4 can be joined together to form a C-C cycloalkyl. In another embodiment, two R attached to adjacent carbons can be 4 can be joined together to form a heterocycloalkyl. In another embodiment, two R attached to adjacent carbons can be 4 can be taken together to form an aryl. In another embodiment, two R 4 can be taken together to form a heteroaryl.

[0108] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, R 5 is independently H, OH, CN, NO, or C-C alkyl. In a further embodiment, R 5 is H, OH, CN, or NO. In further embodiments, R 5 is H, OH, or CN. In further embodiments, R 5 is H or OH. In further embodiments, R 5 is H. In a further embodiment, R 5 is OH. In further embodiments, R 5 is CN. In further embodiments, R 5 is NO. In a further embodiment, R 5 is C1-C4 alkyl.

[0109] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, R 6 are independently H.

[0110] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 6’ are independently H.

[0111] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, two R 6 can be taken together to form an oxo group.

[0112] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, two R 6’ can be taken together to form an oxo group.

[0113] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 7 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 another embodiment, R7 is H, halogen, CN, NO, or OH. In another embodiment, R 7 is H, halogen, CN, or NO. In another embodiment, R 7 is H, halogen, or CN. In another embodiment, R 7 is H or halogen. In a further embodiment, R 7 is H. In another embodiment, R 7 is halogen. In a further embodiment, R 7 is CN. In a further embodiment, R 7 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 C2-C6 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.

[0114] In a further embodiment of the disclosed compound or a pharmaceutically acceptable salt thereof, two R 7 can be joined together to form a C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In another embodiment, two R attached to adjacent carbons can be 7 can be joined together to form a C-C cycloalkyl, heterocycloalkyl, or aryl. In another embodiment, two R attached to adjacent carbons can be 7can be joined together to form a C-C cycloalkyl or heterocycloalkyl. In another embodiment, two R attached to adjacent carbons can be 7 can be joined together to form a C-C cycloalkyl. In another embodiment, two R attached to adjacent carbons can be 7 can be joined together to form a heterocycloalkyl. In another embodiment, two R attached to adjacent carbons can be 7 can be taken together to form an aryl. In another embodiment, two R 7 can be taken together to form a heteroaryl.

[0115] In further embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, m, at each occurrence, is 0, 1, or 2. In another embodiment, m is 0 or 1. In another embodiment, m is 0 or 2. In another embodiment, m is 1 or 2. In another embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2.

[0116] In yet another embodiment of the present disclosure, n, independently at each occurrence, is 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.

[0117] In another embodiment of the present disclosure, p is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, or 8. In another embodiment of the present disclosure, p is 1 or 2. In another embodiment of the present disclosure, p is 1 or 3. In another embodiment of the present disclosure, p is 1 or 4. In another embodiment of the present disclosure, p is 1 or 5. In another embodiment of the present disclosure, p is 1 or 6. In another embodiment of the present disclosure, p is 1 or 7. In another embodiment of the present disclosure, p is 1 or 8. In another embodiment of the present disclosure, p is 2 or 3. In another embodiment of the present disclosure, p is 2 or 4. In another embodiment of the present disclosure, p is 2 or 5. In another embodiment of the present disclosure, p is 2 or 6. In another embodiment of the present disclosure, p is 2 or 7. In another embodiment of the present disclosure, p is 2 or 8. In another embodiment of the present disclosure, p is 3 or 4. In another embodiment of the present disclosure, p is 3 or 5. In another embodiment of the present disclosure, p is 3 or 6. In another embodiment of the present disclosure, p is 3 or 7. In another embodiment of the present disclosure, p is 3 or 8. In another embodiment of the present disclosure, p is 4 or 5. In another embodiment of the present disclosure, p is 4 or 6. In another embodiment of the present disclosure, p is 4 or 7. In another embodiment of the present disclosure, p is 4 or 8. In another embodiment of the present disclosure, p is 5 or 6. In another embodiment of the present disclosure, p is 5 or 7. In another embodiment of the present disclosure, p is 5 or 8. In another embodiment of the present disclosure, p is 6 or 7. In another embodiment of the present disclosure, p is 6 or 8. In another embodiment of the present disclosure, p is 7 or 8. In another embodiment of the present disclosure, p is 8. In another embodiment of the present disclosure, p is 7. In another embodiment of the present disclosure, p is 6. In another embodiment of the present disclosure, p is 5. In another embodiment of the present disclosure, p is 4.In another embodiment of the present disclosure, p is 3. In another embodiment of the present disclosure, p is 2. In another embodiment of the present disclosure, p is 1. In another embodiment of the present disclosure, p is 0.

[0118] In some embodiments, suitable compounds of the present disclosure include: [ka] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); [ka] (4-amino-6-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide); or [ka] (4-amino-6-((1-(3-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)propanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide), or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described herein.

[0120] In some aspects, the present disclosure provides compounds that are isotopic derivatives (eg, isotopically labeled compounds) of any one of the compounds having the formulas described herein.

[0121] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 3, their prodrugs, and pharmaceutically acceptable salts thereof.

[0122] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 3 and pharmaceutically acceptable salts thereof.

[0123] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 3 and pharmaceutically acceptable salts thereof.

[0124] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 3.

[0125] It will be understood that isotopic derivatives can be prepared using a variety of techniques recognized by any skilled artisan. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples disclosed herein, substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0126] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0127] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds having formulas disclosed herein.

[0128] 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 represented by formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound represented by formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34S. In some embodiments, the isotopic derivatives are deuterium-labeled compounds (i.e., deuterium-enriched or labeled with respect to one or more atoms thereof) selected from S. 2 In some embodiments, the compound is 18 In some embodiments, the compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 I-labeled compounds, or any combination thereof. In some embodiments, the compounds are 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 S-labeled compounds, or any combination thereof.

[0129] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using a variety of techniques recognized by any skilled artisan. For example, deuterium-labeled compounds are generally prepared using S-labeled compounds instead of non-isotopic labeling reagents. 18 F, 125 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 They can be prepared using S-labeled reagents by carrying out the procedures disclosed in the schemes and / or examples disclosed herein.

[0130] 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 thereof containing an S atom are within the scope of the 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 offer some therapeutic advantage resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

[0131] For the avoidance of doubt, when a group is modified herein as "as described herein," it is to be understood that such group encompasses the broadest definition appearing first, as well as each and every individual definition associated with such group.

[0132] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as 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. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic include alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., calcium salts or magnesium salts), ammonium salts, or salts with organic bases that provide a pharmaceutically acceptable cation (e.g., salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine).

[0133] It will be understood that a compound of any one of the formulas disclosed herein, and any pharmaceutically acceptable salt thereof, includes stereoisomers, mixtures of stereoisomers, and all isomeric polymorphs of the compound.

[0134] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the order of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of each enantiomer of opposite chirality is called a "racemic mixture."

[0135] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0136] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with two or more chiral centers may exist 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 the chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to a given chiral center are ranked according to the Cahn-Ingold-Prelog ranking rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413. Cahn and Ingold, J. Chem Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0137] As used herein, the term "geometric isomer" refers to diastereomers in which there is restricted rotation at a double bond or cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by the prefixes cis and trans, or Z and E, indicating that the groups are on the same or opposite sides of the double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0138] It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. It should also be understood that when a compound has chiral or geometric isomeric structures, all isomeric structures are intended to be within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric structure, but not all isomers have the same level of activity.

[0139] It should be understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof, and that not all atropisomers have the same activity levels.

[0140] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. This conversion results in the formal migration of a hydrogen atom accompanied by the interchange of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomers in solution. In solution, where tautomerization is possible, a chemical equilibrium of tautomers is achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Among the various types of possible tautomerism, two are commonly observed: keto-enol tautomerism, in which simultaneous electron and hydrogen atom shifts occur. Ring-chain tautomerism occurs as a result of the reaction of an aldehyde group (-CHO) of a sugar molecule with one of the hydroxyl groups (-OH) within the same molecule, forming a ring-like structure, as exemplified by glucose.

[0141] It should be understood that the compounds of the present disclosure may be depicted as different tautomeric forms. Also, when a compound has tautomeric structures, it should be understood that all tautomeric structures are intended to be included within the scope of the present disclosure, and that the naming of the compound does not exclude any isomeric structure. It will be understood that some stereoisomers may have higher activity levels than other stereoisomers.

[0142] Compounds that have the same molecular formula but differ in the nature, order of bonding, or arrangement of atoms in space are called "isomers." Isomers that differ in the arrangement of atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of another stereoisomer 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., when bonded to four different groups, pairs of enantiomers are possible. Enantiomers are characterized by the absolute configuration of the asymmetric center and are described according to the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is determined as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemate."

[0143] The compounds of the present disclosure may have one or more asymmetric centers, and such compounds may be prepared as either (R)- or (S)-stereoisomers, or 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, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers, for example, by synthesis from appropriate active starting materials or by resolving a racemate, are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomer centers (E- or Z-isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereomers, and geometric isomers, and mixtures thereof, that possess inflammasome inhibitory activity.

[0144] Any compound of any formula described herein should be understood to include the compound itself as well as, if applicable, its salt. For example, a salt can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound 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).

[0145] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts. Similarly, salts can also be formed with a cation and a negatively charged group (e.g., carboxylate) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium or diethylamine. The substituted compounds of the present disclosure also include salts containing a quaternary nitrogen atom.

[0146] It should be understood that the compounds of the present disclosure, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form, or solvated with other solvent molecules. Examples of hydrates include, but are not limited to, monohydrates, dihydrates, etc. Examples of solvates include, but are not limited to, ethanol solvates, acetone solvates, etc.

[0147] The term "solvate" as used herein refers to a solvent addition form containing either equivalent or unequal amounts of solvent. Some compounds tend to trap a certain molar ratio of solvent molecules in the crystalline solid state to form solvates. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance in which water retains its molecular state as H2O.

[0148] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but differs slightly in composition (such as by the replacement of an atom with an atom of a different element, or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is similar or equivalent in function and appearance to the reference compound, but not in structure or origin.

[0149] As used herein, the term "derivative" refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0150] It should be understood that a compound represented by any one of the formulas disclosed herein may exist in solvated form, such as, for example, a hydrate, as well as in unsolvated form. Suitable pharmaceutically acceptable solvates include, for example, hydrates such as hemihydrate, monohydrate, dihydrate, or trihydrate, and it should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0151] It is understood that certain compounds represented by any one of the formulas disclosed herein exhibit polymorphism, and the present disclosure encompasses all such forms, or mixtures thereof, that have inflammasome inhibitory activity.Crystalline materials may be analyzed using conventional techniques, such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance (NMR) spectroscopy.The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0152] Compounds of any one of the formulas disclosed herein may exist in a number of different tautomeric structures, and a reference to a compound of formula (I) includes all such structures. For the avoidance of doubt, even if a compound may exist as one of several tautomeric structures and only one form is specifically described or shown, all other structures are included within formula (I). Examples of tautomeric structures include keto-, enol-, and enolate-structures, such as the following tautomeric pairs: keto / enol (as shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro.

[0153] Figure US11319319-20220503-C00141

[0154] The compounds of any one of the formulas disclosed herein may be administered in the form of a prodrug that breaks down in the human or animal body to release the disclosed compound. Prodrugs may be used to alter the physical and / or pharmacokinetic properties of the disclosed compounds. Prodrugs can be formed when the disclosed compounds 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 on the ester or amide group of any of the formulas disclosed herein.

[0155] Thus, the present disclosure includes a compound of any one of the formulae disclosed herein as defined above when it becomes available through organic synthesis and when its prodrug is cleaved and becomes available in the human or animal body. Thus, the present disclosure includes a compound of any one of the formulae disclosed herein that is produced by organic synthesis methods, as well as such compounds that are produced in the human or animal body by metabolism of a precursor compound, i.e., a compound of any one of the formulae disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0156] 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 undesirable pharmacological activity and are free from undue toxicity and are suitable for administration to the human or animal body. Various forms of prodrugs have been described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Prodrugs, edited by H. Bundgaard, (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.

[0157] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a hydroxy group include, for example, in vivo cleavable esters or ethers thereof. Suitable esters or ethers of a compound of any one of the formulae disclosed herein having a hydroxy group include, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). More suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, ethoxycarbonyl groups, N,N-(C1-C6 alkyl)2 carbamoyl groups, 2-dialkylaminoacetyl groups, and C1-C10 alkoxycarbonyl groups such as 2-carboxyacetyl groups. Examples of ring substituents in the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperidin-1-ylmethyl, and 4-(C1-C4 alkyl)piperidin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0158] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulas disclosed herein bearing a carboxy group are, for example, in vivo cleavable amides thereof, including, for example, amides formed with amines such as ammonia; C1-4 alkylamines such as methylamine; (C1-C4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine, or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines such as benzoylamine; and amino acids such as glycine or its esters.

[0159] Suitable pharmaceutically acceptable prodrugs of the compound of any one of the formulas disclosed herein having an amino group are, for example, its amide derivatives, which can be cleaved in vivo.Suitable pharmaceutically acceptable amides from amino groups include, for example, acetyl, benzoyl, phenylacetyl, and C1-C10 alkanoyl groups, such as substituted benzoyl and substituted phenylacetyl groups.Examples of ring substituents in phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperidin-1-ylmethyl, and 4-(C1-C4 alkyl)piperidin-1-ylmethyl.

[0160] The effects of a compound of any one of the formulas disclosed herein in vivo 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 effects of a compound of any one of the formulas disclosed herein in vivo may also be exerted by way of metabolism of a precursor compound (prodrug).

[0161] How to use The compound described herein or its pharmaceutically acceptable salt can be used in an effective amount for treating patients (usually humans) who need it and have disorders mediated by RET, which can be wild-type RET or mutant RET, as generally described herein.In certain embodiments, the compound of the present invention degrades other proteins, such as Aurora kinase or VEGFR2.In certain embodiments, the compound of the present invention degrades RET and Aurora A kinase (AURKA).

[0162] In another aspect of the present invention, there is provided a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or pharmaceutical compound thereof, for use in the manufacture of a medicament for the treatment or prevention of cancer in a patient in need thereof; wherein RET inhibition is required for the treatment or prevention of cancer.

[0163] In certain embodiments, the method comprises administering to a patient in need thereof an effective amount of an active compound described herein or a salt thereof, optionally in a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another bioactive agent or combination of active agents.

[0164] In certain embodiments, the present invention provides a method of treating any of the disorders described herein in a patient in need thereof.

[0165] 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.

[0166] In certain embodiments, the present application provides a method for preventing any of the disorders described herein to a patient in need thereof.

[0167] In certain embodiments, the patient is a human.

[0168] In another aspect of the present invention, there is provided a method for treating or preventing a proliferative disease, the method comprising administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a compound described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0169] In some embodiments, the disease is RET-mediated, eg, RET plays a role in the initiation or development of the disease.

[0170] In certain embodiments, the RET-mediated disorder is benign growth, metastasis, neoplasia, tumor, solid tumor, rhabdoid tumor, cancer, leukemia, cancer, abnormal cell proliferation, amyloid-based proteopathy, proteopathy, fibrotic disorder, inflammation, arthritis, pulmonary disorder, or immune disorder.

[0171] In certain embodiments, RET-mediated disorder is cancer that metastasizes, for example, cancer that metastasizes to the brain.In certain embodiments, RET-mediated disorder is cancer that metastasizes to the brain, lung, bone, liver, abdominal cavity, adrenal gland, skin or muscle.

[0172] In certain embodiments, the compounds of the present invention penetrate the blood-brain barrier and can be used for the treatment of CNS-related cancers or cancers that have metastasized to the brain.

[0173] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0174] In certain embodiments, the RET-mediated disorder is abnormal cell proliferation, including, but not limited to, a tumor or cancer, or a myeloproliferative disorder, or a lymphoproliferative disorder such as B-cell or T-cell lymphoma, multiple myeloma, primary macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder.

[0175] In certain embodiments, the hematological cancer is selected from the group consisting of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), T-cell lymphocytic leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphocytic T-cell leukemia, acute monocytic leukemia, plasma cell neoplasms, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, mixed plasma leukemia (MPL), and / or mixed phenotype leukemia (MMLL). MLL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL)2 and / or BCL6 rearrangements / overexpression [double and triple-hit lymphomas], myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma including bortezomib-resistant mantle cell lymphoma.

[0176] Solid cancers 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, brain cancer, including glioma, glioblastoma, neuroblastoma, and medulloblastoma (including MYC-amplified medulloblastoma), colorectal cancer, Wilms' tumor, Ewing's tumor, Cancers include: rhabdomyosarcoma, ependymoma, head and neck cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer including pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PanNETs), osteosarcoma, giant cell tumor of bone, thyroid cancer, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland tumors, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, GIST (gastrointestinal stromal tumor), neutrophil thyroid cancer, testicular cancer, squamous cell carcinoma, hepatocellular carcinoma (HCC), MYCN-driven solid tumors, and neutrophil thyroid cancer (NMC).

[0177] In further embodiments, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0178] In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0179] In further embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Kaposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningeal sarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0180] In a further embodiment, the disease or disorder is multiple myeloma.

[0181] In another embodiment, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis, and other arthritic conditions, neuroinflammation, allergies, pain, neuropathic pain, fever, lung disorders, pneumonia, adult dyspnea chronic pulmonary disease, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal diseases, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcer disease, gastric ulcer, autoimmune diseases, graft versus host disease, and allograft rejection, cancer, leukemia, lymphoma, colon cancer, brain tumor, bone cancer, epithelial cell-derived neoplasm (epithelial cancer), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell carcinoma, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and acute myeloid leukemia (APL), neoplasms, angiogenesis including metastasis, central nervous system disorders, central nervous system disorders with inflammatory or apoptotic factors, peripheral neuropathy, or B-cell lymphoma.

[0182] In another embodiment, the pharmaceutical composition comprising a compound described herein and the additional pharmaceutical agent are administered simultaneously or sequentially.

[0183] In another embodiment, the disease or disorder is cancer. In yet another embodiment, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, solid tumor, blood cancer, or solid tumor.

[0184] In some embodiments, the method is used to treat or prevent a condition selected from an autoimmune disease, an inflammatory disease, a proliferative and hyperproliferative disease, and an immune-mediated disease, hi another embodiment, the disease is selected from a proliferative disorder.

[0185] In certain embodiments, the RET-mediated disorder is an immune disorder, including, but not limited to, an autoimmune disease (e.g., Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type 1 diabetes).

[0186] Certain aspects of the present application provide 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, adenocarcinoma; bone cancer; colon cancer; colorectal cancer; colorectal adenoma; pancreatic cancer, adenocarcinoma; thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; malignant melanoma; sarcoma; bladder cancer; liver cancer and bile duct cancer; kidney cancer; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cell; buccal cavity and pharynx (oral cavity), lip, lower, mouth, pharynx; small intestine cancer; colorectal cancer, colon cancer, rectal cancer, brain and central nervous system cancer; chronic myeloid leukemia (CML) and leukemia. The term "cancer" includes, but is not limited to, myeloma, lymphoma, or gastric cancer, renal cancer, and cancer selected from the following: head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin's lymphoma, and lung cancer.

[0187] The term "cancer" refers to any cancer (e.g., tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc.) caused by the proliferation of malignant cells. For example, cancers include, but are not limited to, mesothelioma, leukemia, and lymphoma, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell leukemia virus (HTLV) (e.g., adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma), non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors (e.g., brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas), common adult solid tumors (e.g., head and neck cancers such as oral, laryngeal, nasopharyngeal, and esophageal cancers, genitourinary cancers such as prostate, bladder, kidney, uterine, ovarian, and testicular cancers, lung cancers such as small cell and non-small cell lung cancers, breast cancer, pancreatic cancer, malignant melanoma), and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma or meningioma), and liver cancer.

[0188] Examples of other 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.

[0189] Other cancers for which the compounds described herein are useful for prevention, treatment and research include, for example, colon cancer, familial adenomatous polyposis and hereditary nonpolyposis colon cancer, or malignant melanoma. Further, cancers include, but are not limited to, vulvar cancer, pharyngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid cancer and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, malignant melanoma, glioblastoma, astrocytoma, meningioma, medulloblastoma, and brain tumors such as peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In certain aspects of the present application, the present application provides the use of one or more compounds described herein in the manufacture of a medicament for the treatment of cancer (including, but not limited to, the various types of cancer disclosed herein). In some embodiments, the compounds of the present application are useful for treating cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myelofibrosis-associated myelotransformation disease, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis.In some embodiments, the compounds described herein are useful for treating hematopoietic disorders, particularly acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).In some embodiments, 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., human) with lymphoma, or lymphatic or myelogenous proliferative disorders or abnormalities.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 a patient suffering from a non-Hodgkin's lymphoma (including, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small noncleaved cell lymphoma); diffuse small cleaved cell lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; Enteropathic 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 macroglobulinemia.

[0190] In other embodiments, 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) suffering from Hodgkin's lymphoma (e.g., but not limited to, nodular sclerosing classical Hodgkin's lymphoma (CHL); mixed cellularity CHL; lymphocyte-reduced CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL). The present application further encompasses treating or preventing cell proliferative disorders such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that a pathologist can recognize in a biopsy. The compounds may be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to spread or becoming cancerous. Examples of precancerous lesions include those occurring in the skin, esophageal tissue, breast intraepithelial tissue, and cervical intraepithelial tissue.

[0191] In certain embodiments, the compounds of the invention are used to treat the growth of abnormal cells, such as tumors or cancers, that have a RET protein with a mutation at one of the amino acid positions listed below. The mutation may be selected, for example, from one of the example mutations listed in Table 1, or may be a different mutation. [Table 1]

[0192] In a particular embodiment, the RET protein has two mutations selected from Table 1 above. In another embodiment, the RET protein has three mutations selected from Table 1 above. In another embodiment, the RET protein has four or more mutations, which may optionally be selected from Table 1 above.

[0193] In certain embodiments, tumor or cancer has RET protein mutation that is essentially or partially the promoter of tumor or cancer cell growth.In another embodiment, tumor or cancer has RET mutant protein that does not significantly act as the promoter of abnormal cell growth, but can be therapeutically used to kill tumor cells using the selective RET degradation inducer described herein.

[0194] In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein V804L mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein V804M mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein M918T mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein S891A mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein L790F mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein E768D mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein C618S mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein C618R mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein 634 missense mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers caused by the RET protein C634R mutation. In certain embodiments, the compound of the present invention is used for treating tumor or cancer caused by RET protein C634Y mutation.In certain embodiments, the compound of the present invention is used for treating tumor or cancer caused by RET protein C634G mutation.In certain embodiments, the compound of the present invention or its pharmaceutically acceptable salt is used for treating abnormal cell growth, such as tumor or cancer caused by RET protein with G810R mutation.

[0195] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the G810S mutation.

[0196] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with a G810C mutation.

[0197] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the C634W mutation.

[0198] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the M918T mutation.

[0199] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the V804L mutation.

[0200] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell growth, such as tumors or cancers having a RET protein with the V804M mutation.

[0201] 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).

[0202] In certain embodiments, the compound of the present invention or its pharmaceutically acceptable salt is used to treat abnormal cell growth, such as tumors or cancers with CCDC6-RET fusion.In certain embodiments, the compound of the present invention or its pharmaceutically acceptable salt is used to treat abnormal cell growth, such as tumors or cancers with NCOA4-RET fusion.

[0203] 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.

[0204] In accordance with the above, the present application further provides a method for the prevention or treatment of any of the above-mentioned diseases or disorders to a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In any of the above uses, the required dosage will vary depending on the method of administration, the particular condition being treated, and the desired effect.

[0205] Pharmaceutical Compositions and Combination Therapies In some embodiments, an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, either alone or in combination, is used to treat a patient (e.g., a human) with a disorder described herein or a RET-mediated disorder.

[0206] The disclosed compounds described herein can be used in effective amounts, alone or in combination with other compounds of the invention or other bioactive or second therapeutic agents, for the treatment of patients (e.g., humans) with disorders, including but not limited to, the disorders described herein.

[0207] The term "bioactive agent" is used to describe an agent other than the selected compound described herein that can be used in combination or alternation with a compound of the invention to achieve a desired therapeutic result. In some embodiments, the compound of the invention and the bioactive agent are administered in a manner that exhibits in vivo activity over overlapping time periods, e.g., overlapping time periods for Cmax, Tmax, AUC, or other pharmacokinetic parameters. In other embodiments, the compound of the invention and the bioactive agent are administered to a patient in need thereof in a manner that does not overlap in pharmacokinetic parameters, but one therapeutically influences the therapeutic effect of the other.

[0208] In certain aspects 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, and V-domain Ig suppressor of T-cell activation (VISTA) inhibitors), small molecules, peptides, nucleotides, or other inhibitors. In certain aspects, the immunomodulatory agent is an antibody, such as a monoclonal antibody. PD-1 inhibitors, which inhibit the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and thereby inhibit 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, which inhibit the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor and thus inhibit immunosuppression, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors, which 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 PD-1 and LAG-3 dual inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In some embodiments, the checkpoint inhibitor is chosen from nivolumab / Opdivo®; pembrolizumab / Keytruda®; and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS936559, a PDL2 / lg fusion protein such as AMP224, or B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand inhibitor, or a combination thereof.

[0209] In yet another embodiment, an active compound described herein is administered in an effective amount in combination with or in alternation with an effective amount of an estrogen inhibitor (including but not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or other forms of partial or complete estrogen antagonist or agonist) for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer.Partial antiestrogens such as raloxifene and tamoxifen have some estrogenic effects (including estrogenic uterine growth stimulation, and in some cases, the estrogenic effect of substantially stimulating tumor growth during the progression of breast cancer).On the other hand, fulvestrant, a complete antiestrogenic agent, has no estrogenic effect on the uterus and is effective against tamoxifen-resistant tumors. Examples of anti-estrogen compounds are provided in, but not limited to, WO2014 / 19176, WO2013 / 090921, WO2014 / 203129, WO2014 / 203132, assigned to Astra Zeneca, and US2013 / 0178445, assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, and US2015 / 0005286, WO2014 / 205136, and WO2014 / 205138.Examples of other anti-estrogen compounds include, but are not limited to, SERMS (e.g., anordrin, bazedoxifene, broparestriol, chlorotriacenin, clomiphene citrate, cyclophenyl, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant); aromatase inhibitors (e.g., aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole); and antigonadotropins (e.g., 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, WO2011 / 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;US2015 / 0005286;and WO2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO2014 / 191726, WO2012 / 084711;WO2002 / 013802;WO2002 / 004418;WO2002 / 003992;WO2002 / 003991;WO2002 / 003990;WO 2002 / 003989;WO2002 / 003988;WO2002 / 003986;WO2002 / 003977;WO2002 / 003976;WO2002 / 003975;WO 2006 / 078834;US6821989;US2002 / 0128276;US6777424;US2002 / 0016340;US6326392;US6756401;US 2002 / 0013327; US6512002; US6632834; US2001 / 0056099; US6583170; US6479535; WO1999 / 024027; US6005102; EP0802184; US5998402; US5780497, US5880137, WO2012 / 048058, and WO2007 / 087684.

[0210] In other embodiments, the active compounds described herein are administered in combination or alternation with an effective amount of an androgen (e.g., testosterone) inhibitor (including, but not limited to, a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or other forms of partial or complete androgen antagonist) in an effective amount for the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. In some embodiments, the prostate cancer or testicular cancer is androgen-resistant. Examples of anti-androgen compounds are provided in, but not limited to, WO2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Examples of other anti-androgen compounds include, but are not limited to, enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiratenone acetate, and cimetidine.

[0211] In some embodiments, 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.

[0212] In some embodiments, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Giotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-27 2; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[0213] In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0214] In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutumab, rituximab, ofatumumab, britumomab, tositumomab, and ocrelizumab.

[0215] In certain embodiments, the bioactive agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.

[0216] In some embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclacis, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperidin-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]piperidin-1-yl]- [perazin-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-[l,l'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)benzamide) (fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), gossypol acetic acid, 2- amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (oblimersen).

[0217] In some embodiments, the bioactive agent is a kinase inhibitor. In some embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. 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, duvelisib, GS-9820, BKM120, GDC-0032 (taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-trimethyl-2-methyl-4- ... azole-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((S)-methylphosphonic acid hydrogen (2R)-1-phenoxy-2-butanyl; or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-methyl 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-(morpholino)methyl phospholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzoyl)-6-morpholino-lH-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-monohydroxypropan-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) (phenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinazoline), AS252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methylene-(Z)-ylidene]-thiazolidine-2,4-dione), CZ24832 (5-(2-amino-8-fluoro-[l,2, 4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidine- 5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)-2-hydroxypropan-l-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)morpholino-4-ium)-2-oxa-7,10,13,16-Tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-l,3,5-triazin-2-yl)phenyl]urea) (getatricib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l-yl]phenyl}propane nitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxamyl)amino]methylidene]-2,4-thiazolidinedione). Dimethyl)-9a,11a-dimethyl-l,4,7-trioxo-2,3,3a,9,10,ll-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM2016 36, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, 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, (商標)) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine inhibitors, such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics (see U.S. Patent 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 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propanediol), amide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]), CGI-560 (4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl )phenyl)benzamide), CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide ), CTA056 (7-benzoyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyl lysin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), and other molecules capable of inhibiting BTK activity (see, e.g., Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, incorporated herein 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 (dihydrogen phosphate [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], fostamatinib disodium salt ((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 sodium phosphate), BAY61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide hydrochloride), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridine-2 -ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevec; 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), amino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine 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 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), 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), 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), myricetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), and morin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety). In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known, for example, trametinib / GSKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-Dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenylacetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({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-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-l,2-oxazinan-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-733, PD318088. In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known, and examples thereof include vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline), -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-imidazo-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazo-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-imidazo1-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide-1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib). In some embodiments, the bioactive agent is an AKT inhibitor (including but not limited to MK-2206, GSK690693, perifosine, (KRX-0401), GDC-0068, tricirvine, AZD5363, honokiol, PF-04691502, and miltefosine), an FLT-3 inhibitor (including but not limited to P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof). In some embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include, but are not limited to, trametinib / GSKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib), refametinib / BAY869766 / RDEAl19 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenyl)amino)phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol) (cobimetinib), (2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridinamide), 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-methylpyridinamide) [2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX -554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide). In some embodiments, the bioactive agent is a RAS inhibitor. RAS inhibitors include, but are not limited to, leolysin and siG12D LODER.

[0218] In some embodiments, the bioactive agent is an HSP inhibitor, including but not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0219] Other biologically active 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 agents, Aurora kinase inhibitors, PIK-1 regulators, 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, oregovomab, Lep-etu, nolatrexed, azd2171, vatabulin, ofatumumab, zanolimumab, endothecarin, tetrandrine, Rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO140, CC8490, cilengitide, gimatecan, IL13-PE38QQR, INO1001, IPdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta744, Sdx102, talampanel, atrasentan entan), Xr311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, A VE-0005, goserelin acetate, leuprorelin acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016 , lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valporic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil le, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dagalbagin, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycinMitotane, 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 Lysine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin taxin), droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, cremophor-free paclitaxel, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxacin, thiazolinone ... Cifen, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, PEGylated interferon α-2a, interferon α-2a, PEGylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgen, decitabine , hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansterone, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0220] In certain embodiments, the bioactive agent is selected from the group consisting of, but not limited to, imatinib mesylate (Gleevec®), 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 (Zelboraf®), vorinostat, and others. and / or cyclosporine (Zolinza®), romidepsin (Istodax®), bexarotene (Targretin®), alitretinoin (Panretin®), tretinoin (Vesanoid®), carfilzomib (Kyprolis™), pralatrexate (Folotin®), bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), sorafenib (Nexavar®), sunitinib (Sutent®), pazopanib (Votrient®), regorafenib (Stivarga®), and cabozantinib (Cometriq™).

[0221] In some 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, and any agent that is detrimental to the viability of cells and liposomes or other vesicles carrying the chemotherapeutic compound. Common anti-cancer drugs include: vincristine (Oncovin®) or vincristine liposomes (Marquibo®), daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncovin®). Other drugs that are being used include fluticasone (fluticasone), fluoxetine (fluoxetine ... (商標)Other suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamineplatinum(II) (DDP), cisplatin, diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), ), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucovorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclophosphamide, cytarabine, cytochalasin B, Cytoxan, dagalbagin, dactinomycin, dactinomycin (formally actinomycin) , daunorubicin hydrochloride, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxyanthracin dione, docetaxel, dolasetron mesylate, doxorubicin hydrochloride, dronabinol, Escherichia coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide phosphate, citrofluroxin ... Cid, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine hydrochloride, glucocorticoids, goserelin acetate, gramicidin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon α-2b, irinotecan hydrochloride, letrozole, leucovorin calcium, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytansinoids, mechlorethamine hydrochloride, medroxyprogesterone acetate,Megestrol acetate, melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansterone hydrochloride, paclitaxel, pamidronate disodium, pentostatin, pilocarpine hydrochloride, plimycin, carmustine-impregnated polypheprosan 20, porfimer sodium These include tamoxifen, procaine, procarbazine hydrochloride, propranolol, rituximab, sargumamostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thiotepa chlorambucil, thioguanine, thiotepa, topotecan hydrochloride, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0222] In some embodiments, the compounds of the present invention are administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs, and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, urea-substituted anthracenediones, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Exemplary chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its derivatives adozelesin, carzelesin, and and synthetic analogs of bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including their synthetic analogs KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictine; spongistatin; chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, fenesterine, prednimustine, trofosfamide, and nitrogen mustards such as uracil mustard; carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and nitrosoureas such as ranimustine; enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin gamma 11 and calicheamicin omega 11 (e.g., Angew Chem Intl. Ed. Engl. 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycins, actinomycin, ausramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, nightmycins, such as mitomycin C, mycophenone-3, benzodiazepines, nogalamycin, olivomycins, peplomycin, potfilomycin, puromycin, queramycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; fludarabine, 6 - Purine analogues such as mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; aminoglutethimide, mitotane,Antiadrenal drugs such as trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids and ansamitocins such as maytansine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 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 (e.g., Taxol® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), Abraxane®, Cremophor Free, an 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; cisplatin, oxaliplatin,and platinum analogs such as carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; navelbine (registered trademark), vinorelbine; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethyl methyl methacrylate (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail administered in combination with the compound of the present invention. Suitable dosing regimens for combined chemotherapeutic agents are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041-1047 (2000). Additional therapeutic agents that may be administered in combination with the compounds disclosed herein include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, Adrestroukin, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesilate, ritonavir, nelfinavir mesilate, 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 n), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B). In some embodiments, the additional therapy is a monoclonal antibody (MAb). MAbs exist that stimulate an immune response to destroy cancer cells. Similar to antibodies naturally produced by B cells, these MAbs "coat" the surface of cancer cells, causing their destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein hidden in tumor cells and other cells in the tumor microenvironment that promotes tumor vascular progression. When bound to bevacizumab, VEGF cannot interact with its cell receptor, preventing signal transduction that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EDFR), and trastuzumab targets the human epidermal growth factor receptor type 2 (HER2). Mabs that bind to cell surface growth factor receptors prevent the target receptor from sending normal growth-promoting signals. They also induce apoptosis and activate the immune system to destroy tumor cells. In some embodiments of the present invention, the bioactive agent is an immunosuppressant. Immunosuppressants include calcineurin inhibitors, such as cyclosporine or ascomycin (e.g., cyclosporine A (Neoral®), FK506 (tacrolimus), pimecrolimus), mTOR inhibitors, such as rapamycin or analogs thereof (e.g., sirolimus (RAPAMUNE®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9), rapalogs (e.g.,ridaforolimus, azathioprine, Campath-1H), S1P receptor modulators such as fingolimod or analogs thereof, anti-IL-8 antibodies, mycophenolic acid, or a salt thereof (e.g., the sodium salt), or a prodrug thereof (e.g., mycophenolate mofetil (CELLCEPT®)), OKT3 (Orthoclone OKT3®), prednisone, Atgam®, thymoglobulin (registered trademark), registered trademark), brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, leflunomide arava (registered trademark), CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (Simulect (registered trademark), daclizumab (Zenapax (registered trademark), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel (registered trademark), CTLA4lg (Abatacept), belatacept, LFA3lg, etanercept (en from Immunex, 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, 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 bioactive agent, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), which acts as an agonist of a target to stimulate an anti-cancer response or acts as an antagonist of 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); BEXAR® (tositumomab-l-131); RAPTIVA® (efalizumab); ERBITUX® (cetuximab); Avastin® (bevacizumab); TYSABRI® (natalizumab); Actemra® (tocilizumab) b), Vectibix® (panitumumab), Lucentis® (ranibizumab), Soliris® (eculizumab), Cimzia® (certolizumab pegol), Simponi® (golimumab), Ilaris® (canakinumab), Stelara® (ustekinumab), Arzera® (ofatumumab), Pralia® (denosumab), NUMAX® (motavizumab), ABTHRAX® (raxibacumab), Benlysta® (belimumab), Yervoy® (ipilimumab), Adcetris® (brentuximab vedotin), Perjeta® (pertuzumab), Kadcyla® (ado-trastuzumab emtansine), and Gazyva® (obinutumab). Furthermore, antibody-drug conjugates are also included. Combination therapy can also include non-drug therapeutic agents. For example, the compound can be administered in addition to radiation therapy, cryotherapy, hyperthermia, and / or surgical removal of tumor tissue. In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially.The first therapeutic agent may be administered immediately, within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or within 1 to 7, 1 to 14, 1 to 21, or 1 to 30 days before or after the second therapeutic agent. In certain embodiments, the second therapeutic agent is administered on a different dosing schedule than the compounds of the invention. For example, the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments, both the first and second therapeutic agents have a treatment holiday.

[0223] Dosage Form and Administration The compounds of the present disclosure, such as those described herein having Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), and / or I(h), or pharmaceutically acceptable salts thereof, can be administered as the neat chemical, but are more typically administered as a pharmaceutical composition containing an effective amount to a patient (usually a human) in need of such treatment for any of the disorders described herein. Additionally, the present disclosure provides pharmaceutical compositions containing an effective amount of the compound or a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain the compound or salt as the only active agent, or, in other embodiments, may contain the compound and at least one additional active agent.

[0224] Generally, the compositions of the present disclosure are administered in a therapeutically effective amount by any acceptable administration method. The appropriate dosage range depends on various factors, such as the severity of the disease to be treated, the age and related health conditions of the subject, the potency of the compound used, the route and form of administration, the indication for which administration is indicated, and the preferences and experience of the medical professional involved. Those skilled in the art of treating such diseases will be able to determine the therapeutically effective amount of the compositions of the present 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 a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to 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 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 compound or salt thereof.

[0226] In certain embodiments, patients can be treated with low-dose therapy using the compounds of the present invention. For example, the pharmaceutical composition can be in a dosage form containing about 0.1 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 800 μg, or about 200 μg to 600 μg of the 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 its salt.

[0227] In certain embodiments, the dose range is from about 0.01 to 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, mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, at least about 60 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, or at least about 100 mg / kg.

[0228] A pharmaceutically or therapeutically effective amount of the composition is administered to the patient. The precise effective amount will vary from patient to patient and will depend on the species, age, size, and health of the subject, the nature and extent of the condition being treated, the recommendations of the treating physician, and the therapy or combination of therapies administered to the patient. The effective amount for a given situation can be determined by routine experimentation. For purposes of this disclosure, a therapeutic amount may range, for example, from about 0.01 mg / kg to about 250 mg / kg of body weight, more typically from about 0.1 mg / kg to about 10 mg / kg, in at least one dose. The subject may be administered as many times as necessary to reduce and / or alleviate the signs, symptoms, or causes of the disorder in question, or to effect any other desired alteration of a biological system. If desired, formulations are prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.

[0229] In some embodiments, the compounds disclosed or described herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, a compound disclosed or described herein is administered at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or more.

[0230] In certain embodiments, the compound of the present invention is administered once a day, twice a day, three times a day, or four times a day.In certain embodiments, the compound of the present invention is orally administered once a day.In certain embodiments, the compound of the present invention is orally administered three times a day.In certain embodiments, the compound of the present invention is orally administered four times a day.

[0231] In certain embodiments, the compound of the present invention is intravenously administered once a day.In certain embodiments, the compound of the present invention is intravenously administered twice a day.In certain embodiments, the compound of the present invention is intravenously administered three times a day.In certain embodiments, the compound of the present invention is intravenously administered four times a day.

[0232] In some embodiments, the compounds of the present invention are administered with a treatment holiday between treatment cycles. For example, the compounds may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

[0233] The pharmaceutical composition may also include a molar ratio of the active compound and the additional active agent. For example, the pharmaceutical composition may include an anti-inflammatory or immunosuppressant in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.

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

[0235] Pharmaceutical preparations are preferably in unit dosage form.In such dosage form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form may be a packaged preparation in which the package contains individual amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.Also, the unit dosage form may be a capsule, tablet, cachet, lozenge itself, or the appropriate number of any of these in packaged form.

[0236] In certain embodiments, compound is administered as pharmaceutically acceptable salt.The example of pharmaceutically acceptable salt includes, but is not limited to, acetate, adipate, arginate, ascorbate, aspartate, benzylsulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentenepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonic acid, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts, as well as non-toxic ammonium, quaternary, 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 in 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 spray, intra-aortic, intracranial, subcutaneous, intraperitoneal, subcutaneous administration, or other methods of administration with conventional pharmaceutically acceptable carriers. Typical methods of administration are oral, topical, or intravenous administration 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 a tablet, suppository, pill, capsule, powder, liquid, syrup, suspension, cream, ointment, lotion, paste, gel, spray, aerosol, foam, or oil, injectable or infusion solution, transdermal patch, subcutaneous patch, inhalation formulation, in a medical device, suppository, buccal or sublingual formulation, parenteral formulation, or eye drops, preferably in a unit dosage form suitable for single administration of a precise dose.

[0239] Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing an appropriate amount (e.g., an effective amount to achieve a desired purpose) of the active compound. The composition contains an effective amount of a selected drug in combination with a pharmaceutically acceptable carrier, and may further contain other medicinal agents, adjuvants, diluents, buffers, etc. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. Carriers may be inert or may have pharmaceutical benefits of their own. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of substance 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 agents, wetting agents, or solidifying substances. Some carriers can be classified into more than one category; for example, vegetable oils can be used as lubricants in some formulations and as diluents in others. Examples of pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc, petrolatum, lanolin, polyethylene glycol, alcohol, transdermal enhancers, and vegetable oils. Optional active agents that do not substantially interfere with the activity of the compounds 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. Compounds can be provided in the form of, for example, solids, liquids, spray-dried products, microparticles, nanoparticles, controlled-release systems, etc., depending on the therapeutic purpose, if desired. Suitable excipients for non-liquid formulations are also known to those skilled in the art. A thorough discussion of pharmaceutically acceptable excipients and salts can be found in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Additionally, auxiliary substances, such as wetting or emulsifying agents, physiological buffering substances, surfactants, and the like, may be included in such vehicles.Physiological buffers can be any solution that is pharmacologically acceptable and provides the formulation with the desired pH, i.e., a pH within the physiologically acceptable range. Examples of buffers include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, and the like. For solid compositions, conventional non-toxic carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, etc., the active compounds described herein and pharmaceutical adjuvants (e.g., water, saline, aqueous dextrose, glycerol, ethanol, etc.) in any excipient to form a solution or suspension. If desired, the administered pharmaceutical composition can also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. The actual manufacturing method of such dosage forms is known or apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, supra. In yet another embodiment, the use of penetration enhancer excipients is provided, including, for example, 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 can be formulated for oral administration. For oral administration, the composition can generally take the form of a tablet, capsule, softgel capsule, or can also be an aqueous or non-aqueous solution, i.e., a suspension or syrup. Tablets and capsules are typical oral dosage forms.Oral tablets and capsules may contain one or more commonly used carriers (e.g., lactose and cornstarch). Lubricants such as magnesium stearate are also commonly added. In general, the compositions of the present disclosure may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier (e.g., lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.). Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn syrup, natural and synthetic gums (e.g., acacia, tragacanth, or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. When liquid suspensions are used, the active agent may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, and the like) and emulsifying and suspending agents. If desired, flavoring agents, coloring agents, and / or sweetening agents may also be added. Other optional ingredients used in the oral formulation combinations described herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

[0240] For ocular delivery, the compounds may be administered in an immediate or controlled release manner, or via an oncogenic device, for example, via intravitreal, intrastromal, intracameral, subcapsular, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, pararetroscleral, periconeal, or lacrimal injection, or by penetrating a mucosal, mucinous, or mucosal barrier, if desired.

[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 emulsions. Usually, sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, i.e., dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable liquids or suspensions in non-toxic, parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty acid esters, or polyols are conventionally used as solvents or suspending media. In addition, parenteral administration can use sustained-release or sustained-release systems to maintain a constant dosage.

[0242] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, including aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Administration via certain parenteral routes requires the introduction of the formulations of the present disclosure into the patient's body through a needle or catheter, driven by a sterile syringe or some other mechanical device, such as a continuous infusion system. The formulations provided by the present disclosure can be administered using a syringe, infuser, pump, or any device recognized in the parenteral administration field. Preparations according to the present disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtering a bacteria-retaining filter, by adding a sterilizing agent to the composition, by irradiating the composition, or by heat-treating the composition. They can also be prepared using sterile water or some other sterile injectable solvent just before use.

[0243] Sterile injectable solution is prepared by mixing the required amount of one or more compounds of the present disclosure into a suitable solvent containing various other ingredients listed above, and then sterilizing by filtration if necessary.Generally, dispersion is prepared by mixing various sterilized active ingredients into a sterile vehicle containing a basic dispersion solvent and other necessary ingredients selected from the ingredients listed above.When using sterile powder to prepare sterile injectable solution, typical preparation methods are vacuum drying and freeze-drying technology to obtain powder of active ingredient and any additional desired ingredients from the previously sterile filtered solution.Therefore, for example, a parenteral composition suitable for injection administration is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water.The solution is made isotonic with sodium chloride and sterilized.

[0244] Alternatively, the pharmaceutical compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These are prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum and releases 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 well-known techniques in the pharmaceutical formulation art and may be prepared as solutions in saline using benzoyl 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 suitable 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 may also be delivered through the skin or muscle tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches," in which the drug is typically contained within a laminated structure that functions as a drug delivery device for application to the surface of the body. In such structures, the drug composition is typically contained in a "reservoir," a layer underlying an upper backing layer. Laminated devices can contain a single reservoir or multiple reservoirs. In some embodiments, the reservoir consists of a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like.

[0246] Alternatively, the drug-containing reservoir and skin-contact adhesive may be present as separate, discrete layers, with the adhesive underlying the reservoir, which may be a polymeric matrix as described above, a liquid or gel reservoir, or some other form. The backing layer in these laminates, which is the upper surface of the device, serves as the first component of the laminate structure and provides much flexibility to the device. The material selected for the backing layer should be substantially impermeable to the active agent and other substances contained therein.

[0247] The compositions of the present disclosure can be formulated for aerosol administration, particularly for gastrointestinal administration, including nasal administration. The compound can, for example, generally have a small particle size, for example, on the order of 5 microns or less. Such particle size can be obtained by methods known in the art, for example, by atomization. The active ingredient is provided in a pressurized pack with a suitable propellant, such as chlorofluorocarbons (CFCs) (e.g., dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide, or other suitable gas. Advantageously, the aerosol can also contain a surfactant, such as lecithin. The dosage of the drug can be controlled by a metered valve.

[0248] Alternatively, the active ingredient may be provided as a powder mixture in a suitable powder carrier, such as a dry powder, such as lactose, starch, or starch derivatives (e.g., hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP)). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example, in capsules or in cartridges of, for example, gelatin, or blister packs from which the powder may be administered by inhalation.

[0249] Formulations suitable for rectal administration are usually presented as unit-dose suppositories, which are prepared by mixing 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 administration and topical application to the skin, as defined above.

[0251] In certain embodiments, pharmaceutical compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6):318 (1986)), and typically take the form of an appropriately buffered aqueous solution of the active compound.

[0252] In some embodiments, microneedle patches or devices are provided for the delivery of drugs through or into biological tissue, particularly skin, which allows for drug delivery through or into the skin or other tissue barrier at clinically relevant rates with minimal or no tissue damage, pain, or irritation.

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

[0254] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials, or by 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 a person skilled in the art would know how to modify the procedures shown in the examples to obtain the desired product.

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

[0256] Chemical shifts are expressed in parts per million (ppm) downfield from the internal tetramethylsilane (TMS) or TMS position inferred from the deuterated NMR solvent. Apparent multiplicities are designated as follows: singlet (s), doublet (d), triplet (t), quartet (q), or multiplet (m). Broad peaks are further designated as br. Integral values ​​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 be obtained with water peak suppression, which may result in overlapping peaks disappearing or changing their shape and / or integral.

[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, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+).

[0259] Method B: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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, particle size: 1.7 μm; Mobile Phase A: 95:5 acetonitrile:water (containing 0.05% TFA); Mobile Phase B: 95:5 acetonitrile:water (containing 0.05% TFA); Temperature: 50°C; Gradient: 0% B to 100% B over 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 BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile Phase A: 95:5 acetonitrile:water (containing 0.05% TFA); Mobile Phase B: 95:5 acetonitrile:water (containing 0.05% TFA); Temperature: 50°C; Gradient: 0% B to 100% B over 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: Particle Size: 2.5 μm, Mobile Phase A: Water / 5 mM NH4HCO3, Mobile Phase B: Acetonitrile; Acquisition Mode: Scan, Polarity: Positive.

[0263] Method Q: Mode: Binary Gradient, Pump A: LC-40D XR, Pump B: LC-40D XR; Oven Temperature: 40 °C; PDA Model: SPD-M20A, Lamp: D2, Start Wavelength: 190 nm, End Wavelength: 400 nm; Column 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 BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: 95:5 water:acetonitrile (containing 0.05% TFA); Mobile phase B: 95:5 acetonitrile:water (containing 0.05% TFA); Temperature: 50 °C; Gradient: 0% B to 100% B over 2.00 min, then hold at 100% B for 0.50 min; Flow rate: 1.0 mL / min; Detection: MS and UV (254 nm).

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

[0266] Example 1 Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid (12.1 mg, 0.021 mmol) in DMF (500 μL) was added DIPEA (15 μL, 0.085 mmol), followed by BOP (14.07 mg, 0.032 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (19.87 mg, 0.032 mmol) was added to the solution and stirred for 2 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (6.07 μL, 0.106 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 77% yield (16.3 mg). 1H NMR(500 MHz,DMSO-d6)δ 10.99-10.91(m,1H),10.09-10.00(m,1H),9.11-8.92(m,1H),8.36-8.18(m,1H),8.05-7.98(m,1 H),7.70-7.64(m,2H),7.63-7.57(m,1H),7.35-7.29(m,2H),7.19-7.12(m,2H),5.09-4.99(m,1H ), 4.42-4.20 (m, 4H), 3.85-3.52 (m, 2H), 3.30-3.27 (m, 2H), 3.26-3.01 (m, 5H), 2.95-2.82 (m, 1H), 2.44-2.22 (m, 3H), 2.02-1.64 (m, 5H), 1.58-1.45 (m, 4H), 1.44-1.39 (m, 6H), 1.34-1.28 (m, 4H). Low integration due to overlap with suppressed water and obscuration by DMSO signals. Analytical LCMS ESI-MS (+) m / z 885.3 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 1 results: Purity: 98.2%; Observed mass: 885.3; Retention time: 1.65 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 2 results: Purity: 98.9%; Observed mass: 885.3; Retention time: 2.09 min.

[0267] Example 2 Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing the TFA salt of 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoic acid (12.3 mg, 0.022 mmol) in DMF (500 μL) was added DIPEA (15 μL, 0.086 mmol), followed by BOP (14.33 mg, 0.032 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (20.2 mg, 0.032 mmol) was added and stirred for 2 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (6.18 μL, 0.108 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 69% yield (14.8 mg). 1H NMR(500MHz,DMSO-d6) δ 11.05-10.89(m,1H),10.10-9.97(m,1H),9.05-8.93(m,1H),8.31-8.13(m,1H),8.05-7.97(m,1H),7.75-7.6 9(m,1H),7.69-7.64(m,2H),7.48(s,1H),7.44-7.38(m,1H),7.36-7.29(m,2H),5.12-5.03(m,1H),4.48-4.29 (m, 4H), 3.85-3.45 (m, 4H), 3.30-3.26 (m, 3H), 3.17-2.83 (m, 8H), 2.44-2.36 (m, 1H), 2.31-2.19 (m, 2H), 2.09-1.96 (m, 3H), 1.96-1.72 (m, 4H), 1.71-1.61 (m, 2H), 1.58-1.45 (m, 4H), 1.44-1.41 (m, 6H), 1.34-1.27 (m, 4H). Low integration due to overlap with suppressed water and obscuration by DMSO signals. Analytical LCMS ESI-MS (+) m / z 884.4 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 1 results: Purity: 100%; Observed mass: 884.4; Retention time: 1.92 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) (containing 10 mM AA); Mobile phase B: ACN / HO (95:5) (containing 10 mM AA); Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 2 results: Purity: 100%; Observed mass: 884.4; Retention time: 1.6 min.

[0268] Example 3 Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing the TFA salt of 7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid (14.7 mg, 0.026 mmol) in DMF (500 μL) was added DIPEA (18 μL, 0.103 mmol), followed by BOP (17.09 mg, 0.039 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (24.1 mg, 0.039 mmol) was added and stirred for 2 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (7.37 μL, 0.129 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 50% yield (12.9 mg). 1H NMR(500MHz,DMSO-d6) δ 10.10-9.98(m,1H),9.11-8.88(m,1H),8.24-8.11(m,1H),8.03-7.98(m,1H),7.70-7.64(m,2H) ,7.44-7.39(m,1H),7.35-7.28(m,2H),7.27-7.19(m,1H),7.19-7.11(m,1H),5.14-5.03(m,1H), 4.43-4.16 (m, 4H), 3.87-3.58 (m, 2H), 3.31-3.27 (m, 2H), 3.26-2.96 (m, 6H), 2.95-2.78 (m, 2H), 2.41-2.21 (m, 5H), 2.04-1.95 (m, 1H), 1.88-1.74 (m, 2H), 1.56-1.40 (m, 12H), 1.32-1.25 (m, 4H). Low integration due to overlap with suppressed water and obscuration by DMSO signals. Analytical LCMS ESI-MS (+) m / z 885.8 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 1 results: Purity: 98.2%; Observed mass: 885.1; Retention time: 2.06 min. Injection 3 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) (containing 10 mM AA); Mobile phase B: ACN / HO (95:5) (containing 10 mM AA); Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 3 results: Purity: 100%; Observed mass: 885.8; Retention time: 1.59 min.

[0269] Example 4 Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing 7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)heptanoic acid (13.3 mg, 0.023 mmol) in DMF (500 μL) was added DIPEA (16 μL, 0.93 mmol), followed by BOP (15.4 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (21.9 mg, 0.035 mmol) was added to the solution and stirred for 2 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (6.7 μL, 0.117 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 58% yield (13.5 mg). 1H NMR(500MHz,DMSO-d6) δ 10.07-9.98(m,1H),9.10-8.93(m,1H),8.22-8.10(m,1H),8.04-7.98(m,1H),7.72-7. 63(m,2H),7.59-7.48(m,3H),7.38-7.24(m,2H),5.13-5.04(m,1H),4.45-4.22(m,4H), 3.92-3.42 (m, 3H), 3.31-3.28 (m, 2H), 3.26-2.88 (m, 6H), 2.46-2.35 (m, 1H), 2.32-2.19 (m, 4H), 2.06-1.94 (m, 3H), 1.81-1.59 (m, 5H), 1.57-1.40 (m, 12H), 1.31-1.24 (m, 4H). Low integration due to overlap with suppressed water and obscuration by DMSO signals. Analytical LCMS ESI-MS (+) m / z 884.5 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 1 results: Purity: 99.1%; Observed mass: 884.3; Retention time: 1.91 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 2 results: Purity: 99.3%; Observed mass: 884.4; Retention time: 1.61 min.

[0270] Example 5 Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing the TFA salt of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoic acid (12 mg, 0.022 mmol) in DMF (500 μL) was added DIPEA (15 μL, 0.088 mmol), followed by BOP (14.7 mg, 0.033 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (20.7 mg, 0.033 mmol) was added and stirred for 3 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (6.3 μL, 0.111 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 36% yield (7.7 mg). 1H NMR(500MHz,DMSO-d6) δ 10.99-10.86(m,1H),10.06-9.97(m,1H),9.09-8.85(m,1H),8.24-8.10(m,1H),8.04-7.96(m,1H),7.70-7.62(m,2H) ),7.55-7.48(m,1H),7.35-7.28(m,2H),7.10-6.99(m,2H),5.07-4.97(m,1H),4.42-4.36(m,2H),4.36-4.27(m,1H), 4.27-4.17 (m, 1H), 3.86-3.61 (m, 2H), 3.56-3.35 (m, 1H), 3.32-3.22 (m, 5H), 3.18-3.08 (m, 1H), 3.07-3.00 (m, 1H), 2.92-2.83 (m, 1H), 2.41-2.25 (m, 5H), 2.01-1.92 (m, 1H), 1.89-1.74 (m, 2H), 1.59-1.44 (m, 6H), 1.41 (d, J = 7.1 Hz, 6H). Low integration due to overlap with suppressed water and obscuration by the DMSO signal. Analytical LCMS ESI-MS (+) m / z 857.4 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 1 results: Purity: 100%; Observed mass: 857.3; Retention time: 1.96 min. Injection 4 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 4 results: Purity: 100%; Observed mass: 857.4; Retention time: 1.49 min.

[0271] Example 6 Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing the TFA salt of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoic acid (10 mg, 0.018 mmol) in DMF (500 μL) was added DIPEA (13 μL, 0.074 mmol), followed by BOP (12.3 mg, 0.028 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (17.7 mg, 0.028 mmol) was added and the solution was stirred for 3 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (5.3 μL, 0.092 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 65% yield (11.6 mg). 1H NMR(500MHz,DMSO-d6) δ 11.08-10.86(m,1H),10.13-9.95(m,1H),9.12-8.90(m,1H),8.40-8.16(m,1H),8.06-7.99( m,1H),7.71-7.65(m,2H),7.54-7.47(m,1H),7.37-7.27(m,4H),5.12-5.05(m,1H),4.42-4. 33 (m, 3H), 4.28-4.22 (m, 1H), 3.97-3.40 (m, 5H), 3.33-3.24 (m, 3H), 3.20-2.88 (m, 6H), 2.46-2.26 (m, 3H), 2.06-1.94 (m, 1H), 1.94-1.74 (m, 2H), 1.74-1.65 (m, 2H), 1.62-1.18 (m, 12H). Low integration due to overlap with suppressed water and obscuration by DMSO signals. Analytical LCMS ESI-MS (+) m / z 857.3 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 1 results: Purity: 100%; Observed mass: 857.3; Retention time: 1.93 min. Injection 5 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 5 results: Purity: 100%; Observed mass: 857.3; Retention time: 1.5 min.

[0272] Example 7 Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing 5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pentanoic acid (11.3 mg, 0.021 mmol) in DMF (500 μL) was added DIPEA (15 μL, 0.083 mmol), followed by BOP (13.8 mg, 0.031 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (19.5 mg, 0.031 mmol) was added to the solution and stirred for 3 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (6 μL, 0.104 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 65% yield (13.2 mg). 1H NMR(500MHz,DMSO-d6) δ 11.04-10.92(m,1H),10.13-9.96(m,1H),9.28-8.93(m,1H),8.28-8.12(m,1H),8.05- 7.99(m,1H),7.69-7.64(m,2H),7.64-7.57(m,2H),7.55-7.49(m,1H),7.37-7.29(m,2H ), 5.15-5.02 (m, 1H), 4.50-4.27 (m, 4H), 3.86-3.51 (m, 3H), 3.34-3.27 (m, 3H), 3.22-2.81 (m, 8H), 2.45-2.25 (m, 3H), 2.12-1.73 (m, 7H), 1.73-1.47 (m, 6H), 1.44-1.38 (m, 6H). Low integration due to overlap with suppressed water and obscuration by DMSO signal. Analytical LCMS ESI-MS (+) m / z 856.5 [M+H] + . AnalysisLCMS ESI-MS(+)m / z 857.3 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 1 results: Purity: 98.3%; Observed mass: 856.3; Retention time: 1.53 min. Injection 5 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 2 results: Purity: 98.4%; Observed mass: 856.4; Retention time: 1.82 min.

[0273] Example 8 Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing the TFA salt of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoic acid (12 mg, 0.022 mmol) in DMF (500 μL) was added DIPEA (15 μL, 0.088 mmol), followed by BOP (14.7 mg, 0.033 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (20.7 mg, 0.033 mmol) was added and stirred for 3 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (6.3 μL, 0.111 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C; Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 36% yield (7.7 mg). 1H NMR(500MHz,DMSO-d6) δ 10.10-9.95(m,1H),9.09-8.88(m,1H),8.22-8.12(m,1H),8.04-7.98(m,1H),7.70-7. 61(m,3H),7.49-7.43(m,1H),7.40-7.36(m,1H),7.34-7.27(m,2H),5.14-5.03(m,1H), 4.43-4.20 (m, 4H), 3.93-3.57 (m, 3H), 3.32-3.18 (m, 3H), 3.18-2.85 (m, 5H), 2.77-2.60 (m, 2H), 2.41-2.24 (m, 5H), 2.02-1.92 (m, 3H), 1.81-1.66 (m, 4H), 1.60-1.40 (m, 12H). Low integration due to overlap with suppressed water and obscuration by DMSO signal. Analytical LCMS ESI-MS (+) m / z 856.5 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 1 results: Purity: 97.1%; Observed mass: 856.1; Retention time: 1.66 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) (containing 10 mM AA); Mobile phase B: ACN / HO (95:5) (containing 10 mM AA); Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -). Injection 2 results: Purity: 97.4%; Observed mass: 856.5; Retention time: 2 min.

[0274] Example 9 Synthesis of 4-amino-6-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] A. tert-Butyl 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetate. To a stirred solution of 3-(1-oxo-5-(3,9-diazaspiro[5.5]undecan-3-yl)isoindolin-2-yl)piperidine-2,6-dione, HCl (0.020 g, 0.046 mmol) in acetonitrile (0.5 mL), tert-butyl 2-bromoacetate (0.012 g, 0.060 mmol), sodium iodide (3.46 mg, 0.023 mmol), and DIPEA (0.020 mL, 0.115 mmol) were added, and the reaction mixture was heated to 70 °C. After 2 h, the solution was cooled to room temperature and diluted with 10 mL of dichloromethane. The solution was washed with water, and the organic layer was dried over sodium sulfate and evaporated to give the crude mixture, which was used directly in the next step without further purification. Analytical LCMS ESI-MS (+) m / z 511.3 [M+H] + . B. 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetic acid. To a sealable reaction vial containing a stirred solution of tert-butyl 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetate (26 mg, 0.051 mmol) in DCM (550 μL) was added 2,2,2-trifluoroacetic acid (0.097 mL, 1.273 mmol) at 0° C., and the reaction mixture was then slowly warmed to room temperature. The reaction was monitored by LCMS and deemed complete after 6.5 h. The solvent was then evaporated, and the crude reaction mixture was dried under vacuum overnight to remove excess TFA. The resulting mono-TFA salt of the product was used directly in the synthesis of LDD without further purification. C. 4-Amino-6-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide. To a sealable reaction vial containing the TFA salt of 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetic acid (0.023 g, 0.040 mmol) in DMF (1 mL) was added DIPEA (28 μL, 0.160 mmol), followed by BOP (27 mg, 0.060 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (37 mg, 0.060 mmol) was added and the solution was stirred for 3 hours. The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; Flow rate: 20 mL / min; Column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried in a centrifugal evaporator to give the desired product as the mono-TFA salt in 5% yield (2 mg). 1 H NMR(500MHz,DMSO-d6) δ 10.99-10.82(m,1H),10.14-9.93(m,1H),9.15-8.92(m,1H),8.38-8.13(m,1H),8. 06-7.96(m,1H),7.76-7.64(m,2H),7.56-7.47(m,1H),7.41-7.27(m,2H),7.13-6. 88 (m, 1H), 5.08-4.97 (m, 1H), 4.45-4.15 (m, 4H), 3.93-3.67 (m, 2H), 3.31-3.03 (m, 4H), 2.95-2.85 (m, 1H), 2.43-2.31 (m, 1H), 2.01-1.76 (m, 3H), 1.73-1.30 (m, 15H). Low integration due to overlap with suppressed water and obscuration by DMSO signal. Analytical LCMS ESI-MS (+) m / z 883.3 [M+H] +Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 1 results: Purity: 100%; Observed mass: 883.3; Retention time: 1.46 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 2 results: Purity: 100%; Observed mass: 883.6; Retention time: 2.08 min.

[0275] Example 10 Synthesis of 4-amino-6-((1-(3-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)propanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide [ka] To a sealable reaction vial containing the TFA salt of 3-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)propanoic acid (35 mg, 0.050 mmol) in DMF (500 μL) was added DIPEA (35 μL, 0.198 mmol), followed by BOP (33 mg, 0.074 mmol). The reaction mixture was stirred at room temperature for 1 minute, after which the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (46.4 mg, 0.074 mmol) was added and stirred for 3 hours. The reaction mixture was then diluted with 1 mL of DMF, followed by the addition of acetic acid (14 μL, 0.248 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, particle size: 5 μm; flow rate: 20 mL / min; column temperature: 25 °C. Mobile phase A: ACN / HO (5:95) containing 0.05% TFA; Mobile phase B: ACN / HO (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried using a centrifugal evaporator to give the desired product as the mono-TFA salt in 12% yield (5.8 mg). 1H NMR(500MHz,DMSO-d6) δ 10.07-9.98(m,1H),9.08-8.90(m,1H),8.23-8.10(m,1H),8.04-7.98(m,1H),7.68-7.64(m,2H) ,7.52-7.46(m,1H),7.34-7.29(m,2H),7.04-6.97(m,2H),5.07-4.98(m,1H),4.42-4.36(m,2H), 4.36-4.28 (m, 1H), 4.23-4.16 (m, 1H), 3.86-3.63 (m, 2H), 3.19-2.99 (m, 2H), 2.93-2.85 (m, 1H), 2.46-2.29 (m, 7H), 2.01-1.92 (m, 1H), 1.82-1.76 (m, 1H), 1.62-1.55 (m, 1H), 1.53-1.41 (m, 15H). Low integration due to overlap with suppressed water and obscuration by DMSO signals. Analytical LCMS ESI-MS (+) m / z 856.5 [M+H] + Analytical reverse-phase chromatography was used to determine the final purity. Injection 1 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) containing 10 mM AA; Mobile phase B: ACN / HO (95:5) containing 10 mM AA; Temperature: 50 °C; Gradient: 0–100% B (0.0–3.0 min), 100% B (3.0–3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+). Injection 1 results: Purity: 94%; Observed mass: 897.3; Retention time: 1.53 min. Injection 2 conditions: Column: XBridge C18, 2.1 mm x 50 mm, particle size: 1.7 μm; Mobile phase A: ACN / HO (5:95) with 0.05% TFA; Mobile phase B: ACN / HO (95:5) with 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+). Injection 2 results: Purity: 94.1%; Observed mass: 897.5; Retention time: 1.89 min.

[0276] Cellular RET degradation assay The potency of cellular RET degrading compounds was measured using a bead-based luminescence amplification assay—AlphaLISA Surefire Ultra Detection Kit (Perkin-Elmer). The CCDC6-RET fusion-expressing papillary thyroid carcinoma (TPC-1) cell line was selected for screening of potential degrading inducers: the parental line (TPC-1 / CCDC6-RET). Cells were seeded into 384-well culture plates (Greiner Bio-One) at 10,000 cells per well in 50 μL of DMEM (Fisher Scientific) containing 2% FBS serum (Gibro). After cell attachment (4 hours), cells were treated with compounds by dispensing 25 nL of serially diluted compounds (1:3 dilutions: 11 points) directly into the cell culture wells using an Echo-655 acoustic liquid dispenser (Beckman). Low normalization wells contained medium alone, and high normalization wells contained cells treated with DMSO alone. The treated cell plates were placed in an incubator at 37°C and 5% CO2 for 24 hours. After 24 hours, the cell culture medium was removed using a FELIX automated liquid handler (Analytik Jena), and 25 μL of cell lysis buffer (provided in the AlphaLisa kit) was added to each well. 5 μL of cell lysate was transferred to a 384-well microplate (Perkin Elmer), followed by the addition of 2.5 μL of AlphaLISA acceptor bead mix. The plate was sealed and incubated at room temperature for 1 hour before the addition of the donor bead mixture. The donor bead addition was performed in the dark and allowed to incubate for >1 hour, after which AlphaLISA luminescence was measured at RT (excitation 680 nm, emission 615 nm) using an Envision plate reader equipped with an Alphascreen aperture. The amount of RET protein present (and therefore degradation) directly corresponds to the luminescence intensity.

[0277] Intensity was normalized to the average value of 16 wells containing medium only (blank - low) and 16 wells containing cells + DMSO (high). The % degradation in each well was calculated using the standard equation:

number

number

number

[0278] Activity table Each compound in Table 3 was tested in one or more of the degradation assays described above, for example, the tRET AlphaLISA degradation assay using the parental RET TPC-1 cell line, and found to have the activity indicated herein. 50 ) and % degradation response (Ymax) are included in Table 3. [Table 3]

[0279] Implementation Embodiment 1: Formula I: [ka] [In the formula, R 1is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from the group consisting of one or more R 8 may be substituted with; A is an aryl or heteroaryl, and the aryl or heteroaryl is one or more R 9 may be substituted with; B is heterocycloalkyl or C3-C8 cycloalkyl; L1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-, or -(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-; R 2 is NR 10 R 11 and; R 3 is H, halogen, NH2, or C1-C4 alkyl; Each R 4are independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, —NH(C1-C6 alkyl), or —N(C1-C6 alkyl)(C1-C6 alkyl); or Two Rs attached to adjacent carbons 4 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 5 is H, OH, CN, NO2, or C1-C4 alkyl; Each R 6 or R 6’ is H; or The Two R's 6 can be taken together to form an oxo group; or The Two R's 6’ can be taken together to form an oxo group; R 7 , R 8 and R 9 are each independently H, halogen, CN, NO, OH, NH, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two Rs attached to adjacent carbons 7 can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 10 and R 11 are independently H or C1-C4 alkyl; m is an integer from 0 to 2; n is an integer from 0 to 4; and p is an integer from 1 to 8. or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 2: The compound has Formula I(a): [ka] 2. The compound of embodiment 1, having the formula:

[0281] Embodiment 3: The compound has Formula I(b): [ka] 2. The compound of embodiment 1, having the formula:

[0282] Embodiment 4: The compound has Formula I(c): [ka] 2. The compound of embodiment 1, having the formula:

[0283] Embodiment 5: The compound has Formula I(d): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] 2. The compound of embodiment 1, having the formula:

[0284] Embodiment 6: The compound has Formula I(e): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0285] Embodiment 7: The compound has Formula I(f): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0286] Embodiment 8: The compound has Formula I(g): [ka] [In the formula, s1 and s2 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0287] Embodiment 9: The compound has Formula I(h): [ka] [In the formula, s1, s2, s3, and s4 are independently an integer of 1 to 2] or a pharmaceutically acceptable salt thereof.

[0288] Embodiment 10: R 1 or a pharmaceutically acceptable salt thereof.

[0289] Embodiment 11: R 1 11. The compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein is isopropyl.

[0290] Embodiment 12: R 3 12. The compound according to any one of embodiments 1 to 11, wherein is H; or a pharmaceutically acceptable salt thereof.

[0291] Embodiment 13: R 4 13. The compound according to any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is C1-C6 alkyl substituted with one or more C1-C6 alkoxy.

[0292] Embodiment 14: R 4 14. The compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is methoxymethyl.

[0293] Embodiment 15: R6 15. The compound according to any one of embodiments 1 to 14, wherein is H; or a pharmaceutically acceptable salt thereof.

[0294] Embodiment 16: The compound has the following structure: [ka] 16. A compound according to any one of embodiments 1 to 15, represented by TIFF2025540907000048.tif134103, or a pharmaceutically acceptable salt thereof.

[0295] Embodiment 17: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0296] Embodiment 18: A method for treating a RET-mediated disorder, comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, or a pharmaceutically acceptable salt thereof.

[0297] Embodiment 19: The method according to embodiment 18, wherein the patient is a human.

[0298] Embodiment 20: The method of embodiment 18 or 19, wherein the RET-mediated disorder is cancer.

[0299] Embodiment 21: The method described in embodiment 20, wherein the cancer is non-small cell lung cancer.

[0300] Embodiment 22: The method described in embodiment 21, wherein the cancer has metastasized to the brain.

[0301] Embodiment 23: A method according to any one of embodiments 18 to 22, wherein the RET-mediated disorder is mediated by mutant RET.

[0302] Embodiment 24: A method according to any one of embodiments 18 to 21, wherein the RET-mediated disorder is a recurrent or refractory cancer.

[0303] Embodiment 25: A compound according to any one of embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a RET-mediated disorder.

[0304] Embodiment 26: The compound according to embodiment 25, wherein the RET-mediated disorder is cancer.

[0305] Embodiment 27: The compound according to embodiment 26, wherein the cancer is non-small cell lung cancer.

[0306] Embodiment 28: The compound of embodiment 26, wherein the cancer has metastasized to the brain.

[0307] Embodiment 29: A compound according to any one of embodiments 25 to 28, wherein the RET-mediated disorder is mediated by a mutant RET.

[0308] Embodiment 30: A compound according to any one of embodiments 25 to 28, wherein the RET-mediated disorder is a relapsed or refractory cancer.

[0309] Embodiment 31: Use of a compound according to any one of embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the treatment of a RET-mediated disorder.

[0310] Embodiment 32: The use according to embodiment 31, wherein the RET-mediated disorder is cancer.

[0311] Embodiment 33: The use described in embodiment 32, wherein the cancer is non-small cell lung cancer.

[0312] Embodiment 34: The use described in embodiment 33, wherein the cancer has metastasized to the brain.

[0313] Embodiment 35: Use according to any one of embodiments 31 to 34, wherein the RET-mediated disorder is mediated by mutant RET.

[0314] Embodiment 36: The use according to any one of embodiments 31 to 34, wherein the RET-mediated disorder is a recurrent or refractory cancer.

[0315] Embodiment 37: Use of a compound according to any one of embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET-mediated disorder.

[0316] Embodiment 38: The use according to embodiment 37, wherein the RET-mediated disorder is cancer.

[0317] Embodiment 39: The use described in embodiment 38, wherein the cancer is non-small cell lung cancer.

[0318] Embodiment 40: The use described in embodiment 38, wherein the cancer has metastasized to the brain.

[0319] Embodiment 41: Use according to any one of embodiments 37 to 40, wherein the RET-mediated disorder is mediated by mutant RET.

[0320] Embodiment 42: The use described in any one of embodiments 36 to 40, wherein the RET-mediated disorder is a recurrent or refractory cancer.

[0321] equivalent Details of one or more embodiments of the present disclosure are described in the accompanying description above. Although any methods and materials similar or equivalent to the embodiments described herein can be used in practicing or testing the present disclosure, preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the specification and claims. In this specification and the appended claims, the singular form "a," "an," or "the" includes plural references unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0322] The foregoing description has been presented for purposes of illustration only and is not intended to limit the disclosure to the precise form disclosed, but rather is limited only by the scope of the claims appended hereto.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R １ is C １ -C ６ Alkyl, C ３ -C ８ cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from one or more R ８ optionally substituted with; A is an aryl or heteroaryl, and the aryl or heteroaryl is one or more R ９ optionally substituted with; B is heterocycloalkyl or C ３ -C ８ is cycloalkyl; L １ is C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ alkynyl; L ２ is -C(O)-(CH ２ ) ｐ -(4- to 12-heterocycloalkyl)-, -C(O)-(OCH ２ CH ２ ) ｐ -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH ２ ) ｐ -(4- to 12-heterocycloalkyl)-, -C(O)NH-(CH ２ CH ２ O) ｐ -(4- to 12-heterocycloalkyl)-, -C(O)-(CH ２ CH ２ O) ｐ -(4- to 12-heterocycloalkyl)-, -(OCH ２ CH ２ ) ｐ -(4- to 12-heterocycloalkyl)-, -C(O)-(CH ２ ) ｐ -(4- to 12-heterocycloalkyl)-C(O)-, or -(CH ２ ) ｐ -(4- to 12-heterocycloalkyl)-C(O)-; R ２ is NR １０ R １１ and R ３ is H, halogen, NH ２ , or C １ -C ４ is alkyl; Each R ４ is independently C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ alkynyl, wherein the alkyl, alkenyl, or alkynyl is one or more C １ -C ６ Alkoxy, C １ -C ６ Thioalkyl, NH ２ , —NH(C １ -C ６ alkyl), or —N(C １ -C ６ alkyl) (C １ -C ６ alkyl); or Two Rs bonded to adjacent carbons ４ Together, C ３ -C ８ It can form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ５ are H, OH, CN, NO ２ , or C １ -C ４ is alkyl; Each R ６ or R ６’ is H; or Two R's ６ can be taken together to form an oxo group; or Two R's ６’ can be taken together to form an oxo group; R ７ , R ８ and R ９ are each independently 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 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or Two Rs bonded to adjacent carbons ７ Together, C ３ -C ８ It can form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R １０ and R １１ are independently H or C １ -C ４ is alkyl; m is an integer from 0 to 2; n is an integer from 0 to 4; and p is an integer from 1 to 8. or a pharmaceutically acceptable salt thereof.

2. 1. The compound of formula I(a): 【Chemistry 2】 having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. 3. The compound of formula I(b): 【Transformation 3】 having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. 1. The compound of formula I(c): 【Chemistry 4】 having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. Compound, formula I(d): 【Transformation 5】 [In the formula, s １ and s ２ are independently an integer of 1 to 2. having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. 3. The compound of formula I(e): 【Transformation 6】 [In the formula, s １ and s ２ are independently an integer of 1 to 2. having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. 3. The compound of formula I(f): 【Transformation 7】 [In the formula, s １ and s ２ are independently an integer of 1 to 2. having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. 3. The compound of formula I(g): 【Transformation 8】 [In the formula, s １ and s ２ are independently an integer of 1 to 2. having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. 3. The compound of formula I(h): 【Chemistry 9】 [In the formula, s １ , s ２ , s ３ , and s ４ are independently an integer of 1 to 2. having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. R １ is C １ -C ６ is alkyl, 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. R １ is isopropyl; 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ３ is H, 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R ４ There are one or more C １ -C ６ C substituted with alkoxy １ -C ６ is alkyl, 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. R ４ is methoxymethyl; 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. R ６ is H, 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. The compound has the following structure: 【Chemistry 10】 【change】 16. The compound according to any one of claims 1 to 15, wherein:

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

18. 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 16, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

19. The method of claim 18, wherein the RET-mediated disorder is cancer.

20. 20. Use of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, in the manufacture of a medicament for the treatment of a RET-mediated disorder.

Images