Isoindolinone glutarimide and phenyl glutarimide analogs as RET kinase degradation agents

Abstract

The present disclosure relates to a protein degradation-inducing compound for a protooncogene tyrosine protein kinase receptor (RET), which may be in the form of a wild-type RET or a mutant of RET, which is useful in the treatment of diseases and disorders mediated by the protein and has formula (I):

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0002] The present disclosure relates to compounds for degradation of the rearranged during transfection (RET) proto-oncogene tyrosine kinase receptor. The degraders described herein can be used to treat diseases and disorders associated with RET protein regulation. In particular, the present invention relates to compounds and pharmaceutical compositions that degrade proto-oncogene tyrosine kinase receptor (RET) via the ubiquitin proteasome pathway (UPP), methods for using the compounds and pharmaceutical compositions to treat diseases and disorders associated with the RET protein and pathway, and methods for synthesizing the compounds and compositions. Background Art

[0003] Protein degradation is a highly regulated and crucial process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excessive proteins is achieved via the ubiquitin-proteasome pathway (UPP). UPP is crucial for the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, nerve and muscle degeneration, morphogenesis of neural networks, regulation of cell surface receptors, ion channels and secretory pathways, response to stress and extracellular regulators, ribosome biogenesis and viral infection. Multiple ubiquitin molecules are covalently attached to terminal lysine residues by E3 ubiquitin ligases to mark proteins for proteasome degradation, wherein the proteins are digested into small peptides, and ultimately digested into their constituent amino acids, which are used as building blocks for new proteins. Defective proteasome degradation is relevant to a variety of obstacles (including cancer and others).

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

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

[0006] 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). Septinib treatment of patients with non-small cell lung cancer has been shown to induce RET mutations that confer drug resistance, including RET G810R, RET G810S, and RET G810C.

[0007] Other approved tyrosine kinase inhibitors (such as sunitinib, sorafenib, ponatinib, and lenvatinib) have also shown some RET activity in preclinical trials and are currently being studied in multiple 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", F1000 Research 2016, 5: 1005).

[0008] Despite these efforts, there remains an unmet need in the art for novel RET modulators for treating RET-mediated disorders in hosts, including humans, in need thereof. Summary of the Invention

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

[0010] Another aspect of the present disclosure relates to a method of treating RET-mediated disorders and diseases in a subject in need thereof, comprising administering an effective amount of a compound of Formula I to the subject.

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

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

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

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

[0015] The present invention also provides compounds of formula I that bind to and inhibit E3 ligases and further degrade RET proteins. These E3 ligase-binding compounds (degraders) can also be used to treat RET-mediated diseases and cancers, including Hirschsprung 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 agenesis, pheochromocytoma, and parathyroid hyperplasia.

[0016] The present invention further provides compounds that can degrade RET while binding to E3 ligase. In some embodiments, the efficacy-safety profile of the compounds of the present disclosure can be improved relative to other known RET inhibitors. In addition, the technology of the present invention also has the following advantages: it can be used for a variety of different types of diseases, including disorders mediated by RET fusion protein, overexpression or copy number increase, such as papillary thyroid cancer, pancreatic cancer, melanoma, leukemia, acute myeloid leukemia (AML), chronic myelomonocytic leukemia, lung adenocarcinoma, lung cancer, non-small cell lung cancer (NSCLC), non-syndromic paraganglioma, breast cancer, non-hereditary (sporadic) cancer, colorectal cancer or hematological malignancies. Those skilled in the art will understand the additional features and advantages of the technology of the present invention after reading the following specific embodiments. DETAILED DESCRIPTION

[0017] The present disclosure relates to RET-degrading compounds of Formula I, and pharmaceutically acceptable salts thereof, which can inhibit E3 ligase activity and are therefore useful in methods for treating the human or animal body. The present disclosure also relates to methods for preparing these compounds, to pharmaceutical compositions comprising the compounds, and to the use of the compounds or pharmaceutical compositions in treating RET-involved disorders and diseases, such as inflammation, autoimmune diseases, cancer, infections, diseases or disorders of the central nervous system, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, psychological diseases, graft-versus-host disease, hyperalgesia, or RET-related diseases, in subjects identified as carrying germline or somatic mutations of RET. definition

[0018] Unless otherwise stated, the following terms used in the specification and claims have the following meanings as shown 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 aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl groups include moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, a straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight-chain or branched alkyl group has four or fewer carbon atoms.

[0020] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl group or an alkyl group in which one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone are replaced with the specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, 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 that are similar in length and possible substitution to the above-mentioned alkyl groups, but contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyls (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyls. In certain embodiments, straight or branched alkenyls have six or fewer carbon atoms in their backbone (e.g., for straight chains, C2-C6; for branched chains, C3-C6). The term "C2-C6" includes alkenyls containing two to six carbon atoms. The term "C3-C6" includes alkenyls containing three to six carbon atoms.

[0022] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl groups in which one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms are replaced with a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, 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 above-mentioned alkyl groups, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyls (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyls. In certain embodiments, straight-chain or branched-chain alkynyls have six or fewer carbon atoms in their skeleton (e.g., for straight-chain, C2-C6; for branched, C3-C6). The term "C2-C6" includes alkynyls containing two to six carbon atoms. The term "C3-C6" includes alkynyls containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linkers" or "C2-C6 alkynylene linkers" are intended to include C2, C3, C4, C5 or C6 chain (linear 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 group in which one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms are replaced with a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, 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.

[0025] Other optionally substituted moieties such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl include both unsubstituted moieties and moieties having one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

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

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

[0028] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, 7-12 membered bicyclic (fused, bridged or spiro) or 11-14 membered tricyclic ring system (fused, bridged or spiro) having one or more heteroatoms such as O, N, S, P or Se (e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or such as 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from nitrogen, oxygen and sulfur, unless otherwise specified). Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolyl, indolyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2- Oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1, 5'-furo[3,4-b]pyridinyl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7 ,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, etc. In the case of polycyclic heterocycloalkyl groups, only one ring in the heterocycloalkyl group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0029] As used herein, the term "optionally substituted heterocycloalkyl" refers to an unsubstituted heterocycloalkyl group having one or more hydrogen atoms on one or more carbon or heteroatoms replaced with a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, 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.

[0030] Unless otherwise specifically defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. In the case of containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group can optionally be substituted with one or more substituents (e.g., 1 to 5 substituents) at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH2, NH((C-C)alkyl), N((C-C)alkyl)2, -S(O)2-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl)2. The substituents themselves may be optionally substituted. In addition, when containing two or more fused rings, the aryl groups defined herein may have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulyl, and the like.

[0031] Unless specifically defined otherwise, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic group wherein the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl as defined herein also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. Aromatic groups are optionally substituted independently with one or more substituents described herein.Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[3,2-b ... [2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolonyl, dihydrobenzothienyl, 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, tetrazolo[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-1λ2-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 their derivatives.In addition, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, for example, 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, wherein the saturated or partially unsaturated ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se or B, and is optionally substituted with one or more oxo groups. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused to saturated or partially unsaturated rings as described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-11H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,4-c]pyridin-7-one. 2-b]pyrrolazinyl, 8H-pyrido[3,2-b]pyrrolazinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolazinyl, 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)-ol.

[0032] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted at one or more ring positions (e.g., a ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, amino Carbonyl, 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 moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings (which are not aromatic) to form polycyclic ring systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0033] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded and the substitution produces a stable compound. When the substituent is an oxo or keto group (i.e., ═O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. As used herein, a ring double bond is a double bond (e.g., C═C, C═N, or N═N) formed between two adjacent ring atoms. "Stable compound" and "stable structure" are intended to indicate that the compound is robust enough to withstand separation from RM to a useful purity and formulation into an effective therapeutic agent.

[0034] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then the substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which the substituent is bonded to the rest of a compound of a given formula, then the substituent may be bonded via any atom in the 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 0-2 R moieties, the group can be optionally substituted with up to two R moieties, and R at each occurrence is independently selected from the definition of R. Furthermore, 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 groups having -OH or -O-.

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

[0038] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0039] As used herein, the term "optionally substituted haloalkyl" refers to unsubstituted haloalkyl groups having one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms replaced with the designated substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, 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.

[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. Examples of substituted alkoxy groups include haloalkoxy. The alkoxy group can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carbonate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, 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 formula 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] It should be understood that throughout this specification, where a composition is described as having, including, or comprising a particular component, it is intended that the composition also consists essentially of or consists of said component. Similarly, where a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of or consists of said process steps. Furthermore, it should be understood that the order of steps or the order in which certain actions are performed is immaterial so long as the present invention remains practicable. Furthermore, two or more steps or actions may be performed simultaneously.

[0043] It should be understood that the synthetic methods of the present disclosure can tolerate a wide variety of functional groups and therefore can use a variety of substituted starting materials. The methods generally provide the desired final compound at or near the end of the overall method, but in some cases it may be desirable to further convert the compound into a pharmaceutically acceptable salt thereof.

[0044] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates by employing standard synthetic methods and procedures known to those skilled in the art or which will become clear to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for functional group transformations and manipulations can be obtained from the relevant scientific literature in the field or from standard textbooks. Although not limited to any one or more sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), which are incorporated herein by reference.

[0045] Those of ordinary skill in the art will note that during reaction sequence and synthesis scheme as herein described, the order of some steps can be changed, such as the introduction and removal of blocking groups. Those of ordinary skill in the art will recognize that some groups may need to be protected from reaction conditions via the use of blocking groups. Blocking groups can also be used to distinguish similar functional groups in molecules. The list of blocking groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition. John Wiley & Sons. New York, 1999.

[0046] It should be understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of a compound to provide such treatment or prevention, as described herein. It should be further understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of a compound to prepare a medicament to treat or prevent such a condition. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0047] It should be understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to provide such treatment, as described herein. It should be further understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to prepare a medicament to treat such a condition. Treatment includes treating 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," both of which refer to subjects suffering from a disease or an increased risk of developing a disease. "Subject" includes mammals. The mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. In one embodiment, the mammal is a human. The subject in need can be a subject that has previously been diagnosed or identified as having a disease or disorder disclosed herein. The subject in need can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, the subject in need can be a subject whose risk of developing such a disease or disorder relative to the general population increases (i.e., a subject susceptible to such a disorder relative to the general population). A subject in need may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that is unresponsive or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need has received all known effective therapies for the disease or disorder disclosed herein and has failed. In some embodiments, the subject in need has received at least one prior therapy.

[0048] As used herein, the terms "RET kinase inhibitor" and "RET kinase inhibitor" are used interchangeably and describe one or more compounds that are associated with inhibiting the rearranged mitochondrial transfection (RET) kinase protein or its RET kinase protein fragment. The term "RET kinase inhibitor" may also refer to a class of compounds used to treat non-small cell lung cancer and / or thyroid cancer in a subject with a tumor having one or more alterations or mutations in the RET gene. The term "RET kinase inhibitor" may also refer to known inhibitors of RET kinase, such as alectinib, cabozantinib, lenvatinib, pralsetinib, sorafenib, sunitinib, vandetanib, vepafestinib, and their analogs.

[0049] As used herein, the terms "treating" or "treatment" describe the management and care of a patient for the purpose of combating a disease, condition, or disorder, and include the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of, or to eliminate, the disease, condition, or disorder. The term "treatment" may also include the treatment of in vitro cells or animal models. It should be understood that references to "treating" or "treatment" include the alleviation of established symptoms of a condition. Thus, "Treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder, or condition that develops in a human who may have or is susceptible to the condition, disorder, or condition but who does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof; or (3) relieving or palliating the disease, i.e., causing regression of the condition, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0050] It will be appreciated that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs or solvates thereof, can also be used or may be used to prevent related diseases, conditions or disorders, or to identify suitable candidates for such purposes.

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

[0052] It should be understood that for detailed descriptions of known or equivalent techniques discussed herein, those skilled in the art can refer to general reference texts. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual 3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N Y.: 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 ed. (1990). Of course, these texts can also be referenced when preparing or using aspects of the present disclosure.

[0053] It will be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0054] As used herein, the term "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. A unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, a single pump or vial on an aerosol inhaler. The amount of active ingredient (e.g., a formulation of a disclosed compound or its salt, hydrate, solvate, or isomer) 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 it is sometimes necessary to make routine changes to the dosage based on the patient's age and condition. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0055] As used herein, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0056] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition, which excipient is generally safe, non-toxic, and not biologically or otherwise undesirable, 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.

[0057] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (external) and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous application can include the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; an antibacterial agent, such as benzyl alcohol or methyl paraben; 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 agent for regulating tension, such as sodium chloride or dextrose. pH can be adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide). Parenteral formulations can be packaged in ampoules, disposable syringes or multidose bottles made of glass or plastic.

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

[0059] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent used to treat, ameliorate or prevent an identified disease or condition, or to exhibit 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.

[0060] It should be understood that for any compound, the therapeutically effective amount can first be estimated in cell culture assays (e.g., the assay of tumor cells) or in animal models (typically rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED50 (the dose that is therapeutically effective in 50% of the population) and LD50 (the dose that is lethal to 50% of the population). The dose ratio between toxic effects and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions that exhibit a high therapeutic index are preferred. The dosage can vary within this range, depending on the dosage form employed, the sensitivity of the patient, and the route of administration.

[0061] Dosage and administration are adjusted to provide adequate levels of one or more active agents or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, one or more drug combinations, reaction sensitivities, and tolerance / response to therapy.

[0062] Pharmaceutical compositions containing the active compounds of the present disclosure can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, preparing dragees, levigating, emulsifying, encapsulating, embedding or lyophilizing processes. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers (including excipients and / or adjuvants) that help process the active compounds into pharmaceutically useful preparations. Of course, suitable formulations depend on the selected route of administration.

[0063] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM(BASF, Parsippany, New Jersey) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that it is easy to inject. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating effects of microorganisms (such as bacteria and fungi). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by using a coating (such as lecithin), by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Protection against the effects of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, it will be preferred to include an isotonic agent in the composition, such as a sugar, a polyol (such as mannitol and sorbitol), and sodium chloride. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0064] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount into an appropriate solvent optionally with one or a combination of the ingredients listed above, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and freeze drying to produce a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution thereof.

[0065] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound 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 used as a mouthwash, where the compound in the fluid carrier is applied orally and rinsed in the mouth and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate, or orange flavor.

[0066] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0067] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants suitable for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art and, for example, include detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be accomplished by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gel, or cream as generally known in the art.

[0068] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from 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 clear to those skilled in the art. The materials can also be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies directed against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, such as those described in U.S. Patent number 4,522,811.

[0069] It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the present disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0070] In therapeutic applications, in addition to other factors that affect the selected dosage, the dosage of the pharmaceutical composition used according to the present disclosure varies according to the age, weight and clinical condition of the recipient patient and the experience and judgment of the clinician or practitioner administering the therapy. Generally, the dosage should be sufficient to cause a slowing down, and preferably a regression of the symptoms of the disease or disorder disclosed herein, and also preferably to cause a complete regression of the disease or disorder. The dosage range may be from about 0.01 mg / kg / day to about 5000 mg / kg / day. The effective amount of a medicament is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improvements in survival and growth indicate regression. As used herein, the term "dosage effective manner" refers to the amount of an active compound that produces a desired biological effect in a subject or cell.

[0071] It will be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0072] It is to be understood that for compounds of the present disclosure that are capable of further forming salts, all such forms are also contemplated to be within the scope of the claimed disclosure.

[0073] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure wherein the parent compound is modified by preparing an acid salt or a basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrazoline, thia ... Bamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and common amino acids (e.g., glycine, alanine, phenylalanine, arginine, etc.).

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

[0075] 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, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like). It should be understood that in 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, such as 3:1, 2:1, 1:2, or 1:3.

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

[0077] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, by inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0078] The dosage regimen utilizing the compound is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated, the route of administration; the patient's renal and liver function; and the specific compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent the condition, counteract the condition, or arrest the progression of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counteract the condition or arrest the progression of the condition.

[0079] Techniques for preparing and administering the compounds disclosed herein can be found in Remington: the Science and Practice of Pharmacy, 19th ed., Mack Publishing Co, Easton, Pa. (1995). In an embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are combined with a pharmaceutically acceptable carrier or diluent for use in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0080] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure will become apparent from the various embodiments. The examples provided illustrate the various components and methods that can be used to practice the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, those skilled in the art can identify and employ other components and methods that can be used to practice the present disclosure.

[0081] In the synthetic schemes described herein, compounds may be drawn in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regioisomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer, or stereoisomer.

[0082] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents does not constitute an admission that any is relevant prior art and does not constitute any admission of their content or date. Having now described the invention by way of written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and the foregoing description and the following examples are intended to illustrate rather than limit the following claims.

[0083] As used herein, the phrases "compounds of the disclosure," "degradants of the disclosure," and "degradants" refer to those compounds disclosed generally and specifically herein. Compounds of the Disclosure In one aspect, the present disclosure provides, inter alia, compounds of formula (I) and pharmaceutically acceptable salts, solvates, isomers, enantiomers and tautomers, wherein inhibitors of Ring B, Ring D, L1, L2 and RET kinase are defined herein.

[0084] In some embodiments, Ring D is independently L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; L 2 is -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)-, -(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)- or -C(O)NH-(CH2) p -NH-; R 5 is H, halogen, CF3, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6' are independently H, or Two R's 6 can together form an oxo group, or Two R's 6' can together form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or Two conjunctive or consecutive R 7 Together, they may form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; m is an integer from 0 to 2; and p is an integer from 1 to 12.

[0085] In some embodiments of the compounds of the present disclosure, the compounds have Formula Ia: or a pharmaceutically acceptable salt thereof.

[0086] In another embodiment, X 1 are independently N or CR 1 .

[0087] In another embodiment, R 1 are independently H or halogen or C1-C3 alkyl; When R 3 yes: hour, Then R 2 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 aryl or 4- to 12-membered heteroaryl; When R 3 It is C3-C8 alkyl, C3-C8 cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 10 When aryl or 4- to 12-membered heteroaryl, R 2 yes Ring B is independently heterocycloalkyl or C3-C8 cycloalkyl; Ring D is independently L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; L 2 is -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2) p-(4- to 12-membered heterocycloalkyl)-C(O)-, -(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)- or -C(O)NH-(CH2) p -NH-; R 5 is H, halogen, CF3, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6' are independently H, or Two R's 6 can together form an oxo group, or Two R's 6' can together form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or Two conjunctive or consecutive R 7 Together, they may form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; m is an integer from 0 to 2; and p is an integer from 1 to 12.

[0088] In one embodiment of the present disclosure, the compound of the present disclosure has Formula Ia-1: or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ia-2: or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ia-3: or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ia-4: or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ia-5: or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ib: or a pharmaceutically acceptable salt thereof. In another embodiment, R 1 and R 2 are independently H, halogen, NR 10 R 11 or C1-C4 alkyl; When R 4 yes: hour; Then R 3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; When R 4 When it is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, then R 3 yes Ring D is a group selected from the following: L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or heteroaryl; L 2 is -C(O)NH-(CH2) p -、-NHC(O)-(CH2) p -、-C(O)NH-(CH2) p -NH-, -NHC(O)-(CH2) p -NH-, -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2CH2O)p -(4- to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)- or -(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)-; R 5 is H, halogen, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6' are independently H, or Two R's 6 can form an oxo group together, Two R's 6' can together form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or Two conjunctive or consecutive R 7 Together they may form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; m is an integer from 0 to 2; and p is an integer from 1 to 12.

[0094] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ib-1: or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ib-2: or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ib-3: or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ib-4: or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ib-5: or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments of the present disclosure, the compounds of the present disclosure have Formula Ib-6: or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments of the present disclosure, the compound of the present disclosure is selected from: or a pharmaceutically acceptable salt, solvate, isomer, enantiomer or tautomer thereof.

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

[0102] In some embodiments of the present disclosure, the compound of the present disclosure is selected from: or a pharmaceutically acceptable salt thereof.

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

[0104] In certain embodiments of the compounds of the present disclosure, R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl or aryl. 1 is C1-C6 alkyl, C3-C8 cycloalkyl or heterocycloalkyl. 1 is C1-C6 alkyl or C3-C8 cycloalkyl. 1 is C1-C6 alkyl. In other embodiments, R 1 is a C3-C8 cycloalkyl group. In other embodiments, R1 In other embodiments, R 1 In other embodiments, R 1 In another embodiment, R 1 is optionally replaced by one or more R 8 In other embodiments, R 1 is optionally replaced by one or more R 8 In another embodiment, R 1 is optionally replaced by one or more R 8 In another embodiment, R 1 is optionally replaced by one or more R 8 In another embodiment, R 1 is optionally replaced by one or more R 8 Substituted heteroaryl.

[0105] In some embodiments, R 8 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, R 8 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl or aryl. In other embodiments, R 8 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or heterocycloalkyl. In other embodiments, R 8 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl. 8 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In other embodiments, R 8 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl. In other embodiments, R 8 is H, halogen, CN, NO2, OH, NH2 or C1-C6 alkyl. In other embodiments, R 8 is H, halogen, CN, NO2, OH or NH2. In other embodiments, R 8 is H, halogen, CN, NO2 or OH. In other embodiments, R 8is H, halogen, CN or NO2. In other embodiments, R 8 is H, halogen or CN. In other embodiments, R 8 Is H or halogen. In another embodiment, R 8 is H. In another embodiment, R 8 In another embodiment, R 8 is CN. In another embodiment, R 8 is NO2. In another embodiment, R 8 In another embodiment, R 8 is NH2. In another embodiment, R 8 is C1-C6 alkyl. In another embodiment, R 8 is C2-C6 alkenyl. In another embodiment, R 8 is C2-C6 alkynyl. In another embodiment, R 8 is C3-C8 cycloalkyl. In another embodiment, R 8 In another embodiment, R 8 In another embodiment, R 8 It is a heteroaryl group.

[0106] In some embodiments of the compounds of the present disclosure, B is aryl or heteroaryl. In other embodiments, B is aryl. In other embodiments, B is heteroaryl. In other embodiments, B is optionally substituted with one or more R 9 In other embodiments, B is optionally substituted with one or more R 9 In some embodiments of the compounds of the present disclosure, D is aryl or heteroaryl. In other embodiments, D is aryl. In other embodiments, D is heteroaryl. In other embodiments, D is optionally substituted with one or more R 9 In other embodiments, D is optionally substituted with one or more R 9 Substituted heteroaryl.

[0107] In some embodiments, R 9 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, R 9 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl or aryl. In other embodiments, R 9is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or heterocycloalkyl. In other embodiments, R 9 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl. 9 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In other embodiments, R 9 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl. In other embodiments, R 9 is H, halogen, CN, NO2, OH, NH2 or C1-C6 alkyl. In other embodiments, R 9 is H, halogen, CN, NO2, OH or NH2. In other embodiments, R 9 is H, halogen, CN, NO2 or OH. In other embodiments, R 9 is H, halogen, CN or NO2. In other embodiments, R 9 is H, halogen or CN. In other embodiments, R 9 Is H or halogen. In another embodiment, R 9 is H. In another embodiment, R 9 In another embodiment, R 9 is CN. In another embodiment, R 9 is NO2. In another embodiment, R 9 In another embodiment, R 9 is NH2. In another embodiment, R 9 is C1-C6 alkyl. In another embodiment, R 9 is C2-C6 alkenyl. In another embodiment, R 9 is C2-C6 alkynyl. In another embodiment, R 9 is C3-C8 cycloalkyl. In another embodiment, R 9 In another embodiment, R 9 In another embodiment, R 9 It is a heteroaryl group.

[0108] In certain embodiments of the compounds of the present disclosure, B is heterocycloalkyl or C3-C8 cycloalkyl. In further embodiments, B is heterocycloalkyl. In further embodiments, B is C3-C8 cycloalkyl. In certain embodiments of the compounds of the present disclosure, D is heterocycloalkyl or C3-C8 cycloalkyl. In further embodiments, D is heterocycloalkyl. In further embodiments, D is C3-C8 cycloalkyl.

[0109] In some embodiments of the compounds of the present disclosure, L1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In other embodiments, L1 is C1-C6 alkyl or C2-C6 alkenyl. In other embodiments, L1 is C1-C6 alkyl. In other embodiments, L1 is C2-C6 alkenyl. In other embodiments, L1 is C2-C6 alkynyl.

[0110] In some embodiments of the compounds of the present disclosure, 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)-. In another embodiment, L2 can be -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 -(4 to 12 heterocycloalkyl)-C(O)-. In another embodiment, L2 can be -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 -(4 to 12 heterocycloalkyl)-. In another embodiment, L2 can be -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 -(4 to 12 heterocycloalkyl)-. In another embodiment, L2 can be -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 -(4 to 12 heterocycloalkyl)-. In another embodiment, L2 can be -C(O)-(CH2) p -(4 to 12 heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4 to 12 heterocycloalkyl)- or -C(O)NH-(CH2) p -(4 to 12 heterocycloalkyl)-. In another embodiment, L2 can be -C(O)-(CH2) p -(4 to 12 heterocycloalkyl)- or -C(O)-(OCH2CH2) p -(4 to 12 heterocycloalkyl)-. However, in another embodiment, L2 can be -C(O)-(CH2) p -(4 to 12 heterocycloalkyl)-. However, in another embodiment, L2 can be -C(O)-(OCH2CH2) p -(4 to 12 heterocycloalkyl)-. However, in another embodiment, L2 can be -C(O)NH-(CH2) p-(4 to 12 heterocycloalkyl)-. However, in another embodiment, L2 can be -C(O)NH-(CH2CH2O) p -(4 to 12 heterocycloalkyl)-. However, in another embodiment, L2 can be -C(O)-(CH2CH2O) p -(4 to 12 heterocycloalkyl)-. However, in another embodiment, L2 can be -(OCH2CH2) p -(4 to 12 heterocycloalkyl)-. However, in another embodiment, L2 can be -C(O)-(CH2) p -(4 to 12 heterocycloalkyl)-C(O)-. However, in another embodiment, L2 can be -(CH2) p -(4 to 12 heterocycloalkyl)-C(O)-.

[0111] In certain embodiments of the compounds of the present disclosure, R 2 Independently NR 10 R 11 In further embodiments of the present disclosure, R 2 is independently H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0112] In some embodiments of the compounds of the present disclosure, R 10 are independently H or C1-C4 alkyl. In other embodiments, R 10 is H. In other embodiments, R 10 It is a C1-C4 alkyl group.

[0113] In some embodiments of the compounds of the present disclosure, R 11 are independently H or C1-C4 alkyl. In other embodiments, R 11 is H. In other embodiments, R 11 It is a C1-C4 alkyl group.

[0114] In certain embodiments of the compounds of the present disclosure, R 3 is H, halogen, NH2, C1-C4 alkyl, C3-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In another embodiment, R 3 is H, halogen or NH2. In another embodiment, R 3 is H or halogen. However, in another embodiment, R 3 is H. However, in another embodiment, R 3 is halogen. However, in another embodiment, R3 is NH2. However, in another embodiment, R 3 It is a C1-C4 alkyl group.

[0115] In some embodiments of the compounds of the present disclosure, R 4 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In other embodiments, R 4 is C1-C6 alkyl or C2-C6 alkenyl. In other embodiments, R 4 is C1-C6 alkyl. In other embodiments, R 4 is C2-C6 alkenyl. In other embodiments, R 4 It is a C2-C6 alkynyl group.

[0116] In another embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, C1-C6 alkylthio, NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl). In another embodiment, R 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 alkoxy, C1-C6 alkylthio, NH2 or -NH(C1-C6 alkyl). 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 alkoxy groups, C1-C6 thioalkyl groups or NH2. In another embodiment, R 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 alkoxy or C1-C6 thioalkyl groups. However, in other embodiments, R 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 alkoxy groups. However, in another embodiment, R 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 thioalkyl groups. However, in another embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more NH2. However, in another embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more -NH(C1-C6 alkyl). However, in another embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0117] In another embodiment, R 4is a C2-C6 alkenyl group optionally substituted with one or more C1-C6 alkoxy, C1-C6 alkylthio, NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl). In another embodiment, R 4 is optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH 2或 -NH(C1-C6 alkyl)substituted C2-C6 alkenyl. In another embodiment, R 4 is a C2-C6 alkenyl group optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl or NH2. In another embodiment, R 4 is a C2-C6 alkenyl group optionally substituted with one or more C1-C6 alkoxy or C1-C6 thioalkyl groups. However, in another embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkoxy groups. However, in another embodiment, R 4 is a C2-C6 alkenyl group optionally substituted with one or more C1-C6 thioalkyl groups. However, in another embodiment, R 4 is a C2-C6 alkenyl group optionally substituted with one or more NH2. However, in another embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more -NH(C1-C6 alkyl). However, in another embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0118] In another embodiment, R 4 is a C2-C6 alkynyl group optionally substituted with one or more C1-C6 alkoxy, C1-C6 alkylthio, NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl). In another embodiment, R 4 is a C2-C6 alkynyl group optionally substituted with one or more C1-C6 alkoxy, C1-C6 alkylthio, NH2 or -NH(C1-C6 alkyl). 4 is a C2-C6 alkynyl group optionally substituted with one or more C1-C6 alkoxy groups, C1-C6 alkylthio groups or NH2. In another embodiment, R 4 is a C2-C6 alkynyl group optionally substituted with one or more C1-C6 alkoxy or C1-C6 thioalkyl groups. However, in another embodiment, R 4 is C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy groups. However, in another embodiment, R4 is a C2-C6 alkynyl group optionally substituted with one or more C1-C6 alkylthio groups. 4 is C2-C6 alkynyl optionally substituted with one or more NH2. However, in another embodiment, R 4 is C2-C6 alkynyl optionally substituted with one or more -NH(C1-C6 alkyl). However, in another embodiment, R 4 is C2-C6 alkynyl optionally substituted by one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0119] In still other embodiments of the compounds of the present disclosure, two R 4 Together they can combine to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, two R on adjacent carbons 4 Together they can form C3-C8 cycloalkyl, heterocycloalkyl or aryl. In other embodiments, two R 4 Together they can combine to form a C3-C8 cycloalkyl or heterocycloalkyl. In other embodiments, two R 4 Together they can combine to form a C3-C8 cycloalkyl group. In other embodiments, two R 4 Together they can combine to form a heterocycloalkyl group. In other embodiments, two R 4 In other embodiments, two R 4 Together they can combine to form a heteroaryl group.

[0120] In certain embodiments of the compounds of the present disclosure, R 5 is independently H, OH, CN, NO2 or C1-C4 alkyl. In another embodiment, R 5 is H, OH, CN or NO2. In another embodiment, R 5 is H, OH or CN. In another embodiment, R 5 is H or OH. In still other embodiments, R 5 is H. In still other embodiments, R 5 In yet other embodiments, R 5 In yet other embodiments, R 5 is NO2. In still other embodiments, R 5 It is a C1-C4 alkyl group.

[0121] In certain embodiments of the compounds of the present disclosure, R 6 is independently H.

[0122] In some embodiments of the compounds of the present disclosure, R 6' is independently H.

[0123] In certain embodiments of the compounds of the present disclosure, both R 6 They may be combined to form an oxo group.

[0124] In some embodiments of the compounds of the present disclosure, both R 6' They may be combined to form an oxo group.

[0125] In some embodiments of the compounds of the present disclosure, R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl or aryl. In other embodiments, R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl or heterocycloalkyl. In other embodiments, R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl. 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. In other embodiments, R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl or C2-C6 alkenyl. In other embodiments, R 7 is H, halogen, CN, NO2, OH, NH2 or C1-C6 alkyl. In other embodiments, R 7 is H, halogen, CN, NO2, OH or NH2. In other embodiments, R 7 is H, halogen, CN, NO2 or OH. In other embodiments, R 7 is H, halogen, CN or NO2. In other embodiments, R 7 is H, halogen or CN. In other embodiments, R 7 Is H or halogen. In another embodiment, R 7 is H. In other embodiments, R 7 In another embodiment, R7 is CN. In another embodiment, R 7 is NO2. In another embodiment, R 7 In another embodiment, R 7 is NH2. In another embodiment, R 7 is C1-C6 alkyl. In another embodiment, R 7 is C2-C6 alkenyl. In another embodiment, R 7 is C2-C6 alkynyl. In another embodiment, R 7 is C3-C8 cycloalkyl. In another embodiment, R 7 In another embodiment, R 7 In another embodiment, R 7 It is a heteroaryl group.

[0126] In still other embodiments of the compounds of the present disclosure, two R 7 Together they can combine to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, two R on adjacent carbons 7 Together they can form C3-C8 cycloalkyl, heterocycloalkyl or aryl. In other embodiments, two R 7 Together they can combine to form a C3-C8 cycloalkyl or heterocycloalkyl. In other embodiments, two R 7 Together they can combine to form a C3-C8 cycloalkyl group. In other embodiments, two R 7 Together they can combine to form a heterocycloalkyl group. In other embodiments, two R 7 In other embodiments, two R 7 Together they can combine to form a heteroaryl group.

[0127] In additional embodiments of the compounds of the present disclosure, m, at each occurrence, is 0, 1, or 2. In other embodiments, m is 0 or 1. In other embodiments, m is 0 or 2. In other embodiments, m is 1 or 2. In other embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2.

[0128] In still other embodiments of the present disclosure, n is independently at each occurrence 0, 1, 2, 3, or 4. In still other embodiments, n is 1 or 2. In still other embodiments, n is 1 or 3. In still other embodiments, n is 1 or 4. In still other embodiments, n is 2 or 3. In still other embodiments, n is 2 or 4. In still other embodiments, n is 3 or 4. In still other embodiments, n is 1. In still other embodiments, n is 2. In still other embodiments, n is 3. In still other embodiments, n is 4. In still other embodiments, n is 0.

[0129] In still other embodiments of the present disclosure, p is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In still other embodiments of the present disclosure, p is 1 or 2. In still other embodiments of the present disclosure, p is 1 or 3. In still other embodiments of the present disclosure, p is 1 or 4. In still other embodiments of the present disclosure, p is 1 or 5. In still other embodiments of the present disclosure, p is 1 or 6. In still other embodiments of the present disclosure, p is 1 or 7. In still other embodiments of the present disclosure, p is 1 or 8. In still other embodiments of the present disclosure, p is 1 or 9. In still other embodiments of the present disclosure, p is 1 or 10. In still other embodiments of the present disclosure, p is 1 or 11. In still other embodiments of the present disclosure, p is 1 or 12. In still other embodiments of the present disclosure, p is 2 or 3. In still other embodiments of the present disclosure, p is 2 or 4. In still other embodiments of the present disclosure, p is 2 or 5. In still other embodiments of the present disclosure, p is 2 or 6. In still other embodiments of the present disclosure, p is 2 or 7. In still other embodiments of the present disclosure, p is 2 or 8. In still other embodiments of the present disclosure, p is 2 or 9. In still other embodiments of the present disclosure, p is 2 or 10. In still other embodiments of the present disclosure, p is 2 or 11. In still other embodiments of the present disclosure, p is 2 or 12. In still other embodiments of the present disclosure, p is 3 or 4. In still other embodiments of the present disclosure, p is 3 or 5. In still other embodiments of the present disclosure, p is 3 or 6. In still other embodiments of the present disclosure, p is 3 or 7. In still other embodiments of the present disclosure, p is 3 or 8. In still other embodiments of the present disclosure, p is 3 or 9. In still other embodiments of the present disclosure, p is 3 or 10. In still other embodiments of the present disclosure, p is 3 or 11. In still other embodiments of the present disclosure, p is 3 or 12. In still other embodiments of the present disclosure, p is 4 or 5. In still other embodiments of the present disclosure, p is 4 or 6. In still other embodiments of the present disclosure, p is 4 or 7. In still other embodiments of the present disclosure, p is 4 or 8. In still other embodiments of the present disclosure, p is 4 or 9. In still other embodiments of the present disclosure, p is 4 or 10. In still other embodiments of the present disclosure, p is 4 or 11. In still other embodiments of the present disclosure, p is 4 or 12. In still other embodiments of the present disclosure, p is 5 or 6. In still other embodiments of the present disclosure, p is 5 or 7. In still other embodiments of the present disclosure, p is 5 or 8. In still other embodiments of the present disclosure, p is 5 or 9.In still other embodiments of the present disclosure, p is 5 or 10. In still other embodiments of the present disclosure, p is 5 or 11. In still other embodiments of the present disclosure, p is 5 or 12. In still other embodiments of the present disclosure, p is 6 or 7. In still other embodiments of the present disclosure, p is 6 or 8. In still other embodiments of the present disclosure, p is 6 or 9. In still other embodiments of the present disclosure, p is 6 or 10. In still other embodiments of the present disclosure, p is 6 or 11. In still other embodiments of the present disclosure, p is 6 or 12. In still other embodiments of the present disclosure, p is 7 or 8. In still other embodiments of the present disclosure, p is 7 or 9. In still other embodiments of the present disclosure, p is 7 or 10. In still other embodiments of the present disclosure, p is 7 or 11. In still other embodiments of the present disclosure, p is 7 or 12. In still other embodiments of the present disclosure, p is 8 or 9. In still other embodiments of the present disclosure, p is 8 or 10. In still other embodiments of the present disclosure, p is 8 or 11. In still other embodiments of the present disclosure, p is 8 or 12. In still other embodiments of the present disclosure, p is 9 or 10. In still other embodiments of the present disclosure, p is 9 or 11. In still other embodiments of the present disclosure, p is 9 or 12. In still other embodiments of the present disclosure, p is 10 or 11. In still other embodiments of the present disclosure, p is 10 or 12. In still other embodiments of the present disclosure, p is 11 or 12. In still other embodiments of the present disclosure, p is 12. In still other embodiments of the present disclosure, p is 11. In still other embodiments of the present disclosure, p is 10. In still other embodiments of the present disclosure, p is 9. In still other embodiments of the present disclosure, p is 8. In still other embodiments of the present disclosure, p is 7. In still other embodiments of the present disclosure, p is 6. In still other embodiments of the present disclosure, p is 5. In still other embodiments of the present disclosure, p is 4. In still other embodiments of the present disclosure, p is 3. In still other embodiments of the present disclosure, p is 2. In still other embodiments of the present disclosure, p is 1. In still other embodiments of the present disclosure, p is 0.

[0130] In some embodiments, suitable compounds of the present disclosure include: (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(2-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}ethyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}butyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}hexyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(10-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}decyl)cyclobutane-1-carboxamide; (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(4-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}butyl)cyclobutane-1-carboxamide; 3-[5-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[5-(4-{5-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-5-oxopentyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[5-(1-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(4-{5-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-5-oxopentyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(1-{5-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-5-oxopentyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-[6-(1-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperidin-4-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione; 3-(6-{4-[7-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}piperidin-1-yl)-7-oxoheptyl]piperazin-1-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione; 1-{4-[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptylamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(8-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}octyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-{4-[4-(7-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}heptamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-{4-[4-(9-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}nonanamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(10-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}decyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(6-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}hexyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(10-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}decyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 1-(4-{4-[(4-{4-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}butyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide; 9-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]nonanamide; 11-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]undecaneamide; 13-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]tridecamide; 7-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]heptylamide; 13-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]tridecamide; 7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]heptylamide.

[0131] In some embodiments, the compound is a pharmaceutically acceptable salt of any of the compounds described herein.

[0132] In some aspects, the present disclosure provides a compound that is an isotopic derivative (eg, an isotopically labeled compound) of any one of the compounds of the formulae disclosed herein.

[0133] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 7, and prodrugs and pharmaceutically acceptable salts thereof.

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

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

[0136] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 7.

[0137] It should be understood that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives can generally be prepared by implementing the procedures disclosed in the schemes and / or in the examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0138] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0139] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any of the compounds of the formulae disclosed herein.

[0140] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with respect to one or more isotopes or labeled with one or more isotopes compared to the corresponding compound of Formula (I). In some embodiments, an isotopic derivative is enriched with respect to or labeled with one or more atoms selected from the group consisting of: 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 In some embodiments, an isotopic derivative is a deuterium-labeled compound (ie, one or more atoms thereof are enriched in 2 H). In some embodiments, the compound is 18 In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compound or any combination thereof. In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compound or any combination thereof.

[0141] It should be understood that 18 F. 123 I. 124 I. 125 I.129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36 S-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples described herein, by using 18 F. 125 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36 The S-labeled reagent is used to replace the non-isotopically labeled reagent.

[0142] Contains 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 The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof containing one or more of the following: S atoms are within the scope of the present invention. In addition, isotopes (e.g., 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 32 S. 34 S. 35 S and / or 36 S) substitutions may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0143] For the avoidance of doubt, it should be understood that where in this specification a group is defined by "as described herein," that group encompasses the first occurring and broadest definition of that group as well as each and all specific definitions.

[0144] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, sufficiently basic acid addition salts of the compounds of the present disclosure, for example, acid addition salts with, for example, inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid). In addition, suitable pharmaceutically acceptable salts of the compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium salts or potassium salts; alkaline earth metal salts, such as calcium salts or magnesium salts; ammonium salts or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0145] It should be understood that the compounds of any of the formulae disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of the compounds.

[0146] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."

[0147] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0148] As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers (referred to as a "diastereomeric mixture"). When there is one chiral center, the stereoisomer can 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 the chiral center in question are ordered according to the sequence rules of Cahn, Ingold, and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0149] As used herein, the term "geometric isomers" refers to the diastereomers that exist due to hindered rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans or Z and E, which indicate that the groups are located on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0150] It should be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form, and it should be understood that not all isomers may have the same level of activity.

[0151] It should be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It should also be understood that not all atropic isomers may have the same level of activity.

[0152] As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric groups in solution. In a solution that may tautomerize, the chemical equilibrium of the tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be mutually converted by tautomerization is called tautomerism. Among the possible multiple types of tautomerism, two are usually observed. In keto-enol tautomerism, simultaneous transfer of electrons and hydrogen atoms occurs. Ring-chain tautomerism is caused by the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, thereby producing a cyclic (ring-shaped) form as shown by glucose.

[0153] It should be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any tautomeric form. It should be understood that certain tautomers may have higher activity levels than other tautomers.

[0154] Compounds with the same molecular formula but different properties or orders of their atomic bonding or the arrangement of their atoms in space are called "isomers". Isomers with different arrangements of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center (for example, it is bonded to four different groups), a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described according to the R and S ordering rules of Cahn and Prelog or according to the molecular rotation of the plane of polarized light and named as right-handed or left-handed (that is, named as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as a mixture of enantiomers. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0155] The compounds of the present disclosure may have one or more asymmetric centers, so such compounds can be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a specific compound in the specification and claims is intended to include both individual enantiomers and their racemic mixtures or other mixtures. Methods for determining stereochemistry and separating stereoisomers 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), for example, by synthesizing from optically active starting materials or by splitting racemic forms. Some compounds of the present disclosure may have geometric isomerization centers (E and Z isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereomers and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

[0156] It should be understood that compounds of any formula described herein include the compounds themselves, as well as their salts and their solvates (if applicable). For example, salts can be formed between anions and positively charged groups (e.g., amino groups) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylsulfonate, and acetate (e.g., trifluoroacetate).

[0157] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between cations and negatively charged groups (e.g., carboxylates) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0158] It should be understood that the compounds of the present disclosure (e.g., salts of the compounds) can exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0159] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Some compounds have a tendency to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, wherein the water remains in its molecular form as HO.

[0160] As used herein, the term "analog" refers to a chemical compound that is similar in structure to another compound but differs slightly in composition (such as in the replacement of one atom by an atom of a different element, or in the replacement of one functional group by another, as in the case of the presence of a particular functional group). Thus, an analog is a compound that is similar or comparable in function and appearance to a reference compound, but differs from the reference compound in structure or origin.

[0161] As used herein, the term "derivative" refers to compounds having a common core structure and substituted with various groups as described herein.

[0162] It will also be understood that certain compounds of any of the formulae disclosed herein may exist in solvated as well as unsolvated forms (e.g., hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It will be understood that the present disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0163] It should also be understood that some compounds of any one of the formulas disclosed herein may exhibit polymorphism, and the present disclosure encompasses all such forms or mixtures thereof with inflammasome inhibitory activity. It is generally known that conventional techniques (such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy) can be used to analyze crystalline materials. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0164] Any one of the compounds of formula disclosed herein can exist with a variety of different tautomeric forms, and mention that the compound of formula (I) includes all such forms. For the avoidance of doubt, in the case where a compound can exist with one of several tautomeric forms and only clearly describe or show one, all other forms are still all encompassed by formula (I). The example of tautomeric form includes ketone, enol and enolate form, such as in the following tautomerism pair: ketone / enol (hereinafter described), imines / enamine, amides / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol and nitro / acid nitro (aci-nitro).

[0165] The compounds of any of the formulae disclosed herein can be administered as prodrugs that decompose in the human or animal body to release the compounds of the disclosure. Prodrugs can be used to alter the physical and / or pharmacokinetic properties of the compounds of the disclosure. Prodrugs can be formed when the compounds of the disclosure contain suitable groups or substituents for attachment of groups that alter properties. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide groups in any of the formulae disclosed herein.

[0166] Thus, the present disclosure includes those compounds of any of the formulae disclosed herein as defined above, when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of a prodrug thereof. Thus, the present disclosure includes those compounds of any of the formulae disclosed herein that are produced by organic synthesis as well as such compounds produced in the human or animal body by metabolism of a precursor compound, that is, the compounds of any of the formulae disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0167] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein are prodrugs that are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity, based on sound medical judgment. Various forms of prodrugs have been described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, 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 Pro-drugs", edited 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", ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0168] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulas disclosed herein with hydroxyl groups are, for example, esters or ethers that can be cut in vivo. Ester or ether that can be cut in vivo of compounds of any of the formulas disclosed herein containing hydroxyl groups are, for example, pharmaceutically acceptable esters or ethers that are cut in vivo to produce the parent hydroxyl compound in the human or animal body. Suitable pharmaceutically acceptable ester forming groups of hydroxyl groups include inorganic esters, such as phosphates (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester forming groups of hydroxyl groups include C1-C10 alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups; C1-C10 alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0169] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having a carboxyl group are, for example, in vivo cleavable amides thereof, such as amides formed with: amines such as ammonia; C1-4 alkylamines such as methylamine; (C1-(C4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines such as benzylamine; and amino acids such as glycine or its esters.

[0170] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having an amino group are, for example, amide derivatives thereof that can be cleaved in vivo. Suitable pharmaceutically acceptable amides derived from amino groups include, for example, amides formed with C1-C10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0171] The in vivo effects of the compounds of any of the formulae disclosed herein can be exerted in part by one or more metabolites formed in the human or animal body after administration of the compounds of any of the formulae disclosed herein. As described above, the in vivo effects of the compounds of any of the formulae disclosed herein can also be exerted by the metabolism of precursor compounds (prodrugs). How to use

[0172] The compounds described herein can be used in an effective amount to treat a patient (typically a human) in need thereof who suffers from a disorder mediated by RET, which can be wild-type RET or mutant RET as generally described herein. In certain embodiments, the compounds of the invention degrade additional proteins, such as aurora kinase or VEGFR2. In certain embodiments, the compounds of the invention degrade RET and Aurora A kinase (AURKA).

[0173] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in the manufacture of a medicament for treating or preventing cancer in a patient in need thereof; wherein RET inhibition is required for treating or preventing cancer.

[0174] In certain embodiments, the methods comprise administering to a patient in need thereof an effective amount of an active compound or salt thereof as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with another biologically active agent or combination of agents.

[0175] In certain embodiments, the present invention provides methods of treating any of the disorders described herein in a patient in need thereof.

[0176] In other embodiments, an additional therapeutic agent is administered to the patient.In other embodiments, a compound as described herein and an additional therapeutic agent are administered simultaneously or sequentially.

[0177] In certain embodiments, the application provides a method of preventing any of the disorders described herein in a patient in need thereof.

[0178] In certain embodiments, the patient is a human.

[0179] Another aspect of the present invention provides a method for treating or preventing a proliferative disease, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0180] In some embodiments, the disease is mediated by RET, eg, RET plays a role in the initiation or progression of the disease.

[0181] In certain embodiments, the RET-mediated disorder is a benign growth, metastasis, neoplasm, tumor, solid tumor, rhabdoid tumor, carcinoma, leukemia, cancer, abnormal cell proliferation, amyloid-based proteinopathy, proteinopathy, fibrotic disorder, inflammation, arthritis, pulmonary disorder, or immune disorder.

[0182] In certain embodiments, the RET-mediated disorder is a cancer that has metastasized, such as a cancer that has metastasized to the brain. In certain embodiments, the RET-mediated disorder is a cancer that has metastasized to the brain, lung, bone, liver, peritoneum, adrenal gland, skin, or muscle.

[0183] In certain embodiments, compounds of the invention penetrate the blood-brain barrier and are useful in treating cancers involving the CNS or cancers that have metastasized to the brain.

[0184] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0185] In certain embodiments, the RET-mediated disorder is abnormal cell proliferation, including but not limited to a tumor or cancer, or a myelo- or lymphoproliferative disorder, such as a B-cell lymphoma or T-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferative disorder.

[0186] In certain embodiments, the hematological cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryocytic leukemia, acute megakaryocytic leukemia, Leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL) 2 and / or BCL6 rearrangement / overexpression [double-hit and triple-hit lymphomas], myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma (including bortezomib-resistant mantle cell lymphoma).

[0187] Solid tumors that can 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 cancer; liver cancer; kidney cancer; prostate cancer, including castration-resistant prostate cancer (CRPC); brain cancer, including glioma, glioblastoma, neuroblastoma, and medulloblastoma (including MYC-amplified medulloblastoma); colorectal cancer; Wilms' tumor; Ewing's sarcoma; Rhabdomyosarcoma; ependymoma; head and neck cancer, melanoma; squamous cell carcinoma; ovarian cancer; pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PanNET); osteosarcoma; giant cell tumor of bone; thyroid cancer; bladder cancer; urothelial carcinoma; vulvar cancer; cervical cancer; endometrial cancer; mesothelioma; esophageal cancer; salivary gland cancer; gastric cancer; nasopharyngeal cancer; cheek cancer; oral cancer; GIST (gastrointestinal stromal tumor); NUT midline carcinoma; testicular cancer; squamous cell carcinoma; hepatocellular carcinoma (HCC); MYCN-driven solid tumors; and NUT midline carcinoma (NMC).

[0188] In further embodiments, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0189] In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0190] 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.

[0191] In further embodiments, the disease or disorder is multiple myeloma.

[0192] In other embodiments, the disease or disorder is inflammation, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neuroinflammation, allergy, pain, neuropathic pain, fever, pulmonary disorders, lung inflammation, chronic inflammatory lung disease with respiratory distress in adults, and chronic obstructive pulmonary disease (COPD), liver disease and nephritis, gastrointestinal disorders, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative disease, gastric ulcer, autoimmune disease, graft versus host reaction and allogeneic transplant rejection, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer , epithelial cell-derived neoplasia (epithelial cell carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth 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 carcinoma and / or basal cell carcinoma, prostate cancer, renal cell carcinoma and other known cancers affecting epithelial cells throughout the body, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis (including neoplasia), metastasis, central nervous system disorders, central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy or B-cell lymphoma.

[0193] In other embodiments, a pharmaceutical composition comprising a compound as described herein and an additional therapeutic agent are administered simultaneously or sequentially.

[0194] In other embodiments, the disease or disorder is cancer. In further embodiments, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, solid tumor, blood cancer or solid cancer.

[0195] In some embodiments, the method is for treating or preventing a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, and immune-mediated diseases. In other embodiments, the condition is selected from a proliferative disorder.

[0196] In certain embodiments, the RET-mediated disorder is an immune disorder, including but not limited to an autoimmune disorder such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes.

[0197] One aspect of the present application provides compounds that can be used to treat diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer. The term "cancer" includes, but is not limited to, the following cancers: breast cancer; ovarian cancer; cervical cancer; prostate cancer; testicular cancer, genitourinary tract cancer; esophageal cancer; laryngeal cancer, glioblastoma; neuroblastoma; stomach cancer; skin cancer, keratoacanthoma; lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone cancer; colon cancer; colorectal cancer; adenoma; pancreatic cancer, adenocarcinoma; thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder cancer; liver cancer and biliary tract cancer; kidney cancer; myeloid disorders; lymphoid disorders, Hodgkin's disease, hairy cell cancer; oral cavity and pharyngeal (mouth) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer; small intestine cancer; colorectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer; chronic myeloid leukemia (CML) and leukemia. The term "cancer" includes, but is not limited to, myeloma, lymphoma, or a cancer selected from the group consisting of gastric cancer, renal cancer, and head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma, and lung cancer.

[0198] The term "cancer" refers to any cancer caused by the proliferation of malignant cells, such as a tumor, neoplasm, carcinoma, sarcoma, leukemia, lymphoma, etc. For example, cancer includes, but is not limited to, mesothelioma, leukemia, and lymphoma, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphoma associated with human T-cell lymphotropic virus (HTLV) (such as adult T-cell leukemia / lymphoma (ATLL)), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Additional examples include myelodysplastic syndrome; solid tumors in children, such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas; and common solid tumors in adults, such as head and neck cancer (such as oral cancer, laryngeal cancer, nasopharyngeal cancer, and esophageal cancer), genitourinary cancer (such as prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, and testicular cancer), lung cancer (such as small cell lung cancer and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin syndrome (such as medulloblastoma or meningioma), and liver cancer.

[0199] Additional exemplary forms of cancer include, but are not limited to, skeletal or smooth muscle cancer, stomach cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0200] Compounds described herein can be used to prevent, treat and study other cancers such as colon cancer, familial adenomatous polyposis and hereditary non-polyposis colorectal cancer or melanoma. In addition, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary system cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor), gallbladder cancer, bronchogenic carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma. In one aspect of the present application, the present application provides one or more compounds as described herein for use in the manufacture of a medicament for treating cancer (including but not limited to various types of cancer disclosed herein). In some embodiments, the compounds of the present application can be used to treat cancers such as colorectal cancer, thyroid cancer, breast cancer and lung cancer;And myeloproliferative disorders such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia and systemic mast cell disease. In some embodiments, compounds as described herein can be used to treat hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia and acute lymphoblastic leukemia (ALL). In one embodiment, a compound as described herein or its corresponding pharmaceutically acceptable salt or isotope derivative can be used in an effective amount to treat a host (e.g., human) suffering from lymphoma or lymphocyte or myeloproliferative disorder or abnormality. For example, a compound as described herein can be administered to a host having Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may have a non-Hodgkin lymphoma, such as, but not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); diffuse small cleaved cell lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenstrom's macroglobulinemia.

[0201] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts or isotopic derivatives, can be used in an effective amount to treat a patient (e.g., a human) suffering from Hodgkin's lymphoma, such as, but not limited to, nodular sclerosis classical Hodgkin's lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL. The present application further encompasses the treatment or prevention of cell proliferative disorders such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that a pathologist can identify in a biopsy. The compounds can be administered for the purpose of preventing the hyperplasia, dysplasia, or precancerous lesion from continuing to expand or becoming cancerous. Examples of precancerous lesions can be found in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0202] In certain embodiments, the compounds of the invention are used to treat abnormal cell proliferation, such as tumors or cancer, that harbor the RET protein.

[0203] In certain embodiments, the compounds of the present invention are used to treat abnormal cell proliferation, such as tumors or cancer, with a RET protein having a mutation, wherein the mutation is located at one of the amino acid positions listed below. The mutation can be, for example, selected from one of the exemplary mutations listed in Table 1, or can be a different mutation. Table 1. Exemplary RET protein mutations

[0204] In certain embodiments, the RET protein has two mutations selected from the above Table 1. In other embodiments, the RET protein has three mutations selected from the above Table 1. In other embodiments, the RET protein has four or more mutations, which can be optionally selected from the above Table 1.

[0205] In certain embodiments, the tumor or cancer has a mutation in the RET protein that is a substantial or partial driver of tumor cell proliferation. In another embodiment, the tumor or cancer has an altered RET protein that does not significantly function as a driver of abnormal cell proliferation but can be used therapeutically to kill tumor cells using a selected RET degrader as described herein.

[0206] In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a V804L mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a V804M mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a M918T mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a S891A mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a L790F mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a E768D mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a C618S mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a C618R mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a missense mutation in the RET protein 634. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a C634R mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a RET protein C634Y mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers that have a RET protein C634G mutation. In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, that have a RET protein with a G810R mutation.

[0207] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancer, that has a RET protein with a G810S mutation.

[0208] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancer, that has a RET protein with a G810C mutation.

[0209] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancer, that has a RET protein with a C634W mutation.

[0210] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancer, that has a RET protein with an M918T mutation.

[0211] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancer, that has a RET protein with a V804L mutation.

[0212] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancer, that has a RET protein with a V804M mutation.

[0213] In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used to treat abnormal cell proliferation, such as tumors or cancer, having a RET protein fused to another protein (e.g., a fusion selected from the group consisting of 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).

[0214] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, with CCDC6-RET fusions. In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancers, with NCOA4-RET fusions.

[0215] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation, such as tumors or cancer, that harbors a KIF5B-RET fusion.

[0216] In accordance with the foregoing, the present application further provides a method for preventing or treating any of the above-mentioned diseases or disorders in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the specific condition to be treated and the desired effect. Pharmaceutical compositions and combination therapies

[0217] In some embodiments, the compound of formula I as described herein or its pharmaceutically acceptable salt can be administered as a pure chemical, but more typically is administered as a pharmaceutical composition comprising an effective amount for a patient (typically, a human) in need of such treatment for any of the disorders described herein. Therefore, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition can contain a compound or salt as the sole active agent, or, in an alternative embodiment, contain the compound and at least one additional active agent.

[0218] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof can be used alone or in combination in an effective amount to treat a patient (eg, a human) suffering from a disorder as described herein or a RET-mediated disorder.

[0219] The disclosed compounds described herein can be used alone or in combination with another compound of the invention or another biologically active agent or a second therapeutic agent in an effective amount to treat a patient (e.g., a human) suffering from a disorder including, but not limited to, those described herein.

[0220] The term "bioactive agent" is used to describe an agent other than the selected compound according to the present invention, which can be combined with the compound of the present invention or used alternately to achieve the desired therapeutic result. In one embodiment, the compound of the present invention and the bioactive agent are administered in the following manner: they are active in vivo during the overlapping time period, for example, with overlapping Cmax, Tmax, AUC or other pharmacokinetic parameters. In another embodiment, the compound of the present invention and the bioactive agent are administered to patients in need, and the compound and the bioactive agent do not have overlapping pharmacokinetic parameters, however, one has a therapeutic effect on the therapeutic efficacy of another. In one aspect of this embodiment, the bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, including, as non-limiting examples, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V domain Ig inhibitors of T cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody. PD-1 inhibitors that inhibit immunosuppression by blocking the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby inhibiting immunosuppression, include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus).LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In certain embodiments, the checkpoint inhibitor is selected from nivolumab / . Pembrolizumab / and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559, a PDL2 / lg fusion protein, such as an inhibitor of AMP 224 or B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, a B-7 family ligand, or a combination thereof. In another embodiment, one of active compounds as herein described can be combined with an effective amount of an estrogen inhibitor or alternately administered, for the treatment of abnormal tissue (such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer) of the female reproductive system, the estrogen inhibitor includes but is not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader or another form of part or complete estrogen antagonist or agonist. Partial estrogen antagonists (as raloxifene and tamoxifen) retain some estrogen-like effects, including the estrogen-like stimulation of uterine growth, and in some cases, during breast cancer progression, actually stimulate the estrogen-like effect of tumor growth. By contrast, fulvestrant (complete estrogen antagonist) does not have an estrogen-like effect on the uterus, and is effective in tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176, assigned to Astra Zeneca; WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US 2013 / 0178445, all assigned to Olema Pharmaceuticals; and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810; and US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS, such as anordrin, bazedoxifene, bromostriene, chlortrisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors, such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins, such as leuprolide, cetrorelix, allylestradiol, chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Other estrogen ligands that may be used in accordance with the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO 2011 / 156518, U.S. Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US2015 / 0005286; and WO 2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US6821989; US2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US ​​2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; 6005102;EP 0802184; US 5998402; US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684. In another embodiment, the active compounds described herein can be combined or administered alternately in an effective amount with an effective amount of an androgen (such as testosterone) inhibitor for the treatment of abnormal tissues of the male reproductive system (such as prostate cancer or testicular cancer), and the androgen inhibitor includes but is not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, prostate cancer or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topiramide, abiraterone acetate and cimetidine. In one embodiment, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101) and AP26113. In one embodiment, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), omotinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), and neratinib. (HKI-272; PB272); avitinib (AC0010), EAI045, taretinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesivatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer). In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab tiuxetan, tositumomab, and ocrelizumab. In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tofacitinib. In one embodiment, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitola), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethylamino)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) 1-(4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (methanesulfonic acid obarak, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)amino]-1-[ ... [methyl]-4-methoxypyrrole-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 acetate (pogosin), 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylic acid ethyl ester, 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 sodium). In one embodiment, the bioactive agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (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, demethoxychloroquine, perifosine, idelalisib, pitilis, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelithide, GS-9820, BKM120, GDC-0032 (tacilisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2 ,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butyl hydrogen (S)-methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,[2-(trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (Omilide), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2 -a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS -9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-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) )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]-methyl-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Iupanixib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3 ,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,1-(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-morpholino-1,3,5-triazin-2-yl)phenyl]urea) (Gidalisel), LY3023414, BEZ235 (2-methyl-2-{4 -[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile)(datolis), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-pyridyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3a R,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonoliside), LY294002, AZD8186, PF-4989216, pilaliside, GNE-317, PI-3065, PI-103, N U7441 (KU-57788), HS173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, votalis, apellis, IC-87114, TGI100713, CH5132799, PKI-402, copanelix (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, Apitolide (GDC-0980; RG7422). Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica, TM)(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), diphenylaminopyrimidine-based inhibitors (such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide))(Avila Therapeutics (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-bromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)thiazole-5-carboxamide]), CGI-5604-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5 -dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals),PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, such as Akinleye et al., Journal of BTK inhibitors disclosed in Hematology & Oncology, 2013, 6:59 (incorporated herein by reference in its entirety). Syk inhibitors include, but are not limited to, seletinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entoctinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fotantinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino]- ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate, sodium salt of fotantinib, and BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N -(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine),PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), )bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, 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), luteolin (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),Apigenin (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), quercetin (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), fisetin (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), myricetin (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), Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, incorporated herein in its entirety), morin (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). In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimaticin / AS703026 / MSC 1935369 ((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),Rifatinib / 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-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), T AK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxylate amine), 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-oxo- In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, 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-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide),RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoaldisine (2-Bromoaldisine, 2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2

[0015] The present invention relates to the treatment of leukemia and schizolin-1H- 1H -chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol, sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-picolinamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encaufenib). In one embodiment, the bioactive agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine; a FLT-3 inhibitor, including but not limited to P406, dovitinib, quizartinib (AC220), amvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449; or a combination thereof. In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include but are not limited to rapamycin and its analogs, everolimus (Afinitor), temsirolimus, defostiolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include, but are not limited to, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylphenyl)acetamide), and GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide). imidazole-5-carboxamide), pimathiotetracycline / 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),Rifatinib / 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-dihydroxypropyloxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4 1-Methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridinyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide). In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER. In one embodiment, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol. Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, Aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, panitumumab, amrubicin, ogavuzumab,Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zalimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, tesimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-fluorouridine, Vincristine, Temozolomide, ZK-304709, Celicib; 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-(methylsulfonylpiperidinylmethyl)-indolyl]-quinolone, vatalanib, AG-013736, AVE-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, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, K RN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, BCG vaccine, doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprorelin, levamisole, lomustine, nitrogen mustard,Melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer sodium, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, neivastat, BMS-275291, horn Squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin, gefitinib, bortezomib, paclitaxel, paclitaxel without hydrogenated castor oil, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronic acid, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa -2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol acetate, immune globulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan, androgens, decitabine, altretinoin, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronic acid, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopranolol, netupitant, NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol,Dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof. In one embodiment, the bioactive agent is selected from but is not limited to imatinib mesylate, Dasatinib Nilotinib Bosutinib Trastuzumab Trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib Gefitinib Erlotinib Cetuximab Panitumumab Vandetanib Vemurafenib Vorinostat Romidepsin Bexarotene alitretinoin retinoic acid Carfilzomib (Kyprolis™), pralatrexate Bevacizumab Aflibercept Sorafenib Sunitinib Pazopanib Regorafenib and cabozantinib (Cometriq™). In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, another therapeutic agent, or an immunosuppressant. Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents, which include any agent that is detrimental to cell viability), and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer agents include: vincristine or liposomal vincristine Daunorubicin (daunorubicin or ) or doxorubicin Cytosine arabinoside (ara-C or ), L-asparaginase or PEG-L-asparaginase (pegaspargase or ), etoposide (VP-16), teniposide 6-Mercaptopurine (6-MP or ), methotrexate, cyclophosphamide Prednisone, dexamethasone (Decadron), imatinib Dasatinib Nilotinib Bosutinib and ponatinib (Iclusig TMExamples of additional suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, aldesleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum (II) (DDP, cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, folinate, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), benbuterol Acid mustard, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclophosphamide, cytarabine, cytarabine, cytochalasin B, cyclophosphamide (Cytoxan), dacarbazine, dactinomycin, dactinomycin (formerly actinomycin D), daunorubicin HCL, daunorubicin citrate, denileukin, dexrazoxane, dibromomannitol, dihydroxy anthracin dione, docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, Escherichia coli (E. coli) L-asparaginase, emetine, epoetin-alpha, Erwinia (E. coli) L-asparaginase Amidase, esterified estrogen, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide aurantium factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole, folinate calcium, leuprorelin acetate, levamisole HCL, lidocaine, lomustine, maytansine, nitrogen mustard HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptopurine, mesna, methotrexate, methyltestosterone, Mitomycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polyphenylpropan 20 and carmustine implants, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, paclitaxel, teniposide, tenoposide, testolactone, tetracaine, thiotepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0221] In some embodiments, the compound of the present invention is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compounds that can be used to treat cancer). The example of a chemotherapeutic agent includes an alkylating agent, antimetabolite, a folic acid analog, a pyrimidine analog, a purine analog and a related inhibitor, a vinca alkaloid, an epipodophyllotoxin, an antibiotic, an L-asparaginase, a topoisomerase inhibitor, an interferon, a platinum coordination complex, an urea substituted with anthracene dione, a methylhydrazine derivative, an adrenocortical inhibitor, an adrenocortical steroid, a progestogen, an estrogen, an antiestrogen, an androgen, an antiandrogen and a gonadotropin-releasing hormone analog. Also included are 5-fluorouracil (5-FU), folinic acid (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimines and methylmelamines including hexamethylmelamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylenemelamine; thylolomelamine); polyacetylcholine (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adolesin, carzelesin, and biszelesin); candidins (especially candidin 1 and candidin 8); dolastatin; duocarmycin (including the synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratine (including its synthetic analogues KW-2189 and CB1-TM1); statin); sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, methoxychlor hydrochloride, melphalan, nembixin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozolin, fotemustine, lomustine, nimustine, and ranimnustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma 11 and calicheamicin omega 11 (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicins; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycins, actinomycins, authramycins, azaserine, bleomycins, cactinomycins, carabicins, carminomycins, carzinophilins, chromomycins, dactinomycins, daunomycins, detorubicin, 6-diazo-5-oxo-L-norleucine, (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrroline-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid, nogamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozotocin, tubercidin, ubenimex, ex), zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone and dromostanolone propionate. propionate, epitiostanol, mepitiostane, testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglucuronolide; aldophosphamide glycoside; aminolevulinic acid acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptonium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine;Maytansine-like drugs, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; Pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-acetylhydrazine; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), (a hydrogenated castor oil-free albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, IL)) and Docetaxel ( -Poulenc Rorer, Antony, France); chlorambucil; Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; noxious line; vincristine; Vinorelbine; Mitoxantrone; Teniposide; Edatrexate; Daunorubicin; Aminopterin; Xeloda; Ibandronate; Irinotecan (e.g., CPT-1 1); Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DMFO); Retinoids such as retinoic acid; Capecitabine; And pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in combination with the compounds of the present invention in a mixture. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a (1999) and Douillard et al., Lancet355(9209):1041-1047 (2000). Additional therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, irrituzumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovir Tinib, fentocillin, atacicept, rituximab, alemtuzumab, aldesleukin, atezolizumab, tocilizumab, temsirolimus, everolimus, rucamumab, daclizumab, HLL1, huN901-DM1, atimod, natalizumab, bortezomib, carfilzomib, marizomib, tanspiramycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate Wei, belinostat, panobinostat, mapatumumab, lexalimumab, dulalemin, ABT-737, oblimersen sodium, prilotide, tapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, Ribociclib (LEE011), Abemaciclib (LY2835219), HDM201, Fulvestrant (Faslodex), Exemestane (Aromasin), PIM447, Ruxolitinib (INC424), BGJ398, Nexituzumab, Pemetrexed (Alimta) and Ramucirumab (IMC-1121B). In one embodiment, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells, thereby triggering the immune system to destroy cancer cells. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes tumor blood vessel development.When combined with bevacizumab, VEGF can not interact with its cell receptor, thereby preventing the signal conduction that causes new blood vessel growth. Similarly, cetuximab and panitumumab target epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs combined with cell surface growth factor receptors prevent the targeted receptor from sending its normal growth promotion signal. They can also trigger apoptosis and activate the immune system to destroy tumor cells. In one aspect of the present invention, the bioactive agent is an immunosuppressant. The immunosuppressant can be a calcineurin inhibitor, such as cyclosporin or ascomycin, such as cyclosporin A. FK506 (tacrolimus), pimecrolimus; mTOR inhibitors, such as rapamycin or its derivatives, such as sirolimus Everolimus Temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapamycin analogs (e.g., dafolimus), azathioprine, Campas 1H; S1P receptor modulators, such as fingolimod or its analogs, anti-IL-8 antibodies, mycophenolic acid or its salts (e.g., sodium salt) or its prodrugs (e.g., mycophenolate mofetil) );OKT3(ORTHOCLONE ), prednisone, Buquina sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, treperolimus, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab Daclizumab Mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (by Immunex Sales), Adalimumab Infliximab Anti-LFA-1 antibody, natalizumab Enmolumabin, Gawimolumabin, anti-thymocyte immunoglobulin, siplizumab, alefacept, efalizumab, pantequinoxaline, mesalazine, ansacol, codeine phosphate, benolate, fenbufen, naproxen, diclofenac, etodolac and indomethacin, aspirin and ibuprofen. In some embodiments, the biologically active agent is a therapeutic agent used in cancer treatment, which is a biological product, such as a cytokine (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological product is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof), that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important to cancer. Such agents include (rituximab); (daclizumab); (basiliximab); (palivizumab); (infliximab); (trastuzumab); (gemtuzumab ozogamicin); (alemtuzumab); (ibritumomab tiuxetan); (adalimumab); (omalizumab); (tositumomab-l-131); (efalizumab); (cetuximab); (bevacizumab); (natalizumab); (tocilizumab); (panitumumab); (ranibizumab); (eculizumab); (pecilizumab); (golimumab); (canakinumab); (Ustekinumab); (ofatumumab); (denosumab); (motavizumab); (Rixibacumab); (belimumab); (ipilimumab); (Bentuximab); (Pertuzumab); (Ado-enmei-trastuzumab); and (Otuzumab). Antibody-drug conjugates are also included. Combination therapy may include therapeutic agents as non-drug treatments. For example, in addition to radiotherapy, cryotherapy, hyperthermia and / or surgical resection of tumor tissue, a compound may also be administered. In certain embodiments, the first therapeutic agent and the second therapeutic agent are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered immediately before or after the second therapeutic agent, before or after the second therapeutic agent at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours, at most 24 hours or at most 1-7, 1-14, 1-21 or 1-30 days. In certain embodiments, the second therapeutic agent is administered with a dosage schedule different from that of the compound of the present invention. For example, the second therapeutic agent can have a drug 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 drug holiday. For example, the first therapeutic agent can have a drug 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 therapeutic agent and the second therapeutic agent have a drug holiday.

[0222] Typically, the compositions of the present disclosure will be administered in a therapeutically effective amount by any of the generally recognized modes of administration. Suitable dosage ranges depend on many factors, such as the severity of the disease to be treated, the age and relative health of the subject, the effectiveness of the compound used, the route of administration and form, the indications for which administration is directed, and the preferences and experience of the relevant medical practitioners. Those of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and based on personal knowledge and the disclosure of this application, that the compositions of the present disclosure are effective amounts for the treatment of a given disease.

[0223] In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and, optionally, from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms having at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof.

[0224] In certain embodiments, a patient can be treated with a low-dose therapy using a compound of the present invention. For example, a pharmaceutical composition can be in a dosage form containing about 0.1 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 800 μg, or about 200 μg to about 600 μg of the active compound. Examples are dosage forms having at least about 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 μg of the active compound or a salt thereof.

[0225] In certain embodiments, the dosage range is about 0.01-100 mg / kg of patient body weight, for example, 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 ... About 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 45 mg / kg, at least about 50 mg / kg, at least about 55 mg / kg, at least about 60 mg / kg, at least about 65 mg / kg, at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, or at least about 100 mg / kg.

[0226] The composition of pharmaceutically effective dose or therapeutically effective dose will be delivered to the patient. Definite effective dose will vary because of the patient, and will depend on species, age, the body shape of experimenter and health status, the character and degree of the illness being treated, the advice of the treatment physician and the therapeutic agent or the combination of therapeutic agent that are selected for use.The effective dose for given situation can be determined by routine experiments. For the purpose of the present disclosure, in at least one dose, therapeutic dose can be for example in the scope of about 0.01mg / kg to about 250mg / kg body weight, more generally about 0.1mg / kg to about 10mg / kg. The dosage of desired amount can be used to reduce and / or alleviate the sign, symptom or the cause of disease of the obstacle in question to the experimenter, or cause the change of any other expectation of biological system. When desired, preparation can be prepared as the enteric coating with the slow release or controlled release that is suitable for active component.

[0227] In some embodiments, the compounds disclosed herein or as used as described are administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, the compounds disclosed herein or as used as described are administered at least once a day for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer.

[0228] In certain embodiments, the compounds of the present invention are administered once a day, twice a day, three times a day, or four times a day. In certain embodiments, the compounds of the present invention are administered orally once a day. In certain embodiments, the compounds of the present invention are administered orally twice a day. In certain embodiments, the compounds of the present invention are administered orally three times a day. In certain embodiments, the compounds of the present invention are administered orally four times a day.

[0229] In certain embodiments, the compound of the present invention is administered intravenously once a day. In certain embodiments, the compound of the present invention is administered intravenously twice a day. In certain embodiments, the compound of the present invention is administered intravenously three times a day. In certain embodiments, the compound of the present invention is administered intravenously four times a day.

[0230] In some embodiments, the compounds of the present invention are administered with a drug rest period between treatment cycles. For example, the compound can have a drug rest period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

[0231] The pharmaceutical composition can also comprise a certain molar ratio of the active compound and the additional active agent. For example, the pharmaceutical composition can contain an anti-inflammatory agent 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.

[0232] These compositions can contain any amount of active compound to achieve the desired result, for example, between 0.1% and 99% by weight (wt.%) of the compound, and typically at least about 5% by weight of the compound. Some embodiments contain from about 25% to about 50% by weight or from about 5% to about 75% by weight of the compound.

[0233] Pharmaceutical formulations are preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged formulation containing discrete quantities of the formulation, such as individual tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the unit dosage form can be the appropriate number of any of these packaged forms.

[0234] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0235] Thus, the compositions of the present disclosure can be administered as pharmaceutical formulations, including formulations 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, intraaortically, intracranial, subdermal, intraperitoneal, subcutaneous or other administration routes containing conventional pharmaceutically acceptable carriers. Typical administration routes are oral, topical or intravenous, using a convenient daily dosage regimen that can be adjusted according to the degree of affliction.

[0236] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semisolid or liquid dosage form, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, lotions, pastes, gels, sprays, aerosols, foams or oils, injectable or infusible solutions, transdermal patches, subcutaneous patches, inhalation formulations, in medical devices, suppositories, buccal or sublingual formulations, parenteral formulations or ophthalmic solutions, etc., preferably in unit dosage form suitable for single administration of a precise dose.

[0237] Some dosage forms (such as tablets and capsules) are subdivided into appropriately sized unit doses containing an appropriate amount of active ingredient (e.g., an effective amount to achieve the desired purpose). The composition will contain an effective amount of a combination of the selected drug and a pharmaceutically acceptable carrier, and may additionally contain other agents, adjuvants, diluents, buffers, etc. Carriers include excipients and diluents and must have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the patient being treated. The carrier can be inert, or it can have its own pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide the material for administration in the actual amount of compound per unit dose. The categories 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 materials. Some carriers may be listed in more than one category, for example, vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin; talc, wax, lanolin, polyethylene glycol, alcohol, transdermal enhancers, and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the invention. Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. Depending on the therapeutic goal, the compound may be provided, for example, in the form of a solid, liquid, spray-dried material, microparticles, nanoparticles, controlled-release systems, and the like. Suitable excipients for non-liquid formulations are also known to those skilled in the art. A comprehensive discussion of pharmaceutically acceptable excipients and salts can be found in Remington's Pharmaceutical Sciences, 18th edition (Easton, Pennsylvania: Mack Publishing Company, 1990). In addition, auxiliary substances, such as wetting or emulsifying agents, biological buffers, surfactants, and the like may be present in such vehicles. Biological buffer can be any solution that is pharmacologically acceptable and provides the formulation with the desired pH, i.e., a pH within a physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, and the like. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade 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 compound as described herein and an optional pharmaceutical adjuvant in an excipient such as water, saline, aqueous glucose solution, glycerol, ethanol, and the like, to form a solution or suspension.If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffers, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods for preparing such dosage forms are known or will become apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, referenced above. In yet another embodiment, the use of a penetration enhancer excipient comprising a polymer is provided, 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-thiobutyramidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates). The pharmaceutical composition / combination may be formulated for oral administration. For oral administration, the composition will generally take the form of tablets, capsules, soft capsules, or can be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. Typically, the compositions of the present disclosure can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. In addition, when desired or necessary, suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. When using a liquid suspension, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.) and with an emulsifier and a suspending agent. If necessary, flavorings, coloring agents, and / or sweeteners can also be added. Other optional components for incorporation into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[0238] For ocular delivery, the compounds can be administered, for example, via intravitreal, intrastromal, intracameral, sub-tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericornaline, or lacrimal injection, or via mucus, mucin, or mucosal barriers, in an immediate or controlled release manner or via an ocular device, as desired.

[0239] Parenteral formulations can be prepared in conventional forms (as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquids before injection, or as emulsions). Typically, sterile injectable suspensions are prepared using suitable carriers, dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in acceptable non-toxic parenteral acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty esters, or polyols are conventionally used as solvents or suspending media. In addition, parenteral administration can involve the use of slow-release or sustained-release systems to maintain a constant dosage level.

[0240] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, antibacterial agents and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickeners, stabilizers and preservatives. Administration via certain parenteral routes may involve introducing the formulation of the present disclosure into the patient's body via a needle or catheter, propelled by a sterile syringe or some other mechanical device (such as a continuous infusion system). The formulation provided by the present disclosure can be administered using a syringe, a syringe, a pump or any other device recognized in the art for parenteral administration. 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 are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin, and injectable organic esters (such as ethyl oleate). Such dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. They may be sterilized, for example, by filtering through a bacteria-retaining filter, by incorporating a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. They may also be manufactured using sterile water or some other sterile injectable medium just before use.

[0241] Sterile injectable solutions are prepared by incorporating one or more of the compounds of the present disclosure in the desired amount in an appropriate solvent with the various other ingredients listed above, as needed, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a base dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, typical preparation methods are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0242] Alternatively, the pharmaceutical compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0243] The pharmaceutical composition of the present disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to the technology known in the field of pharmaceutical formulations, and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers, propellants such as fluorocarbons or nitrogen and / or other conventional solubilizers or dispersants that enhance bioavailability. Preparations for buccal administration include tablets, lozenges, gels, etc. Alternatively, buccal administration can be achieved using a transmucosal delivery system well known to those skilled in the art. The compound of the present disclosure can also be delivered via skin or mucosal tissue using a conventional transdermal drug delivery system (i.e., transdermal "patch"), wherein the medicament is generally contained in a layered structure used as a drug delivery device to be attached to the body surface. In this structure, the pharmaceutical composition is generally contained in a layer or "reservoir" below the upper backing layer. The layered device can contain a single reservoir, or it can contain multiple reservoirs. In one embodiment, the reservoir comprises a polymer matrix of a pharmaceutically acceptable contact adhesive material, which is used to attach the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxane, polyisobutylene, polyacrylate, polyurethane, and the like.

[0244] Alternatively, the drug-containing reservoir and the skin contact adhesive exist as separate and distinct layers, wherein the adhesive is located below the reservoir, in which case the reservoir may be a polymer matrix as described above, or it may be a liquid or gel reservoir, or may take some other form. The backing layer used as the upper surface of the device in these layered materials serves as the primary structural element of the layered structure and makes the device have most of its flexibility. The material selected for the backing layer should be substantially impervious to the active agent and any other material present.

[0245] The compositions of the present disclosure can be formulated for aerosol administration, particularly for respiratory administration and including intranasal administration. For example, the compound can generally have a small particle size, for example, approximately 5 microns or less. This particle size can be obtained by means known in the art (for example, by micronization). The active ingredient is provided in a pressurized bag with a suitable propellant, such as chlorofluorocarbons (CFCs) (for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), carbon dioxide or other suitable gases. Aerosols can also conveniently contain surfactants, such as lecithin. The dosage of the medicine can be controlled by a metering valve.

[0246] Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hypromellose and polyvinylpyrrolidone (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 cartridges of, for example, gelatin or blister packs from which the powder can be administered with the aid of an inhaler.

[0247] Formulations suitable for rectal administration are typically presented as unit-dose suppositories. These suppositories can be prepared by mixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0248] In certain embodiments, the pharmaceutical composition is adapted for topical application to the skin using the modes of administration defined above.

[0249] In certain embodiments, pharmaceutical compositions suitable for transdermal administration can be present as discrete patches that are suitable for maintaining close contact with the recipient's epidermis for an extended period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3(6): 318(1986)), and typically take the form of an optionally buffered aqueous solution of the active compound.

[0250] In one embodiment, a microneedle patch or device for delivering a drug through or into biological tissue, particularly skin, is provided. The microneedle patch or device allows for delivery of a drug through or into the skin or other tissue barrier at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0251] Preparations suitable for administration to the lung can be delivered by a single dose / multiple dose dry powder inhaler (DPI) of a variety of passive breath-driven and actively driven methods. The device most commonly used for respiratory delivery comprises a nebulizer, a metered dose inhaler, and a dry powder inhaler. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable lung delivery devices depends on multiple parameters, such as the pathophysiology of the properties, site of action, and lung of the drug and its preparation. Example

[0252] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or 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 one skilled in the art will know how to modify the procedures described in the examples to obtain the desired products. Analytical methods and procedures NMR

[0253] Proton nuclear magnetic resonance (NMR) spectra were obtained using the following conditions: NMR spectra were collected on a 400 MHz or 500 MHz Bruker instrument using DMSO-d6 or CDCl3 as solvent and internal standard. Raw NMR data were analyzed using ACD Spectrus version 2015-01 or MestReNova software from ADC Labs.

[0254] Chemical shifts are reported in parts per million (ppm) downfield relative to internal tetramethylsilane (TMS) or relative to the TMS position inferred from deuterated NMR solvents. Apparent multiplicities are reported as: singlet - s, doublet - d, triplet - t, quartet - q, or multiplet - m. Peaks exhibiting broadening are further denoted as br. Integration is approximate. It should be noted that integrated intensity, peak shape, chemical shift, and coupling constant may depend on solvent, concentration, temperature, pH, and other factors. In addition, peaks that overlap or exchange with water or solvent peaks in the NMR spectrum may not provide reliable integrated intensity. In some cases, NMR spectra can be obtained using water peak suppression, which may cause overlapping peaks to be invisible or to have altered shapes and / or integrals. Liquid chromatography

[0255] The following preparative and / or analytical (LC / MS) liquid chromatography methods were used.

[0256] Method A: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: ACN / H2O (5:95) (containing 10 mM AA); Mobile phase B: ACN / H2O (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+).

[0257] Method B: Column: XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: ACN / H2O (5:95) (containing 0.05% TFA); Mobile phase B: ACN / H2O (95:5) (containing 0.05% TFA); Temperature: 50°C; Gradient: 0-100% B (0.0-3.0 min), 100% B (3.0-3.5 min); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI+).

[0258] Method Column 6: Column: Waters Acquity BEH C18 2.1 x 50 mm 1.7 μm particles; 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).

[0259] UHPLC method D: Column: Waters Acquity BEH C18 2.1 x 50 mm 1.7 μm particles; Mobile phase A: 95:5 acetonitrile:water (with 0.05% TFA); Mobile phase B: 95:5 acetonitrile:water (with 0.05% TFA); Temperature: 50°C; Gradient: 0% B to 100% B 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).

[0260] Method P: Mode: binary gradient, Pump A: LC-20ADXR, Pump B: LC-20ADXR, Total flow rate: 1.5000 mL / min, B concentration: 30.0%, Column 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, Internal diameter: 4.6 mm, Description: 2.5 μm particles, Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Acquisition mode: Scan, Polarity: Positive.

[0261] Method Q: Mode: binary gradient, Pump A: LC-40D XR, Pump B: LC-40DXR; Column 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, Internal 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;

[0262] LCMS5: Waters Acquity BEH C18 2.1 x 50 mm 1.7 μm particles; 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) Acronyms and abbreviations

[0263] Table 2 provides a list of acronyms and abbreviations used in this specification and their meanings. Synthesis method

[0264] A suitable general route for preparing the compounds of the present application can be described in Scheme 1 herein. Solution 1

[0265] Unless otherwise stated, the examples provided herein were synthesized according to the general procedures presented in Schemes 2-9. case Option 3 Option 4 Option 5 Example A1. Synthesis of (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide Step A. tert-Butyl 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoate.

[0266] To a mixture of 3-(1-oxo-5-(piperazine-1-yl)isoindolin-2-yl)piperidine-2,6-dione HCl (320.0 mg, 0.88 mmol) in MeCN (12 mL) at room temperature was added tert-butyl 7-bromoheptate (256.0 mg, 0.97 mmol) followed by sodium iodide (32.9 mg, 0.22 mmol) and DIEA (0.23 mL, 1.32 mmol). The vial was sealed and the mixture was stirred at 80 ° C. After 15 h, the mixture was concentrated in vacuo and then purified by flash chromatography on silica gel to give the desired product (310.4 mg, 69% yield) as an off-white solid. MS: m / z 513.3 [M+H] + (Method column 6). Step B. 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid.

[0267] To a mixture of tert-butyl 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoate (310.4 mg, 0.61 mmol) in DCM (15 mL) was added TFA (1.0 mL, 12.98 mmol) at room temperature under nitrogen. The reaction was stirred at ambient temperature for four hours and then concentrated in vacuo to remove volatiles. The resulting residue was treated with MeCN, frozen, and then lyophilized overnight to give the desired product as a solid as a TFA salt (279.0 mg, 81% yield), which was used without further purification. MS: m / z 457.2 [M+H] + (Method column 6).

[0268] Alternatively, the compound in step B is obtained as follows (steps A' to D'): Step A'. Oct-7-enoic acid tert-butyl ester.

[0269] To a stirred solution of oct-7-enoic acid (1000 mg, 7.03 mmol) in DCM (20 mL) and tert-butanol (20 mL) was added DCC (1740 mg, 8.44 mmol) and DMAP (85 mg, 0.70 mmol), and the mixture was stirred at room temperature overnight. The precipitate was filtered, and the filtrate was concentrated, then the residue was washed with Et o, and the filtrate was concentrated to obtain the product (1.3 g, 93% yield) as a colorless oil, which was used in the next step without further purification. Step B'. tert-Butyl 7-oxoheptanoate.

[0270] To a mixture solution of tert-butyl octyl-7-enoate (100 mg, 0.50 mmol) in tert-butanol (10 mL) and water (10 mL) was added potassium citrate (15 mg, 0.05 mmol), NMO (120 mg, 1.01 mmol) and citric acid (195 mg, 1.01 mmol), the resulting mixture was stirred at room temperature for 1 h, then the reaction was cooled to 0 ° C, sodium periodate (220 mg, 1.01 mmol) was added, and the mixture was stirred for 0.5 h. The reaction mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC to obtain tert-butyl 7-oxoheptanoate (80 mg, 79% yield) as a colorless oil. 1H NMR (300 MHz, CHLOROFORM-d) δ 9.77 (t, J = 1.8 Hz, 1H), 2.44 (td, J = 7.4, 1.8 Hz, 2H), 2.22 (t, J = 7.4 Hz, 2H), 1.63 (ddt, J = 15.1, 13.0, 7.4 Hz, 4H), 1.44 (s, 9H), 1.42-1.32 (m, 1H), 1.37-1.16 (m, 1H). Step C'. Tert-butyl 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoate.

[0271] To a stirred solution of 3-(1-oxo-5-piperazine-1-yl-isoindolin-2-yl)piperidine-2,6-dione (50 mg, 0.15 mmol) in DCM (5 mL) was added tert-butyl 7-oxoheptanoate (60 mg, 0.30 mmol) and DIEA (0.02 mL, 0.30 mmol). The mixture was stirred at room temperature for 5 min and then AcOH (0.02 mL, 0.30 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. The reaction was cooled to 0 ° C, followed by addition of NaBH (OAc) 3 (65 mg, 0.30 mmol), and the mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was concentrated. The obtained residue was purified by preparative HPLC to obtain the desired product (50 mg, 64% yield) as a pale white semi-solid. MS: m / z 513.2 [M+H] + Step D'. 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid.

[0272] To a stirred solution of tert-butyl 7-[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]heptanoate (150 mg, 0.29 mmol) in DCM (10 mL) was added TFA (2 mL), and the mixture solution was stirred at room temperature for 3 h. After completion, the reaction was concentrated to give the desired product (120 mg, 86% yield) as an off-white semisolid. MS: m / z 457.3 [M+H] + .

[0273] Step C. tert-Butyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate. In a 250 ml round-bottom flask, 3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 g, 5.43 mmol), tert-butyl 3-hydroxycyclobutanecarboxylate (1403.47 mg, 8.15 mmol), PPh3 (5700 mg, 21.73 mmol) and DTBAD (5004 mg, 21.73 mmol) were suspended in toluene (100 mL). The reaction was placed under vacuum, sonicated and backfilled with nitrogen. The mixture was stirred at 100 ° C for 2 h. It was concentrated and the crude product was purified by reverse phase column chromatography to give the product tert-butyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (2 g, 57.8% yield) as an off-white solid. Analytical LCMS: m / z 411.2 [M+H] + , RT = 1.00 min (Method Q). Analytical LCMS: m / z 523.3 [M+H] + , RT = 1.15 min (Method Q). Step D. 3-[4-Amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid

[0274] To a solution of tert-butyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (500 mg, 0.96 mmol) in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 1 h. It was concentrated to give the crude product, which was used directly in the next step without further purification. MS: m / z 467.1 [M+H] + . Step E. 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid methyl ester

[0275] To a solution of 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid (1 g, 2.14 mmol) in DMF (10 mL) was added MeOH (0.87 mL, 21.45 mmol), HATU (1223.31 mg, 3.22 mmol), DIEA (0.49 mL, 6.43 mmol). The mixture was stirred at room temperature for 2 h. The crude product was purified by reverse phase column chromatography to give the product methyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (800 mg, 77.7% yield) as a yellow solid. Analytical LCMS: m / z 481.1[M+H] + , RT = 0.98 min (Method Q). Step F. Methyl 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate

[0276] In a 5 ml microwave vial, methyl 3-[4-amino-3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (300 mg, 0.62 mmol), tributyl(2-pyridyl)stannane (344.94 mg, 0.94 mmol), PdCl2[P(cy)3]2 (46.11 mg, 0.06 mmol), and CsF (237.37 mg, 1.56 mmol) were suspended in toluene (20 mL). The reaction was placed under vacuum, sonicated, and purged with nitrogen. The resulting mixture was stirred at 100 ° C for 48 h. The reaction was filtered, concentrated, and the crude product was purified by preparative TLC (DCM:MeOH=20:1) to give methyl 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridinyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (100 mg, 37.1% yield) as a yellow solid. MS: m / z 432.2 [M+H] + . Step G. 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid

[0277] To a solution of methyl 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylate (1.21 g, 2.8 mmol) in methanol (30 mL) and THF (10 mL) was added LiOH (2 M, 1 mL). The mixture was stirred at room temperature for 2 h. The reaction was concentrated, and the crude product was purified by reverse phase column chromatography (0.5% TFA in water / MeCN) to give the product 3-[4-amino-3-[5-cyclopropyl-4-(2-pyridyl)isoxazol-3-yl]pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutanecarboxylic acid (1.03 g, 85.1% yield) as an off-white solid. Analytical LCMS: m / z 418.1 [M+H] + , RT = 1.14 min (Method Q). 1 H NMR(400MHz,DMSO-d6)δ8.70-8.64(m,1H),8.21(s,1H),8.06(s,1H),7.96-7.83(m,2H),7.69-7.61(m ,1H),7.45-7.41(m,1H),5.41-5.34(m,1H),2.48-2.30(m,4H),2.28-2.19(m,2H),1.28-0.99(m,4H). Step H. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-(6-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}hexyl)cyclobutane-1-carboxamide.

[0278] (1r,3r)-3-(4-amino-3-(5-cyclopropyl-4-(pyridin-2-yl)isoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclobutane-1-carboxylic acid, 2TFA (315 mg) was dissolved in 4.5 ml DMF, and BOP (260 mg) was dissolved in DMF (4.5 mL). To each reaction vial containing the acidic component was added (1r,3r)-3-(4-amino-3-(5-cyclopropyl-4-(pyridin-2-yl)isoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclobutane-1-carboxylic acid, 2TFA (0.100 ml, 10.84 μmol), BOP (0.099 ml, 0.013 mmol) and DIEA (0.011 ml, 0.065 mmol). The mixture was then placed in a Bohdan Miniblock XT and stirred at 400 rpm overnight at room temperature. The crude material was diluted with 1.5 ml of DMF and a drop of AcOH and submitted for final purification by RP preparative HPLC to give the title compound. The product was 2.9 mg with an estimated purity of 96.1% by reverse phase analysis. The crude material was purified by preparative reverse phase chromatography using the following conditions: column: XBridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25°C. Fraction collection was triggered by UV (220 nm) and MS (ESI+). Fractions containing the desired product were combined and dried via centrifugal evaporation. HPLC conditions: mobile phase A (ACN / H2O (5:95) containing 10 mM AA), mobile phase B (ACN / H2O (95:5) containing 10 mM AA): from 85% A and 15% B at 0 min to 45% A and 55% B at 20 min, then maintained at 100% B for 4 min. Analytical LCMS: m / z 827.4 [M+H] + , RT = 1.54 min, purity: 97.7% (Method A); m / z 827.3 [M+H] + , RT=1.1 min, purity: 96.1% (Method B). 1H NMR (500MHz, DMSO-d6) δ8.68(br d,J=4.6Hz,1H),8.22(s,1H),8.04(br d,J=6.3Hz,1H),7.99-7.85(m,2H),7.81(br t,J=5.8Hz,1H),7.65(d,J=7.9Hz,1H),7.52(d,J=9.3Hz,1H),7.42(t,J=6.4Hz,1H),7.10-7.01(m,2H),5.38(brt,J=7.8Hz,1H),5.03(br dd,J=13.3,5.1Hz,1H),4.32(br d,J=17.1Hz,1H),4.20(d,J=16.6Hz,1H),3.26(br d,J=4.3Hz,2H),3.17-3.03(m,2H),2.96-2.82(m,1H),2.74(ddd,J=13.0,9.2,3.6Hz ,1H),2.64-2.56(m,2H),2.55(DMSO),2.49-2.28(m,10H),2.11-1.92(m,1H),1.82(br s,1H),1.50-1.27(m,8H),1.20-1.06(m,4H)ppm.

[0279] The following examples as shown in Table 3 were prepared according to the preparation of Example A1. Table 3. Characterization of Examples A2-A11

[0280] Following similar synthetic procedures as shown in Example A1 Step C to Step G, the following target binding moieties (TBMs) containing an amino or carboxylic acid group or their corresponding ethylamides were synthesized.

[0281] Example B1. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclobutane-1-carboxylic acid;

[0282] Example B2. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethylcyclobutane-1-carboxamide;

[0283] Example B3. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethyl-N-methylcyclobutane-1-carboxamide;

[0284] Example B4. 3-{[(1R,3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}propanoic acid;

[0285] Example B5. 3-{[(1R,3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}propanoic acid;

[0286] Example B6. 1-[(1S,3R)-3-(2-aminoethoxy)cyclopentyl]-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0287] Example B7. 1-[(1R,3R)-3-(2-aminoethoxy)cyclopentyl]-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0288] Example B8. N-(2-{[(1R,3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}ethyl)propanamide;

[0289] Example B9. N-(2-{[(1R,3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}ethyl)propionamide;

[0290] Example B10. 3-{[(1R,3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}-N-ethylpropionamide;

[0291] Example B11. 3-{[(1R,3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}cyclopentyl]oxy}-N-ethylpropionamide;

[0292] Example B12. 3-[5-Cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0293] Example B13. 3-[5-Cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1-[(3S)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0294] Example B14. 1-[(3S)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}piperidin-1-yl]propan-1-one;

[0295] Example B15. 1-[(3R)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}piperidin-1-yl]propan-1-one;

[0296] Example B16. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethylcyclobutane-1-carboxamide;

[0297] Example B17. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethyl-N-methylcyclobutane-1-carboxamide;

[0298] Example B18. (1r,3r)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-ethyl-N-methylcyclobutane-1-carboxamide;

[0299] Example B19. (1r,3r)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-N-ethylcyclobutane-1-carboxamide;

[0300] Example B20. (1r,3r)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutane-1-carboxylic acid;

[0301] Example B21. (1s,3s)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-N-ethylcyclobutane-1-carboxamide;

[0302] Example B22. (1s,3s)-3-{4-amino-3-[5-cyclopropyl-4-(pyridin-2-yl)-1,2-oxazol-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-N-[2-(2-aminoethoxy)ethyl]cyclobutane-1-carboxamide;

[0303] Example B23. 1-[(1R,3R)-3-(2-aminoethoxy)cyclopentyl]-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0304] Example B24. 1-[(1S,3R)-3-(2-aminoethoxy)cyclopentyl]-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0305] Example B25. N-(2-{[(1R,3R)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclopentyl]oxy}ethyl)propionamide;

[0306] Example B26. N-(2-{[(1R,3S)-3-[4-amino-3-(5-cyclopropyl-1,2-oxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclopentyl]oxy}ethyl)propionamide; Example A12. Synthesis of 3-[5-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione Step A. 3-(5-Cyclopropylisoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine.

[0307] To a mixture of 3-(5-cyclopropylisoxazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (5.g, 20.64mmol) and 2-bromopropane (2.79g, 22.7mmol) in DMF (60mL) was added K2CO3 (26.83g, 82.56mmol). The resulting mixture was stirred at 80°C for 2h. After completion, the resulting solution was quenched with ice water, extracted with EtOAc and washed with brine. The extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain 3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (5.5g, 93.7% yield) as a light yellow solid crude product. Analytical LCMS: m / z 285.2[M+H] + , RT = 0.91 min (Method Q). Step B. 3-(5-Cyclopropyl-4-iodo-isoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine.

[0308] To a mixture of 3-(5-cyclopropylisoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (5 g, 17.59 mmol) and N-iodosuccinimide (5.93 g, 26.38 mmol) in MeCN (50 mL) was added TFA (10 mL, 130.59 mmol). The resulting mixture was stirred at room temperature overnight. After completion, the resulting solution was concentrated. The residue was purified by silica gel column chromatography (PE / EA=1:1) to obtain 3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (5.5 g, 76.2% yield) as an off-white solid. Analytical LCMS: m / z 411.2[M+H] + , RT = 1.00 min (Method Q). Step C. tert-Butyl 4-(4-iodoimidazol-1-yl)piperidine-1-carboxylate.

[0309] To a mixture of tert-butyl 4-methylsulfonyloxypiperidine-1-formate (10 g, 35.8 mmol) and 4-iodo-1H-imidazoles (10.42 g, 53.7 mmol) in MeCN (250 mL), CsCO(34.9 g, 107.39 mmol) was added, and the resulting mixture was stirred at 80 °C for 3 h. After completion, the mixture was cooled at room temperature. The resulting mixture was filtered, the filter cake was washed with ACN (10 mL x 2), and the filtrate was concentrated. The crude product was first purified by reverse phase flash chromatography and then by PREP-SFC (column: DAICEL DCpak P4VP, 3*25 cm, 5 μm; mobile phase A: CO 2 , mobile phase B: MeOH (0.5% 2M NH 3 -MeOH); flow rate: 100 mL / min; gradient: isocratic 15% B; column temperature (° C.): 35; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 2.18; RT2 (min): 2.85; sample solvent: MEOH (0.1% 2M NH 3 -MEOH); injection volume: 2 mL; number of runs: 75) to obtain tert-butyl 4-(4-iodoimidazol-1-yl)piperidine-1-carboxylate (3.8 g, 28.1% yield) as a white solid. Analytical LCMS: m / z 378.2 [M+H] + , RT = 0.97 min (Method Q). The structure of the desired compound was confirmed by the NOE correlation observed between the proton at the C-5 position of the imidazole ring and the proton at the C-3' (5') position of the piperidine ring. Step D. tert-Butyl 4-(4-tributylstannylimidazol-1-yl)piperidine-1-carboxylate

[0310] To a mixture of tert-butyl 4-(4-iodoimidazole-1-yl)piperidine-1-formate (1000 mg, 2.65 mmol) in THF (20 mL) was added dropwise i-PrMgCl (2 M, 2 mL, 4 mmol) in THF at -20 ° C. Tributyl(chloro)stannane (949.21 mg, 2.92 mmol) was then added to the above reaction mixture. After stirring for 1 h at -20 ° C, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to obtain tert-butyl 4-(4-tributylstannylimidazol-1-yl)piperidine-1-formate (600 mg, 41.9% yield) as a light yellow oil. MS: m / z: 542.3 [M+H] + . Step E. 4-[4-[3-(4-Amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-5-cyclopropyl-isoxazol-4-yl]imidazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester

[0311] In a 20 ml microwave vial, tert-butyl 4-(4-tributylstannylimidazol-1-yl)piperidine-1-carboxylate (1053.84 mg, 1.95 mmol), 3-(5-cyclopropyl-4-iodo-isoxazol-3-yl)-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 0.98 mmol), PdCl2[P(cy)3]2 (73.82 mg, 0.10 mmol) and CsF (370.54 mg, 2.44 mmol) were suspended in toluene (9 mL). The mixture was stirred at 100 ° C. under N2 for 60 h. It was filtered, concentrated and purified by preparative TLC and then by preparative HPLC to afford tert-butyl 4-[4-[3-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-5-cyclopropyl-isoxazol-4-yl]imidazol-1-yl]piperidine-1-carboxylate (560 mg, 70% yield) as a white solid. Analytical LCMS: m / z 534.3 [M+H] + , RT = 1.17 min (Method Q). Step F. 3-[5-Cyclopropyl-4-[1-(4-piperidinyl)imidazol-4-yl]isoxazol-3-yl]-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine

[0312] To a solution of tert-butyl 4-[4-[3-(4-amino-1-isopropyl-pyrazolo[3,4-d]pyrimidin-3-yl)-5-cyclopropyl-isoxazol-4-yl]imidazol-1-yl]piperidine-1-carboxylate (1800 mg, 3.37 mmol) in DCM (30 mL) was added TFA (10.0 mL) and the mixture was stirred at room temperature for 2 h. The reaction was concentrated and the crude product was purified by reverse phase flash chromatography (0.5% TFA in water / ACN) to afford 3-[5-cyclopropyl-4-[1-(4-piperidinyl)imidazol-4-yl]isoxazol-3-yl]-1-isopropyl-pyrazolo[3,4-d]pyrimidin-4-amine (990.1 mg, 66% yield) as an off-white solid. Analytical LCMS: m / z 434.3 [M+H] + , RT = 1.03 min (Method Q). 1 H NMR (300MHz, DMSO-d6) δ9.41 (s, 1H), 8.36 (s, 1H), 8.14 (d, J = 1.6Hz, 1H), 5.10-4.90 (m, 1H), 4.81-4.65 (m, 1H), 3.5 8-3.47(m,2H),3.19-3.06(m,2H),2.47-2.28(m,3H),2.22-2.02(m,2H),1.30(d,J=6.6Hz,6H),1.28-1.13(m,4H). Step G. 3-[5-(4-{7-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]-7-oxoheptyl}piperazin-1-yl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione.

[0313] 3-(5-Cyclopropyl-4-(1-(piperidin-4-yl)-1H-imidazol-4-yl)isoxazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 2TFA (308 mg) was dissolved in 4.5 ml of DMF, and BOP (247 mg) was dissolved in DMF (4.5 mL). To each reaction vial containing the acidic component was added 3-(5-cyclopropyl-4-(1-(piperidin-4-yl)-1H-imidazol-4-yl)isoxazol-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, 2TFA (0.100 ml, 10.84 μmol), BOP (0.099 ml, 0.013 mmol), and DIEA (0.011 ml, 0.065 mmol). The mixture was then placed in a Bohdan Miniblock XT and stirred at 400 rpm overnight at room temperature. The crude material was diluted with 1.5 ml of DMF and a drop of AcOH and submitted for final purification by RP preparative HPLC to obtain the title compound. The recovered amount of the product was 4.2 mg, and its purity estimated by reverse phase analysis was 97.1%. The crude material was purified by preparative reverse phase chromatography using the following conditions: column: XBridge C18, 19 mm x 200 mm, 5 μm particles; flow rate: 20 mL / min; column temperature: 25 ° C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). The fractions containing the desired product were combined and dried via centrifugal evaporation. HPLC conditions: Mobile phase A (ACN / H2O (5:95), containing 10 mM AA), Mobile phase B (ACN / H2O (95:5), containing 10 mM AA): from 75% A and 25% B at 0 min to 55% A and 45% B at 20 min, then hold at 100% B for 4 min. Analytical LCMS: m / z 872.3 [M+H] + , RT = 1.55 min, purity: 97.1% (Method A); m / z 872.3 [M+H] + , RT=1.08 min, purity: 97.9% (Method B). 1H NMR(500MHz,DMSO-d6)δ8.23(s,1H),7.95-7.82(m,3H),7.80(s,1H),7.52(d,J=8.6Hz,1H),7.07-7.00(m,2H),5.13-5.00(m ,2H),4.59-4.50(m,1H),4.43-4.37(m,1H),4.35-4.28(m,1H),4.25-4.17(m,1H),4.06-3.97(m,1H),3.49(brs,1H),3.25(br s,2H),3.22-3.10(m,1H),3.06-2.97(m,1H),2.93-2.84(m,1H),2.67(brd,J=15.1Hz,1H),2.59(br dd,J=17.4,2.3Hz,1H),2.49-2.27(m,9H),2.13-2.00(m,2H),2.00-1.94(m,1H),1.91(s,1H),1.83-1.63(m,2H),1.55-1.49(m,2H),1.45(br d,J=6.1Hz,8H),1.31(br s,4H),1.27(br s,1H),1.20-1.07(m,4H).

[0314] The following examples as shown in Table 4 were prepared according to the preparation of Example A12. Table 4. Characterization of Examples A13-A19

[0315] Following similar synthetic procedures as shown in Example A12 Steps A to F, the following target binding moieties (TBMs) containing amino or carboxylic acid groups or their corresponding ethylamides were synthesized.

[0316] Example B27. 3-[4-(4-aminocyclohexyl)-5-cyclopropyl-1,2-oxazol-3-yl]-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0317] Example B28. 3-{4-[1-(4-aminobutyl)-1H-imidazol-4-yl]-5-cyclopropyl-1,2-oxazol-3-yl}-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine;

[0318] Example B29. N-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}cyclohexyl)propionamide;

[0319] Example B30. N-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)butyl]propionamide;

[0320] Example B31. 1-[4-(4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-1H-imidazol-1-yl)piperidin-1-yl]propan-1-one;

[0321] Example B32. 3-[4-Amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazole-4-carboxylic acid;

[0322] Example B33. 3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-N-(2-aminoethyl)-5-cyclopropyl-1,2-oxazole-4-carboxamide;

[0323] Example B34. 4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}-N-(2-aminoethyl)cyclohexane-1-carboxamide;

[0324] Example B35. (1s,4s)-4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}cyclohexane-1-carboxylic acid;

[0325] Example B36. (1r,4r)-4-{3-[4-amino-1-(propan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-cyclopropyl-1,2-oxazol-4-yl}cyclohexane-1-carboxylic acid; Example A20. 1-{4-[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptylamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4- Synthesis of Methoxypiperidine-4-carboxamide Step A. (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (A2DF5-107)

[0326] In a 500 ml round-bottom flask, 2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (4.38 g, 17.96 mmol), (S)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (5.20 g, 14.97 mmol) and DIPEA (20.92 mL, 120 mmol) were placed in butan-1-ol (50 mL) to give a solution. The reaction mixture was heated to 70° C. with stirring overnight. 2,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.644 g, 6.74 mmol) was added. After 2 h, the reaction was cooled and evaporated under reduced pressure and dried under high vacuum. The crude product was dissolved in a small amount of DCM and loaded onto a 220 g silica gel cartridge, which was eluted with a gradient from 0% to 100% Hex / EtOAc over 15 column volumes to afford (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (4.2 g, 50.6%). Analytical LCMS: m / z 555.1 [M+H] + , RT = 1.33 min (UHPLC method D). Step B. (S)-tert-Butyl(4-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)butyl)carbamate

[0327] In a 5 ml screw cap vial, tert-butyl but-3-yn-1-ylcarbamate (1.375 mL, 7.93 mmol), (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (1100 mg, 1.982 mmol), TEA (1.381 mL, 9.91 mmol) and copper(I) iodide (151 mg, 0.793 mmol) were placed in MeOH (50 mL) to give a suspension. During the subsequent addition, nitrogen was bubbled through the solution. Bis(triphenylphosphine)palladium(II)dichloride (278 mg, 0.396 mmol) was added. The reaction mixture was heated to 110° C. with stirring. After 3h, the reactant is distributed with ethyl acetate (200mL) and 10% LiCl aqueous solution (100mL). The organic phase merged is washed with saturated NH4Cl (50mL). The organic layer is dried with Na2SO4, filtered and concentrated. The crude product is dissolved in a small amount of DCM and loaded on 80g silica gel cartridges, which are eluted with 15 column volumes from 0% to 5%CH2Cl2 / MeOH gradient. Required fractions are merged and the gained solid is diluted with MeOH (50mL). Pd-C (5% wet C) (500mg, 0.235mmol) is added. The reaction is vacuum purged three times, purged three times with nitrogen, then purged three times with vacuum and hydrogen. Then it is stirred at 60 ℃ under hydrogen and spend the night. The reaction mixture is filtered on diatomite. Pd-C (5% wet C) (500mg, 0.235mmol) is added to the filtrate. It is heated to 60 ℃ and continues for 6h under H2. The reaction mixture was filtered on celite and evaporated under reduced pressure. The crude product was dissolved in a small amount of DCM and loaded on an 80 g silica gel cartridge, which was eluted with a gradient of 0% to 5% CH2Cl2 / MeOH over 15 column volumes to afford (S)-(4-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)butyl)carbamic acid tert-butyl ester (1.3 g, 95%) as an off-white solid. Analytical LCMS: m / z 692.3 [M+H] + , RT = 1.71 min, purity: 100% (method B); m / z 692.4 [M+H] + , RT=2.13 min, purity: 100% (Method A). 1H NMR(500MHz,DMSO-d6)δ9.26-9.13(m,1H),8.73-8.65(m,1H),8.55-8.48(m,1H),8.46-8.41 (m,1H),8.04-7.97(m,1H),7.95-7.85(m,2H),6.84-6.70(m,1H),5.15-5.00(m,1H),4.42-4 0.26 (m, 2H), 3.23-3.10 (m, 3H), 2.98-2.87 (m, 2H), 2.41-2.31 (m, 2H), 2.26-2.17 (m, 3H), 1.95-1.88 (m, 1H), 1.88-1.67 (m, 4H), 1.63-1.53 ​​(m, 2H), 1.52-1.46 (m, 3H), 1.46-1.33 (m, 12H). One CH3 was lost due to water seal suppression. Step C. (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide

[0328] In a 100 ml round-bottom flask was placed (S)-tert-butyl(4-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)butyl)carbamate (240 mg, 0.347 mmol) in MeOH (1 mL) and DCM (10 mL) to give a solution. HCl (4N in dioxane) (2 mL, 8.00 mmol) was added. The reaction was stirred at room temperature for 1 h. It was evaporated under reduced pressure and dried under high vacuum.

[0329] The reaction mixture was diluted 3 times with MeOH (1 mL x) and evaporated, dried under high vacuum to give crude (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide, 2HCl (225 mg, 98%), which was used as is without further purification. Analytical LCMS: m / z 592.4 [M+H] + , RT = 1.05 min (UHPLC method D). Step D. 1-{4-[4-(7-{4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}heptylamido)butyl]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide.

[0330] (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide, 2HCl (308.0 mg) was dissolved in 8.8 mL of DMF. BOP (266.5 mg) was dissolved in 4.4 mL of DMF. To each reaction vial containing the amine component was added the above (S)-1-(4-(4-aminobutyl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide, 2HCl (0.199 mL, 10.53 μmol), BOP (0.099 ml, 0.014 mmol) and DIEA (0.011 mL, 0.063 mmol). The mixture was then placed in a Bohdan Miniblock XT and stirred at 400 rpm overnight at room temperature. The crude material was diluted with 1.5 ml of DMF / MeOH (2: 1) and submitted for final purification. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water (with 0.05% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (with 0.05% trifluoroacetic acid); Gradient: 13% B for 0 min, 13% to 53% B over 20 min, then 100% B for 0 min; Flow rate: 20 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation. The yield of product was 3.0 mg. Analytical LCMS: m / z 1030.40 [M+H] + , RT = 1.38 min, purity: 93.3% (Method B); m / z 1030.30 [M+H] + , RT=1.62 min, purity: 86.6% (Method A). 1H NMR (500MHz, DMSO-d6) δ10.96(s,1H),8.66(d,J=4.3Hz,1H),8.57(brd,J=7.9Hz,1H),8.50-8.35(m,2H),7.99( dd,J=8.5,1.8Hz,1H),7.91(d,J=4.0Hz,1H),7.88(d,J=8.5Hz,1H),7.84-7.72(m,1H),7.60(d,J=8.5Hz,1H),7. 29(s,1H),7.22-7.11(m,2H),5.17-5.01(m,2H),4.45-4.30(m,1H),4.30-4.15(m,2H),3.22-3.03(m,5H),3.00( s,2H),2.98-2.79(m,3H),2.69(s,1H),2.65-2.57(m,2H),2.55(DMSO),2.49-2.30(m,2H),2.24(s,3H),2.06(br t,J=7.5Hz,2H),2.02-1.80(m,4H),1.66(br s,2H),1.64-1.42(m,9H),1.34-1.15(m,9H). Example A21. 1-(4-{4-[(8-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}octyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidine-2-yl 1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine Synthesis of 4-formamide Step A. (S)-Ethyl 5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoate

[0331]

[0147] In a 5 ml screw cap vial, ethyl pent-4-ynoate (1.055 mL, 8.36 mmol), (S)-1-(4-chloro-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-N-(1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-4-methoxypiperidine-4-carboxamide (1160 mg, 2.09 mmol), TEA (1.457 mL, 10.45 mmol) and copper(I) iodide (159 mg, 0.836 mmol) were placed in MeOH (50 mL) to give a suspension. During the subsequent addition, nitrogen was bubbled through the solution. Bis(triphenylphosphine)palladium(II)dichloride (293 mg, 0.418 mmol) was added. The reaction mixture was heated to 110°C with stirring. At 4 DEG C, 80 DEG C of 40 DEG C, 100mL ethyl acetate (200mL) and 10%LiCl aqueous solution (100mL) are distributed.With the organic phase merging with saturated NH Cl (50mL) washing.With organic layer Na SO Drying, filter and concentrate.Crude product is dissolved among a small amount of DCM and is loaded on 80g silica gel cartridge, with it with 15 column volumes from 0% to 5% CH Cl / MeOH gradient elution.

[0332] The required fractions are merged and the obtained solid is diluted with MeOH (50mL). Pd-C (5% wet C) (500mg, 0.235mmol) is added. The reaction is vacuum purged three times, purged three times with nitrogen, and then purged three times with vacuum and hydrogen. It is then stirred at 60 ℃ under hydrogen and spent the night. The reaction mixture is filtered on diatomaceous earth. Pd-C (5% wet C) (500mg, 0.235mmol) is added to the filtrate. It is heated to 60 ℃ and spent the night under H2. The reaction mixture is filtered on diatomaceous earth and evaporated under reduced pressure. The crude product was dissolved in a small amount of DCM and loaded onto an 80 g silica gel cartridge, which was eluted with a gradient of 0% to 5% CHCl / MeOH over 15 column volumes to afford (S)-ethyl 5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoate (600 mg, 46.1%). Analytical LCMS: m / z 649.20 [M+H] + , RT = 1.69 min, purity: 97.6% (Method B); m / z 649.20 [M+H] + , RT=2.14 min, purity: 98.2% (Method A). 1H NMR (500MHz, DMSO-d6) δ9.16 (br s, 1H), 8.66 (d, J = 4.3Hz, 1H), 8.49 (br d,J=8.2Hz,1H),8.45-8.39(m,1H),7.97(dd,J=8.4,2.0Hz,1H),7.93-7.84(m,2H),6.31-6.14(m,1H),6.10(br s,1H),5.04(br t,J=7.3Hz,1H),4.32(br dd,J=17.5,13.9Hz,2H),4.03(q,J=7.1Hz,2H),3.23-3.08(m,4H),2.55(s,5H),2.41-2.25(m,4 H),2.19(s,3H),1.92(s,1H),1.85-1.74(m,3H),1.74-1.65(m,1H),1.62-1.51(m,4H),1.47(br d,J=7.0Hz,3H),1.15(t,J=7.0Hz,3H) Step B. (S)-5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoic acid

[0333] In a 100 ml round-bottom flask was placed (S)-ethyl 5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoate (600 mg, 0.925 mmol) and NaOH (2.5 N) (3.70 mL, 9.25 mmol) in THF (15 mL) to give a solution. The mixture was heated to 50° C. overnight. The reaction was partitioned between DCM (10% MeOH) (100 mL) and brine (50 mL), and the aqueous phase was extracted with DCM (10% MeOH) (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give crude (S)-5-(2-(4-((1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)carbamoyl)-4-methoxypiperidin-1-yl)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)pentanoic acid (485 mg, 84%) which was used as is without further purification. Analytical LCMS: m / z 621.20 [M+H] +, RT = 1.36 min (method B); 1 H NMR (500MHz, DMSO-d6) δ8.66(d,J=4.6Hz,1H),8.50(br d,J=7.9Hz,1H),8.46-8.38(m,1H),7.98(dd,J=8.5,2.1Hz,1H),7.93-7.85(m,2H),5.05(br t,J=7.3Hz,1H),4.40-4.18(m,2H),3.16(s,2H),3.00(s,1H),2.55(s,5H),2.49- 2.32(m,2H),2.31-2.11(m,5H),1.92(s,1H),1.88-1.67(m,4H),1.62-1.43(m,7H) Step C. 1-(4-{4-[(8-{[4-(2,6-dioxopiperidin-3-yl)phenyl]amino}octyl)carbamoyl]butyl}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)-N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl]-4-methoxypiperidine-4-carboxamide.

[0334] Following a similar procedure as described in step D of Example A20, the title compound was obtained. Analytical LCMS: m / z 934.4 [M+H] + , RT = 1.99 min, purity: 100% (method A); 1H NMR(500MHz,DMSO-d6)δ10.90-10.71(m,2H),8.66(br s,1H),8.63-8.52(m,1H),8.45-8.26(m,2H),8.05-7.84(m,3H),7.83-7.6 8(m,1H),7.44-7.26(m,2H),7.26-7.16(m,2H),7.15-7.02(m,2H),6.92(br d,J=6.7Hz,2H),6.67-6.49(m,2H),5.19-4.99(m,1H),4.35-4.14(m,2H),3.77-3.59(m,1H),3.57-3.34(m,2H),3.22(br s,1H),3.17(br s,2H),3.07-2.88(m,5H),2.64(br d,J=1.8Hz,1H),2.59(br s,1H),2.57-2.54(DMSO),2.48-2.34(m,2H),2.31-2.18(m,3H),2.12-2.04(m,3H),2.02-1.84(m,4H),1.60(br s,1H),1.55(br s,3H),1.52-1.41(m,5H),1.39-1.28(m,4H),1.24(br s,5H),1.21-0.99(m,5H)

[0335] The following examples as shown in Table 5 were prepared according to the preparation of Example A20 and Example A21. Table 5. Characterization of Examples A22-A28 Example A29. Synthesis of 9-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]nonanamide Step A. tert-Butyl (4-(6-bromopyridin-3-yl)-4-oxobutyl)carbamate.

[0336] At -78 DEG C, nBuLi (1.6M, 23.74mL, 38.0mmol) in THF is added dropwise to a stirred solution of 2,5-dibromopyridine (7.5g, 31.7mmol) in ether (105mL) and tetrahydrofuran (45mL). The resulting mixture is stirred for 45min at -78 DEG C. Then, a solution of 2-oxopyrrolidine-1-tert-butyl formates (5.86g, 31.7mmol) in tetrahydrofuran (50mL) is added and stirred for 30min at -78 DEG C. The reaction is monitored by TLC. The reaction mixture is quenched with saturated NH4Cl solution (50mL) and diluted with water (100mL) and extracted with ethyl acetate (2x 150mL). The organic layer merged is washed with saturated saline solution (200mL), through anhydrous Na2SO4 drying, filtered and concentrated under reduced pressure. The crude products obtained from two other batches were mixed and purified by column chromatography (Biotage isolera, 120g+50snap, dry filler) by eluting with 30%-40% ethyl acetate in petroleum ether. The desired fractions were combined and concentrated under reduced pressure. The obtained crude product was ground together with 10% ethyl acetate to obtain tert-butyl (4-(6-bromopyridin-3-yl)-4-oxobutyl)carbamate (9 g, 61.1% yield) as a light brown solid. LCMS: RT=2.078 min (ACN / H2O (containing 5 mm ammonium formate), Kinetex XB-C18 (75x 3.0) mm, 2.6 μm, gradient 5 min, wavelength=220 nm); MS (ES): m / z=288.8 [M+H] + (tert-butyl fragment mass). Step B. tert-Butyl (4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-oxobutyl)carbamate

[0337] At ambient temperature, (4-(6-bromopyridin-3-yl)-4-oxobutyl) tert-butyl carbamate (9g, 26.2mmol) is added to the fluoro-1H-pyrazoles of 4- (2.48g, 28.8mmol) and K cO (9.06g, 65.6mmol) in the stirred suspension in DMF (150mL). The gained mixture is heated to 100 ℃ and stirred for 16h at said temperature. The reaction is monitored by UPLC. The reaction mixture is concentrated under reduced pressure. The residue obtained is diluted with water (200mL) and extracted with ethyl acetate (2x 200mL). The organic layer merged is washed with saturated saline solution (200mL), through anhydrous Na sO dried, filtered and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (Biotage isolera, 100+50g snap, dry packing) on ​​silica gel (230-400 mesh) by eluting with 40%-50% ethyl acetate in petroleum ether. The desired fractions were combined and concentrated under reduced pressure, and the obtained residue was ground together with 10% ethyl acetate in petroleum ether to obtain tert-butyl (4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-oxobutyl)carbamate (4.85 g, 46.9% yield) as a light brown solid. LCMS: RT=2.46 min (ACN / H2O (containing 5 mm ammonium formate), Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm, gradient 5 min, wavelength = 220 nm); MS (ES): m / z = 292.9 [M+H] + (tert-butyl fragment mass). Step C. tert-Butyl ((S)-4-(((R)-tert-Butylsulfinyl)amino)-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate

[0338] Titanate (IV) ethyl ester (1.350mL, 5.74mmol) is added to a stirred solution of (4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-oxobutyl)carbamate (1g, 2.87mmol) and (R)-2-methylpropane-2-sulfinamide (0.348g, 2.87mmol) in tetrahydrofuran (20mL) at ambient temperature. The resulting mixture is heated to 75°C and stirred at said temperature for 16h. The reaction is monitored by TLC. The reaction mixture is cooled to -78°C, then 1M lithium tri-sec-butylborohydride (L-selectride, 8.61mL, 8.61mmol) in THF is added dropwise over a period of 5min. The reaction mixture is allowed to reach 0°C and stirred at said temperature for 10min. The reaction mixture is cooled to -50°C, quenched with methanol (5mL), poured into water (60mL) and stirred for 15min. The 1-H-pyridine-1-yl) 4-(6-(4-fluoro-1H-pyrazole-1-yl) pyridin-3-yl) butyl) t-butyl carbamate (730mg, 54.6% productive rate) of the organic layer saturated brine solution (100mL) of merging is washed, through anhydrous Na SO Drying is filtered and is under reduced pressure concentrated.The crude product obtained is passed through column chromatography (Biotage isolera, 50g snap, dry filler) on silica gel (230-400 mesh) by being eluted with 90%-100% ethyl acetate in petroleum ether and purifying.Required fraction is merged together and is under reduced pressure concentrated, to obtain ((S)-4-(((R)-tert-butylsulfinyl) amino)-4-(6-(4-fluoro-1H-pyrazole-1-yl) pyridin-3-yl) butyl) t-butyl carbamate (730mg, 54.6% productive rate) in light brown solid. LCMS: RT = 2.35 min (ACN / H2O (containing 5 mm ammonium formate), Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm, gradient 5 min, wavelength = 220 nm); MS (ES): m / z = 452.4 [MH] - Step D. (S)-tert-Butyl(4-amino-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate

[0339] At 0 ℃, 1.25M HCl (1.29mL, 1.61mmol) in MeOH is added to the stirred solution of ((S)-4-(((R)-tert-butylsulfinyl) amino)-4-(6-(4-fluoro-1H-pyrazole-1-yl) pyridin-3-yl) butyl) tert-butyl carbamate (730mg, 1.609mmol) in methyl alcohol (15mL).Allow the gained mixture to reach ambience temperature through the time period of 1h and stir 1h at described temperature.By TLC monitoring reaction, starting material is exhausted.Reaction mixture is diluted with water (80mL), uses 10% NaHCO solution alkalizes and is extracted with ethyl acetate (2x 100mL). The combined organic layers were washed with saturated brine solution (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford tert-butyl (S)-(4-amino-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate (550 mg, 82% yield) as a light brown gum. LCMS: RT = 1.11 min (ACN / H0 (with 5 mm ammonium formate), Kinetex XB-C18 (75 x 3.0) mm, 2.6 μm, gradient 5 min, wavelength = 220 nm); MS (ES): m / z = 350.1 [M+H] + . Step E. (S)-tert-Butyl(4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-(4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamido)butyl)carbamate

[0340] To a stirred solution of (S)-tert-butyl(4-amino-4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)carbamate (2.2 g, 6.30 mmol), 4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid, lithium salt (2.67 g, 7.56 mmol) and triethylamine (3.51 mL, 25.2 mmol) in N,N-dimethylformamide (30 mL) at 0°C was added TBTU (4.04 g, 12.59 mmol). The resulting mixture was stirred at ambient temperature for 16 h. The reaction mixtures from two other batches were combined, diluted with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The organic layer that is combined is washed with water (150mL), saturated saline solution (50mL), through anhydrous Na SO Drying, filter and under reduced pressure concentrate.The crude product that is obtained is purified by column chromatography (Biotage isolera, 120g snap) by eluting with 80%-100% ethyl acetate in petroleum ether.Required fractions are merged together and under reduced pressure concentrate.Gained residue is purified by column chromatography (Biotage isolera, 120g snap) by eluting with 4%-5% methanol in dichloromethane.Required fractions are merged together and under reduced pressure are concentrated into two fractions (4g).It is further purified as eluent by reverse phase column chromatography (combi flash) by using ammonium formate in water and ACN.Required fractions are collected into three fractions.Acetonitrile is removed under reduced pressure; The residual water layer is alkalized with 10% NaHCO solution and extracted (2x) with 5% methanol in dichloromethane. The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the desired product, (S)-tert-butyl(4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-(4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamido)butyl)carbamate (2.99 g) MS: m / z 678.2 [M+H] + . Step F. (S)-N-(4-amino-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)-4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamide, HCl

[0341] 4 M HCl in dioxane (1.881 mL, 7.52 mmol) was added to a stirred solution of tert-butyl (S)-(4-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)-4-(4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamido)butyl)carbamate (1.02 g, 1.505 mmol) in dichloromethane (20 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure and then lyophilized to give (S)-N-(4-amino-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)butyl)-4-methoxy-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperidine-4-carboxamide, HCl as a light yellow solid. LCMS: RT = 1.65 min (ACN / HO (with TFA), XBridge C8 (50 x 4.6 mm) 5 μm, gradient 6 min, wavelength = 220 nm); MS (ES): m / z = 578.2 [M+H] + HPLC purity: 90 / 10 to 10 / 90 H2O / ACN / 0.05% TFA, flow rate = 1 mL / min, gradient 15 min, Kinetex EVO C18 (100X4.6) mm, 2.6 μm, RT = 7.09 min, purity: 97.0%, Kinetex Biphenyl (100X4.6) mm, 2.6 μm, RT = 4.34 min, purity: 96.9%. 1 H-NMR: 400MHz (DMSO-d6): δ12.19 (brs, 1H), 11.05 (brs, 1H), 8.68 (d, J = 4.80Hz, 2H), 8.46 ( d,J=2.00Hz,2H),8.18-8.05(m,2H),8.04-8.01(m,1H),7.95-7.86(m,2H),6.34(s,1H),6.1 7(s,1H),4.98-4.89(m,1H),4.43-4.28(m,2H),3.48-3.32(m,2H),3.18(s,3H),2.83-2.78 (m,2H),2.37(s,3H),2.25(s,3H),2.03-1.79(m,6H),1.73-1.68(m,1H),1.61-1.51(m,1H). Step G. 9-{[3-(2,6-dioxopiperidin-3-yl)phenyl]amino}-N-[(4S)-4-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]nonanamide.

[0342] Following a similar procedure as described in step D of Example A20, the title compound was obtained. Analytical LCMS: m / z 920.4 [M+H] + , RT = 1.95 min, purity: 100% (method A); 1 H NMR (500MHz, DMSO-d6) δ10.77(s,1H),9.31-9.12(m,1H),8.67-8.64(m,1H),8.52(br d,J=8.7Hz,1H),8.42(s,1H),7.98(br d,J=8.5Hz,1H),7.91-7.85(m,2H),7.76(br s,1H),7.00(t,J=7.7Hz,1H),6.42(br d,J=8.2Hz,1H),6.39-6.32(m,2H),6.27-6.05(m,2H),4.93-4.87(m,1H),4.35-4.25(m,2H),3.90(d,J=2.1Hz,1H),3.67(br dd,J=9.5,4.8Hz,1H),3.43-3.36(m,2H),3.22-3.00(m,5H),2.92(br s,2H),2.66-2.56(m,2H),2.55(DMSO),2.49-2.33(m,2H),2.20-1.98(m,10H),1.92- 1.74(m,4H),1.74-1.64(m,2H),1.54-1.45(m,5H),1.45-1.27(m,4H),1.23(brs,6H).

[0343] The following examples as shown in Table 6 were prepared according to the preparation of Example A29. Table 6. Characterization of Examples A30-A34

[0344] According to a similar synthetic procedure as shown in Example A29 steps A to F, the following target binding moieties (TBMs) containing an amino group or its corresponding ethylamide were synthesized.

[0345] Example B37. N-[(S)-(azetidin-3-yl)[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]methyl]-4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidine-4-carboxamide

[0346] Example B38. N-[(S)-[6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl](1-propionylazetidin-3-yl)methyl]-4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidine-4-carboxamide

[0347] Example B39. N-[(4S)-4-[6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl]-4-[(4-methoxy-1-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}piperidin-4-yl)formamido]butyl]propanamide Cellular RET degradation assay

[0348] A bead-based luminescent amplification assay, the AlphaLISASurefire Ultra detection kit (Perkin-Elmer), was used to determine the potency of cellular RET degradation compounds. A papillary thyroid carcinoma (TPC-1) cell line expressing the CCDC6-RET fusion was selected for screening potential degraders: parent (TPC-1 / CCDC6-RET). Cells were plated at 10,000 cells / well in 50ul / well of DMEM (Fisher Scientific) containing 2% FBS serum (Gibco) in a 384-well culture plate (Greiner Bio-One). After cell adhesion (4h), cells were treated with compounds by dispensing 25nl of serially diluted compounds (1:3 dilution: 11 points) directly into the cell culture wells using an Echo-655 acoustic liquid dispenser (Beckman). Low normalization wells were culture medium only, and high normalization wells were cells treated with DMSO only. The treated cell plates were placed in a 37°C and 5% CO2 incubator for 24h. At 24 h, the cell culture medium was removed by a FELIX automated liquid handler (Analytik Jena), and 25 ul cell lysis buffer (provided in the AlphaLisa test kit) was added to each well. 5 ul cell lysate was transferred to a 384-well microplate (Perkin Elmer), followed by the addition of 2.5 ul AlphaLISA acceptor bead mixture. The plate was sealed and kept at room temperature for 1 h, followed by the addition of donor beads. Donor beads were added in the dark and incubated for >1 h, followed by measurement of AlphaLISA luminescence (excitation 680 nm, emission 615 nm) on an Envision plate reader with an Alphascreen aperture at room temperature. RET protein abundance (and therefore degradation) directly corresponds to luminescence intensity.

[0349] The intensity was normalized to the mean of 16 wells containing medium only (blank - low) and 16 wells containing cells + DMSO (high). The % degradation for each well was determined using the standard equation, where DC for each compound tested 50 (IC50) values ​​were calculated by analyzing plots of % degradation versus compound concentration and fitting to a standard 4-parameter logistic curve, where The upper and lower limits are the degradation percentages at infinite and infinitesimal compound concentrations, respectively, while the half-maximum (Halfmax) is the compound concentration that produces a degradation percentage corresponding to 1 / 2 the upper limit - the lower limit, and N is the Hill coefficient. DC is calculated according to the following relationship 50 value, Compound replicates were performed in independent assays.Maximum degradation (YMax) was defined as the maximum % degradation value from the 4-parameter logistic equation as described previously. Biological activity.

[0350] Each of the compounds in Table 7 was tested and found to be active in one or more of the degradation assays indicated above (e.g., the tRET AlphaLISA degradation assay using the parental RET TPC-1 cell line). 50 ) are included in Table 7. Table 7. Biological activity data Example No. Cell density TPC-1 / CCDC6-RET IC50 (nM) A1 0.82 A2 3.17 A3 10.16 A4 6.51 A5 9.27 A6 6.42 A7 5.32 A8 17.37 A9 22.02 A11 57.62 A12 1.77 A14 2.02 A16 3.99 A17 43.19 A19 27.77 A29 4.88 A32 0.53 A34 13.17 Listed implementation plans Enumerated embodiments 1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: The inhibitor of RET kinase is a RET kinase inhibitor portion; Ring B is a 4- to 12-membered heterocycloalkyl group, a C3-C8 cycloalkyl group, or is omitted; Ring D is the cereblon binding portion; L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or heteroaryl; L 2 is -C(O)NH-(CH2) p -、-NHC(O)-(CH2) p -、-C(O)NH-(CH2) p -NH-, -NHC(O)-(CH2) p -NH-, -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2CH2O)p -(4- to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)-, -(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)- or -C(O)NH-(CH2) p -NH-; and p is an integer from 1 to 12. Enumerated Embodiment 2. The compound of Enumerated Embodiment 1 having Formula Ia-1 or Formula Ia-2: or a pharmaceutically acceptable salt thereof, in: X 1 Is N or CR 1 ; R 1 is H, halogen or C1-C3 alkyl; R 2 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 aryl or 4- to 12-membered heteroaryl; R 3 It is C3-C8 alkyl, C3-C8 cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 10 aryl or 4- to 12-membered heteroaryl; Ring D is independently R 5 is H, halogen, CF3, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6' are independently H, or Two R's 6 can together form an oxo group, or Two R's 6' can together form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or Two conjunctive or consecutive R 7The carbon atoms may be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; and m is an integer from 0 to 2. Enumerated Embodiment 3. The compound of Enumerated Embodiment 2 having Formula Ia-3: Enumerated Embodiment 4. The compound of Enumerated Embodiment 2 having Formula Ia-4: Enumerated Embodiment 5. The compound of Enumerated Embodiment 2 having Formula Ia-5: Enumerated Embodiment 6. The compound of Enumerated Embodiment 2 having Formula Ia-6: Enumerated Embodiment 7. The compound of Enumerated Embodiment 2 having Formula Ia-7: Enumerated Embodiment 8. The compound of Enumerated Embodiment 1 having Formula Ib-1 or Formula Ib-2: or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently H, halogen, NR 10 R 11 or C1-C4 alkyl; R 3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R 4 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Ring D is a group selected from the following: R 5 is H, halogen, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6' are independently H, or Two R's 6can together form an oxo group, or Two R's 6' can together form an oxo group; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or Two conjunctive or consecutive R 7 can together form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; and m is an integer from 0 to 2. Enumerated Embodiment 9. The compound of Enumerated Embodiment 8 having Formula Ib-1, Formula Ib-2, Formula Ib-3, or Formula Ib-4: Enumerated Embodiment 10. The compound of Enumerated Embodiment 1, wherein the compound is selected from the group consisting of: Enumerated Embodiment 11. The compound of Enumerated Embodiment 1 selected from the group consisting of: Enumerated Embodiment 12. The compound of Enumerated Embodiment 1 selected from the group consisting of: Enumerated Embodiment 13. The compound of Enumerated Embodiment 1 selected from the group consisting of: Enumerated embodiment 14. A pharmaceutical composition comprising a compound according to any one of enumerated embodiments 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Enumerated embodiment 15. A method of treating a RET-mediated disorder, comprising administering to a patient in need thereof an effective amount of a compound according to any one of enumerated embodiments 1-13, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition. Enumerated embodiment 16. The method of enumerated embodiment 15, wherein the patient is human. Enumerated embodiment 17. The method of any one of enumerated embodiments 15-16, wherein the RET-mediated disorder is cancer. Enumerated embodiment 18. The method of enumerated embodiment 17, wherein the cancer is non-small cell lung cancer. Enumerated Embodiment 19. The method of claim 17, wherein the cancer has metastasized to the brain. Enumerated embodiment 20. The method of any one of enumerated embodiments 15-19, wherein the RET-mediated disorder is mediated by mutant RET. Enumerated embodiment 21. The method of any one of enumerated embodiments 15-19, wherein the RET-mediated disorder is a relapsed or refractory cancer. Enumerated Embodiment 22. A compound according to any one of Enumerated Embodiments 1-17, or a pharmaceutically acceptable salt thereof, for use in treating a RET-mediated disorder, optionally in a pharmaceutical composition. Enumerated embodiment 23. The compound of enumerated embodiment 22, wherein the RET-mediated disorder is cancer. Enumerated Embodiment 24. The compound of Enumerated Embodiment 23, wherein the cancer is non-small cell lung cancer. Enumerated Embodiment 25. The compound of Enumerated Embodiment 24 wherein the cancer has metastasized to the brain. Enumerated embodiment 26. A compound according to any one of enumerated embodiments 22-25, wherein the RET-mediated disorder is mediated by mutant RET. Enumerated embodiment 27. A compound according to any one of enumerated embodiments 22-26, wherein the RET-mediated disorder is a relapsed or refractory cancer. Enumerated Embodiment 28. Use of a compound according to any one of Enumerated Embodiments 1-17, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for treating a RET-mediated disorder. Enumerated embodiment 29. The use of enumerated embodiment 28, wherein the RET-mediated disorder is cancer. Enumerated embodiment 30. The use of enumerated embodiment 29, wherein the cancer is non-small cell lung cancer. Enumerated Embodiment 31. The use of Enumerated Embodiment 29 wherein the cancer has metastasized to the brain. Enumerated embodiment 32. The use of any one of enumerated embodiments 28-30, wherein the RET-mediated disorder is mediated by mutant RET. Enumerated embodiment 33. The use according to any one of enumerated embodiments 28-30, wherein the RET-mediated disorder is a relapsed or refractory cancer. Enumerated Embodiment 34. Use of a compound according to any one of Enumerated Embodiments 1-17, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a RET-mediated disorder, optionally in a pharmaceutical composition. Enumerated embodiment 35. The use of enumerated embodiment 34, wherein the RET-mediated disorder is cancer. Enumerated embodiment 36. The use of enumerated embodiment 34, wherein the cancer is non-small cell lung cancer. Enumerated embodiment 37. The use of enumerated embodiment 34 wherein the cancer has metastasized to the brain. Enumerated embodiment 38. The use of any one of enumerated embodiments 34-37, wherein the RET-mediated disorder is mediated by mutant RET. Enumerated embodiment 39. The use according to any one of enumerated embodiments 34-37, wherein the RET-mediated disorder is a relapsed or refractory cancer.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: The inhibitor of RET kinase is a RET kinase inhibitor portion; Ring B is a 4- to 12-membered heterocycloalkyl group, a C3-C8 cycloalkyl group, or is omitted; Ring D is the cereblon binding portion; L 1 is a bond, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or heteroaryl; L 2 is -C(O)NH-(CH2) p -、-NHC(O)-(CH2) p -、-C(O)NH-(CH2) p -NH-, -NHC(O)-(CH2) p -NH-, -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-, -NHC(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2) p -(4- to 12-membered heterocycloalkyl)-NH-, -C(O)NH-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2CH2O) p -(4- to 12-membered heterocycloalkyl)-, -(OCH2CH2) p -(4- to 12-membered heterocycloalkyl)-, -C(O)-(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)-, -(CH2) p -(4- to 12-membered heterocycloalkyl)-C(O)- or -C(O)NH-(CH2) p -NH-; and p is an integer from 1 to 12.

2. The compound according to claim 1, which has formula Ia-1 or formula Ia-2: or a pharmaceutically acceptable salt thereof, in: X 1 Is N or CR 1 ; R 1 is H, halogen or C1-C3 alkyl; R 2 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 aryl or 4- to 12-membered heteroaryl; R 3 It is C3-C8 alkyl, C3-C8 cycloalkyl, 4 to 12 membered heterocycloalkyl, C6-C 10 aryl or 4- to 12-membered heteroaryl; Ring D is independently R 5 is H, halogen, CF3, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6' are independently H, or Two R's 6 can together form an oxo group, or Two R's 6' Can form an oxo group together; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or Two conjunctive or consecutive R 7 The carbon atoms can be taken together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; and m is an integer from 0 to 2.

3. The compound according to claim 2, which has the formula Ia-3:

4. The compound according to claim 2, which has the formula Ia-4:

5. The compound according to claim 2, which has the formula Ia-5:

6. The compound according to claim 2, which has the formula Ia-6:

7. The compound according to claim 2, which has the formula Ia-7:

8. The compound according to claim 1, wherein the compound has Formula Ib-1 or Formula Ib-2: or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are independently H, halogen, NR 10 R 11 or C1-C4 alkyl; R 3 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R 4 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Ring D is a group selected from the following: R 5 is H, halogen, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6' are independently H, or Two R's 6 can together form an oxo group, or Two R's 6' Can form an oxo group together; R 7 is H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, or Two conjunctive or consecutive R 7 can together form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; and m is an integer from 0 to 2;.

9. The compound of claim 8, wherein the compound has Formula Ib-1, Formula Ib-2, Formula Ib-3, or Formula Ib-4:

10. The compound according to claim 1, wherein the compound is selected from:

11. The compound according to claim 1, wherein the compound is selected from:

12. The compound according to claim 1, wherein the compound is selected from:

13. The compound according to claim 1, wherein the compound is selected from: 14 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method of treating a RET-mediated disorder, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

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

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

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

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

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

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