RET-LDD protein degradation agent

Abstract

The present disclosure relates to compounds that elicit degradation of proteins against the protooncogene tyrosine protein kinase receptor (RET), which may be a wild-type RET or a mutant form of RET, for use in the treatment of diseases and disorders mediated by said proteins and having formula (I). # imgabs0 #

Description

[0001] Related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 422,741, filed on November 4, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure relates to compounds for degradation of the rearranged during transfection (RET) proto-oncogene tyrosine protein kinase receptor. The degraders described herein can be used to treat diseases and conditions associated with RET protein regulation. In particular, the present invention relates to compounds and pharmaceutical compositions that degrade proto-oncogene tyrosine protein kinase receptor (RET) via the ubiquitin proteasome pathway (UPP), methods of using the compounds and pharmaceutical compositions to treat diseases and conditions associated with the RET protein and pathway, and methods of synthesizing the compounds and compositions. Background Art

[0004] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective recognition and removal of damaged, misfolded or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is crucial for the regulation of virtually all cellular processes, including antigen processing, apoptosis, organelle reproductive development, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neuronal and muscle degeneration, morphogenesis of neural networks, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular regulators, ribosome biogenesis and viral infection. The covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases marks proteins for proteasomal degradation, where they are digested into small peptides and ultimately into the constituent amino acids that serve as building blocks for new proteins. Defects in proteasomal degradation are associated with a variety of pathologies, including cancer and other diseases.

[0005] Cereblon forms part of the E3 ubiquitin ligase complex, reacts with damaged DNA binding protein 1, and forms an E3 ubiquitin ligase complex with Cullin 4 and E2-binding protein ROC1 (called RBX1). The function of Cereblon is to select proteins for ubiquitination as a substrate receptor. 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 causessselective degradation of IKZF1 and IKZF3 in multiple myeloma cells" Science, 2014, 343: 301-305).

[0006] The rearranged during transfection (RET) proto-oncogene tyrosine protein kinase receptor is a cell surface tyrosine kinase receptor that is widely recognized for its important role in cell survival, differentiation, proliferation, migration and chemotaxis. RET germline missense point variants and somatic mutations lead to medullary thyroid carcinoma (MTC) and neuroendocrine tumors, while RET fusion proteins, overexpression and copy number gain are present in a wide range of other cancers, such as papillary thyroid carcinoma, pancreatic cancer, melanoma, leukemia, lung adenocarcinoma and breast cancer. (Liu Xuan et al., “RET kinase alterations in targeted cancer therapy”, Cancer Drug Resist, 2020; and Mulligan LM., “RE Trevisited: expanding the oncogenic portfolio”, Nat Rev Cancer., 2014, 14(3), 173–186).

[0007] 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). Selpercatinib treatment of patients with non-small cell lung cancer has been shown to induce RET mutations that are presumed to confer resistance, including RET G810R, RET G810S, and RET G810C mutations.

[0008] 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 many 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).

[0009] Despite these efforts, there remains an unmet need in the art for new RET modulators for treating disorders mediated by RET in hosts in need thereof, including humans. Summary of the Invention

[0010] A first aspect of the present disclosure relates to compounds of formula I:

[0011]

[0012] or a pharmaceutically acceptable salt thereof,

[0013] in

[0014] R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace;

[0015] A is an aryl or heteroaryl group, wherein the aryl or heterocyclic group is optionally replaced by one or more R 9 replace;

[0016] B is a heterocycloalkyl group or a C3-C8 cycloalkyl group;

[0017] L1 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0018] 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)-;

[0019] R 2 It is NR 10 R 11 ;

[0020] R 3 is H, halogen, NH2 or C1-C4 alkyl;

[0021] Each R 4 is independently C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl); or

[0022] Two R on adjacent carbons 4Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;

[0023] R 5 is H, OH, CN, NO2 or C1-C4 alkyl;

[0024] Each R 6 or R 6’ is H; or

[0025] Two R's 6 May combine to form an oxo group; or

[0026] Two R's 6’ Can combine to form oxo groups;

[0027] R 7 、R 8 and R 9 each independently H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or

[0028] Two R on adjacent carbons 7 Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;

[0029] R 10 and R 11 are independently H or C1-C4 alkyl;

[0030] m is an integer from 0 to 2;

[0031] n is an integer from 0 to 4; and

[0032] p is an integer from 1 to 8.

[0033] Another aspect of the present disclosure relates to methods of treating RET-mediated conditions and diseases in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0034] Another aspect of the present disclosure relates to a method for regulating RET protein. The method comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof. In some embodiments, the method for treating RET-mediated conditions and diseases in a subject comprises regulating RET protein in the subject.

[0035] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, a diluent, or a surfactant. The pharmaceutical composition can be effective for treating a disease or condition associated with RET regulation in a subject in need thereof. The pharmaceutical composition can include a compound of the present invention for treating the diseases described herein. The composition can comprise at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0036] Another aspect of the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease associated with RET regulation. The present invention also provides the use of the compound described herein in the preparation of a medicament for treating a disease associated with RET.

[0037] The present invention also provides methods for treating diseases or conditions by degrading RET using the compounds of Formula I and pharmaceutically acceptable compositions of the compounds of Formula I of the present invention.

[0038] The present disclosure also provides a compound of formula I, which binds to and inhibits E3 ligase and further degrades RET protein. 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.

[0039] The present disclosure further provides a compound that can degrade RET while binding to E3 ligase. In some embodiments, the effectiveness-safety of the compounds of the present invention can be improved compared to other known RET inhibitors. In addition, the present technology also has the advantage of being able to be used for a variety of different types of diseases, including conditions 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. After reading the following specific embodiments, the additional features and advantages of the present technology will be apparent to those skilled in the art. DETAILED DESCRIPTION

[0040] The present disclosure relates to RET-degrading compounds of Formula I or pharmaceutically acceptable salts thereof, which can inhibit E3 ligase activity and are therefore useful in methods of treating the human or animal body. The present disclosure also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating conditions and diseases involving RET (such as inflammation, autoimmune diseases, cancer, infection, central nervous system diseases or conditions, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatism, psychological diseases, graft-versus-host disease, allodynia, or RET-related diseases) in subjects identified as carrying germline or somatic mutations in RET.

[0041] definition

[0042] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0043] 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 1 to 6 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 6 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 4 or fewer carbon atoms.

[0044] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl group or an alkyl group having specified substituents replacing one or more hydrogen atoms (e.g., 1, 2, 3, 4, or more carbons) on one or more carbons (e.g., 1, 2, 3, 4, or more carbons) of the hydrocarbon backbone. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

[0045] As used herein, the term "alkenyl" is included in unsaturated aliphatic groups similar to the above-mentioned alkyl in length and possible substitution, but it contains at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (for example, vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, straight chain or branched alkenyl groups have 6 or less carbon atoms (for example, C2-C6 for straight chain, C3-C6 for side chain) in its main chain. The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0046] As used herein, the term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having specified substituents replacing one or more hydrogen atoms (e.g., 1, 2, or 3 hydrogen atoms) on one or more (e.g., 1, 2, 3, 4, or more) hydrocarbon backbone carbon atoms. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

[0047] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar to the above-mentioned alkyl groups in length and possible substitution, but it contains at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched chain alkynyl groups. In certain embodiments, straight chain or branched chain alkynyl groups have 6 or less carbon atoms (e.g., C2-C6 for straight chain, C3-C6 for branched chain) in its backbone. The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5 or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0048] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms (e.g., 1, 2, or 3 hydrogen atoms) on one or more (e.g., 1, 2, 3, 4, or more) hydrocarbon backbone carbon atoms. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

[0049] Other optionally substituted moieties, such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, include unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyl groups include those substituted with one or more (e.g., 1, 2, 3, 4, or more) alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0050] As used herein, the term "cyano" refers to a nitrile group (eg, -CN).

[0051] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (e.g., fused ring, bridged ring, or spirocyclic) hydrocarbon 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.

[0052] As used herein, unless otherwise indicated, 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 for example 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur). Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, 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-oxepanyl, 2-oxepanyl, -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]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, ] thienyl, 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]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thienyl, etc. In the case of polycyclic heterocycloalkyl, only one ring of the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0053] As used herein, the term "optionally substituted heterocycloalkyl" refers to unsubstituted heterocycloalkyl or heterocycloalkyl having specified substituents replacing one or more (e.g., 1, 2, 3, 4, or more) hydrogen atoms on one or more (e.g., 1, 2, 3, 4, or more) carbon or heteroatoms. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

[0054] 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). When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group can be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group can be optionally 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, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.

[0055] Unless expressly 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 means a bicyclic heteroaryl group, wherein the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl as defined herein also means a tricyclic heteroaryl group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. Aryl groups are optionally substituted independently with one or more substituents described herein.Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzofuranyl, isothiazolyl, thiazolyl, thiadiazolyl, indazolyl, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3- c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothienyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, 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]pyrimidinyl, dibenzo[b,d]thienyl, 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]pyridinyl, [1,2,4]triazolo[1,5-b]pyridinyl, [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]oxadiazolyl, 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 (e.g., a 5-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaryl ring containing 1 to 3 nitrogen atoms), wherein the saturated or partially unsaturated rings include 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and are 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 with saturated or partially unsaturated rings as described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, 3,4-dihydro-11H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2- b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl or benzo[c][1,2]oxaborolan-1(3H)-ol.

[0056] The cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted at one or more (e.g., 1, 2, 3, 4 or more) ring positions (e.g., a ring-forming carbon or heteroatom such as N) with substituents such as alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, Alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amide (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 and heterocyclic rings that are non-aromatic to form polycyclic ring systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0057] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced by a selection from a designated group, provided that the normal valence of the designated atom is not exceeded and that the substitution produces a stable compound. When the substituent is an oxo or keto group (i.e., =O), 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 formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently stable to withstand isolation from an RM to a useful purity and formulation into an effective therapeutic agent.

[0058] 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 to which it is bonded to the rest of the 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.

[0059] 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 may 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.

[0060] As used herein, the term "hydroxy" or "hydroxyl" includes groups having -OH or -O-.

[0061] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0062] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms.

[0063] As used herein, the term "optionally substituted haloalkyl" refers to unsubstituted haloalkyl or haloalkyl having specified substituents replacing one or more (e.g., 1, 2, 3, 4, or more) hydrogen atoms on one or more (e.g., 1, 2, 3, 4, or more) hydrocarbon backbone carbon atoms. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or an aromatic or heteroaromatic moiety.

[0064] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently attached to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include haloalkoxy groups. The alkoxy group can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), amido (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), 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.

[0065] It is 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 and the schemes shown in the examples.

[0066] It should be understood that throughout this specification, when a composition is described as having, comprising, or including specific components, it is contemplated that the composition also consists essentially of, or consists of, those components. Similarly, when a method or process is described as having, comprising, or including specific process steps, the process also consists essentially of, or consists of, those process steps. Furthermore, it should be understood that the order of steps or the order in which certain actions are performed is immaterial as long as the present invention remains operable. Furthermore, two or more steps or actions may be performed simultaneously.

[0067] It will be appreciated that the synthetic methods of the present disclosure can tolerate a variety of functional groups and therefore can use a variety of alternative starting materials. The methods generally provide the desired final compound at or near the end of the overall method, although in some cases it may be necessary to further convert the compound into a pharmaceutically acceptable salt thereof.

[0068] It will 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 available intermediates using standard synthetic methods and procedures known to those skilled in the art or apparent from the teachings herein. Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Although not limited to any one or more sources, textbooks such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) are incorporated herein by reference and are useful and recognized reference textbooks on organic synthesis known to those skilled in the art.

[0069] Those of ordinary skill in the art will note that during reaction process described herein and synthesis scheme, the order of some steps can change, such as introducing and removing blocking group. Those of ordinary skill in the art will recognize that some group may need to be protected from the impact of reaction conditions by using blocking group. Blocking group also can be used to distinguish similar functional groups in molecules. The list of blocking group and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, the 3rd edition. John Wiley & Sons. New York, 1999.

[0070] It is to be understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of a compound to provide treatment or prevention as described herein. It is to be further understood that, unless otherwise indicated, any description of a method of treatment or prevention includes the use of the compound in the preparation of a medicament for treating or preventing such conditions. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0071] It should be understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to provide a treatment as described herein. It should be further understood that, unless otherwise stated, any description of a method of treatment includes the use of the compound to prepare a medicament for treating such a condition. Such treatment includes treating humans or non-human animals, including rodents and other disease models. As used herein, the term "subject" can be used interchangeably with the term "subject in need thereof," both of which refer to a subject suffering from a disease or having an increased risk of developing the 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. A subject in need may be a subject previously diagnosed or confirmed to have a disease or condition disclosed herein. A subject in need may also be a subject suffering from a disease or condition disclosed herein. Alternatively, a subject in need may be a subject with an increased risk of developing such a disease or condition relative to the general population (i.e., a subject prone to developing such a disease relative to the general population). A subject in need may suffer from a refractory or resistant disease or condition disclosed herein (i.e., a disease or condition that is unresponsive or has not yet responded to treatment as disclosed herein). The subject may be resistant at the start of treatment or may develop resistance during treatment. In some embodiments, the subject in need has been treated with all known therapies for the disease or condition disclosed herein but has failed. In some embodiments, the subject in need has received at least one prior therapy.

[0072] As used herein, the terms "treating" or "treat" 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 thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treatment" may also include treatment of in vitro cells or animal models. It should be understood that references to "treating" or "treat" include alleviating established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition in a person who may be suffering from 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 disease or its recurrence (in the case of maintenance therapy) or the development of at least one clinical or subclinical symptom thereof, or (3) remitting or alleviating the disease, i.e., causing recovery of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0073] It will be appreciated that the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be or may also be used to prevent related diseases, conditions or disorders, or to identify suitable candidates for such purposes.

[0074] As used herein, the terms "preventing," "prevent," or "preventing" describe reducing or eliminating the occurrence of symptoms or complications of these diseases, conditions, or disorders.

[0075] It should be understood that those skilled in the art can refer to general references for detailed descriptions of known or equivalent techniques discussed herein. These include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005), Sambrook et al., Molecular Cloning, A Laboratory Manual 3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, 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 edition (1990). Of course, these references can also be cited when making or using one aspect of the present disclosure.

[0076] 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.

[0077] As used herein, the term "pharmaceutical composition" is a preparation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a single pump or bottle on a capsule, an intravenous bag (IV bag), a tablet, an aerosol inhaler. The amount of the active ingredient (e.g., a preparation of a disclosed compound or its salt) in the unit dose composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that it is sometimes necessary to make routine changes to the dosage according to the age and condition of the patient. The dosage also depends on the route of administration. It encompasses a variety of routes, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. The dosage forms for topical or transdermal administration of the compound 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.

[0078] 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 humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0079] As used herein, the term "pharmaceutically acceptable excipient" means an excipient used to prepare a pharmaceutical composition that is generally safe, non-toxic, and free of biological or other undesirable effects, and includes excipients that can be used for veterinary and human pharmaceutical use. As used in this specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0080] It should be understood that the pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, for example, intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (external) and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous administration may include the following components: sterile diluents such as water for injection, saline solutions, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and reagents for regulating tonicity such as sodium chloride or glucose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be packaged in ampoules, disposable syringes or multidose vials made of glass or plastic.

[0081] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject using many 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 administered via a skin patch. The selected dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. During treatment and for a reasonable period after treatment, the patient's disease condition (e.g., a disease or condition disclosed herein) and health status should preferably be closely monitored.

[0082] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents a recognized disease or condition, or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective dose for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapy or combination of therapies 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.

[0083] It should be understood that for any compound, the therapeutically effective amount can initially be estimated in cell culture assays, such as 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 of administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical methods in cell culture or experimental animals, such as ED50 (the dose that is therapeutically effective for 50% of the population) and LD50 (the dose that is lethal to 50% of the population). The dose ratio of toxicity to therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions that exhibit a larger therapeutic index are preferred. The dosage can vary within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration.

[0084] Dosage and administration methods are adjusted to provide adequate levels of the active agent 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, drug combination, reaction sensitivity and tolerance / response to treatment.

[0085] Pharmaceutical compositions containing the active compound of the present disclosure can be prepared in a manner generally known to the public, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or freeze-drying methods. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers (including excipients and / or adjuvants that promote the active compound to be processed into pharmaceutically usable preparations). Of course, suitable preparations depend on the selected route of administration.

[0086] 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, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid that is easy to inject. It must be stable under the conditions of preparation and storage and must be preserved to prevent the contamination of microorganisms (such as bacteria and fungi). The carrier can be a solvent or dispersion medium, which contains, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.), and a mixture that is suitable for it. For example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by using a surfactant to maintain appropriate fluidity. The effect of preventing microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents (for example, sugar, polyols such as mannitol and sorbitol and sodium chloride) in the composition. The extended absorption of the injection composition can be achieved by including an agent (for example, aluminum monostearate and gelatin) that delays absorption in the composition.

[0087] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound into an appropriate solvent with one or a combination of the above-mentioned ingredients, as desired, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile carrier containing a basic dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and lyophilization, which produce a powder of the active ingredient and any additional desired ingredients from a previously sterile-filtered solution.

[0088] Oral compositions typically contain an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be mixed 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, wherein the compound is orally administered in the fluid carrier and gargled and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, xanthan gum, 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.

[0089] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0090] Systemic administration can also be carried out transmucosal or transdermal. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished using nasal sprays or suppositories. For transdermal administration, the active compound is formulated as an ointment, salves, gel, or cream as is generally known in the art.

[0091] The active compound can be prepared using a pharmaceutically acceptable carrier that protects the compound from rapid removal 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 these preparations will be apparent to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells 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, for example, according to the method described in U.S. Patent No. 4,522,811.

[0092] Formulating oral or parenteral compositions in unit dosage form is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unitary dosages for the subject to be treated, each unit containing 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 is determined by and directly depends on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0093] In therapeutic applications, the dosage of the pharmaceutical composition used in accordance with the present disclosure varies according to the agent, the age, weight and clinical condition of the patient receiving the therapy, the experience and judgment of the clinical practitioner administering the therapy, and other factors affecting the selected dosage. Generally, the dosage should be sufficient to cause a reduction in and preferably a reduction in the symptoms of the disease or condition disclosed herein, and preferably also to cause complete regression of the disease or condition. The dosage range may be from about 0.01 mg / kg per day to about 5000 mg / kg per day. The effective amount of the agent is an amount that provides an objectively identifiable improvement 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 the active compound that produces the desired biological effect in a subject or cell.

[0094] It will be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0095] It should be understood that for the compounds of the present disclosure that are capable of further forming salts, all of these forms are also encompassed within the scope of protection claimed in the present disclosure.

[0096] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present disclosure wherein the parent compound is modified by preparing acid addition or base addition salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 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, ethylenediaminetetraacetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, sulfonic), maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and common amino acids, for example, glycine, alanine, phenylalanine, arginine, etc.

[0097] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, potassium salt, calcium salt, magnesium salt, diethylamine salt, choline salt, meglumine salt, benzathine salt, tromethamine salt, ammonium salt, arginine salt, or lysine salt.

[0098] Other examples of pharmaceutically acceptable salts include hexanoate, cyclopentanepropionate, pyruvate, malonate, 3-(4-hydroxybenzoyl)benzoate, cinnamate, 4-chlorobenzene methanesulfonate, 2-naphthaleneethanesulfonate, 4-toluenesulfonate, camphorsulfonate, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylate, 3-phenylpropionate, pivalate, tertiary butylacetic acid, muconic acid, etc. 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 (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). In salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1 or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0099] 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.

[0100] The dosage regimen for using 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 hepatic function; and the specific compound or salt thereof used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to counter, or arrest the progression of the condition.

[0101] Techniques for the preparation and administration of the compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co, Easton, Pa. (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with pharmaceutically acceptable carriers or diluents in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile water or organic solutions. These compounds will be present in these pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0102] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the various examples. The examples provided illustrate different components and methodologies useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, a skilled artisan can identify and use other components and methods useful in practicing the present disclosure.

[0103] In the synthetic schemes described herein, for simplicity, compounds may be drawn in a particular configuration. This particular configuration should not be construed as limiting the invention to one or the other of an isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0104] 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. Citation of publications and patent documents is not intended to be an admission that any is relevant prior art and does not constitute any admission as to their content or date. Having now described the invention in writing, one skilled in the art will recognize that the invention can be implemented in various embodiments, and the foregoing description and the following examples are intended to illustrate rather than limit the claims.

[0105] As used herein, the phrases "compounds of the present disclosure," "degradants of the present disclosure," and "degradants" refer generally and specifically to those compounds disclosed herein.

[0106] Compounds of the present disclosure

[0107] In one aspect, the present disclosure provides compounds of formula (I):

[0108]

[0109] or a pharmaceutically acceptable salt thereof,

[0110] in

[0111] R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more (e.g., 1, 2, 3, 4 or more) R 8 replace;

[0112] A is aryl or heteroaryl, wherein the aryl or heterocyclic group is optionally substituted with one or more (e.g., 1, 2, 3, 4 or more) R 9 replace;

[0113] B is a heterocycloalkyl group or a C3-C8 cycloalkyl group;

[0114] L1 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0115] 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)-;

[0116] R 2 It is NR 10 R 11 ;

[0117] R 3 is H, halogen, NH2 or C1-C4 alkyl;

[0118] Each R 4 is independently C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more (e.g., 1, 2, 3, 4 or more) C1-C6 alkoxy, C1-C6 thioalkyl, NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl); or

[0119] Two R on adjacent carbons 4 Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;

[0120] R 5 is H, OH, CN, NO2 or C1-C4 alkyl;

[0121] Each R 6 or R6’ is H; or

[0122] Two R's 6 May combine to form an oxo group; or

[0123] Two R's 6’ Can combine to form oxo groups;

[0124] R 7 、R 8 and R 9 each independently H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or

[0125] Two R on adjacent carbons 7 Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;

[0126] R 10 and R 11 are independently H or C1-C4 alkyl;

[0127] m is an integer from 0 to 2;

[0128] n is an integer from 0 to 4; and

[0129] p is an integer from 1 to 8.

[0130] In some embodiments, A, B, L1, L2, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 6’ 、R 7 , m and n are as described in this disclosure.

[0131] In some embodiments, the present disclosure relates to compounds of Formula I(a):

[0132]

[0133] or a pharmaceutically acceptable salt thereof.

[0134] In other embodiments, the compounds of the present disclosure have Formula I(b):

[0135]

[0136] or a pharmaceutically acceptable salt thereof.

[0137] In other embodiments, the compounds of the present disclosure have Formula I(c):

[0138]

[0139] or a pharmaceutically acceptable salt thereof.

[0140] In other embodiments, the compounds of the present disclosure have Formula I(d):

[0141]

[0142] or a pharmaceutically acceptable salt thereof,

[0143] wherein s1 and s2 are independently integers from 1 to 2.

[0144] In other embodiments, the compounds of the present disclosure have Formula I(e):

[0145]

[0146] or a pharmaceutically acceptable salt thereof, wherein s1 and s2 are independently an integer from 1 to 2.

[0147] In other embodiments, the compounds of the present disclosure have Formula I(f):

[0148]

[0149] or a pharmaceutically acceptable salt thereof,

[0150] wherein s1 and s2 are independently integers from 1 to 2.

[0151] In other embodiments, the compounds of the present disclosure have Formula I(g):

[0152]

[0153] or a pharmaceutically acceptable salt thereof, wherein s1 and s2 are independently an integer from 1 to 2.

[0154] In other embodiments, the compounds of the present disclosure have Formula I(h):

[0155]

[0156] or a pharmaceutically acceptable salt thereof, wherein s1, s2, s3 and s4 are independently an integer from 1 to 2.

[0157] In certain embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl or aryl.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, R 1 In other embodiments, R 1 In other embodiments, R 1 In a further 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 a further embodiment, R 1 is optionally replaced by one or more R 8 In a further embodiment, R 1 is optionally replaced by one or more R 8 In a further embodiment, R 1 is optionally replaced by one or more R 8 Substituted heteroaryl.

[0158] 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, R8 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 8 is 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 a further embodiment, R 8 is H. In a further embodiment, R 8 In a further embodiment, R 8 is CN. In a further embodiment, R 8 is NO2. In a further embodiment, R 8 In a further embodiment, R 8 is NH2. In a further embodiment, R 8 is C1-C6 alkyl. In a further embodiment, R 8 In a further embodiment, R 8 is C2-C6 alkynyl. In a further embodiment, R 8 is a C3-C8 cycloalkyl group. In a further embodiment, R 8 In a further embodiment, R 8 In a further embodiment, R 8 It is a heteroaryl group.

[0159] In some embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, A is aryl or heteroaryl. In other embodiments, A is aryl. In other embodiments, A is heteroaryl. In other embodiments, A is optionally substituted with one or more R 9 In other embodiments, A is optionally substituted with one or more R 9 Substituted heteroaryl.

[0160] 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, R9 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 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 a further embodiment, R 9 is H. In a further embodiment, R 9 In a further embodiment, R 9 is CN. In a further embodiment, R 9 is NO2. In a further embodiment, R 9 In a further embodiment, R 9 is NH2. In a further embodiment, R 9 is C1-C6 alkyl. In a further embodiment, R 9 In a further embodiment, R 9 is C2-C6 alkynyl. In a further embodiment, R 9 is a C3-C8 cycloalkyl group. In a further embodiment, R 9 In a further embodiment, R 9 In a further embodiment, R 9 It is a heteroaryl group.

[0161] In certain embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, B is heterocycloalkyl or C3-C8 cycloalkyl. In further embodiments, B is heterocycloalkyl. In further embodiments, B is C3-C8 cycloalkyl.

[0162] In some embodiments of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, L1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In 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.

[0163] In some embodiments of the disclosed compounds or pharmaceutically acceptable salts thereof, L2 is -C(O)-(CH2) p –(4- to 12-heterocycloalkyl)–, –C(O)-(OCH2CH2) p –(4- to 12-heterocycloalkyl)–, –C(O)NH-(CH2) p –(4- to 12-heterocycloalkyl)–, –C(O)NH–(CH2CH2O) p –(4- to 12-heterocycloalkyl)–, –C(O)-(CH2CH2O) p –(4- to 12-heterocycloalkyl)–, –(OCH2CH2) p –(4- to 12-heterocycloalkyl)–, –C(O)-(CH2) p –(4- to 12-heterocycloalkyl)–C(O)– or –(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-. In a further embodiment, L2 may 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 a further embodiment, L2 may 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 a further embodiment, L2 may 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 a further embodiment, L2 may 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 a further embodiment, L2 may 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 a further embodiment, L2 may be -C(O)-(CH2) p –(4- to 12-heterocycloalkyl)– or –C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-. However, in further embodiments, L2 may be -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-. However, in further embodiments, L2 may be -C(O)-(OCH2CH2) p-(4- to 12-heterocycloalkyl)-. However, in further embodiments, L2 may be -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-. However, in further embodiments, L2 may be -C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-. However, in further embodiments, L2 may be -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-. However, in further embodiments, L2 may be -(OCH2CH2) p -(4- to 12-heterocycloalkyl)-. However, in further embodiments, L2 may be -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-. However, in further embodiments, L2 may be -(CH2) p –(4- to 12-heterocycloalkyl)–C(O)–.

[0164] In certain embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 2 Independently NR 10 R 11 .

[0165] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, 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.

[0166] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, 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.

[0167] In certain embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 3 is H, halogen, NH2 or C1-C4 alkyl. In a further embodiment, R 3 is H, halogen or NH2. In a further embodiment, R 3 is H or halogen. However, in a further embodiment, R 3 is H. However, in a further embodiment, R 3 is halogen. However, in a further embodiment, R 3is NH2. However, in a further embodiment, R 3 It is a C1-C4 alkyl group.

[0168] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 4 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl. 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.

[0169] In a further 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 a further 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). In a further embodiment, R 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 alkoxy groups, C1-C6 thioalkyl groups or NH2. In a further 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 a further embodiment, R 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 alkoxy groups. However, in a further embodiment, R 4 is a C1-C6 alkyl group optionally substituted with one or more C1-C6 thioalkyl groups. However, in a further embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more NH2. However, in a further embodiment, R 4 is C1-C6 alkyl optionally substituted with one or more -NH(C1-C6 alkyl). However, in further embodiments, R 4 is C1-C6 alkyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0170] In a further 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 a further embodiment, R 4 is a C2-C6 alkenyl group optionally substituted with one or more C1-C6 alkoxy, C1-C6 alkylthio, NH2 or -NH(C1-C6 alkyl). In a further embodiment, R 4 is a C2-C6 alkenyl group optionally substituted with one or more C1-C6 alkoxy groups, C1-C6 thioalkyl groups or NH2. In a further 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 a further embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more C1-C6 alkoxy groups. However, in a further embodiment, R 4 is a C2-C6 alkenyl group optionally substituted with one or more C1-C6 thioalkyl groups. However, in a further embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more NH2. However, in a further embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more -NH(C1-C6 alkyl). However, in a further embodiment, R 4 is C2-C6 alkenyl optionally substituted with one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0171] In a further 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 a further 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). In a further embodiment, R 4 is a C2-C6 alkynyl group optionally substituted with one or more C1-C6 alkoxy groups, C1-C6 thioalkyl groups or NH2. In a further 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 a further embodiment, R 4 is C2-C6 alkynyl optionally substituted with one or more C1-C6 alkoxy groups. However, in a further embodiment, R 4is C2-C6 alkynyl optionally substituted with one or more C1-C6 alkylthio groups. However, in a further embodiment, R 4 is C2-C6 alkynyl optionally substituted with one or more NH2. However, in a further embodiment, R 4 is C2-C6 alkynyl optionally substituted with one or more -NH(C1-C6 alkyl). However, in a further embodiment, R 4 is C2-C6 alkynyl optionally substituted by one or more -N(C1-C6 alkyl)(C1-C6 alkyl).

[0172] In further embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, two R 4 Can be combined together to form C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, two R on adjacent carbons 4 Can be combined together to form C3-C8 cycloalkyl, heterocycloalkyl or aryl. In other embodiments, two R on adjacent carbons 4 Can be combined together to form a C3-C8 cycloalkyl or heterocycloalkyl. In other embodiments, two R on adjacent carbons 4 Can be combined together to form a C3-C8 cycloalkyl. In other embodiments, two R on adjacent carbons 4 Can be combined together to form a heterocycloalkyl. In other embodiments, two R on adjacent carbons 4 Can be combined together to form an aryl group. In other embodiments, two R 4 Can be combined together to form a heteroaryl group.

[0173] In certain embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 5 is independently H, OH, CN, NO2 or C1-C4 alkyl. In a further embodiment, R 5 is H, OH, CN or NO2. In a further embodiment, R 5 is H, OH or CN. In a further embodiment, R 5 is H or OH. In a further embodiment, R 5 is H. In a further embodiment, R 5 In a further embodiment, R 5 is CN. In a further embodiment, R 5 is NO2. In a further embodiment, R 5 It is a C1-C4 alkyl group.

[0174] In certain embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R6 are independently H.

[0175] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, R 6’ are independently H.

[0176] In certain embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, both R 6 Can combine to form an oxo group.

[0177] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, both R 6’ Can combine to form an oxo group.

[0178] In some embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, 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 a further embodiment, R 7is H. In other embodiments, R 7 In a further embodiment, R 7 is CN. In a further embodiment, R 7 is NO2. In a further embodiment, R 7 In a further embodiment, R 7 is NH2. In a further embodiment, R 7 is C1-C6 alkyl. In a further embodiment, R 7 In a further embodiment, R 7 is C2-C6 alkynyl. In a further embodiment, R 7 is a C3-C8 cycloalkyl group. In a further embodiment, R 7 In a further embodiment, R 7 In a further embodiment, R 7 It is a heteroaryl group.

[0179] In further embodiments of the compounds of the present disclosure or pharmaceutically acceptable salts thereof, two R 7 Can be combined together to form C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In other embodiments, two R on adjacent carbons 7 Can be combined together to form C3-C8 cycloalkyl, heterocycloalkyl or aryl. In other embodiments, two R on adjacent carbons 7 Can be combined together to form a C3-C8 cycloalkyl or heterocycloalkyl. In other embodiments, two R on adjacent carbons 7 Can be combined together to form a C3-C8 cycloalkyl. In other embodiments, two R on adjacent carbons 7 Can be combined together to form a heterocycloalkyl. In other embodiments, two R on adjacent carbons 7 Can be combined together to form an aryl group. In other embodiments, two R 7 Can be combined together to form a heteroaryl group.

[0180] In further embodiments of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, 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.

[0181] In other embodiments of the present disclosure, n is independently at each occurrence 0, 1, 2, 3, or 4. In other embodiments, n is 1 or 2. In other embodiments, n is 1 or 3. In other embodiments, n is 1 or 4. In other embodiments, n is 2 or 3. In other embodiments, n is 2 or 4. In other embodiments, n is 3 or 4. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3. In other embodiments, n is 4. In other embodiments, n is 0.

[0182] In other embodiments of the present disclosure, p is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, or 8. In other embodiments of the present disclosure, p is 1 or 2. In other embodiments of the present disclosure, p is 1 or 3. In other embodiments of the present disclosure, p is 1 or 4. In other embodiments of the present disclosure, p is 1 or 5. In other embodiments of the present disclosure, p is 1 or 6. In other embodiments of the present disclosure, p is 1 or 7. In other embodiments of the present disclosure, p is 1 or 8. In other embodiments of the present disclosure, p is 2 or 3. In other embodiments of the present disclosure, p is 2 or 4. In other embodiments of the present disclosure, p is 2 or 5. In other embodiments of the present disclosure, p is 2 or 6. In other embodiments of the present disclosure, p is 2 or 7. In other embodiments of the present disclosure, p is 2 or 8. In other embodiments of the present disclosure, p is 3 or 4. In other embodiments of the present disclosure, p is 3 or 5. In other embodiments of the present disclosure, p is 3 or 6. In other embodiments of the present disclosure, p is 3 or 7. In other embodiments of the present disclosure, p is 3 or 8. In other embodiments of the present disclosure, p is 4 or 5. In other embodiments of the present disclosure, p is 4 or 6. In other embodiments of the present disclosure, p is 4 or 7. In other embodiments of the present disclosure, p is 4 or 8. In other embodiments of the present disclosure, p is 5 or 6. In other embodiments of the present disclosure, p is 5 or 7. In other embodiments of the present disclosure, p is 5 or 8. In other embodiments of the present disclosure, p is 6 or 7. In other embodiments of the present disclosure, p is 6 or 8. In other embodiments of the present disclosure, p is 7 or 8. In other embodiments of the present disclosure, p is 8. In other embodiments of the present disclosure, p is 7. In other embodiments of the present disclosure, p is 6. In other embodiments of the present disclosure, p is 5. In other embodiments of the present disclosure, p is 4. In other embodiments of the present disclosure, p is 3. In other embodiments of the present disclosure, p is 2. In other embodiments of the present disclosure, p is 1. In other embodiments of the present disclosure, p is 0.

[0183] In some embodiments, suitable compounds of the present disclosure include:

[0184] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0185] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0186] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0187] (4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0188] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0189] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0190] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0191] (4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide);

[0192] (4-amino-6-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)acetyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide; or

[0193] (4-amino-6-((1-(3-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)propanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide),

[0194] or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described herein.

[0196] 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.

[0197] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3, and prodrugs and pharmaceutically acceptable salts thereof.

[0198] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3 and pharmaceutically acceptable salts thereof.

[0199] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 3 and the pharmaceutically acceptable salts of the compounds.

[0200] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3.

[0201] It will be appreciated that the isotopic derivatives can be prepared using various techniques recognized in the art. For example, the isotopic derivatives can generally be prepared by carrying out the procedures in the schemes and / or examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0202] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0203] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0204] As used herein, the term "isotopic derivative" refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of Formula (I). In some embodiments, an isotopic derivative is selected from 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., one or more atoms thereof are enriched or labeled with 2 H enriched). 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.

[0205] It should be understood that18 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 various techniques recognized in the art. For example, deuterium-labeled compounds can be prepared generally by carrying out the methods disclosed in the schemes and / or examples described herein, by using 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 reagents were used to replace non-isotopic labeled reagents.

[0206] Contains one or more of the above 8 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 thereof containing no S atom are within the scope of the present invention. 8 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 (e.g., increased in vivo half-life or reduced dosage requirements).

[0207] For the avoidance of doubt, it will be understood that where in this specification a group is defined "as described herein", that group encompasses the broadest definition that first occurs as well as each and every specific definition for that group.

[0208] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of sufficiently basic compounds of the present invention, for example, acid addition salts formed with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present invention are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts or salts formed with organic bases that provide pharmaceutically acceptable cations, such as salts formed with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0209] It is to be understood that the compounds of any formula disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0210] As used herein, the term "isomers" 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."

[0211] As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

[0212] As used herein, the term "chiral isomer" refers to a compound with at least one chiral center. Compounds with more than one chiral center may exist as individual diastereomers or as a mixture of diastereomers (referred to as a "diastereomeric mixture"). When one chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) about that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center in question are ordered according to the order 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).

[0213] As used herein, the term "geometric isomers" refers to isomers that exist due to hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans or Z and E, which indicate that the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0214] It should be understood that the compounds of the present disclosure may be described 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 in 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.

[0215] It is to be understood that the structures and other compounds discussed in this disclosure encompass all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0216] As used herein, the term "tautomer" refers to 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 sets in solution. In a solution where tautomerism may occur, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers converting into each other through tautomerism is called tautomerism. Of the various possible types of tautomerism, two are usually observed. In keto-enol tautomerism, electrons and hydrogen atoms are simultaneously displaced. Ring-chain tautomerism is caused by the reaction of an aldehyde group (-CHO) in a sugar chain molecule with a hydroxyl group (-OH) in the same molecule, resulting in a ring (cyclic) form as shown in glucose.

[0217] It should be understood that the compounds of the present disclosure can be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included in 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 levels of activity than other tautomers.

[0218] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or the arrangement of their atoms in space are called "isomers". Isomers whose atoms are arranged differently in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and those 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 may form. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and designated as right- or left-handed (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0219] The compounds of the present disclosure may have one or more asymmetric centers, and these compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include individual enantiomers and mixtures thereof, racemic or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see "Advanced Organic Chemistry", 4th edition J.March, John Wiley and Sons, New York, 2001 Chapter 4), for example, by synthesizing from optically active starting materials and splitting by racemic form. Some compounds of the present disclosure may have geometric isomerization centers (E- and Z-isomers). It should be understood that the present disclosure includes all optical, diastereoisomers and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

[0220] It should be understood that the compounds of any of the formulae described herein include the compounds themselves and their salts (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, glucuronide, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0221] As used herein, the term "pharmaceutically acceptable anion" refers to an anion that is 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 ions, such as tetramethylammonium or diethylamine. The substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

[0222] 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.

[0223] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend 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 association of one or more water molecules with a molecule of a substance, wherein the water remains in its molecular form as HO.

[0224] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another compound but slightly different in composition (e.g., the replacement of an atom with an atom of a different element or the presence of a particular functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or comparable to a reference compound in function and appearance, but different in structure or origin.

[0225] As used herein, the term "derivative" refers to compounds having a common core structure and substituted with various groups described herein.

[0226] It will also be understood that certain compounds of any of the formulae disclosed herein may exist in solvated as well as unsolvated forms (such as, for example, hydrated forms). For example, suitable pharmaceutically acceptable solvates are hydrates such as hemihydrates, monohydrates, dihydrates, or trihydrates. It will be understood that the present disclosure encompasses all solvated forms that have inflammasome inhibitory activity.

[0227] It will also be understood that certain compounds of any of the formulae disclosed herein may exhibit polymorphic forms, and the present disclosure encompasses all such forms or mixtures thereof having inflammasome inhibitory activity. It is well known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of these crystalline materials can be determined using Karl Fischer analysis.

[0228] The compound of any one of the chemical formulas disclosed herein can exist in a variety of different tautomeric forms, and mentioning of compounds of formula (I) includes all of these forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only specifically describes or shows one, all other forms are included in formula (I). The example of tautomeric form includes keto-, enol- and enolate-forms, for example, the following tautomeric pairs: keto / enol (as shown below), imines / enamines, amides / imino alcohols, amidines / amidines, nitroso / oximes, thioketones / thiol and nitro / acid nitro.

[0229] Figure US11319319-2220503-C00141

[0230] The compounds of any of the formulae disclosed herein can be administered in the form of prodrugs that decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents to which property-modifying groups can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide groups of any of the formulae disclosed herein.

[0231] Accordingly, the present disclosure includes compounds of any of the formulae disclosed herein as defined above when obtained by organic synthesis and when obtained in the human or animal body by cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any of the formulae disclosed herein produced by organic synthesis methods, as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., a compound of any of the formulae disclosed herein may be a synthetically produced compound or a metabolically produced compound.

[0232] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein are prodrugs that are suitable, based on sound medical judgment, for administration to humans or animals without adverse pharmacological activity and without undue toxicity. Various forms of prodrugs have been described, for example in the following literature: a) Methods in Enzymology, Volume 42, pages 309-396, K. Widder, et al., eds. (Academic Press, 1985); b) Design of Pro-drugs, H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard, eds., Chapter 5 "Design and Application of Pro-drugs", H. Bundgaard, pages 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", ACSSyposium Series, Volume 14; and h) E. Roche (Editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0233] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having hydroxyl groups are, for example, esters or ethers thereof that are cleavable in vivo. An in vivo cleavable ester or ether of a compound of any of the formulae disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for hydroxyl groups include inorganic esters such as phosphates (including phosphoramidocyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for 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 groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinylmethyl, 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 groups.

[0234] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein having a carboxyl group are, for example, in vivo cleavable amides thereof, for example amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-C4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine and amino acids such as glycine or its esters.

[0235] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein having an amino group are, for example, amide derivatives thereof that are cleavable 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, morpholinylmethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0236] 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).

[0237] How to use

[0238] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used in an effective amount to treat a patient, typically a human, in need thereof, suffering from a condition 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).

[0239] 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 or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing cancer in a patient in need thereof; wherein inhibition of RET is required for treating or preventing cancer.

[0240] In some embodiments, the methods comprise administering to a patient in need thereof an effective amount of an active compound as described herein, or a salt thereof, optionally comprising a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), or optionally in combination or alternation with a combination of other biologically active agents or agents.

[0241] In certain embodiments, the present invention provides methods of treating any of the conditions described herein in a patient in need thereof.

[0242] In other embodiments, an additional therapeutic agent is administered to the patient.In other embodiments, the compound as described herein and the additional therapeutic agent are administered simultaneously or sequentially.

[0243] In certain embodiments, the present application provides a method of preventing any of the conditions described herein in a patient in need thereof.

[0244] In certain embodiments, the patient is a human.

[0245] 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 described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0246] In some embodiments, the disease is mediated by RET, eg, RET plays a role in the initiation or progression of the disease.

[0247] 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 disease, protein conformational disease, fibrotic disease, inflammation, arthritis, liver disease, or an immune disorder.

[0248] 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.

[0249] 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.

[0250] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0251] In certain embodiments, the RET-mediated disorder is abnormal cell proliferation, including but not limited to a tumor or cancer, or a myeloproliferative or lymphoproliferative disorder such as B- or T-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferative disorder.

[0252] In certain embodiments, the hematological cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphocytic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia (MCL), or LL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphocytic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell leukemia, Myc and B-cell leukemia (BCL) 2 and / or BCL6 rearrangement / overexpression [double- and triple hit lymphoma], myelodysplasia / myeloproliferative neoplasms, mantle cell lymphoma, including bortezomib-resistant mantle cell lymphoma.

[0253] 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 carcinomas, liver cancer, kidney cancer, prostate cancer, including castration-resistant prostate cancer (CRPC), brain cancer, including gliomas, glioblastomas, neuroblastomas, and medulloblastomas, including MYC-amplified medulloblastomas, colorectal cancer, Wilms' tumor, Ewing's sarcoma, and glioma. 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 cancer, testicular cancer, squamous cell carcinoma, hepatocellular carcinoma (HCC), MYCN-driven solid tumors and NUT-midline carcinoma (NMC).

[0254] In other embodiments, the disease or condition is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0255] In other embodiments, the disease or condition is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0256] In other embodiments, the disease or condition is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, meningiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0257] In other embodiments, the disease or disorder is multiple myeloma.

[0258] In other embodiments, the disease or condition is inflammation, arthritis, rheumatoid arthritis, spondyiarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, neuroinflammation, allergies, pain, neuropathic pain, fever, lung disorders, lung inflammation, chronic inflammatory lung disease and chronic obstructive pulmonary disease (COPD) in adults, liver disease and nephritis, gastrointestinal diseases, inflammatory bowel disease, Crohn's disease, disease), gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative disease, gastric ulcer, autoimmune disease, graft-versus-host reaction and allograft rejection, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, tumors of epithelial cell origin (epithelial cancer), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell 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 tumors, metastasis, central nervous system disease, central nervous system disorders with inflammatory or apoptotic components, peripheral neuropathy or B-cell lymphoma.

[0259] In other embodiments, pharmaceutical compositions comprising a compound as described herein and an additional therapeutic agent are administered simultaneously or sequentially.

[0260] In other embodiments, the disease or condition is cancer. In other 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.

[0261] In some embodiments, the method is for treating or preventing a condition selected from autoimmune diseases, inflammatory diseases, proliferative diseases and hyperproliferative diseases and immune-mediated conditions. In other embodiments, the condition is selected from proliferative disorders.

[0262] In certain embodiments, the RET-mediated disorder is an immune disorder, including but not limited to an autoimmune disorder such as Addison disease, Celiac disease, dermatomyositis, Graves disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes.

[0263] 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. These diseases include, but are not limited to, proliferative diseases 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; bone marrow disorders; lymphatic diseases, 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 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, or and head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin's lymphoma, and lung cancer.

[0264] 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 lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndrome, solid tumors in children such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors and soft tissue sarcomas, common solid tumors in adults such as head and neck cancer (e.g., oral cancer, laryngeal cancer, nasopharyngeal cancer and esophageal cancer), genitourinary cancers such as prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, 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's syndrome such as medulloblastoma or meningioma, and liver cancer.

[0265] 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.

[0266] The compounds described herein can also be used to prevent, treat, and study other cancers, such as colon cancer, familial adenomatous polyposis carcinoma, 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 carcinoma and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urethral cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor), gallbladder cancer, bronchial cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma. In one aspect of the present application, the present application provides one or more compounds disclosed herein for use in the preparation 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 are used to treat cancers such as colorectal cancer, thyroid cancer, breast cancer and lung cancer; and myeloproliferative diseases such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, eosinophilic syndrome, juvenile myelomonocytic leukemia and systemic mastocytosis. In some embodiments, the compounds 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, the compounds described herein or their corresponding pharmaceutically acceptable salts or isotopic derivatives can be used in effective doses to treat hosts, such as humans, with lymphomas or lymphocyte or myeloproliferative diseases or abnormalities. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma.For example, the host may be suffering from a non-Hodgkin's lymphoma, which includes, but is not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; primitive NK cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); diffuse small cleaved cell lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; Langerhans cell histiocytosis (Langerhans cell histiocytosis); cellhistiocytosis); or Waldenstrom's Macroglobulinemia.

[0267] In another embodiment, the compounds as described herein, or their corresponding pharmaceutically acceptable salts or isotopic derivatives, can be used in an effective amount to treat patients, such as humans, with Hodgkin's lymphoma (such as, but not limited to, nodular sclerosis classical Hodgkin's lymphoma (CHL); mixed cellularity CHL; lymphocytopenic CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin's lymphoma; or nodular lymphocyte-predominant HL). The present application also 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 to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to expand or develop into cancer. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0268] In certain embodiments, the compounds of the present invention are used to treat abnormal cell proliferation such as tumors or cancers with a mutated RET protein, wherein the mutation is located at one of the amino acid positions listed below. For example, the mutation can be selected from one of the exemplary mutations listed in Table 1 or can be a different mutation.

[0269]

[0270] 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.

[0271] In certain embodiments, the tumor or cancer has a RET protein mutation that is a primary or partial driver of tumor or cancer cell proliferation. In another embodiment, the tumor or cancer has a RET altered protein that does not significantly act as a driver of abnormal cell proliferation but can be used to therapeutically kill tumor cells using a selected RET degrader as described herein.

[0272] In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a V804L mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a V804M mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a M918T mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a S891A mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a L790F mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with an E768D mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a C618S mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a C618R mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a missense mutation in the RET protein 634. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers with a C634R mutation in the RET protein. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers associated with the RET protein C634Y mutation. In certain embodiments, the compounds of the present invention are used to treat tumors or cancers associated with the RET protein C634G mutation. In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are used to treat abnormal cell proliferation (such as tumors or cancers) with the G810R mutant RET protein.

[0273] 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 having a G810S mutant RET protein.

[0274] 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 having a G810C mutant RET protein.

[0275] 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 having a C634W mutant RET protein.

[0276] 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 having the M918T mutant RET protein.

[0277] 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 having a V804L mutant RET protein.

[0278] 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 having a V804M mutant RET protein.

[0279] 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 in which the RET protein is fused to another protein (e.g., a fusion protein selected from CCDC6-RET, NCOA4-RET, KIF5B-RET, PRKAR1A-RET, TRIM24-RET, TRIM33-RET, GOLGA5-RET, HOOK3-RET, KTN1-RET, ERC1-RET, MBD1-RET, TRIM27-RET, BRC-RET, FGFR10P-RET, PCM1-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, CUX1-RET, KIAA1468-RET, and KIAA1217-RET).

[0280] 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 having a CCDC6-RET fusion protein. 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 having a NCOA4-RET fusion protein.

[0281] 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 having a KIF5B-RET fusion protein.

[0282] In accordance with the foregoing, the present application further provides a method for preventing or treating any of the above-mentioned diseases or conditions 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.

[0283] Pharmaceutical compositions and combination therapies

[0284] In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be used in an effective amount (alone or in combination) to treat a patient, such as a human, suffering from a disorder or a RET-mediated disorder as described herein.

[0285] 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 (such as a human) suffering from a disorder including, but not limited to, those described herein.

[0286] The term "biologically active agent" is used to describe an agent other than a selected compound according to the present invention that can be used in combination with or in alternation with the compounds of the present invention to obtain a desired therapeutic result. In one embodiment, the compounds of the present invention and the biologically active agent are administered in such a manner that they are active in vivo over overlapping time periods (e.g., over time periods with overlapping Cmax, Tmax, AUC or other pharmacokinetic parameters). In another embodiment, the compounds of the present invention and the biologically active agent are administered to a subject in need thereof, and the compounds and the biologically active agent do not have overlapping pharmacokinetic parameters, yet one has a therapeutic impact on the therapeutic efficacy of the other.

[0287] In one aspect of the present 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 T cell activation inhibitory factor (VISTA) inhibitors, small molecules, peptides, nucleotides or other inhibitors. In certain 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 and thereby inhibit 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, tesimumab (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 AMP 224 or a B7-H3 inhibitor (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.

[0288] In another embodiment, one of active compounds described herein can be combined or alternately administered with an effective amount of an estrogen inhibitor of an effective amount for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer, wherein 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 a partial or complete estrogen antagonist or agonist. Partial anti-estrogen such as raloxifene and tamoxifen retain some estrogen-like effects, including estrogen-like uterine growth stimulation, and, in some cases, actually stimulates the estrogen-like effect of tumor growth during the development of breast cancer. On the contrary, fulvestrant (Fulvestrant) is a complete anti-estrogen, which does not have an estrogen-like effect on the uterus and is effective for tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 to Astra Zeneca, WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US 2013 / 0178445 to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, and US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, 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, delmadinone acetate, dydrogesterone acetate, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.Other estrogen ligands that can be used according to the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO 2011 / 156518, U.S. Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015 / 0005286; and WO 2014 / 205138, US 2016 / 0175289, US 2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO 2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO2006 / 078834; US 6821989; US2002 / 0128276; US 6777424; US2002 / 0016340; US 6326392; US6756401; US2002 / 0013327; US 6512002; US 5,780,497, US 5,880,137, WO 2012 / 048058 and WO 2007 / 087684.

[0289] In another embodiment, the active compound described herein can be combined with an effective amount of an androgen (such as testosterone) inhibitor or alternately administered 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 another form of a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or a partial or complete androgen antagonist. In one embodiment, the 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. Other non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone (canrenone), drospirenone, ketoconazole, topiramide (topilutamide), abiraterone acetate and cimetidine (cimetidine).

[0290] 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.

[0291] In one embodiment, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI- 2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[0292] In one embodiment, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, trastuzumab emtansine, and pertuzumab.

[0293] In one embodiment, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.

[0294] In one embodiment, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0295] 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]piperazine -1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylmercaptobutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholinyl-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide) acyl) benzamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-4-methoxypyrrole-2-ylidene] indole methanesulfonate), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, 2-amino-6-bromo-4-(1-cyano-2-ethoxy)-1,2-diamino-2-thiazol-3-ylamino ... benzopyran-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).

[0296] 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, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine -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} )), 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-quinolyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl- 2-(Morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzene Formic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-monohydroxypropane-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]-methylene-(Z)-yl]-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), Buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonamide)] [3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentanoyl-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholinyl-4-ammonium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-olate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2, 3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile) (dactolisib), 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 ([(3aR,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 sonolisib), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS173, VS-5584 (SB2343), CZC24832, TG100-115 , A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (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), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics) (see U.S. Patent Publication No. 2011 / 0117073, which is 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)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-Butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-Butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methyl-pyridine-2-carboxamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline oxopiperazine-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,

[0015] The present invention relates to a novel BTK inhibitor comprising a novel BTK inhibitor comprising a 1-hydroxy-2-[((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride, a 1-hydroxy-2-[((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride, a 1-hydroxy-2-[((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), ... BTK inhibitors disclosed in Hematology & Oncology, 2013, 6:59 (incorporated herein by reference in its entirety). Syk inhibitors include, but are not limited to, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib dihydrogen phosphate ([6-(5-fluoro-2- [(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl ester), fotantinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide (HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxamide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3- {[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,(2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azadiyl))biphenyl)bis(2,3'-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), Phenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein),3614-3643, the entire contents of which are incorporated herein), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the entire contents of which are incorporated herein). In one embodiment, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroaniline)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimax Pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEA119 (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[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfonamidoamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromene-2- ketone), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinane-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, bemetinib, SL-327, TAK-733, PD318088. In one embodiment, the bioactive agent is a Raf inhibitor. Raf inhibitors are well known and include, for example, Vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), Sorafenib Tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide; 4-methylbenzene methanesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), 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-bromoformylpurine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepanyl-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (conefenib). 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), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076 and KW-2449 or a combination thereof. In one embodiment, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include but are not limited to rapamycin and its analogs, everolimus (Afinitor), temsirolimus, lidafornix, sirolimus and deforolimus. Examples of MEK inhibitors include, but are not limited to, tametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinob (6-(4-bromo-2-chloroaniline)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib (GSK1120212), and selumetinob (6-(4-bromo-2-chloroaniline)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide). / 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 / RDEA19 (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-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide amine), R05126766 (3-[[3-fluoro-2-(methylsulfonamidoamino)-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-oxazinane-2yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide). In one embodiment, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0297] In one embodiment, the bioactive agent is a HSP inhibitor.HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

[0298] Additional biologically active compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.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 (mek ) inhibitors, VEGF decoy antibodies, pemetrexed, panitumumab, amrubicin, ogavuzumab, Lep-etu, nolatrexed, AZD2171, batabulin, ofatumumab, zanolimumab, edotecan, tetrandrine, rubitecan, telostatin, obinutuzumab, tesimumab, ipilimumab, gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatidecan, IL13-PE38QQR, INO1001, IPdR1 KRX-0402, methionone, LY317615, neuradiab, vitespan, Rta 744, Sdx102, talapanel, atrasentan, Xr311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouracil, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5- [5-(Methylsulfonyl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anazol, 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 acetate), leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone acetate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guérin (BCG)Calmette-Guerin (BCG) vaccine), doxorubicin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone acetate, 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, mitoflash oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis retinoic acid, phenylalanine mustard, uracil mustard, estramustine, hexamethylmelamine, floxuridine, 5-deoxyuridine, cytarabine, 6-mercaptopurine, deoxycoformycin, cin), calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxane, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitacin, droloxifene, idoxyfene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diffutoxin x), gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, 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 / ZK222584, VX-745, PD184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, polyethylene glycol filgrastim (PEG-filgrastim), darbepoetin, erythropoietin, granulocyte colony-stimulating agent 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, altretamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, erythropoietin alfa, darbepoetin alfa, and mixtures thereof.

[0299] In one embodiment, the bioactive agent is selected from, but not limited to, imatinib mesylate Dasatinib Nilotinib Bosutinib Trastuzumab Trastuzumab-DM1, pertuzumab (Perjeta™), lapatinib Gefitinib Nilotinib Cetuximab Panitumumab Vandetini Vemurafenib Vorinostat Romidep Besarodine Alitretinoin retinoic acid Carfilizomib (Kyprolis™), pralatrexate Bevacizumab Ramucirumab (Ziv-aflibercept) Sorafenib Sunitinib Pazopanib Regorafenib and cabozantinib (Cometriq™).

[0300] In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an adjunctive 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 survival), and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer agents include: vincristine Liposomal vincristine Daunomycin (daunomycin or ) or doxorubicin Cytarabine (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 other 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, BCG live vaccine (intravesical injection), betamethasone sodium phosphate and betamethasone acetate, Bicalutamide, bleomycin sulfate, busulfan, folinic acid, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cytosphamide, cytarabine, cytosphamide, cytochalasin B, cyclophosphamide (Cytoxan), dacarbazine, dactinomycin D, dactinomycin (formerly known as actinomycin) actinomycin), daunorubicin hydrochloride, daunorubicin citrate, denileukin, dexrazoxane, dibromomannitol, dihydroxyanthracenedione, docetaxel, dolasetron mesylate, doxorubicin hydrochloride, dronabinol, Escherichia coli L-asparaginase, emetine, erythropoietin-α, Erwinia lactone L-asparaginase, esterified androgens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folic acid, gemcitabine hydrochloride, glucocorticoids, goserelin acetate acetate), gramicidin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon alfa-2b, irinotecan hydrochloride, letrozole, folinate calcium, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytansinoids, nitrogen mustard hydrochloride, medroxyprogesterone acetate, megestrol acetate, melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron hydrochloride, paclitaxel, pamidronate disodium, pentostatin, pilocarpine hydrochloride, plimycin, polifeprosan 20 with carmustine implantcarmustine implant), porfimer sodium, procaine, procarbazine hydrochloride, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, paclitaxel, teniposide, teniposide, testolactone, tetracaine, thiotepa, chlorambucil, thioguanine, thiotepa, topotecan hydrochloride, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0301] In some embodiments, the compound of the present invention is administered in combination with a chemotherapeutic agent (for example, a cytotoxic agent or other chemical compounds for treating cancer). The example of a chemotherapeutic agent includes an alkylating agent, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, podophyllotoxins (epipodopyyllotoxins), antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracene dione substituted urea, methyl hydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogen, antiestrogen, androgen, antiandrogen and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), folinic acid (LV), ranotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel.Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, sulfamethoxazole, and piposulfan; monoheterocyclic propanes such as benzodopa, carboquinone, methoprene, and uredopa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; annonaceous lactones (particularly bratacin and bratacinone); camptothecins (including the synthetic analogue topotecan); bryostatin; callistatin. statin); CC-1065 (including its synthetic analogs adolesin, cardzelesin, and biszelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; asarcodictyin; sea cucumber spongistatin; nitrogen mustards such as chlorambucil, naphthyl mustard, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nembixin, phenylephrine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; anti- and cyclophosphamide. These antibiotics include enediynes (e.g., calicheamicins, particularly calicheamicin gamma 1 and calicheamicin omega 1 (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromophores. Aldenediyne antibiotic chromophores), aclacinomycins, actinomycins, authramycin, azaserine, bleomycin, actinomycin C, carabicin, caminomycin, carzinophilin, chromomycinis, actinomycin D, daunomycin, detoxibacin, 6-diaza-5-oxo-L-norleucine,. (doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolidino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tuberculin, ubenimex, zoloft, daunorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethylformamide, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs such as cyclocytidine, azacitidine, 6-azauridine, camovir, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as captestosterone, drostanolone propionate, cyclothiosteroid, melastane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as linolenic acid; acetylglucosidase; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; amustine; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoxantrone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid acid); 2-ethylhydrazide; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizolan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), Cremopor-free, albumin-engineered nanoparticle paclitaxel formulation (American Pharmaceutical Partners, Schaumberg, IL) and docetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; novantrone; teniposide; edatrexate; daunorubicin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylguanylate (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. Two or more chemotherapeutic agents can be used in combination with the compounds of the present invention in a cocktail. Suitable dosing regimens for combined chemotherapy are known in the art. For example, the combined dosing regimen is as described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18: 233a (1999) and Douillard et al., Lancet 355 (9209): 1041-1047 (2000). Additional therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, edarizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, fentolimumab, a Celecoxib, rituximab, alemtuzumab, aldesleukin, atazolizumab, tocilizumab, sirolimus, everolimus, rucamumab, daclizumab, HLL1, huN901-DM1, atimud, natalizumab, bortezomib, carfilzomib, marizomib, tanspiramycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexalimumab, dulanamine (dula nermin), ABT-737, oblimersen, priticycline, tapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lanalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin, PD0332991, ribociclib (LE E011), amebaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).In one embodiment, the additional treatment is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells, triggering the immune system to destroy them. 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 bound to bevacizumab, VEGF cannot interact with its cell receptors, thereby preventing the signaling that leads to new blood vessel growth. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending its normal growth-promoting signals. They can also trigger apoptosis and activate the immune system to destroy tumor cells. In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant can be a calcineurin inhibitor, for example, cyclosporine or ascomycin, such as cyclosporine A. FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives such as sirolimus Everolimus Temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapamycin analogs such as lidafoni, azathioprine, campath 1H, S1P receptor modulators such as fingolimod or its analogs, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, such as the sodium salt, or a prodrug thereof, such as montelukast inosinate OKT3 (ORTHOCLONE ),prednisone, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, Triperimox, Leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab Daclizumab Mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (through Immunex as Sales), Adalimumab Infliximab Anti-LFA-1 antibody, natalizumab Enmolomab, gavilimomab, anti-thymocyte immunoglobulin, siplizumab, Alefacept, pentasa, mesalamine, asacol, codeine phosphate, benolate, fenbufen, naproxen, diclofenac, etodolac and indomethacin, aspirin and ibuprofen. In some embodiments, the biologically active agent is a therapeutic agent, which is a biological agent used in cancer treatment, such as a cytokine (e.g., interferon or interleukin (e.g., IL-2)). In some embodiments, the biological agent is an anti-angiogenin agent, such as an anti-VEGF agent, for example, bevacizumab. In some embodiments, the biologic is an immunoglobulin-based biologic, for example, a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a fusion fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. These 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); (Cetol bead alone); (golimumab); (canakinumab); (ustekinumab); (ofatumumab); (denosumab); (motavizumab); (raxibacumab); (belimumab); (ipilimumab); (vetuximab); (Pertuzumab); (ado-trastuzumab emtansine); and (obinutuzumab). Antibody-drug conjugates are also included. The combination therapy may include a non-drug therapeutic agent. For example, the compound can be administered outside of radiotherapy, cryotherapy, hyperthermia and / or surgical resection of tumor tissue. In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially in any order. The first therapeutic agent can be administered immediately, 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, at most 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 before or after the administration of the second therapeutic agent. In certain embodiments, the second therapeutic agent is administered at a different dosage regimen than the compounds of the invention. For example, the second therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments, both the first and second therapeutic agents have a treatment holiday.

[0302] Dosage form and administration

[0303] As described herein, the compounds of the present disclosure (e.g., compounds of Formula I, I(a), I(b), I(c), I(d), I(e), I(f), I(g), and / or I(h)), or pharmaceutically acceptable salts thereof, can be administered as pure chemicals, but are more typically administered as pharmaceutical compositions comprising an effective amount for a patient (typically a human) in need of such treatment for any of the conditions described herein. Accordingly, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound or pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical compositions may contain the compound or salt as the sole active agent, or, in alternative embodiments, contain the compound and at least one additional active agent.

[0304] In general, the compositions of the present invention will be administered in a therapeutically effective amount by any acceptable mode 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 efficacy of the compound used, the route of administration and form, the indication for which administration is directed, and the preferences and experience of the medical practitioners involved. Those of ordinary skill in the art treating these diseases will be able to determine the therapeutically effective amount of the compositions of the present invention for a given disease without undue experimentation and relying on personal knowledge and the disclosure of this application.

[0305] In certain embodiments, the pharmaceutical composition is 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.

[0306] In certain embodiments, patients can be treated with low-dose therapy using the compounds of the present invention. For example, the pharmaceutical composition can be in a dosage form containing from about 0.1 μg to about 2000 μg, from about 10 μg to about 1000 μg, from about 100 μg to about 800 μg, or from about 200 μg to about 600 μg of 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 active compound or a salt thereof.

[0307] 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.

[0308] The composition of pharmaceutical or therapeutically effective amount will be delivered to the patient. The precise effective amount varies from patient to patient and will depend on species, age, the size and health status of the experimenter, the nature and degree of the condition being treated, the advice of the treating physician, and the therapeutic agent or therapeutic combination selected for use. The effective amount for a particular situation can be determined by routine experiments. For the purposes of this disclosure, the therapeutic amount can be, for example, in the range of about 0.01mg / kg to about 250mg / kg body weight in at least one dose, more typically in the range of about 0.1mg / kg to about 10mg / kg. Multiple doses can be administered to the experimenter as needed to reduce and / or alleviate the signs, symptoms or causes of the condition being discussed, or to bring about any other desired changes in the biological system. When necessary, a preparation with an enteric coating can be prepared for sustained or controlled release administration of the active ingredient.

[0309] In some embodiments, the compound disclosed herein or used is administered once a day (QD), twice a day (BID) or three times a day (TID). In some embodiments, the compound disclosed herein or used is 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.

[0310] 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.

[0311] In certain embodiments, the compounds of the present invention are administered intravenously once a day. In certain embodiments, the compounds of the present invention are administered intravenously twice a day. In certain embodiments, the compounds of the present invention are administered intravenously three times a day. In certain embodiments, the compounds of the present invention are administered intravenously four times a day.

[0312] In some embodiments, the compounds of the invention have a treatment holiday between treatment cycles. For example, the compounds may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle.

[0313] The pharmaceutical composition can also include 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.

[0314] These compositions can contain any amount of active compound to achieve the desired result, for example, between 0.1 and 99 weight percent (wt.%) of the compound, and typically at least about 5 wt.% of the compound. Some embodiments contain from about 25 wt.% to about 50 wt.% or from about 5 wt.% to about 75 wt.% of the compound.

[0315] The pharmaceutical formulation is 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 packaged tablets, capsules, and powders in vials or ampoules. Alternatively, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of the foregoing in packaged form.

[0316] In certain embodiments, the compound is administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfonate, heptanoate, hexanoate, hydrobromide, hydrochloric acid, The salts of the present invention include, but are not limited to, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate,

[0317] Therefore, the compositions of the present disclosure can be administered as pharmaceutical preparations suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous), injection, inhalation or spray, intraaortic, intracranial, subcutaneous (subdermal), intraperitoneal, subcutaneous (subcutaneous) or other administration methods containing conventional pharmaceutically acceptable carriers. Typical administration methods are oral, topical or intravenous injection, using a convenient daily dosage regimen, which can be adjusted according to the degree of pain.

[0318] Depending on the intended mode of administration, the pharmaceutical composition can be in a solid, semisolid or liquid dosage form, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, syrups, suspensions, creams, ointments, emulsions, pastes, gels, sprays, aerosols, foams or oils, injectable or infusible solutions, transdermal patches, subcutaneous patches, inhalation formulations, medical devices, suppositories, buccal or sublingual formulations, parenteral formulations or ophthalmic solutions, etc., preferably in a unitary dosage form suitable for single administration of a precise dosage.

[0319] Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an appropriate amount of active ingredient, for example, an effective amount to achieve the intended purpose. The composition will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other agents, adjuvants, diluents, buffers, etc. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the patient being treated. Carriers may be inert or may themselves have pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide the actual amount of material administered per unit dose of the compound. Classes 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 others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc, petrolatum, lanolin, polyethylene glycol, alcohols, transdermal enhancers, and vegetable oils. The pharmaceutical compositions may include optional active agents 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 compounds may be provided in the form of solids, liquids, spray-dried materials, microparticles, nanoparticles, controlled-release systems, and the like. Suitable excipients for non-liquid formulations are also well known to those skilled in the art. A detailed discussion of pharmaceutically acceptable excipients and salts is provided in Remington's Pharmaceutical Sciences, 18th edition (Easton, Pennsylvania: Mack Publishing Company, 1990). Additionally, auxiliary substances (such as wetting or emulsifying agents, biological buffers, surfactants, and the like) may be present in these carriers. Biological buffers can be any pharmacologically acceptable solution and provide the desired pH value for the formulation, i.e., a physiologically acceptable pH 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. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, etc., the active compound as described herein and optional pharmaceutical adjuvants in an excipient (such as, for example, 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. The actual methods for preparing these dosage forms are known to those skilled in the art or will be apparent; for example, see Remington's Pharmaceutical Sciences cited above. In another embodiment, the use of permeation enhancing excipients is provided, including polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethylchitosan, polyacrylic acid); and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione complex). The pharmaceutical composition / combination can be formulated for oral administration. For oral administration, the composition typically takes the form of tablets, capsules, soft gelatin capsules, and may also be an aqueous or non-aqueous solution, suspension, or syrup. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use may include one or more common carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also usually added. Generally, 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 necessary or necessary, suitable binders, lubricants, disintegrants and colorants can also be added to 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, wax, 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 a liquid suspension is used, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.), and combined with an emulsifier and suspending agent. If desired, flavorings, colorants and / or sweeteners can also be added. Other optional components of the oral formulations incorporated herein include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[0320] For ocular delivery, the compounds can be injected, for example, intravitreally, intrastromally, intracamerally, sub-tenonally, subretinally, retrobulbarly, peribulbarly, suprachorodially, conjunctivally, subconjunctivally, suprascleraly, periocularly, transscleraly, retrobulbarly, posterior juxtascleraly, pericornaly, or tear ductally, or through mucus, mucin, or mucosal barriers, in an immediate or controlled release manner, or as needed via an ocular device.

[0321] Parenteral formulations can be prepared in conventional forms (liquid solutions or suspensions, solid forms suitable for dissolving or being suspended in a liquid before injection, or 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 nontoxic parenteral diluents or solvents. Operable acceptable carriers and solvents are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty acid esters, or polyols are typically used as solvents or suspension media. In addition, parenteral administration can involve the use of slow-release or sustained-release systems to maintain constant dosage levels.

[0322] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions that can contain antioxidants, buffers, antibacterial agents and solutes that make the preparation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickeners, stabilizers and preservatives. Administering via certain parenteral routes can involve pushing the preparation of the present disclosure through a needle or catheter by a sterile syringe or some other mechanical devices (such as a continuous infusion system) to introduce the preparation into the patient's body. The preparation provided by the present disclosure can be administered using a syringe (syringe), an injector (injector), a pump or any other device recognized in the art for parenteral administration. According to the disclosure, the preparation for parenteral administration includes a sterile aqueous solution or a non-aqueous solution, a suspension or an emulsion. The example of a non-aqueous solvent or carrier is propylene glycol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin and injectable organic esters (such as ethyl oleate). These dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by adding a sterilizing agent to the composition, by irradiating the composition, or by heating the composition. They may also be prepared using sterile water or some other sterile injectable medium immediately before use.

[0323] Sterile injectable solutions are prepared by adding one or more compounds of the present disclosure in the desired amount to an appropriate solvent with the various other ingredients listed above as needed, followed by sterilization by filtration. Typically, dispersants are prepared by adding various sterilized active ingredients to a sterile carrier containing a basic dispersion medium and the other required ingredients listed above. For sterile powders used to prepare sterile injectable solutions, typical preparation methods are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional required ingredients from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for 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.

[0324] Alternatively, the pharmaceutical compositions of the present disclosure may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent 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 agent. Such materials include cocoa butter, beeswax, or polyethylene glycol.

[0325] Pharmaceutical compositions of the present disclosure can also be applied by nasal aerosol or inhalation. These compositions are prepared according to the technology known in the pharmaceutical preparation field, and benzyl alcohol or other suitable preservatives, absorption enhancers (improving bioavailability), propellants such as fluorocarbons or nitrogen and / or other conventional solubilizing agents or dispersants can be used to prepare saline solutions. Preparations for buccal administration include tablets, lozenges, gels, etc. Or alternatively, buccal administration can be realized using a transmucosal delivery system well known to those skilled in the art. Compounds of the present disclosure can also be delivered by skin or mucosal tissues by conventional transdermal drug delivery systems (i.e., transdermal " patches"), wherein medicament is generally included in a laminated structure, and the structure is fixed on the body surface as a drug delivery device. In this structure, the pharmaceutical composition is generally contained in one deck or " reservoir (reservior) ", below the upper lining layer. The laminated device can contain a single reservoir, or can contain multiple reservoirs. In one embodiment, the reservoir includes a polymer matrix of a pharmaceutically acceptable contact adhesive material for fixing the system on 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.

[0326] Alternatively, the drug-containing reservoir and the skin-contact adhesive may be present as separate and distinct layers, with the adhesive being located beneath the reservoir, in which case the reservoir may be a polymer matrix as described above, or may be a liquid or gel reservoir, or may be in some other form. The backing layer in these laminates serves as the upper surface of the device, serving as the primary structural element of the laminate structure and providing significant flexibility to the device. The material selected for the backing layer should be substantially impermeable to the active agent and any other materials present.

[0327] Compositions disclosed herein can be formulated for aerosol administration, particularly for the respiratory tract and including intranasal administration. For example, the compound can generally have a small particle size, for example, 5 microns or less of the order of magnitude. This particle size can be obtained, for example, by micronization, by means known in the art. The active ingredient is provided in a pressurized package with a suitable propellant (such as chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gases). The aerosol can also conveniently contain a surfactant such as lecithin. The dosage of the medicine can be controlled by a metering valve.

[0328] Alternatively, the active ingredient may be provided in the form of a dry powder, for example as a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder mix may be presented in unit dosage form, for example in capsules or boxes such as gelatin or blister packs, from which the powder can be administered by inhaler.

[0329] Formulations suitable for rectal administration are conveniently presented as unit-dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers (eg, cocoa butter) and then shaping the resulting mixture.

[0330] In certain embodiments, the pharmaceutical composition is suitable for external application to the skin using the administration methods defined above.

[0331] In certain embodiments, pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches adapted to maintain close contact with the epidermis of the recipient for extended periods of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3(6):318(1986)) and are typically in the form of optionally buffered aqueous solutions of the active compound.

[0332] In one embodiment, a microneedle patch or device for delivering a drug through or into biological tissue, particularly the skin, is provided. The microneedle patch or device allows for the delivery of a drug through or into the skin or other tissue barriers at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[0333] Preparations suitable for pulmonary administration can be delivered by a variety of passive respiratory driven and active powered single dose / multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating screen nebulizers. The selection of suitable pulmonary delivery devices depends on parameters such as the pathophysiology of the properties, site of action, and lungs of the drug and its preparation.

[0334] Example

[0335] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. By way of example and not limitation, compounds of Formula I can be prepared according to the methods outlined in the Examples listed herein. It should be noted that one skilled in the art will know how to modify the methods listed in the Examples to obtain the desired products.

[0336] Analytical methods

[0337] NMR

[0338] The following conditions were used to obtain proton nuclear magnetic resonance (NMR) spectra: 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 2015-01 version (provided by ADC Labs) or MestReNova software.

[0339] Chemical shifts are reported in parts per million (ppm) and are shifted downfield relative to the internal standard tetramethylsilane (TMS), or relative to the position of TMS inferred in the deuterated NMR solvent. Apparent multiplicities are reported as: singlet - s, doublet - d, triplet - t, quartet - q, or multiplet - m. Peaks that exhibit broadening are further denoted as br. Integration values ​​are 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 peaks or solvent peaks in the NMR spectrum may not provide reliable integrated intensities. In some cases, NMR spectra may be obtained using water peak suppression, which may result in overlapping peaks being invisible or having altered shapes and / or integrations.

[0340] Liquid chromatography

[0341] The following preparative and / or analytical (LC / MS) liquid chromatography methods were used.

[0342] 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+).

[0343] 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+).

[0344] 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).

[0345] 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).

[0346] Method P: Mode: binary gradient, Pump A: LC-20ADXR, Pump B: LC-20ADXR, Total flow rate: 1.5000 mL / min, BConc.: 30.0%, Oven temperature: 40°C, PDA mode: SPD-M20A, Lamp: D2, Starting wavelength: 190 nm, End wavelength: 400 nm, Column name: XBridge BEH Shield RP18, Length: 30 mm, Inner diameter: 4.6 mm, Description: 2.5 um particles, Mobile phase A: Water / 5 mM NH4HCO3, Mobile phase B: Acetonitrile; Acquisition mode: Scan, Polarity: Positive.

[0347] Method Q: Mode: binary gradient, Pump A: LC-40D XR, Pump B: LC-40D XR; Oven temperature: 40°C; PDA mode: SPD-M20A, Lamp: D2, Start wavelength: 190 nm, Stop 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, Stop time: 3.00 min, Acquisition mode: Scan, Polarity: Positive;

[0348] 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)

[0349] Acronyms and abbreviations

[0350] Table 2 provides a list of acronyms and abbreviations used in this specification and their meanings.

[0351]

[0352]

[0353]

[0354] Example 1: Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0355]

[0356] To a sealable reaction vial containing the TFA salt of 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid (12.1 mg, 0.021 mmol) in DMF (500 μl) was added DIPEA (15 μl, 0.085 mmol) followed by BOP (14.07 mg, 0.032 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (19.87 mg, 0.032 mmol) was added to the solution and stirred for 2 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (6.07 μl, 0.106 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 77% yield (16.3 mg). 1 H NMR(500MHz,DMSO-d6)δ10.99-10.91(m,1H),10.09-10.00(m,1H),9.11-8.92(m,1H),8.36-8.18(m,1H) ),8.05-7.98(m,1H),7.70-7.64(m,2H),7.63-7.57(m,1H),7.35-7.29(m,2H),7.19-7.12(m,2H),5.09 =-4.99 (m, 1H), 4.42-4.20 (m, 4H), 3.85-3.52 (m, 2H), 3.30-3.27 (m, 2H), 3.26-3.01 (m, 5H), 2.95-2.82 (m, 1H), 2.44-2.22 (m, 3H), 2.02-1.64 (m, 5H), 1.58-1.45 (m, 4H), 1.44-1.39 (m, 6H), 1.34-1.28 (m, 4H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 885.3 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 98.2%; Observed mass: 885.3; Retention time: 1.65 minutes. Injection 2 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 2 results: Purity: 98.9%; Observed mass: 885.3; Retention time: 2.09 minutes.

[0357] Example 2: Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0358]

[0359] To a sealable reaction vial containing the TFA salt of 7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)heptanoic acid (12.3 mg, 0.022 mmol) in DMF (500 μl) was added DIPEA (15 μl, 0.086 mmol) followed by BOP (14.33 mg, 0.032 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (20.2 mg, 0.032 mmol) was added to the solution and stirred for 2 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (6.18 μl, 0.108 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 69% yield (14.8 mg). 1 H NMR(500MHz,DMSO-d6)δ11.05-10.89(m,1H),10.10-9.97(m,1H),9.05-8.93(m,1H),8.31-8.13(m,1H),8.05-7.97 (m,1H),7.75-7.69(m,1H),7.69-7.64(m,2H),7.48(s,1H),7.44-7.38(m,1H),7.36-7.29(m,2H),5.12-5.03(m,1H) ,4.48-4.29 (m, 4H),3.85-3.45 (m, 4H),3.30-3.26 (m, 3H),3.17-2.83 (m, 8H),2.44-2.36 (m, 1H),2.31-2.19 (m, 2H),2.09-1.96 (m, 3H),1.96-1.72 (m, 4H),1.71-1.61 (m, 2H),1.58-1.45 (m, 4H),1.44-1.41 (m, 6H),1.34-1.27 (m, 4H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 884.4 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 100%; Observed mass: 884.4; Retention time: 1.92 minutes. Injection 2 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 2 results: Purity: 100%; Observed mass: 884.4; Retention time: 1.6 minutes.

[0360] Example 3: Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0361]

[0362] To a sealable reaction vial containing the TFA salt of 7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)heptanoic acid (14.7 mg, 0.026 mmol) in DMF (500 μl) was added DIPEA (18 μl, 0.103 mmol) followed by BOP (17.09 mg, 0.039 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (24.1 mg, 0.039 mmol) was added to the solution and stirred for 2 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (7.37 μl, 0.129 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 50% yield (12.9 mg). 1 H NMR(500MHz,DMSO-d6)δ10.10-9.98(m,1H),9.11-8.88(m,1H),8.24-8.11(m,1H),8.03-7.98(m,1H), 7.70-7.64(m,2H),7.44-7.39(m,1H),7.35-7.28(m,2H),7.27-7.19(m,1H),7.19-7.11(m,1H),5.14-5 0.03 (m, 1H), 4.43-4.16 (m, 4H), 3.87-3.58 (m, 2H), 3.31-3.27 (m, 2H), 3.26-2.96 (m, 6H), 2.95-2.78 (m, 2H), 2.41-2.21 (m, 5H), 2.04-1.95 (m, 1H), 1.88-1.74 (m, 2H), 1.56-1.40 (m, 12H), 1.32-1.25 (m, 4H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 885.8 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 98.2%; Observed mass: 885.1; Retention time: 2.06 minutes. Injection 3 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 3 results: Purity: 100%; Observed mass: 885.8; Retention time: 1.59 minutes.

[0363] Example 4: Synthesis of 4-amino-6-((1-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)heptanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0364]

[0365] To a sealable reaction vial containing the TFA salt of 7-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)heptanoic acid (13.3 mg, 0.023 mmol) in DMF (500 μl) was added DIPEA (16 μl, 0.93 mmol) followed by BOP (15.4 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (21.9 mg, 0.035 mmol) was added to the solution and stirred for 2 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (6.7 μl, 0.117 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 58% yield (13.5 mg). 1 H NMR(500MHz,DMSO-d6)δ10.07-9.98(m,1H),9.10-8.93(m,1H),8.22-8.10(m,1H),8.04-7.9 8(m,1H),7.72-7.63(m,2H),7.59-7.48(m,3H),7.38-7.24(m,2H),5.13-5.04(m,1H),4.45-4 0.22 (m, 4H), 3.92-3.42 (m, 3H), 3.31-3.28 (m, 2H), 3.26-2.88 (m, 6H), 2.46-2.35 (m, 1H), 2.32-2.19 (m, 4H), 2.06-1.94 (m, 3H), 1.81-1.59 (m, 5H), 1.57-1.40 (m, 12H), 1.31-1.24 (m, 4H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 884.5 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 99.1%; Observed mass: 884.3; Retention time: 1.91 minutes. Injection 2 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 2 results: Purity: 99.3%; Observed mass: 884.4; Retention time: 1.61 minutes.

[0366] Example 5: Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0367]

[0368] To a sealable reaction vial containing the TFA salt of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)pentanoic acid (12 mg, 0.022 mmol) in DMF (500 μl) was added DIPEA (15 μl, 0.088 mmol) followed by BOP (14.7 mg, 0.033 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (20.7 mg, 0.033 mmol) was added to the solution and stirred for 3 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (6.3 μl, 0.111 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 36% yield (7.7 mg). 1 H NMR(500MHz,DMSO-d6)δ10.99-10.86(m,1H),10.06-9.97(m,1H),9.09-8.85(m,1H),8.24-8.10(m,1H),8.04-7.96(m,1H) ,7.70-7.62(m,2H),7.55-7.48(m,1H),7.35-7.28(m,2H),7.10-6.99(m,2H),5.07-4.97(m,1H),4.42-4.36(m,2H),4.36-4 0.27 (m, 1H), 4.27-4.17 (m, 1H), 3.86-3.61 (m, 2H), 3.56-3.35 (m, 1H), 3.32-3.22 (m, 5H), 3.18-3.08 (m, 1H), 3.07-3.00 (m, 1H), 2.92-2.83 (m, 1H), 2.41-2.25 (m, 5H), 2.01-1.92 (m, 1H), 1.89-1.74 (m, 2H), 1.59-1.44 (m, 6H), 1.41 (d, J = 7.1 Hz, 6H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 857.4 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 100%; Observed mass: 857.3; Retention time: 1.96 minutes. Injection 4 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 4 results: Purity: 100%; Observed mass: 857.4; Retention time: 1.49 minutes.

[0369] Example 6: Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0370]

[0371] To a sealable reaction vial containing the TFA salt of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)pentanoic acid (10 mg, 0.018 mmol) in DMF (500 μl) was added DIPEA (13 μl, 0.074 mmol) followed by BOP (12.3 mg, 0.028 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (17.7 mg, 0.028 mmol) was added to the solution and stirred for 3 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (5.3 μl, 0.092 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 65% yield (11.6 mg). 1 H NMR(500MHz,DMSO-d6)δ11.08-10.86(m,1H),10.13-9.95(m,1H),9.12-8.90(m,1H),8.40-8.16(m ,1H),8.06-7.99(m,1H),7.71-7.65(m,2H),7.54-7.47(m,1H),7.37-7.27(m,4H),5.12-5.05(m,1 H), 4.42-4.33 (m, 3H), 4.28-4.22 (m, 1H), 3.97-3.40 (m, 5H), 3.33-3.24 (m, 3H), 3.20-2.88 (m, 6H), 2.46-2.26 (m, 3H), 2.06-1.94 (m, 1H), 1.94-1.74 (m, 2H), 1.74-1.65 (m, 2H), 1.62-1.18 (m, 12H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 857.3 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 100%; Observed mass: 857.3; Retention time: 1.93 minutes. Injection 5 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 5 results: Purity: 100%; Observed mass: 857.3; Retention time: 1.5 minutes.

[0372] Example 7: Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0373]

[0374] To a sealable reaction vial containing the TFA salt of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-1-yl)pentanoic acid (11.3 mg, 0.021 mmol) in DMF (500 μl) was added DIPEA (15 μl, 0.083 mmol) followed by BOP (13.8 mg, 0.031 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (19.5 mg, 0.031 mmol) was added to the solution and stirred for 3 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (6 μl, 0.104 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 65% yield (13.2 mg). 1 H NMR(500MHz,DMSO-d6)δ11.04-10.92(m,1H),10.13-9.96(m,1H),9.28-8.93(m,1H),8.28-8 .12(m,1H),8.05-7.99(m,1H),7.69-7.64(m,2H),7.64-7.57(m,2H),7.55-7.49(m,1H),7.37 =-7.29 (m, 2H), 5.15-5.02 (m, 1H), 4.50-4.27 (m, 4H), 3.86-3.51 (m, 3H), 3.34-3.27 (m, 3H), 3.22-2.81 (m, 8H), 2.45-2.25 (m, 3H), 2.12-1.73 (m, 7H), 1.73-1.47 (m, 6H), 1.44-1.38 (m, 6H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 856.5 [m+H] + Analytical LCMS ESI-MS (+) m / z 857.3 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 98.3%; Observed mass: 856.3; Retention time: 1.53 minutes. Injection 5 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 2 results: Purity: 98.4%; Observed mass: 856.4; Retention time: 1.82 minutes.

[0375] Example 8: Synthesis of 4-amino-6-((1-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0376]

[0377] To a sealable reaction vial containing the TFA salt of 5-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)pentanoic acid (12 mg, 0.022 mmol) in DMF (500 μl) was added DIPEA (15 μl, 0.088 mmol) followed by BOP (14.7 mg, 0.033 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (20.7 mg, 0.033 mmol) was added to the solution and stirred for 3 hours. The reaction was then diluted with 1 mL of DMF before the addition of acetic acid (6.3 μl, 0.111 mmol). The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as its mono-TFA salt in a 36% yield (7.7 mg). 1 H NMR(500MHz,DMSO-d6)δ10.10-9.95(m,1H),9.09-8.88(m,1H),8.22-8.12(m,1H),8.04-7.9 8(m,1H),7.70-7.61(m,3H),7.49-7.43(m,1H),7.40-7.36(m,1H),7.34-7.27(m,2H),5.14-5 0.03 (m, 1H), 4.43-4.20 (m, 4H), 3.93-3.57 (m, 3H), 3.32-3.18 (m, 3H), 3.18-2.85 (m, 5H), 2.77-2.60 (m, 2H), 2.41-2.24 (m, 5H), 2.02-1.92 (m, 3H), 1.81-1.66 (m, 4H), 1.60-1.40 (m, 12H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 856.5 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 97.1%; Observed mass: 856.1; Retention time: 1.66 minutes. Injection 2 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+ / -). Injection 2 results: Purity: 97.4%; Observed mass: 856.5; Retention time: 2 minutes.

[0378] Example 9: Synthesis of 4-amino-6-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)acetyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0379]

[0380] A. tert-Butyl 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)acetate. To a stirred solution of 3-(1-oxo-5-(3,9-diazaspiro[5.5]undec-3-yl)isoindolin-2-yl)piperidine-2,6-dione HCl (0.020 g, 0.046 mmol) in acetonitrile (0.5 mL) was added tert-butyl 2-bromoacetate (0.012 g, 0.060 mmol), sodium iodide (3.46 mg, 0.023 mmol), and DIPEA (0.020 mL, 0.115 mmol), and the reaction mixture was heated to 70°C. After 2 hours, the solution was cooled to room temperature and diluted with 10 mL of dichloromethane. The solution was washed with water and the organic layer was dried over sodium sulfate and evaporated to give a crude mixture which was directly carried on to the next step without further purification. Analytical LCMS ESI-MS (+) m / z 511.3 [m+H] + .

[0381] B. 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)acetic acid. To a sealable reaction vial containing a stirred solution of tert-butyl 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)acetate (26 mg, 0.051 mmol) in DCM (550 μl) at 0°C was added 2,2,2-trifluoroacetic acid (0.097 mL, 1.273 mmol), and the reaction mixture was slowly warmed to room temperature. The reaction was monitored by LCMS and was deemed complete after 6.5 hours. The solvent was then evaporated and the crude reaction mixture was dried in vacuo overnight to remove excess TFA. The mono-TFA salt of the obtained product was directly used in the synthesis of LDD without further purification.

[0382] C. 4-Amino-6-((1-(2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)acetyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide. To a sealable reaction vial containing the TFA salt of 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)acetic acid (0.023 g, 0.040 mmol) in DMF (1 ml) was added DIPEA (28 μl, 0.160 mmol) followed by BOP (27 mg, 0.060 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (37 mg, 0.060 mmol) was added to the solution and stirred for 3 hours. The crude material was then purified by preparative reverse-phase chromatography using the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 μm particles; Flow rate: 20 mL / min; Column temperature: 25°C. Mobile phase A: ACN / H2O (5:95) with 0.05% TFA; Mobile phase B: ACN / H2O (95:5) with 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to provide the desired compound as a mono-TFA salt in a 5% yield (2 mg). 1 H NMR(500MHz,DMSO-d6)δ10.99-10.82(m,1H),10.14-9.93(m,1H),9.15-8.92(m,1H),8.3 8-8.13(m,1H),8.06-7.96(m,1H),7.76-7.64(m,2H),7.56-7.47(m,1H),7.41-7.27(m,2 H), 7.13-6.88 (m, 1H), 5.08-4.97 (m, 1H), 4.45-4.15 (m, 4H), 3.93-3.67 (m, 2H), 3.31-3.03 (m, 4H), 2.95-2.85 (m, 1H), 2.43-2.31 (m, 1H), 2.01-1.76 (m, 3H), 1.73-1.30 (m, 15H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 883.3 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 100%; Observed mass: 883.3; Retention time: 1.46 minutes. Injection 2 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 2 results: Purity: 100%; Observed mass: 883.6; Retention time: 2.08 minutes.

[0383] Example 10: Synthesis of 4-amino-6-((1-(3-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)propanoyl)piperidin-4-yl)ethynyl)-7-isopropyl-N-(4-(methoxymethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide

[0384]

[0385] To a sealable reaction vial containing the TFA salt of 3-(9-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)propanoic acid (35 mg, 0.050 mmol) in DMF (500 μl) was added DIPEA (35 μl, 0.198 mmol) followed by BOP (33 mg, 0.074 mmol). The reaction mixture was stirred at room temperature for 1 minute before the TFA salt of 4-amino-7-isopropyl-N-(4-(methoxymethyl)phenyl)-6-(piperidin-4-ylethynyl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (46.4 mg, 0.074 mmol) was added to the solution and stirred for 3 hours. The reaction was then diluted with 1 mL of DMF, and acetic acid (14 μl, 0.248 mmol) was added. The crude material was then 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. Mobile phase A: ACN / H2O (5:95) containing 0.05% TFA; mobile phase B: ACN / H2O (95:5) containing 0.05% TFA. Fraction collection was triggered by MS (ESI+). Fractions containing the desired product were combined and dried by centrifugal evaporation to afford the desired compound as a mono-TFA salt in a 12% yield (5.8 mg). 1 H NMR(500MHz,DMSO-d6)δ10.07-9.98(m,1H),9.08-8.90(m,1H),8.23-8.10(m,1H),8.04-7.98(m,1H), 7.68-7.64(m,2H),7.52-7.46(m,1H),7.34-7.29(m,2H),7.04-6.97(m,2H),5.07-4.98(m,1H),4.42-4 0.36 (m, 2H), 4.36-4.28 (m, 1H), 4.23-4.16 (m, 1H), 3.86-3.63 (m, 2H), 3.19-2.99 (m, 2H), 2.93-2.85 (m, 1H), 2.46-2.29 (m, 7H), 2.01-1.92 (m, 1H), 1.82-1.76 (m, 1H), 1.62-1.55 (m, 1H), 1.53-1.41 (m, 15H). Low integration due to overlap with suppressed water and obscuration of DMSO signal. Analytical LCMS ESI-MS (+) m / z 856.5 [m+H] +Final purity was determined using analytical reversed-phase chromatography. Injection 1 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 1 results: Purity: 94%; Observed mass: 897.3; Retention time: 1.53 minutes. Injection 2 conditions: 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 minutes), 100% B (3.0-3.5 minutes); Flow rate: 1.0 mL / min; Detection: UV (220 nm) and mass spectrometry (ESI+). Injection 2 results: Purity 94.1%; Observed mass: 897.5; Retention time: 1.89 minutes.

[0386] Cellular RET degradation assay

[0387] The potency of cellular RET-degrading compounds was determined using a bead-based fluorescence amplification assay—the AlphaLISA Surefire Ultra assay kit (Perkin-Elmer). A papillary thyroid carcinoma (TPC-1) cell line expressing the CCDC6-RET fusion protein, the parental (TPC-1 / CCDC6-RET) line, was selected for screening potential degraders. Cells were seeded at 10,000 cells / well in 50 μl / well DMEM (Fisher Scientific) supplemented with 2% FBS serum (Gibco) in 384-well plates (Greiner Bio-One). After cell adhesion (4 hours), cells were treated with compounds by dispensing 25 μl of serially diluted compounds (1:3 dilutions, 11 points) directly into the cell culture wells using an Echo-655 ultrasonic liquid dispenser (Beckman). Low-normalization wells contained medium alone, and high-normalization wells contained cells treated with DMSO alone. Treated cell plates were incubated at 37°C and 5% CO₂ for 24 hours. At 24 hours, the cell culture medium was removed by a FELIX automated liquid handler (AnalytikJena) and 25ul cell lysis buffer (provided by the AlphaLisa test kit) was added to each well. 5ul cell lysate was transferred to a 384-well microplate (Perkin Elmer) and 2.5ul AlphaLISA acceptor bead mixture was added. The plate was sealed and kept at room temperature for 1 hour, and then the donor bead mixture was added. Donor beads were added in the dark and incubated for >1 hour, and then AlphaLISA fluorescence was measured at RT (excitation light 680nm, emission light 615nm) on an Envision plate reader with an Alphascreen aperture. RET protein abundance (and therefore degradation) corresponds directly to fluorescence intensity.

[0388] 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 For each compound tested, the DC 50 IC50 values ​​were calculated by analyzing the relationship between the degradation percentage and compound concentration and fitting a standard 4-parameter logistic curve, where Top and bottom values ​​are the % degradation at infinite and infinitesimal compound concentrations, respectively, while half-maximum is the compound concentration that produces a % degradation corresponding to 1 / 2 top value - bottom value, and N is the Hill coefficient. 50 Values ​​based on relationships Calculations. Compound replicates were performed in independent assays. Maximum degradation (YMax) was defined as the maximum % degradation by the 4-parameter logistic equation as described previously.

[0389] Active Table

[0390] Each compound in Table 3 was tested and found to be active in one or more of the above degradation assays, for example, the tRET AlphaLISA degradation assay using the parental RETTPC-1 cell line. 50 ) and % degradation response (Ymax) are included in Table 3.

[0391] Table 3

[0392]

[0393]

[0394] Implementation Plan

[0395] Embodiment 1. Compound of formula I:

[0396]

[0397] or a pharmaceutically acceptable salt thereof,

[0398] in

[0399] R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace;

[0400] A is an aryl or heteroaryl group, wherein the aryl or heterocyclic group is optionally replaced by one or more R 9 replace;

[0401] B is a heterocycloalkyl group or a C3-C8 cycloalkyl group;

[0402] L1 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0403] 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)-;

[0404] R 2 It is NR 10 R 11 ;

[0405] R 3 is H, halogen, NH2 or C1-C4 alkyl;

[0406] Each R 4 is independently C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl); or

[0407] Two R on adjacent carbons 4 Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;

[0408] R 5 is H, OH, CN, NO2 or C1-C4 alkyl;

[0409] Each R 6 or R 6’ is H; or

[0410] Two R's 6 May combine to form an oxo group; or

[0411] Two R's 6’ Can combine to form oxo groups;

[0412] R 7 、R 8 and R 9 each independently H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or

[0413] Two R on adjacent carbons 7 Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;

[0414] R 10 and R11 are independently H or C1-C4 alkyl;

[0415] m is an integer from 0 to 2;

[0416] n is an integer from 0 to 4; and

[0417] p is an integer from 1 to 8.

[0418] Embodiment 2. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(a):

[0419]

[0420] Embodiment 3. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(b):

[0421]

[0422] Embodiment 4. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(c):

[0423]

[0424] Embodiment 5. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(d):

[0425]

[0426] wherein s1 and s2 are independently integers from 1 to 2.

[0427] Embodiment 6. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(e):

[0428]

[0429] wherein s1 and s2 are independently integers from 1 to 2.

[0430] Embodiment 7. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(f):

[0431]

[0432] wherein s1 and s2 are independently integers from 1 to 2.

[0433] Embodiment 8. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(g):

[0434]

[0435] wherein s1 and s2 are independently integers from 1 to 2.

[0436] Embodiment 9. The compound of Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(h):

[0437]

[0438] wherein s1, s2, s3 and s4 are independently integers from 1 to 2.

[0439] Embodiment 10. The compound according to any one of embodiments 1-9 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C1-C6 alkyl group.

[0440] Embodiment 11. The compound according to any one of embodiments 1-10 or a pharmaceutically acceptable salt thereof, wherein R 1 It is isopropyl.

[0441] Embodiment 12. The compound according to any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, wherein R 3 It’s H.

[0442] Embodiment 13. The compound according to any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a C1-C6 alkyl group substituted by one or more C1-C6 alkoxy groups.

[0443] Embodiment 14. The compound according to any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein R 4 It is methoxymethyl.

[0444] Embodiment 15. The compound according to any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein R 6 It’s H.

[0445] Embodiment 16. The compound according to any one of Embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0446]

[0447]

[0448] Embodiment 17. A pharmaceutical composition comprising the compound according to any one of embodiments 1 to 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0449] Embodiment 18. 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 embodiments 1-16 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

[0450] Embodiment 19. The method of embodiment 18, wherein the patient is human.

[0451] Embodiment 20. The method of embodiment 18 or 19, wherein the RET-mediated disorder is cancer.

[0452] Embodiment 21. The method of embodiment 20, wherein the cancer is non-small cell lung cancer.

[0453] Embodiment 22. The method of embodiment 21, wherein the cancer has metastasized to the brain.

[0454] Embodiment 23. The method of any one of embodiments 18-22, wherein the RET-mediated disorder is mediated by mutant RET.

[0455] Embodiment 24. The method of any one of embodiments 18-21, wherein the RET-mediated disorder is relapsed or refractory cancer.

[0456] Embodiment 25. A compound according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, for use in treating a RET-mediated disorder, optionally in a pharmaceutical composition.

[0457] Embodiment 26. The compound of embodiment 25, wherein the RET-mediated disorder is cancer.

[0458] Embodiment 27. The compound of Embodiment 26, wherein the cancer is non-small cell lung cancer.

[0459] Embodiment 28. The compound of Embodiment 26, wherein the cancer has metastasized to the brain.

[0460] Embodiment 29. The compound of any one of embodiments 25-28, wherein the RET-mediated disorder is mediated by mutant RET.

[0461] Embodiment 30. The compound according to any one of embodiments 25-28, wherein the RET-mediated disorder is relapsed or refractory cancer.

[0462] Embodiment 31. Use of a compound according to any one of Embodiments 1-16, or a pharmaceutically acceptable salt thereof, in the treatment of a RET-mediated disorder, optionally in a pharmaceutical composition.

[0463] Embodiment 32. The use according to embodiment 31, wherein the RET-mediated disorder is cancer.

[0464] Embodiment 33. The use according to embodiment 32, wherein the cancer is non-small cell lung cancer.

[0465] Embodiment 34. The use according to embodiment 33, wherein the cancer has metastasized to the brain.

[0466] Embodiment 35. The use according to any one of embodiments 31 to 34, wherein the RET-mediated disorder is mediated by mutant RET.

[0467] Embodiment 36. The use according to any one of embodiments 31 to 34, wherein the RET-mediated disorder is relapsed or refractory cancer.

[0468] Embodiment 37. Use of a compound according to any one of Embodiments 1-16, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a RET-mediated disorder, optionally in a pharmaceutical composition.

[0469] Embodiment 38. The use according to embodiment 37, wherein the RET-mediated disorder is cancer.

[0470] Embodiment 39. The use according to embodiment 38, wherein the cancer is non-small cell lung cancer.

[0471] Embodiment 40. The use according to embodiment 38, wherein the cancer has metastasized to the brain.

[0472] Embodiment 41. The use according to any one of embodiments 37-40, wherein the RET-mediated disorder is mediated by mutant RET.

[0473] Embodiment 42. The use according to any one of embodiments 36 to 40, wherein the RET-mediated disorder is relapsed or refractory cancer.

[0474] equivalent

[0475] The details of one or more embodiments of the present disclosure are set forth in the description attached above. Although any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, preferred methods and materials are now described. Other features, objects and advantages of the present disclosure will be apparent from the specification and claims. In this specification and the appended claims, unless the context clearly indicates otherwise, singular forms include plural referents. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. All patents and disclosures cited in this specification are incorporated by reference.

[0476] The foregoing description is presented for purposes of illustration only and is not intended to limit the disclosure to the precise form disclosed, except as defined by the claims appended hereto.

Claims

1. Compound of formula I: or a pharmaceutically acceptable salt thereof, in R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more R 8 replace; A is an aryl or heteroaryl group, wherein the aryl or heterocyclic group is optionally replaced by one or more R 9 replace; B is a heterocycloalkyl group or a C3-C8 cycloalkyl group; L1 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; L2 is -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-; -C(O)-(OCH2CH2) p -(4- to 12-heterocycloalkyl)-; -C(O)NH-(CH2) p -(4- to 12-heterocycloalkyl)-; –C(O)NH-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-; -C(O)-(CH2CH2O) p -(4- to 12-heterocycloalkyl)-; -(OCH2CH2) p -(4- to 12-heterocycloalkyl)-; -C(O)-(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-; or -(CH2) p -(4- to 12-heterocycloalkyl)-C(O)-; R 2 It is NR 10 R 11 ; R 3 is H, halogen, NH2 or C1-C4 alkyl; Each R 4 is independently C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more C1-C6 alkoxy, C1-C6 thioalkyl, NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)(C1-C6 alkyl); or Two R on adjacent carbons 4 Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; R 5 is H, OH, CN, NO2 or C1-C4 alkyl; Each R 6 or R 6’ is H; or Two R's 6 May combine to form an oxo group; or Two R's 6’ Can combine to form oxo groups; R 7 、R 8 and R 9 each independently H, halogen, CN, NO2, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or Two R on adjacent carbons 7 Can be combined together to form a C3-C8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; R 10 and R 11 are independently H or C1-C4 alkyl; m is an integer from 0 to 2; n is an integer from 0 to 4; and p is an integer from 1 to 8.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula I(a):

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula I(b):

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula I(c):

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula I(d): wherein s1 and s2 are independently integers from 1 to 2.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(e): wherein s1 and s2 are independently integers from 1 to 2.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula I(f): wherein s1 and s2 are independently integers from 1 to 2.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(g): wherein s1 and s2 are independently integers from 1 to 2.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula I(h): wherein s1, s2, s3 and s4 are independently integers from 1 to 2.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C1-C6 alkyl group.

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

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

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a C1-C6 alkyl group substituted by one or more C1-C6 alkoxy groups.

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

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

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

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

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

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

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

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