Small molecule degrading agent for POLYBROMO-1 (PBRM1)

Abstract

To provide a compound that inhibits PB1 for the treatment of diseases including cancer.SOLUTION: The present invention provides a bivalent compound having a structure represented by formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof (where, the targeting ligand represents a moiety that binds an SWI / SNF bromodomain protein including PB1, the degron represents a moiety that binds an E3 ubiquitin ligase, and the linker represents a moiety that covalently connects the degron and the targeting ligand).SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of priority under § 119(e) of the United States Patent Act, based on U.S. Provisional Patent Application No. 62 / 664,592, filed on 30 April 2018, which is incorporated in its entirety herein. [Background technology]

[0002] Chromatin is a complex combination of deoxyribonucleic acid (DNA) and proteins that make up chromosomes. Chromatin is found inside the nucleus of eukaryotic cells and is divided into heterochromatin (condensed) and euchromatin (elongated) forms. The main components of chromatin are DNA and proteins. Chromatin functions as a mechanism that packages DNA into a small volume to fit within the cell, strengthens DNA to enable mitosis and meiosis, and regulates expression and DNA replication.

[0003] Histones are the major protein components of chromatin, acting as spools around which DNA wraps. Chromatin structure is controlled by a series of post-translational modifications to histones, particularly histones H3 and H4. Of all classes of proteins, histones are especially susceptible to post-translational modifications. Histone modifications are dynamic; they can be added or removed in response to specific stimuli. These modifications dictate both structural changes in chromatin and changes in gene transcription.

[0004] Bromodomains, approximately 110 amino acids long, are found in numerous chromatin-related proteins, including histones. These have been identified in approximately 70 human proteins. The interaction between bromodomains and modified histones may be a crucial mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins are involved in the pathogenesis and progression of diseases, including cancer, inflammation, and viral replication.

[0005] Cell type specificity and proper tissue functionality require the strict control of distinct transcriptional programs closely influenced by their environment. Alterations in this transcriptional homeostasis are directly linked to numerous disease conditions, particularly cancer, immuno-inflammatory diseases, neurological disorders, and metabolic disorders. Bromodomains reside within key chromatin modification complexes that help regulate specific disease-associated transcriptional pathways. An example of such a complex is the switch / sucrose non-fermentable (SWI / SNF) chromatin remodeling complex, a nucleosome remodeling complex containing a group of proteins that associate to remodel how DNA is packaged within cells. The SWI / SNF chromatin remodeling complex has been reported to be involved in gene regulation, cell lineage specialization, and development, and includes several bromodomain-containing subunits, including the Brahma-associated gene-1 (BRG1 (SWI / SNF-associated chromatin, matrix-associated, actin-dependent regulator, subfamily A, member 4 (SMARCA4))), brahma (BRM) (also known as SMARCA2), and the protein polybromo-1 (PBRM1) (also known as PB1). PB1 has six distinct bromodomains, which are associated with genomic instability and aneuploidy. Inactivating mutations in SWI / SNF subunits have been reported to be found in nearly 20% of human cancers. For example, mutations in the bromodomain of PB1 have been found in clear cell renal cell carcinoma. BRM has been identified as a synthetic legitimate target for BRG1-deficient cancers (Hoffman et al., PNAS 111(8):3128-3133(2014); Oike et al.). al., Cancer Research, 73(17):5508-5518(2013). Further studies have shown that certain cancers lacking SWI / SNF mutations are sensitive to BRG1 inhibition. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Hoffman et al., PNAS 111(8):3128-3133(2014) [Non-Patent Document 2] Oike et al., Cancer Research, 73(17):5508-5518(2013) [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Therefore, compounds that inhibit PB1 are needed to treat diseases such as cancer. [Means for solving the problem]

[0008] A first aspect of the present invention is formula I: [ka] The present invention relates to a divalent compound represented by (wherein the formula, the targeting ligand represents a portion that binds to the SWI / SNF bromodomain protein containing PB1, degron represents a portion that binds to the E3 ubiquitin ligase, and linker represents a portion that covalently connects degron and the targeting ligand), or to a pharmaceutically acceptable salt or stereoisomer thereof.

[0009] In another embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of the divalent compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0010] In another embodiment, a method for preparing the divalent compound of the present invention is provided.

[0011] A further aspect of the present invention relates to a method for treating a disease or disorder characterized by or mediated by dysfunctional SWI / SNF activity (e.g., dysfunctional PB1 activity), comprising the step of administering a therapeutically effective amount of a divalent compound, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need. [Brief explanation of the drawing]

[0012] [Figure 1] Figures 1A to 1C are graphs plotting the green fluorescent protein / red fluorescent protein (GFP / RFP) ratio as a function of the concentration of compounds 1 to 3 of the present invention, respectively, as prepared from a cell cereblon (CRBN) binding assay. [Figure 2] Figure 2 is a graph plotting the relative abundance (AU) of compounds 1-3 of the present invention as a function of their respective concentrations, compared to a control (lenalidomide), from a PBRM1 bromodomain 5 (PB5) GFP / RFP degradation assay (triple). [Figure 3] Figures 3A to 3J are graphs plotting the relative abundance (AU) of compounds 3 to 8 (A to F) and compounds 11 to 13 (H to J) of the present invention as a function of their respective concentrations, compared to the control (i.e., negative compound (G)). The concentrations are expressed in logarithmic units (for the compounds of the present invention). [Figure 4] Figure 4 is a Western blot showing the degradation of PBRM1 by glyceraldehyde 3-phosphate dehydrogenase (GAPDH) at 10 μM compound 1 at 6 hours, and at 10 μM, 1 μM, and 0.1 μM compound 1 at 24 hours, compared to a control (dimethyl sulfoxide (DMSO)). [Modes for carrying out the invention]

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the subject matter of this specification pertains. Where used herein and in the appended claims, unless otherwise specified, the following terms have the meanings provided for the convenience of understanding the present invention.

[0014] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context explicitly indicates otherwise. Thus, for example, a reference to "a composition" includes a mixture of two or more such compositions, a reference to "an inhibitor" includes a mixture of two or more such inhibitors, and so on.

[0015] Unless otherwise specified, the term "approximately" means within 10% (e.g., within 5%, 2%, or 1%) of the specific value modified by the term "approximately".

[0016] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is comprehensive or open-ended and does not exclude additional unlisted elements or method steps. In contrast, the transitional phrase "consisting of" excludes elements, steps, or components not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that "do not substantially affect the basic and novel characteristics" of the claimed invention.

[0017] With respect to the divalent compounds of the present invention, and to the extent that the following terms are used herein to further illustrate them, the following definitions apply.

[0018] As used herein, the term “aliphatic” refers to an acyclic hydrocarbon group, including branched and unbranched alkyl, alkenyl, or alkynyl groups.

[0019] As used herein, the term "alkyl" refers to a saturated, linear or branched monovalent hydrocarbon group. In one embodiment, the alkyl group is C1-C 18It is a group. In other embodiments, the alkyl group is C0-C6, C0-C5, C0-C3, C1-C 12 These are C1-C8, C1-C6, C1-C5, C1-C4, or C1-C3 groups (C0 alkyl refers to a bond). Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. In some embodiments, the alkyl group is a C1-C3 alkyl group. In some embodiments, the alkyl group is a C1-C2 alkyl group.

[0020] As used herein, the term "alkylene" refers to a linear or branched divalent hydrocarbon chain in which the remainder of the molecule consists solely of carbon and hydrogen, contains no unsaturated atoms, and is linked to a radical group having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may be linked to the remainder of the molecule through single bonds and to the radical group through single bonds. In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, the alkylene group contains 1 carbon atom (C1 alkylene).

[0021] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein that is substituted with one or more (e.g., one, two, three, or four) halo groups.

[0022] As used herein, the term “alkenyl” refers to a monovalent hydrocarbon group that has at least one carbon-carbon double bond, either linear or branched. Alkenyls include groups having “cis” and “trans” orientations, or “E” and “Z” orientations. For example, an alkenyl group may have a C2-C double bond. 18 It is a group. In other embodiments, the alkenyl group is C2-C 12 , C2~C 10 These are C2-C8, C2-C6, or C2-C3 groups. Examples include ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl.

[0023] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group having at least one carbon-carbon triple bond, whether linear or branched. For example, the alkynyl group may have a C2-C bond. 18 It is a group. In other examples, the alkynyl group is C2~C 12 , C2~C 10 These are C2-C8, C2-C6, or C2-C3. Examples include ethinyl, propa-1-inyl, propa-2-inyl, buta-1-inyl, buta-2-inyl, and buta-3-inyl.

[0024] As used herein, the term “aldehyde” is represented by the formula -C(O)H. The terms “C(O)” and “C=O” are used interchangeably herein.

[0025] As used herein, the term "alkoxyl" or "alkoxy" refers to an alkyl group as defined above to which an oxygen group is attached. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by oxygen. Thus, the alkyl substituent that makes an alkyl into an ether is an alkoxyl, or is like an alkoxyl, such that it can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0026] As used herein, the term "halogen" (or "halo" or "halide") refers to fluorine, chlorine, bromine or iodine.

[0027] As used herein, the term "oxo" refers to =O or (=O)2.

[0028] As used herein, the term "carboxylic acid" is represented by the formula -C(O)OH, and "carboxylate" is represented by the formula -C(O)O-.

[0029] As used herein, the term "ester" is of the formula -OC(O)Z 1 or -C(O)OZ 1 (wherein Z 1 can all be an alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group as described herein).

[0030] As used herein, the term "ether" is of the formula Z 1 OZ 2 (wherein Z 1 and Z 2(These are independently represented by alkyl, alkyl halide, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groups, all of which are described herein.)

[0031] As used herein, the term "ketone" refers to formula Z 1 C(O)Z 2 (In the formula, A 1 and A 2 (All of which are independently represented by alkyl, alkyl halide, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groups as described herein.)

[0032] As used herein, the term "sulfonyl" refers to the formula -S(O)2Z 1 (In the formula, Z 1 This refers to a sulfo-oxo group represented by hydrogen, alkyl, alkyl halide, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groups, as described herein.

[0033] As used herein, the term "sulfonylamino" (or "sulfonamide") is represented by the formula -S(O)2NH2.

[0034] As used herein, the term "thiol" is represented by the formula -SH.

[0035] As used herein, the term “cyclic group” is used alone or as part of a larger part and broadly refers to any group containing saturated, partially saturated, or aromatic ring systems, such as carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl groups. A cyclic group may have one or more (e.g., fused) ring systems. Thus, for example, a cyclic group may contain one or more carbocyclic groups, heterocyclic groups, aryl, or heteroaryl groups.

[0036] As used herein, the term “carbocyclic” (also called “carbocyclyl”) is used alone or as part of a larger part and refers to a group containing a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms, which is alone or part of a larger part (e.g., an alkcarbocyclic group). The term carbocyclyl includes mono-, di-, tri-, condensed, bridging, and spiro-ring systems, as well as combinations thereof. In one embodiment, a carbocyclyl has 3 to 15 carbon atoms (C3-C3). 15 ) contains. In one embodiment, the carbocyclyl contains 3 to 12 carbon atoms (C3 to C 12 ) contains. In another embodiment, carbocyclyl is C3-C8, C3-C 10 Or C5~C 10 In another embodiment, the carbocyclyl as a monoring comprises C3-C8, C3-C6 or C5-C6. In some embodiments, the carbocyclyl as a biring comprises C7-C 12 It includes. In another embodiment, carbocyclyl as a spirosystem is C5-C 12Includes. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, perduteriocyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicyclic carbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Typical examples of spirocarbocyclyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The term carbocyclyl includes aryl ring systems as defined herein. The term carbocyclyl also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, di-, or spiro-carbocyclic rings). The term carbocyclic group also includes carbocyclic rings fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., aryl or heterocyclic rings) whose groups or bonds are located on the carbocyclic ring.

[0037] Therefore, the term "carbocyclic formula" also refers to formula -R when used herein. c -Carbocyclyl (in the formula, R c The term carbocyclic formula also includes carbocyclylalkyl groups, which refer to the groups of an alkylene chain. The term carbocyclic formula also refers to the formula -OR as used herein. c -Carbocyclyl (in the formula, R c This also includes carbocyclylalkoxy groups, which refer to groups bonded through the oxygen atom of an alkylene chain.

[0038] As used herein, the term “heterocyclyl” is used alone or as part of a larger part to refer to a “carbocyclyl” containing a saturated, partially unsaturated, or aromatic ring system in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes mono-, di-, tri-, condensed, bridging, and spiro-ring systems, as well as combinations thereof. In some embodiments, heterocyclyl refers to a 3- to 15-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5- to 14-membered heteroaryl ring system. The term heterocyclyl also includes C3-C8 heterocycloalkyls, which are saturated or partially unsaturated mono-, ne-, or spiro-ring systems containing 3-8 carbon atoms and one or more (1, 2, 3, or 4) heteroatoms.

[0039] In some embodiments, the heterocyclyl group includes monocyclic, dicyclic, tricyclic, and spirocyclic systems containing 3 to 12 ring atoms, where the ring atoms are carbon and 1 to 5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes a 3 to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes a 4 to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl includes a 3-membered monocyclic ring. In some embodiments, the heterocyclyl includes a 4-membered monocyclic ring. In some embodiments, the heterocyclyl includes a 5 to 6-membered monocyclic ring. In some embodiments, the heterocyclyl group contains 0 to 3 double bonds. In any of the embodiments, the heterocyclyl includes 1, 2, 3, or 4 heteroatoms. The nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2), and the nitrogen heteroatoms may optionally be quaternized (e.g., [NR4]). + Cl - [NR4] + OH -Typical examples of heterocyclyls include oxyranil, azilidinil, thiranil, azetidinil, oxetanil, thietanil, 1,2-dithietanil, 1,3-dithietanil, pyrrolidinil, dihydro-1H-pyrrolyl, dihydrofuranil, tetrahydropyranil, dihydrothienyl, tetrahydrothienyl, imidazolidinil, piperidinil, piperazinil, morpholinil, thiomorpholinil, 1,1-dioxo-thiomorpholinil, dihydropyranil, tetrahydropyranil, hexahydrothiopyranil, hexahydropyrimidinil, oxadi Nanyl, thiadinyl, thioxanil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, oxazepinyl, oxazepanil, diazepanil, 1,4-diazepanil, diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranil, oxazolidinil, thiazolidinil, isothiazolidinil, 1,1-dioxoisothiazolidinol, oxazolidinol, imidazolidinol, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzo [d]Imidazolyl, 1,6-dihydroimidazole [4,5-d]pyrrolo [2,3-b]pyridinyl, thiadinyl, thiophenyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinil, 2-pyrrolinil, 3-pyrrolinil, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinil, py Lazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1] Octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decane-2-only, azaspiro[5.5] Examples include undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, and 1,1-dioxohexahydrothiopyranil. Examples of five-membered heterocyclyls containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms are thiazolyls containing thiazole-2-yl and thiazole-2-yl N-oxide, thiadiazolyls containing 1,3,4-thiadiazole-5-yl and 1,2,4-thiadiazole-5-yl, oxazolyl, e.g., oxazol-2-yl, and oxadiazolyls, e.g., 1,3,4-oxadiazole-5-yl and 1,2,4-oxadiazole-5-yl. Examples of five-membered heterocyclyl rings containing 2 to 4 nitrogen atoms include imidazolyls such as imidazole-2-yl; triazolyls such as 1,3,4-triazole-5-yl; and tetrazolyls such as 1,2,3-triazole-5-yl, 1,2,4-triazole-5-yl, and 1H-tetrazole-5-yl. Representative examples of benzo-condensed five-membered heterocyclyls are benzoxazole-2-yl, benzothiazole-2-yl, and benzimidazole-2-yl. Examples of six-membered heterocyclyl groups include pyridyls such as pyrido-2-yl, pyrido-3-yl, and pyrido-4-yl; pyrimidyls such as pyrimido-2-yl and pyrimido-4-yl; triazinyls such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyls, especially pyridazin-3-yl, and pyrazinyls. Pyridine N-oxide and pyridazine N-oxide and pyridyl, pyrimido-2-yl, pyrimido-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl groups are yet another example of heterocyclyl groups. In some embodiments, the heterocyclic group comprises a heterocyclic ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring), where the group or bond site is located on the heterocyclic ring, and in some embodiments, the bond site is a heteroatom contained within the heterocyclic ring.

[0040] Therefore, as used herein, the term heterocyclic refers to a heterocyclyl group containing at least one nitrogen atom, and includes N-heterocyclyl groups, where the remaining bonds between the heterocyclyl group and the molecule are mediated by the nitrogen atom of the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. The term heterocyclic also, as used herein, refers to a heterocyclyl group containing at least one heteroatom, and includes C-heterocyclyl groups, where the remaining bonds between the heterocyclyl group and the molecule are mediated by the carbon atom of the heterocyclyl group. Representative examples of C-heterocyclyl groups include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term "heterocyclic algebra" is also used, as disclosed above, for equation -R c -heterocycline (wherein R is R in the formula) c The term heterocyclic formula also includes heterocyclylalkyl groups, which refer to the groups of an alkylene chain. The term heterocyclic formula also refers to the formula -OR when used herein. c -heterocycline (wherein R is R in the formula) c This also includes heterocyclylalkoxy groups, which refer to groups bonded through the oxygen atom of an alkylene chain.

[0041] As used herein, the term “aryl,” used alone or as part of a larger part (e.g., “aralkyl” where the terminal carbon atoms of an alkyl group are the bonding sites, e.g., a benzyl group, “aralkoxy” where the oxygen atom is the bonding site, or “aloxyalkyl” where the bonding site is on an aryl group), refers to a group comprising a monocyclic, bicyclic, or tricyclic carbocyclic system including a fused ring, in which at least one ring of the system is aromatic. In some embodiments, the aralkoxy group is a benzoxy group. The term “aryl” may be used interchangeably with the term “aryl ring.” In one embodiment, aryl comprises a group having 6 to 18 carbon atoms. In another embodiment, aryl comprises a group having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthrasyl, biphenyl, phenantrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthilidinyl, and others, which may be substituted or independently substituted by one or more substituents described herein. The specific aryl group is phenyl. In some embodiments, the aryl group comprises an aryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., a carbocyclic or heterocyclic ring) whose group or bond site is located on the aryl ring.

[0042] Therefore, the term aryl is defined as formula -R, as disclosed above. c -aryl(in the formula, R) c The term aryl, as used herein, refers to a group of an alkylene chain (such as methylene or ethylene), and includes an aralkyl group (e.g., benzyl). In some embodiments, the aralkyl group is optionally a substituted benzyl group. c -aryl(in the formula, R) c This also includes aralkoxy groups, which refer to groups bonded through an oxygen atom of an alkylene chain (such as methylene or ethylene).

[0043] As used herein, the term "heteroaryl," used alone or as part of a larger phrase (e.g., "heteroarylalkyl" (also called "heteroaralkyl") or "heteroarylalkoxy" (also called "heteroaralkoxy")), refers to a monocyclic, bicyclic, or tricyclic system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, the heteroaryl comprises a 4 to 6-membered monocyclic aromatic group in which one or more ring atoms are independently, optionally substituted, nitrogen, sulfur, or oxygen. In another embodiment, the heteroaryl comprises a 5 to 6-membered monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Typical examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, teto Lazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidinil, imidazopyridyl, pyrazinil, pyridadinil, triazinil, tetradinil, tetrazolo[1,5-b]pyridazinil, purinyl, deazapurinil, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazole-2-yl, 1,3,4-triazole-5-yl, 1,3-oxazole-2 Examples include -yl, 1,3,4-oxadiazole-5-yl, 1,2,4-oxadiazole-5-yl, 1,3,4-thiadiazole-5-yl, 1H-tetrazole-5-yl, 1,2,3-triazole-5-yl, and pyrido-2-yl N-oxide. The term "heteroaryl" also includes groups in which the heteroaryl is condensed to one or more cyclic rings (e.g., carbocyclyl or heterocyclyl), where the group or bond site is located on a heteroaryl ring.Non-limiting examples include indolyl, indolidinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic, bicyclic, or tricyclic. In some embodiments, the heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., a carbocyclic ring or a heterocyclic ring), where the group or bond site is located on the heteroaryl ring, and in some embodiments, the bond site is a heteroatom contained in the heterocyclic ring.

[0044] Therefore, as used herein, the term heteroaryl refers to a heteroaryl group defined above, which contains at least one nitrogen atom, and includes N-heteroaryl groups, where the bond between the heteroaryl group and the rest of the molecule is via the nitrogen atom of the heteroaryl group. The term heteroaryl also refers to a heteroaryl group defined above, which also includes C-heteroaryl groups, where the bond between the heteroaryl group and the rest of the molecule is via the carbon atom of the heteroaryl group. The term heteroaryl also refers to a heteroaryl group of formula -R, as disclosed above. c -heteroaryl(wherein R) c The term heteroaryl also includes heteroarylalkyl groups (which are alkylene chains as defined above). The term heteroaryl also refers to the formula -OR when used herein. c -heteroaryl(wherein R) c This also includes heteroaralcoxy (or heteroarylalkoxy) groups, which refer to groups bonded through the oxygen atom of an alkylene group (as defined above).

[0045] Any of the groups described herein may be substituted or unsubstituted. As used herein, the term “substituted” broadly refers to all permissible substituents, provided that such substitutions are subject to the permissible valencies of the substituted atom and substituent, and implicitly result in a stable compound, i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc. Typical substituents include halogens, hydroxyl groups, and any other organic groups that may contain one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as oxygen, sulfur, and nitrogen atoms, grouped in linear, branched, or cyclic structural forms, and containing any number of carbon atoms, e.g., 1 to 14 carbon atoms.

[0046] Therefore, typical examples of substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyclic, substituted cyclic, carbocyclic, substituted carbocyclic, heterocyclic, substituted heterocyclic, aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted phenyl), heteroaryl, substituted heteroaryl, or NR6R7 (wherein R6 and R7 each independently represent H, optionally substituted aryl, or optionally substituted aralkyl), halo, hydroxyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amide, substituted amide, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, amino acid, peptide, and polypeptide groups.

[0047] The term "binding," when relating to the interaction between a target ligand and a targeted protein, which in this invention is at least one SWI / SNF bromodomain protein containing PB1, typically refers to an intermolecular interaction that may be preferential or substantially specific in that the binding of the targeted ligand to other non-SWI / SNF protein entities, including PB1, which may be present intracellularly, is not functionally important. The divalent compound can preferentially bind to and recruit at least one SWI / SNF protein containing PB1. In some embodiments, the divalent compound can also bind to BRG1 and / or BRM for targeted degradation.

[0048] The term "binding," in the context of the interaction between degron and E3 ubiquitin ligase, typically refers to an intermolecular interaction where the affinity level is sufficient to achieve the mobilization of the ligase to targeted degradation and the selective degradation of the targeted protein, although this may or may not be greater than the affinity between the targeted ligand and the target protein.

[0049] In general, the divalent compounds of the present invention are of formula I: [ka] (In the formula, the targeting ligand represents a portion that binds to the SWI / SNF bromodomain protein containing PB1, degron represents a portion that binds to the E3 ubiquitin ligase, and the linker represents a portion that covalently connects degron and the targeting ligand), or has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0050] SWI / SNF (e.g., PB1) targeted ligands The functional modality of this divalent compound, the SWI / SNF-targeting ligand (TL), binds to PB1. In some embodiments, the TL may also bind to BRG1 and / or BRM.

[0051] In some embodiments, the SWI / SNF-targeting ligand (also referred to herein as the PB1-targeting ligand) has the following structure: [ka] or its pharmaceutically acceptable salt or stereoisomer (In the formula, R 1 is, -R b , -OR b -S(O)2R b and -C(O)-N(R b Selected from the group consisting of )2; Each R b is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Independently selected from the group consisting of alkynyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl, each C 1~6 Alkyl, C 2~6 Alkinyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl are R c , oxo, halo, -NO2, -N(R c )2, -CN, -C(O)-N(R c )2, -S(O)-N(R c )2, -S(O)2--N(R c )2, -OR c , -SR c -OC(O)-R c , -C(O)-R c , -C(O)-OR c ,-S(O)-R c -S(O)2-R c , -N(R c )-C(O)-R c , -N(R c )-S(O)-R c , -N(R c )-C(O)-N(R c )2 and -N(R c )-S(O)2-R c -May optionally be substituted with one or more elements independently selected from; Each R c is hydrogen, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, independently selected from 3- to 15-membered carbocyclic and 3- to 15-membered heterocyclic, each C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, 3- to 15-membered carbocyclic and 3- to 15-membered heterocyclic are optionally substituted with one or more groups independently selected from R d ; or two Rs c together with the nitrogen to which they are attached form a heterocyclic optionally substituted with one or more groups independently selected from oxo, halo and oxo and halo and optionally substituted with one or more groups independently selected from C 1~3 alkyl; each R d is oxo, halo, -NO2, -N(R e )2, -CN, -C(O)-N(R e )2, -S(O)-N(R e )2, -S(O)2-N(R e )2, -S-R e , -O-C(O)-R e , -C(O)-R e , -C(O)-O R e , -S(O)-R e , -S(O)2-R e , -N(R e )-C(O)-R e , -N(R e )-S(O)-R e , -N(R e )-C(O)-N(R e )2, -N(R e )-S(O)2-R e , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, independently selected from 3- to 15-membered carbocyclic and 3- to 15-membered heterocyclic, any C<00001十一3>Alkyl, C 2~6 Alkenyl, C 2~6Alkinyl, 3-15 membered carbocyclyl, and 3-15 membered heterocyclyl are R e , oxo, halo, -NO2, -N(R e )2, -CN, -C(O)-N(R e )2, -S(O)-N(R e )2, -S(O)2-N(R e )2, -OR e , -SR e -OC(O)-R e , -C(O)-R e , -C(O)-OR e ,-S(O)-R e -S(O)2-R e , -N(R e )-C(O)-R e , -N(R e )-S(O)-R e , -N(R e )-C(O)-N(R e )2 and -N(R e )-S(O)2-R e It is optionally replaced by one or more groups independently selected from; Each R e is hydrogen, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, carbocyclyl and carbocyclyl (C 1~3 Independently selected from the group consisting of alkyls; R2 is H, C 1~6 Alkyl or -C(=O)-C 1~6 It is alkyl; R 3 is H or C 1~6 It is alkyl; R 4 It is substituted with hydroxyl (e.g., 2-hydroxy, 3-hydroxy, 4-hydroxy, 5-hydroxy, and 6-hydroxy), halo, cyano, trifluoromethyl, trifluoromethoxy, C 1~3 Alkyl and C 1~3 (A phenyl compound optionally further substituted with one or more groups independently selected from the alkoxy.) It is represented by [this].

[0052] Regarding TL-1, in some embodiments, R 2 is H, methyl, or acetyl; R 3 H is R 4 As defined above, R 1 but, [ka] [ka] [ka] [ka] It is a group selected from (wherein A is any atom except H). For example, A is C, O, S, or N.

[0053] In some embodiments, R 2 is H, methyl, or acetyl; R 3 H is H.

[0054] In some embodiments, R 2 H is R 3 H is H.

[0055] In some embodiments, R 4 However, it is a 2-hydroxyphenyl that is optionally substituted with one or more halo groups, which may be the same or different.

[0056] In some embodiments, R 4 However, it is 2-hydroxyphenyl, which may be substituted with one or more fluoro groups.

[0057] In some embodiments, R 4 These are 2-hydroxyphenyl, 3-fluoro-2-hydroxyphenyl, 4-fluoro-2-hydroxyphenyl, 5-fluoro-2-hydroxyphenyl, or 3,5-difluoro-2-hydroxyphenyl.

[0058] Therefore, in some embodiments, the divalent compound of the present invention is formula I-1: [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0059] In some embodiments, the R1 group [ka] The divalent compound of the present invention is of formula I-1a: [ka] It has a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0060] Representative examples of other entities that may be suitable for use as PB1-targeting ligands in the divalent compounds of the present invention are disclosed, for example, in paragraphs 71-83 of U.S. Patent Application Publication No. 2018 / 0086720.

[0061] Linker The linker ("L") provides a covalent bond to the targeting ligand and degron. The structure of the linker may not be important as long as it does not substantially hinder the activity of the targeting ligand or degron. In some embodiments, the linker is -O-, -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2-, -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C3~C 12 The alkylene chain may be interrupted by at least one of a carbosislene, a 3-12 member heterocyclene, a 5-12 member heteroarylene, or any combination thereof (wherein R' is H or a C1-C6 alkyl group), and / or terminated by at least one of them (at either or both ends), wherein the interrupting group and one or both terminal groups may be the same or different.

[0062] In some embodiments, the linker is -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O)2-, -OS(O)-, -S(O)O-, -S(O)-, -OS(O)2- , -S(O)2O-, -N(R')S(O)2-, -S(O)2N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O)2N(R')-, -N(R')S(O)N(R')-, C 3~12 The polyethylene glycol chain may be terminated at least one of carbosislene, 3-12 member heterocyclene, 5-12 member heteroarylene, or any combination thereof (wherein R' is H or C1-C6 alkyl) (at either or both ends), and one or both terminal groups may be the same or different.

[0063] "Carbocyclene" refers to a divalent carbon ring group that may be substituted in some cases.

[0064] "Heterocyclene" refers to a divalent heterocyclyl group that may be substituted in some cases.

[0065] "Heteroarylene" refers to a divalent heteroaryl group that may be substituted in some cases.

[0066] Typical examples of linkers that may be suitable for use in the present invention include alkylene chains: [ka] (In the formula, n is an integer from 1 to 10 including both ends, for example, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 9, 6 to 8, 6 to 7, 7 to 10, 7 to 9, 7 to 8, 8 to 10, 8 to 9, 9 to 10 and 1, 2 to 3, 4 to 5, 6 to 7, 8 to 9 and 10), examples include: [ka] Examples of alkylene chains terminated with various functional groups (as described above) are as follows: [ka] Examples of alkylene chains interrupted by various functional groups (as described above) are as follows: [ka] Alkylene chains interrupted or terminated by heterocyclene groups, for example, [ka] (In the formula, m and n are independent integers between 0 and 10), an example is: [ka] Alkylene chains interrupted by amide, heterocyclene, and / or aryl groups, examples of which include: [ka] Examples of heterocyclenes and alkylene chains interrupted by aryl groups and heteroatoms include: [ka] Furthermore Alkylene chains interrupted by heteroatoms such as N, O, or B, for example [ka] (In the formula, n is an integer from 1 to 10, for example, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, 6 to 10, 6 to 9, 7 to 8, 8 to 10, 8 to 9, 9 to 10, and 1, 2 to 3, 4 to 5, 6 to 7, 8 to 9 and 10, and R is H or a C1 to C4 alkyl group), the example is [ka] That is These are some examples.

[0067] In some embodiments, the linker is a polyethylene glycol linker, and examples of such linkers include the following: [ka] (In the formula, n is an integer between 2 and 10), examples include: [ka] [ka] In some embodiments, the polyethylene glycol linker may be terminated with a functional group, the following examples: [ka]

[0068] In some embodiments, the divalent compound of the present invention may include TL-1 linked to degron via any one of L1 to L9. Typical examples of divalent compounds include: [ka] [ka] [ka] Examples include pharmaceutically acceptable salts or stereoisomers thereof.

[0069] In some embodiments, the divalent compound of the present invention is represented by the following formula (degron is generally shown): [ka] [ka] [ka] It has a structure represented by either a pharmaceutically acceptable salt or stereoisomer thereof.

[0070] Deglon The ubiquitin-proteasome pathway (UPP) is a vital cellular pathway that regulates proteins, which are key regulatory factors, and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes. When defective or unbalanced, this can lead to the development of various diseases. The covalent binding of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases comprise over 500 different proteins and are classified into numerous classes defined by their structural elements of E3 functional activity.

[0071] Degron, which constitutes one of the functional modalities of this divalent compound, binds to an E3 ubiquitin ligase. The ligase catalyzes the covalent bonding of ubiquitin to a target protein, thereby inducing degradation of the target protein by the natural proteasome. Thus, the divalent compound of the present invention is designed in a way that utilizes a natural cellular degradation process, but the degradation is caused by an undesirable target protein involved in the pathogenesis of disease.

[0072] In some embodiments, degron binds to cerebron. A typical degron that binds to cerebron is given by formula D1: [ka] (In the formula, Y represents a bond, C, N, O, S, (CH2) 1~6 , (CH2) 0~6 -O, (CH2) 0~6 -C(O)NR 2’ , (CH2) 0~6 -NR 2’ C(O), (CH2) 0~6 -NH or (CH2) 0~6 -NR2 is; X is either C(O) or C(R6)²; X' is either NH or CH2; Each R1 is independently a halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy; Each R3 is independently H or C1-C3 alkyl; Each R2 is independently H or C1-C3 alkyl; Each R4 is independently H or C1-C3 alkyl; Alternatively, R2 and R4, together with the carbon atoms to which they are bonded, form a four-membered, five-membered, or six-membered heterocycle containing one or two heteroatoms selected from C(O), C3-C6 carbon rings, or N and O; R5 can be H, deuterium, C1-C3 alkyl, F, or Cl; R6 is H or C1-C3 alkyl; m is 0, 1, 2, or 3; n is 0, 1, or 2. It can be represented by:

[0073] Therefore, in some embodiments, the divalent compound of the present invention is formula I-D1: [ka] or its pharmaceutically acceptable salts, isotopic derivatives, or stereoisomers (wherein X, X', Y, R1, R2, R3, R4, R5, m, and n are as defined above) or have a structure represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0074] Therefore, in some embodiments, the divalent compound of the present invention is [ka] It is represented by an expression selected from the group consisting of [the specified elements].

[0075] Therefore, in some embodiments, the divalent compound of the present invention is [ka] [ka] It is represented by a formula selected from the group consisting of, or by a pharmaceutically acceptable salt, isotopic derivative, or stereoisomer thereof.

[0076] Further degrons that can be bound to cereblon and may be suitable for use in the present invention are disclosed in U.S. Patent No. 9,770,512, and U.S. Patent Publication Nos. 2018 / 0015087, 2018 / 0009779, 2016 / 0243247, 2016 / 0235731, 2016 / 0235730 and 2016 / 0176916, as well as International Patent Publication Brochures Nos. 2017 / 197055, 2017 / 197051, 2017 / 197036, 2017 / 197056 and 2017 / 197046.

[0077] In some embodiments, the E3 ubiquitin ligase bound by degron is the von Hipper-Lindau (VHL) tumor suppressor. See Iwai, et al., Proc. Nat'l. Acad. Sci. USA 96:12436-41 (1999).

[0078] In some embodiments, the degron coupled to the VHL is represented by the following formula: [ka] [ka] (In the formula, Y' is a bond, N, O, or C); [ka] (wherein Z is a cyclic group, which in some embodiments is a C5-6 carboncyclic group or a heterocyclic group). In certain embodiments, the cyclic group is [ka] That is the case.

[0079] In some embodiments, the divalent compound of the present invention is one of the following formulas: [ka] [ka] (In the formula, Y' is a bond, N, O, or C) [ka] (wherein Z is as defined above), or has a structure represented by a pharmaceutically acceptable salt, isotopic isomer, or stereoisomer thereof.

[0080] In some embodiments, the cyclic group is phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl, or isoquinolinyl. In certain embodiments, the cyclic group is [ka] That is the case.

[0081] Further degrons that bind to VHL and may be suitable for use in the present invention are disclosed in U.S. Patent Application Publication No. 2017 / 0121321. Further examples of degrons that may be suitable for use in the present invention are described in U.S. Patent Application Publication No. 2018 / 0015085 (e.g., indolones such as isoindolinone and isoindolin-1,3-dione, which are contained in formulas IA and IA' therein, and crosslinked cycloalkyl compounds, which are contained in formulas IB and IB' therein).

[0082] Accordingly, in some embodiments, the divalent compounds of the present invention have structures represented by any structure produced by a combination of degron structures described herein, including structures TL-1, L1-L9, and D1-D5 or pharmaceutically acceptable salts or stereoisomers thereof.

[0083] Thus, in some embodiments, the bivalent compounds of the invention have a structure represented by the following formula (where the PB1 targeting ligand is generally shown):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0084] The above structure is a representative divalent compound of the present invention containing cereblon-targeted degron (D1). VHL-targeted degrons (D2-D5) can replace cereblon-targeted degron (D1) of the above structure to represent further divalent compounds of the present invention.

[0085] A further representative divalent compound of the present invention has the following structure: [ka] [ka] [ka] (In the formula, Y' is a bond, N, O, or C) [ka] (wherein Z is as defined above), or represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[0086] In some embodiments, the divalent compound of the present invention has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] or it has a pharmaceutically acceptable salt or stereoisomer thereof.

[0087] The divalent compounds of the present invention may be in the form of free acids or free bases, or pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, that does not invalidate the biological activity or properties of the compound and is relatively non-toxic; that is, the material can be administered to a subject without causing undesirable biological effects (such as dizziness or stomach upset) or interacting in a harmful manner with any of the components of the composition in which it is contained. The term “pharmaceutically acceptable salt” refers to a product obtained by the reaction of the divalent compound of the present invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the divalent compounds of the present invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn, and Mn salts. Examples of pharmaceutically acceptable, non-toxic acid addition salts include salts of amino groups formed by inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, or p-toluenesulfonate. Certain divalent compounds of the present invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine, or metformin.

[0088] In some embodiments, the divalent compound of the present invention may be an isotopic derivative in that it has at least one desired isotopic substitution of an atom in an amount exceeding the natural abundance of the isotope, i.e., a concentrated amount. In one embodiment, the divalent compound comprises deuterium or a plurality of deuterium atoms. Deuterium, i.e. 2Substitution with heavier isotopes such as H results in certain therapeutic advantages derived from higher metabolic stability, for example, an increase in the in vivo half-life or a decrease in the dosage requirement, and thus can be advantageous depending on the situation.

[0089] The bivalent compounds of the present invention may have at least one chiral center and thus, as used herein, can be in the form of stereoisomers encompassing all isomers of the individual compounds that differ only in the orientation of their atoms in space. The term stereoisomers includes enantiomers (including (R-) or (S-) configurations of the compound), mixtures of enantiomers of the compound (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of the compound, and isomers of compounds having two or more chiral centers that are not mirror images of each other (diastereoisomers). Since the chiral centers of the compounds can undergo epimerization in vivo, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Accordingly, the bivalent compounds of the present invention can be prepared and used in the form of the individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, such as racemic mixtures of stereoisomers.

[0090] Synthesis methods In another aspect, the present invention relates to a method for preparing a bivalent compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof. Broadly speaking, the bivalent compounds of the present invention, or pharmaceutically acceptable salts or stereoisomers thereof, can be prepared by any method known to be applicable to the preparation of chemically related compounds. The bivalent compounds of the present invention will be better understood in relation to the synthetic schemes described in various examples, which illustrate non-limiting methods for preparing the bivalent compounds of the present invention.

[0091] Pharmaceutical compositions In some embodiments, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a divalent compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier. The divalent compound of the present invention can be formulated into several different types of pharmaceutical compositions comprising a therapeutically effective amount of the divalent compound and a pharmaceutically acceptable carrier.

[0092] In general, the divalent compounds of the present invention can be formulated into a given type of composition according to conventional pharmaceutical procedures such as conventional mixing, dissolution, granulation, sugar-coated tablet production, wet grinding, emulsification, encapsulation, sealing, and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. ARGennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection, or infusion techniques, intra-arterial, intramedullary, intrathecal, intraventricular, percutaneous, intradermal, rectal, vaginal, intraperitoneal, topical mucosa, nasal, buccal, sublingual, endotracheal, bronchial, and / or inhalation). Generally, the most appropriate route of administration depends on various factors, including, for example, the properties of the drug (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (whether the subject can tolerate oral administration). In some embodiments, the composition is formulated for oral or intravenous administration (e.g., systemic intravenous injection).

[0093] The term “pharmaceutically acceptable carrier” as known in the art refers to a pharmaceutically acceptable material, composition, or vehicle suitable for administering the divalent compound of the present invention to a mammal. Suitable carriers may include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids) that function to carry or transport the compound from one organ or part of the body to another. The carrier is “acceptable” in the sense that it is physiologically inert to other components of the formulation, compatible with other components of the formulation, and non-toxic to the subject or patient. Depending on the type of formulation, the composition may further include one or more pharmaceutically acceptable excipients.

[0094] Therefore, divalent compounds of formula I can be formulated into solid compositions (e.g., powders, tablets, dispersible granules, capsules, cachets and suppositories), liquid compositions (e.g., solutions in which the compound is dissolved, suspensions in which solid particles of the compound are dispersed, emulsions and solutions containing liposomes, micelles or nanoparticles, syrups and elixirs); semi-solid compositions (e.g., gels, suspensions and creams); and gases (e.g., sprays for aerosol compositions). Divalent compounds can also be formulated for rapid release, intermediate release or extended release.

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active divalent compound is supported by a carrier such as sodium citrate or dicalcium phosphate, and also by: a) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) water-retaining agents, e.g., glycerol; and d) disintegrants, e.g., cross-linked polymers (e.g., cross-linked polyvinylpyrrolidone (crospovidone), cross-linked carboxymethylcellulose). It is mixed with additional carriers or excipients such as sodium croscarmellose (croscarmellose sodium), sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders, e.g., paraffin, f) absorption enhancers, e.g., quaternary ammonium compounds, g) wetting agents, e.g., cetyl alcohol and glycerol monostearate, h) absorbents, e.g., kaolin and bentonite clay, and i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings. These may further contain opacifying agents.

[0096] In some embodiments, the divalent compound of formula I can be formulated into hard or soft gelatin capsules. Typical excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose, and sodium croscarmellose. The gelatin shell may contain gelatin, titanium dioxide, iron oxide, and colorants.

[0097] In some embodiments, the divalent compound of formula I can be formulated into tablets that may contain excipients such as lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium tartrate, and hydrophobic colloidal silica.

[0098] These can be formulated as solutions for parenteral and oral delivery forms, especially as long as they are water-soluble. Parenteral administration can also be advantageous in that the compound can be administered relatively quickly, such as in single-dose treatments and / or in cases of acute conditions.

[0099] Injectable preparations for parenteral administration may include sterile aqueous solutions or oily suspensions. These can be formulated according to standard techniques using appropriate dispersants or wetting and suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, US Pharmacopeia, and isotonic sodium chloride solutions. Furthermore, sterile non-volatile oils have conventionally been used as solvents or suspension media. For this purpose, non-volatile oils of any brand, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations. Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use. The effects of a compound can be prolonged by slowing its absorption, which can be achieved by using a liquid suspension or a crystalline or amorphous material with low water solubility. Long-term absorption of a compound from parenteral formulations can also be achieved by suspending the compound in an oily vehicle.

[0100] In certain embodiments, the divalent compound of formula I may be administered topically rather than systemically, often in depot or sustained-release formulations, for example, by direct injection of a conjugate into an organ. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Depot formulations for injection are prepared by forming a microcapsule matrix of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoester), and poly(anhydride). The release rate of the compound can be controlled by varying the ratio of compound to polymer and the properties of the particular polymer used. Depot injection formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, such as liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ.

[0101] Liquid dosage forms for oral administration include liquids, suspensions, emulsions, microemulsions, syrups, and elixirs. In addition to compounds, liquid dosage forms may contain aqueous or non-aqueous carriers commonly used in the art (depending on the solubility of the compound), such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, as well as mixtures thereof. Oral compositions may also contain excipients such as wetting agents, suspending agents, colorants, sweeteners, flavoring agents, and fragrances.

[0102] The composition can be formulated for buccal or sublingual administration, examples of which include tablets, lozenges, and gels.

[0103] The composition of Formula I can be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosols, mists, or powders. The pharmaceutical composition can be delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer, using a suitable spraying agent (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol can be determined by providing a valve for delivering a measured amount. In some embodiments, capsules and cartridges containing gelatin for use in inhalers or injectors can be formulated, for example, containing the compound and a powder mixture with a suitable powder base such as lactose or starch.

[0104] The divalent compounds of Formula I, as used herein, can be formulated for topical administration, referring to intradermal administration by inventions of formulations for the epidermis. These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions, and sprays.

[0105] Typical examples of carriers useful for formulating compositions for topical application include solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes, powders, emulsions, microemulsions, and buffers (e.g., hypotonic or buffered saline). Creams can be formulated using saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmitoleic acid, cetyl, or oleyl alcohol. Creams may also contain nonionic surfactants such as polyoxy-40-stearate.

[0106] In some embodiments, topical formulations may also include excipients, such as penetration enhancers. These agents can deliver pharmacologically active compounds through the stratum corneum to the epidermis or dermis, preferably with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in increasing the rate of drug penetration through the skin. For example, see Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which investigates the use and testing of various skin penetration enhancers, and Buyuktimkin et al., Chemical Means of Transdermal Drug Permeation Enhancement in Transdermal and Topical Drug Delivery Systems, Gosh TK, Pfister WR, Yum SI (eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997). Typical examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glyceryl monooleate, and propylene glycol monooleate), and N-methylpyrrolidone.

[0107] Representative examples of other excipients that can be included in topical and other types of formulations (to the extent that they are compatible) include preservatives, antioxidants, humectants, emollients, buffers, solubilizers, skin protectants, and surfactants. Suitable preservatives include alcohols, quaternary amines, organic acids, parabens, and phenols. Suitable antioxidants include ascorbic acid and its esters, sodium bisulfite, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, and chelating agents such as EDTA and citrate. Suitable humectants include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol. Suitable buffers include citrate, hydrochloric acid, and lactate buffer. Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbate. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0108] Transdermal formulations typically utilize transdermal delivery devices and transdermal delivery patches in which the compound is formulated in a lipophilic emulsion or buffered aqueous solution and dissolved and / or dispersed in a polymer or adhesive. Patches can be configured for continuous, pulsed, or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoresis patches. Transdermal patches can provide controlled delivery of compounds whose absorption rate is delayed by using a rate-controlled membrane or by trapping the compound within a polymer matrix or gel. Absorption may be increased using absorption enhancers, examples of which include absorbable, pharmaceutically acceptable solvents that aid in passage through the skin.

[0109] Ophthalmic preparations include eye drops.

[0110] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retained enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone and PEG. Compositions for rectal or vaginal administration may also be formulated as suppositories, which can be prepared by mixing the compound with a suitable non-irritating carrier and excipient, such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository wax, and combinations thereof, which melt in the rectal or vaginal cavity to release the compound, since all of them are solid at ambient temperature but liquid at body temperature.

[0111] As used herein, the term “therapeutically effective dose” means an amount of the divalent compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof that is effective in producing a desired therapeutic response in a particular patient suffering from a disease or disorder. Accordingly, the term “therapeutically effective dose” includes an amount of the divalent compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof that, when administered, induces a positive modification in the disease or disorder being treated (e.g., selectively inhibits / degrades PB1), or prevents the onset or progression of the disease or disorder, or is sufficient to alleviate to some extent one or more symptoms of the disease or disorder being treated in a subject, or simply kills or inhibits the proliferation of diseased (e.g., cancer) cells, or reduces the amount of PB1 in diseased cells.

[0112] The total daily dose of a compound and its use may be determined by the attending physician using sound medical judgment, in accordance with standard medical practice. Therefore, the specific therapeutically effective dose for any particular subject may depend on various factors, including those well known in the medical field, such as the disease or disorder being treated and its severity (e.g., its current condition); the subject's age, weight, overall health, sex, and diet; the time of administration, route of administration, and elimination rate of the specific compound used; the duration of treatment; and other drugs used in combination with or concurrently with the specific compound used (see, for example, Goodman and Gilman's, “The Pharmacological Basis of Therapeutics”, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001).

[0113] The divalent compound of formula I may be effective over a wide dose range. In some embodiments, the total daily dose (for example, for adults) may range from about 0.001 to about 1000 mg, 0.01 to about 1000 mg, 0.01 to about 500 mg, about 0.01 to about 100 mg, about 0.5 to about 100 mg, 1 to about 100 to 400 mg / day, about 1 to about 50 mg / day, and about 5 to about 40 mg / day, or in yet other embodiments, about 10 to about 30 mg / day. Individual doses may be formulated to contain the desired dose depending on the number of times the compound is administered per day. For example, capsules may be formulated with about 1 to about 200 mg of the compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg).

[0114] How to use In some embodiments, the present invention relates to a method for treating a disease or disorder involving dysfunctional or dysregulated SWI / SNF chromatin remodeling complex activity (including PB1 activity), comprising the step of administering a therapeutically effective amount of the divalent compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof to a subject in need.

[0115] A disease or disorder may be said to be characterized by, or mediated by, dysfunctional SWI / SNF chromatin remodeling complex activity (including PB1 activity) (e.g., elevated protein levels or functional abnormality compared to a non-pathological state). A “disease” is generally considered a health condition of an object in which the object is unable to maintain homeostasis and, if the disease does not improve, the object’s health continues to deteriorate. In contrast, a “disorder” of an object is a health condition in which the object is able to maintain homeostasis, but the object’s health condition is less desirable than that of the absence of the disorder. If left untreated, the disorder does not necessarily lead to a further deterioration of the animal’s health condition. In some embodiments, the divalent compounds of the present invention may be useful in the treatment of proliferative disorders and disorders (e.g., cancer or benign neoplasms). As used herein, the term “proliferative disorder or disorder” refers to a condition characterized by disregulated or abnormal cell proliferation, or both, including neoplasms, precancerous conditions, benign tumors and other noncancerous conditions, and cancer.

[0116] As used herein, the term “subject” (or “patient”) includes all members of the animal kingdom who are susceptible to or suffering from the indicated disease or disorder. In some embodiments, the subject is a mammal, e.g., human or non-human mammal. The method is also applicable to companion animals such as dogs and cats, as well as livestock such as cattle, horses, sheep, goats, and pigs, as well as other domesticated and wild animals. A subject “in need of” treatment according to the present invention “suffers from or is suspected of suffering from” a specific disease or disorder, and may have been clearly diagnosed with or exhibiting a sufficient number of risk factors or a sufficient number or combination of signs or symptoms to allow a medical professional to diagnose or suspect that the control has the disease or disorder. Thus, subjects suffering from and suspected of suffering from a specific disease or disorder are not necessarily two different groups.

[0117] Exemplary types of non-cancerous (e.g., proliferative) diseases or disorders that can be treated with the divalent compounds of the present invention include inflammatory diseases and conditions, autoimmune diseases, neurodegenerative diseases, heart diseases, viral diseases, chronic and acute kidney diseases or injuries, vascular diseases, metabolic diseases, as well as allergic and genetic diseases.

[0118] Specific examples of non-cancerous diseases and disorders include rheumatoid arthritis, alopecia areata, lymphoproliferative states, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, anhidrotic ectodermal dysplasia, euerythrocytic anemia, and idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock, dacryoadenitis, cryopyrin-associated periodic syndromes (CAPS), endotoxin shock, endometritis, gram-negative bacterial sepsis, keratoconjunctivitis sicca, toxic shock syndrome, asthma, and adult conditions. Respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pneumonia, chronic graft rejection, hidradenitis suppurativa, inflammatory bowel disease, Crohn's disease, Behçet's syndrome, systemic lupus erythematosus, multiple sclerosis, juvenile-onset diabetes mellitus, autoimmune uveoretinitis, autoimmune vasculitis, thyroiditis, Addison's disease, lichen planus, appendicitis, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, myasthenia gravis, immunoglobulin A nephropathy, autoimmune thyroiditis or Hashimoto's disease, Sjögren's syndrome, vitiligo, Wegener's granulomatosis, testicular sarcoma, autoimmune ovarian disease Inflammation, sarcoidosis, rheumatic carditis, ankylosing spondylitis, Graves' disease, autoimmune thrombocytopenic purpura, psoriasis, psoriatic arthritis, eczema, herpetiform dermatitis, ulcerative colitis, pancreatic fibrosis, hepatitis, hepatic fibrosis, CD14-mediated sepsis, non-CD14-mediated sepsis, acute and chronic kidney disease, irritable bowel syndrome, heartburn, restenosis, cerebral malaria, cervicitis, stroke and ischemic injury, neurological trauma, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, congestive heart failure, acute coronary syndrome, cachexia, malaria, leprosy Diseases, leishmaniasis, Lyme disease, Reiter's syndrome, acute synovitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, hernia, ruptured or herniated disc syndrome, osteoporosis, thrombosis, restenosis, silicosis, pulmonary sarcosis, bone resorption disorders such as osteoporosis, graft-versus-host reaction, fibromyalgia, AIDS and other viral diseases such as herpes zoster, herpes simplex virus type 1 or 2, influenza virus and cytomegalovirus, type 1 and type 2 diabetes, obesity, insulin resistance and diabetic retinopathy, 22q11.These include 2-deletion syndrome, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, color blindness, cat-meow syndrome, Down syndrome, cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sudden infant death syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome, urea cycle disorders, thalassemia, otitis media, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, cystic fibrosis, uveitis, polymyositis, proctitis, interstitial pulmonary fibrosis, dermatomyositis, arteriosclerosis, atherosclerosis, amyotrophic lateral sclerosis, antisocial behavior, immune responses, varicose veins, vaginitis (including chronic recurrent yeast vaginitis), depression, sudden infant death syndrome, obesity, and varicose veins.

[0119] In other embodiments, the method is intended to treat subjects with cancer. Generally, the divalent compounds of the present invention may be effective in treating carcinomas (solid tumors including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers that originate in the blood, including lymphocytes, bone marrow, and / or lymph nodes), such as leukemia, lymphoma, and multiple myeloma. This includes adult tumors / cancers and pediatric tumors / cancers. The cancer may be angiogenic, non-angiogenic, or non-angiogenic tumors.

[0120] Typical examples of cancer include adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's disease and AIDS-related lymphoma), appendiceal cancer, childhood cancers (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, and urinary bladder cancer. Cancer, brain cancer (e.g., glioma and glioblastoma, e.g., brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primordial neuroectodermal tumor, optic tract and hypothalamic glioma), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, nervous system cancer (e.g., central nervous system cancer, central nervous system lymphoma), cervical cancer, chronic myeloproliferative disorders, colorectal cancer (e.g., colon cancer, rectal cancer), lymphoid neoplasms, mycosis fungoides, Sézary syndrome Group, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, ocular cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST)), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, head and neck cancer, Hodgkin lymphoma, leukemia, lymphoma, multiple myeloma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, pancreatic islet cell tumor (endocrine pancreas), renal cancer (e.g., Wilms' tumor, clear cell renal cell carcinoma), Liver cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), Waldenström macroglobulinemia, melanoma, intraocular melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of unknown primary origin for the neck, multiple endocrine neoplasia (MEN), myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer (e.g., oral cancer, lip cancer, oral cancer, tongue cancer, oropharyngeal cancer, pharyngeal cancer, laryngeal cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, ovarian germ cell tumor, ovarian low-grade malignancy) These include tumors such as pancreatic cancer, islet cell pancreatic cancer, sinus cancer and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial uterine cancer, uterine sarcoma, endometrial cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary tract, urethral cancer, gestational trophoblastoma, vaginal cancer and vulvar cancer.

[0121] Sarcomas that may be treatable with the divalent compounds of the present invention include both soft tissue and bone cancers, and typical examples include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesosarcoma or mesothelioma (under the membrane of the body cavity), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), and mesenchymal or mixed mesodermal tumors (mixed connective tissue type).

[0122] In some embodiments, the methods of the present invention involve the treatment of subjects having cell proliferation disorders or disorders of the blood system, liver (hepatocytes), brain, lungs, colorectal (e.g., colon), pancreas, prostate, skin, ovaries, breasts, skin (e.g., melanoma), and endometrium.

[0123] As used herein, “cytoproliferative disorders or disorders of the hematological system” includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal immunoglobulinemia, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown cause, and essential thrombocythemia. Therefore, typical examples of hematological cancers include multiple myeloma, lymphoma (T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g., diffuse large B-cell lymphoma (e.g., germinal center B-cell-like diffuse large B-cell lymphoma or activated B-cell-like diffuse large B-cell lymphoma)), Burkitt lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and lymphoplasmosis Examples include cystic lymphoma / Waldenström macroglobulinemia, B-cell non-Hodgkin lymphoma selected from refractory B-cell non-Hodgkin lymphoma and relapsed B-cell non-Hodgkin lymphoma, pediatric lymphoma, and lymphocytic and cutaneous lymphomas, e.g., small lymphocytic lymphoma, primary CNS lymphoma (PCNSL), marginal zone lymphoma (MZL), leukemia (including chronic lymphocytic leukemia (CLL), pediatric leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms, and mast cell neoplasms.

[0124] As used herein, “cellular proliferative disorders or disorders of the lung” include all forms of cellular proliferative disorders that occur in lung cells. Cellular proliferative disorders of the lung include lung cancer, precancerous and precancerous conditions of the lung, benign proliferation or lesions of the lung, lung hyperplasia, metaplasia and dysplasia, and metastatic lesions of tissues and organs of the body other than the lungs. Lung cancer includes all forms of cancer of the lung, such as malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors and atypical carcinoid tumors. Lung cancer includes small cell lung cancer ("SLCL"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma and mesothelioma. Lung cancer may also include “scar carcinoma,” bronchioloveolar carcinoma, giant cell carcinoma, spindle cell carcinoma and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms that exhibit histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0125] As used herein, “cytoproliferative disorders or disorders of the colon” ​​include all forms of cytoproliferative disorders that occur in colonic cells, including colon cancer, precancerous or precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Colon cancer includes sporadic and hereditary colon cancer, malignant colonic neoplasms, carcinoma in situ, typical and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer may be associated with hereditary syndromes such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcott syndrome, and juvenile polyposis. Cytoproliferative disorders of the colon may also be characterized by colonic hyperplasia, metaplasia, or dysplasia.

[0126] As used herein, “cytoproliferative disorders or disorders of the pancreas” includes all forms of cytoproliferative disorders that occur in pancreatic cells. Pancreatic cytoproliferative disorders may include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign proliferation or lesions of the pancreas, as well as malignant proliferation or lesions of the pancreas, and metastatic lesions of tissues and organs of the body other than the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclastoid giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreaticblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, as well as pancreatic neoplasms having histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0127] As used herein, “proliferative disorders or conditions of the prostate” include all forms of proliferative disorders that occur in the prostate. Proliferative disorders of the prostate may include prostate cancer, precancerous or precancerous conditions of the prostate, benign proliferative disorders or lesions of the prostate, malignant proliferative disorders or lesions of the prostate, and metastatic lesions of tissues and organs of the body other than the prostate. Proliferative disorders of the prostate may include prostatic hyperplasia, metaplasia, and dysplasia.

[0128] As used herein, “proliferative disorders or conditions of the skin” include all forms of proliferative disorders that occur in skin cells. Proliferative disorders of the skin may include precancerous or precancerous conditions of the skin, benign proliferations or lesions of the skin, melanoma, malignant melanoma or other malignant proliferations or lesions of the skin, and metastatic lesions of tissues and organs of the body other than the skin. Proliferative disorders of the skin may include hyperplasia, metaplasia and dysplasia of the skin.

[0129] As used herein, “ovarian proliferative disorders or disorders” include all forms of cytoproliferative disorders that occur in the cells of the ovaries. Ovarian proliferative disorders may include precancerous or precancerous conditions of the ovaries, benign proliferations or lesions of the ovaries, ovarian cancer, and metastatic lesions of tissues and organs of the body other than the ovaries. Ovarian proliferative disorders may include ovarian hyperplasia, metaplasia, and dysplasia.

[0130] As used herein, “cytoproliferative disorders or disorders of the breast” include all forms of cytoproliferative disorders that occur in breast cells. Cytoproliferative disorders of the breast may include breast cancer, precancerous or precancerous conditions of the breast, benign proliferations or lesions of the breast, and metastatic lesions of tissues and organs of the body other than the breast. Cytoproliferative disorders of the breast may include breast hyperplasia, metaplasia, and dysplasia.

[0131] In some embodiments, the divalent compound or pharmaceutically acceptable salt or stereoisomer of the present invention is used to treat high-risk neuroblastoma (NB).

[0132] In some embodiments, the disease or disorder is acute myeloid leukemia (AML), multiple myeloma (MM), melanoma, rhabdomyosarcoma, or diffuse large B-cell lymphoma. In other embodiments, the disease or disorder is a small solid tumor. In other embodiments, the disease or disorder is colon cancer, rectal cancer, gastric cancer, breast cancer, or pancreatic cancer.

[0133] In some embodiments, the divalent compound of the present invention is used to treat lung cancer (e.g., NSLC), progressive and metastatic solid tumors, ALK-positive anaplastic large cell lymphoma, central nervous system tumors, neuroblastoma, breast cancer, cholangiocarcinoma, colorectal cancer, head and neck neoplasms, neuroendocrine tumors, ovarian cancer, pancreatic cancer, papillary thyroid cancer, primary brain tumors, renal cell carcinoma, sarcoma, salivary gland cancer, metastatic anaplastic thyroid cancer, glioblastoma, brain metastases, progressive malignant solid neoplasms, metastatic pancreatic adenocarcinoma, stage III and IV pancreatic cancer, melanoma (progressive and unresectable), CD30-positive neoplastic cells, BRAF / NRAS wild-type stage III-IV melanoma, progressive, refractory and recurrent malignant solid neoplasms, and Ann Arbor may be used to treat pediatric non-Hodgkin lymphoma of stage III and stage IV, histiocytosis, relapsed pediatric central nervous system neoplasms and non-Hodgkin lymphoma, refractory central nervous system tumors, ROS1-positive refractory non-Hodgkin lymphoma, pediatric Langerhans cell histiocytosis, histiocytic sarcoma, juvenile xanthogranuloma, malignant glioma, relapsed pediatric ependymoma, malignant germ cell tumor, and medulloblastoma, relapsed pediatric non-Hodgkin lymphoma, rhabdomyosarcoma, and soft tissue sarcoma, relapsed Ewing's sarcoma, glioma, hepatoblastoma, neuroblastoma, osteosarcoma, and peripheral primitive neuroectodermal tumors.

[0134] The divalent compound of formula (I) of the present invention may be administered to patients, such as cancer patients, as monotherapy, in combination therapy, and as first-line therapy or subsequent therapy for patients unresponsive to first-line therapy. The therapy may be “first-line,” i.e., as initial treatment in patients who have not previously received an anti-cancer treatment regimen, either alone or in combination with other treatments; or as “second-line,” as treatment in patients who have previously received an anti-cancer treatment regimen, either alone or in combination with other treatments; or as “third-line,” “fourth-line,” etc., as treatment, either alone or in combination with other treatments. The therapy may also be administered to patients who have received previous treatments that have been partially successful but are intolerant to a particular treatment. The therapy may also be administered as adjuvant therapy, i.e., in patients who do not currently have detectable disease, or to prevent cancer recurrence after surgical removal of a tumor. Accordingly, in some embodiments, the compound may be administered to patients who have received other therapies such as chemotherapy, radioimmunotherapy, surgery, immunotherapy, radiotherapy, targeted therapy, or any combination thereof.

[0135] The method of the present invention may involve administering the divalent compound of Formula I or a pharmaceutical composition thereof to a patient in a single dose or multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20 or more doses). For example, the frequency of administration may range from once a day to about once every 8 weeks. In some embodiments, the frequency of administration ranges from about once a day for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments, it involves a 28-day cycle including daily administration for 3 weeks (21 days). In other embodiments, the divalent compound may be administered twice a day (BID) (total of 5 doses) over a 2.5-day cycle, or once a day (QD) (total of 2 doses) over a 2-day cycle. In other embodiments, the divalent compound may be administered once a day (QD) over a 5-day cycle.

[0136] Combination therapy The divalent compound of formula I of the present invention may be used in combination with or concurrently with at least one other active agent, such as an anticancer agent or regimen, in the treatment of diseases and disorders. In this context, the terms “combined” and “concurrently” mean that the drugs are administered simultaneously, which includes substantially simultaneous administration as the same or distinct dosage forms and by the same or different modes of administration, or sequentially, for example, as part of the same treatment regimen or as a sequential treatment regimen. Thus, when administered sequentially, at the start of administration of the second compound, the first compound of the two compounds may still be detectable at an effective concentration at the treatment site. The order and time intervals may be determined so that they can act together (for example, synergistically to provide an increased benefit than if they were administered in any other way). For example, therapeutic agents may be administered simultaneously or sequentially in any order at different time points; however, if not administered simultaneously, they may be administered at sufficiently close intervals to provide the desired therapeutic effect, which may be in a synergistic manner. Thus, these terms are not limited to administering the active agents exactly simultaneously.

[0137] In some embodiments, a treatment regimen may include administering the divalent compound of Formula I of the present invention in combination with one or more additional therapeutic agents known for use in the treatment of a disease or condition (e.g., cancer). The dose of the additional anticancer therapeutic agent may be the same as or even less than known or recommended doses. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. For example, anticancer agents that can be used in combination with the divalent compound of the present invention are known in the art. See, for example, U.S. Patent No. 9,101,622 (Section 5.2) and U.S. Patent No. 9,345,705 (Sections 12-18). Typical examples of additional activators and treatment regimens include radiotherapy, chemotherapeutic agents (e.g., mitotic inhibitors, angiogenesis inhibitors, antihormones, autophagy inhibitors, alkylating agents, antibiotic inserts, growth factor inhibitors, antiandrogens, signaling pathway inhibitors, microtubule inhibitors, platinum-coordinated complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulators, therapeutic antibodies (e.g., monospecific and bispecific antibodies), and CAR-T therapy.

[0138] In some embodiments, the divalent compound of formula I may be used in combination with other anticancer agents for treating melanoma, such as aldesleukin, vinimetinib, cobimetinib, dabrafenib, dacarbazine, encorafenib, Imlygic®, ipilimumab, nivolumab, pegylated interferon alfa-2b, pembrolizumab, tarimozine laharpalepbek, trametinib, and vemurafenib.

[0139] In some embodiments, the divalent compound of Formula I of the present invention and additional anticancer drugs may be administered at intervals of less than 5 minutes, less than 30 minutes, less than 1 hour, about 1 hour, about 1 to about 2 hours, about 2 to about 3 hours, about 3 to about 4 hours, about 4 to about 5 hours, about 5 to about 6 hours, about 6 to about 7 hours, about 7 to about 8 hours, about 8 to about 9 hours, about 9 to about 10 hours, about 10 to about 11 hours, about 11 to about 12 hours, about 12 to 18 hours, 18 to 24 hours, 24 to 36 hours, 36 to 48 hours, 48 ​​to 52 hours, 52 to 60 hours, 60 to 72 hours, 72 to 84 hours, 84 to 96 hours, or 96 to 120 hours. Two or more anticancer drugs may be administered to the same patient during a single visit.

[0140] In some embodiments, the divalent compound of formula I of the present invention and an additional agent or therapeutic agent (e.g., an anticancer drug) are administered periodically. Cycling therapy involves administering one anticancer drug for a certain period, followed by administering a second anticancer drug for a certain period, and repeating this sequential administration, i.e., cycle, in order to reduce the development of resistance to one or both anticancer drugs, to avoid or reduce the side effects of one or both anticancer drugs, and / or to improve the effectiveness of the therapy. In one example, cycling therapy involves administering a first anticancer drug for a certain period, followed by administering a second anticancer drug for a certain period, and optionally followed by administering a third anticancer drug for a certain period, and repeating this sequential administration, i.e., cycle, in order to reduce the development of resistance to one or both anticancer drugs, to avoid or reduce the side effects of one or both anticancer drugs, and / or to improve the effectiveness of the anticancer drug.

[0141] Medical kit This composition can be assembled into a kit or pharmaceutical system. A kit or pharmaceutical system according to this aspect of the present invention includes a carrier or package such as a box, carton, tube, etc., which tightly encloses one or more containers, such as vials, tubes, ampoules, or bottles, containing the divalent compound or pharmaceutical composition of Formula I of the present invention. The kit or pharmaceutical system of the present invention may also include printed instructions for using the compound and composition.

[0142] These and other embodiments of the present invention will be further understood by considering the following embodiments, which are intended to illustrate certain specific embodiments of the present invention but are not intended to limit the scope defined by the claims.

[0143] Examples Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra were acquired at 500 MHz for protons using a Bruker AVANCE spectrometer. Spectra are shown in ppm(δ), and the coupling constant J is reported in Hertz. The solvent peak was used as a reference peak for the proton spectrum. Liquid chromatography-mass spectra were acquired using a Waters ultrafast liquid chromatography (UPLC) ion-trap electrospray ionization (ESI) mass spectrometer.

[0144] Example 1: Synthesis of 3-(4-((2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (1) [ka] tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazine-1-carboxylate To a solution of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)piperazine-1-carboxylate (200 mg, 0.64 mmol) in dioxane / H2O (10 mL / 1 mL), (2-hydroxyphenyl)boronic acid (114 mg, 0.83 mmol), Xphos-Pd-G3 (54 mg, 0.064 mmol), and K2CO3 (180 mg, 1.28 mmol) were added. The reaction mixture was stirred overnight at 90°C under N2 protection. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (140 mg, 59% yield). LCMS (m / z): 372 [M+H] + .

[0145] 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-carboxylate (140 mg, 0.38 mmol) was dissolved in dioxane (5 mL), to which 4N HCl / dioxane (3 mL) was added. The reaction mixture was stirred at room temperature (rt) for 1 hour. The solid was filtered to obtain the desired product (100 mg, 85%) as an HCl salt. LCMS (m / z): 272 [M+H] + .

[0146] 3-(4-((2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione(1) To a mixture of dimethyl fumarate (DMF) (0.5 mL), 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (10 mg, 0.032 mmol), 3-(2-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)amino)ethoxy)propanoic acid (12 mg, 0.032 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HATU) (20 mg, 0.05 mmol), and N,N-diisopropylethylamine (DIPEA) (0.03 mL, 0.16 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with ethyl acetate (EA) (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 10.4 mg, yield 52%). LCMS(m / z):629[M+H] + . 11H NMR (500MHz, DMSO-d6)δ 14.15(s,1H),11.01(s,1H),8.12-7.78(m,1H),7.52(s,1H),7.36-7.14(m,2 H),7.02-6.85(m,3H),6.81(d,J=8.0Hz,1H),6.41(s,2H),5.58(t,J=5.6Hz,1 H),5.13(dd,J=13.3,5.2Hz,1H),4.38-4.14(m,2H),3.81-3.55(m,8H),3.33( m, 2H), 3.24-2.85 (m, 5H), 2.73-2.57 (m, 3H), 2.31 (m, 1H), 2.09-1.95 (m, 1H).

[0147] Example 2: Synthesis of 3-(4-((2-(2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-3-oxopropoxy)ethoxy)ethyl)amino)-1-oxoisoindorin-2-yl)piperidine-2,6-dione(2) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (10 mg, 0.032 mmol) and 3-(2-(2-((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)amino)ethoxy)ethoxy)propanoic acid (14 mg, 0.032 mmol) was added to DMF (0.5 mL), to which HATU (20 mg, 0.05 mmol) and DIPEA (0.03 mL, 0.16 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 10.7 mg, yield 50%). LCMS(m / z):673[M+H] + . 1H NMR(500MHz,DMSO-d6)δ 14.08(s,1H),10.93(s,1H),7.86-7.81(m,1H),7.45(s,1H),7.24-7.13(m,2H),6.87(d,J=7.4Hz,1H),6. 81(m,2H),6.71(d,J=8.1Hz,1H),6.34(s,2H),5.48(t,J=5.8Hz,1H),5.04(dd,J=13.2,5.1Hz,1H),4.15( d,J=17.1Hz,1H),4.05(d,J=17.1Hz,1H),3.60(m,6H),3.52(t,J=5.9Hz,2H),3.47(m,4H),3.23(d,J=5.6 Hz,2H),3.03-2.98(m,2H),2.96(m,2H),2.85(m,1H),2.56(m,1H),2.43(m,4H),2.24(m,1H),1.96(m,1H).

[0148] Example 3: Synthesis of 4-((9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione(3) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (10 mg, 0.032 mmol) and 9-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)nonanoic acid (14 mg, 0.032 mmol) was added to DMF (0.5 mL), to which HATU (20 mg, 0.05 mmol) and DIPEA (0.03 mL, 0.16 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 8.9 mg, yield 41%). LCMS (m / z): 684 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 11.03(s,1H),7.77-7.70(m,1H),7.54(d,J=7.7Hz,1H),7.47-7.39(m,2H),7.37(d,J=7.3Hz,1H),7.31(t,J=7. 7Hz,1H),7.28(s,2H),6.96(d,J=8.2Hz,1H),6.91(t,J=7.5Hz,1H),5.01(dd,J=12.8,5.5Hz,1H),4.13(t,J=6.4 Hz,2H),3.61(t,J=5.0Hz,4H),3.20(s,2H),3.15(t,J=5.1Hz,2H),2.86-2.75(m,1H),2.52(m,1H),2.50-2.38(m ,2H),2.28(t,J=7.5Hz,2H),1.96(tt,J=7.7,4.6Hz,1H),1.69(p,J=6.8Hz,2H),1.41(m,4H),1.33-1.21(m,6H).

[0149] Example 4: Synthesis of 4-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (4) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (20 mg, 0.065 mmol) and 2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetic acid (22 mg, 0.065 mmol) was added to DMF (1 mL), to which HATU (37 mg, 0.1 mmol) and DIPEA (0.06 mL, 0.33 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 6.7 mg, yield 18%). LCMS (m / z): 586 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 11.11(s,1H),7.80(m,1H),7.60(dd,J=7.8,1.7Hz,1H),7.52(s,1H),7.48(m,1H),7.45-7.37(m,2H),7.19(m,1H),7.08-6.97(m,2H),5.2 6(s,2H),5.14-5.07(m,1H),3.72(m,4H),3.39(s,2H),3.30(s,2H),2 .94-2.84(m,1H),2.66-2.52(m,2H),2.50(m,2H),2.10-2.00(m,1H).

[0150] Example 5: Synthesis of 4-((11-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-11-oxoundecyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (5) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (16 mg, 0.052 mmol) and 11-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)undecanoic acid (24 mg, 0.052 mmol) was added to DMF (1 mL), to which HATU (30 mg, 0.078 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 6.9 mg, yield 19%). LCMS (m / z): 712 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 14.09(s,1H),11.03(s,1H),7.84(dd,J=8.5,1.6Hz,1H),7.73(dd,J=8.6,7.2Hz,1H),7.48-7.40(m,2H),7.37(d,J=7.2H) z,1H),7.17(td,J=7.7,1.6Hz,1H),6.85-6.78(m,2H),6.33(s,2H),5.01(dd,J=12.8,5.4Hz,1H),4.12(t,J=6.4Hz,2H), 3.61(t,J=5.2Hz,4H),2.99(dd,J=21.3,5.3Hz,4H),2.81(ddd,J=16.8,13.8,5.4Hz,1H),2.56-2.38(m,2H),2.27(t,J=7 .5Hz,2H),2.03-1.91(m,1H),1.68(p,J=6.6Hz,2H),1.44(s,2H),1.37(q,J=7.2Hz,2H),1.27(s,2H),1.24-1.20(m,8H).

[0151] Example 6: Synthesis of 4-((8-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-8-oxooctyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (6) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (16 mg, 0.052 mmol) and 8-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)octanoic acid (22 mg, 0.052 mmol) was added to DMF (1 mL), to which HATU (30 mg, 0.078 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 7.7 mg, yield 22%). LCMS (m / z): 670 [M+H]+ . 1 H NMR(500MHz,DMSO-d6)δ 11.02(s,1H),7.73(dd,J=8.5,7.2Hz,1H),7.53(dd,J=7.8,1.7Hz,1H),7.47-7.39(m,2H),7.37(d, J=7.2Hz,1H),7.35-7.28(m,1H),6.96(d,J=8.3Hz,1H),6.91(t,J=7.5Hz,1H),5.00(dd,J=12.8,5. 4Hz,1H),4.13(t,J=6.4Hz,2H),3.61(m,7H),3.18(m,4H),2.81(m,1H),2.56-2.44(m,1H),2.42(m, 1H),2.29(t,J=7.4Hz,2H),1.95(m,1H),1.69(m,2H),1.46(m,2H),1.39(m,2H),1.34-1.22(m,4H).

[0152] Example 7: Synthesis of 4-((7-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-7-oxoheptyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (7) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (15 mg, 0.049 mmol) and 7-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)heptanoic acid (20 mg, 0.049 mmol) was added to DMF (1 mL), to which HATU (28 mg, 0.074 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 7.5 mg, yield 23%). LCMS (m / z): 656 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 11.10(s,1H),7.81(t,J=7.9Hz,1H),7.61-7.54(m,1H),7.52(d,J=8.5Hz,1H),7.48(s,1H),7.45(d ,J=7.2Hz,1H),7.40(t,J=7.8Hz,1H),7.07-6.96(m,2H),5.08(dd,J=12.9,5.4Hz,1H),4.21(t,J=6 .4Hz,4H),3.69(t,J=4.7Hz,4H),3.29(s,1H),3.24(s,1H),3.10(m,1H),2.93-2.82(m,2H),2.62-2 .52(m,2H),2.38(t,J=7.4Hz,2H),2.03(m,1H),1.77(m,2H),1.52(m,4H),1.38(m,2H),1.18(m,1H).

[0153] Example 8: Synthesis of 4-((10-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-10-oxodecyl)oxy)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (8) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (15 mg, 0.049 mmol) and 10-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)decanoic acid (22 mg, 0.049 mmol) was added to DMF (1 mL), to which HATU (28 mg, 0.074 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 14.7 mg, yield 43%). LCMS (m / z): 698 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 14.17(s,1H),11.10(s,1H),7.94-7.89(m,1H),7.80(dd,J=8.5,7.2Hz,1H),7.55-7.48(m,2H ),7.44(d,J=7.3Hz,1H),7.24(td,J=7.6,1.6Hz,1H),6.89(m,2H),6.41(s,2H),5.08(dd,J=1 2.8,5.5Hz,1H),4.20(t,J=6.4Hz,2H),3.69(m,4H),3.18(m,1H),3.06(m,4H),2.89(m,1H),2 .64-2.51(m,2H),2.35(t,J=7.5Hz,2H),2.03(m,1H),1.76(m,2H),1.49(m,4H),1.33(m,7H).

[0154] Example 9: Synthesis of 3-(4-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-6-oxohexa-1-in-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (9) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (15 mg, 0.049 mmol) and 6-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)hexa-5-ic acid (17 mg, 0.049 mmol) was added to DMF (1 mL), to which HATU (28 mg, 0.074 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 9 mg, yield 15%). LCMS (m / z): 608 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 14.17(s,1H),10.99(s,1H),7.92(dd,J=8.4,1.6Hz,1H),7.57(m,1H),7.53(s,1H),7. 50-7.42(m,2H),7.25(td,J=7.5,1.6Hz,1H),6.89(m,2H),6.41(s,2H),5.14(dd,J=13 .3,5.1Hz,1H),4.48(d,J=17.1Hz,1H),4.33(d,J=17.1Hz,1H),3.68(s,4H),3.13-2.9 8(m,4H),2.66(t,J=7.7Hz,2H),2.37(t,J=7.4Hz,2H),1.62(m,4H),1.45-1.29(m,2H).

[0155] Example 10: Synthesis of 3-(4-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-6-oxohexyl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (10) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (15 mg, 0.049 mmol) and 6-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)hexanoic acid (18 mg, 0.049 mmol) was added to DMF (1 mL), to which HATU (28 mg, 0.074 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 12 mg, yield 20%). LCMS (m / z): 612 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 14.16(s,1H),11.00(s,1H),7.90(dd,J=8.5,1.6Hz,1H),7.72(dd,J=7.6,1.0Hz,1H),7.67(dd,J=7. 7,1.0Hz,1H),7.56-7.46(m,2H),7.28-7.20(m,1H),6.89(m,2H),6.41(s,2H),5.15(dd,J=13.3,5.1H z,1H),4.49(d,J=17.7Hz,1H),4.34(d,J=17.7Hz,1H),3.71(t,J=5.0Hz,4H),3.18(d,J=5.1Hz,1H), 3.07(dt,J=21.7,4.9Hz,4H),2.91(m,1H),2.63-2.53(m,5H),2.46(m,1H),2.01(m,1H),1.86(m,2H).

[0156] Example 11: Synthesis of 4-((9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononyl)oxy)-2-(1-methyl-2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (compound G) [ka] A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (14 mg, 0.045 mmol) and 9-((2-(1-methyl-2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)nonanoic acid (20 mg, 0.045 mmol) was added to DMF (1 mL), to which HATU (26 mg, 0.07 mmol) and DIPEA (0.03 mL, 0.16 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 5.3 mg, yield 17%). LCMS (m / z): 698 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 7.81(dd,J=8.5,7.2Hz,1H),7.61(dd,J=7.8,1.7Hz,1H),7.56-7.47(m,2H),7.45(d,J=7.3Hz,1H),7.42-7.25(m, 1H),7.03(d,J=8.2Hz,1H),6.98(t,J=7.5Hz,1H),5.15(dd,J=13.0,5.4Hz,1H),4.20(t,J=6.4Hz,2H),3.68(m,4H) ),3.25(m,4H),3.02(s,3H),2.95(m,J=17.2,13.9,5.4Hz,1H),2.76(ddd,J=17.2,4.5,2.5Hz,1H),2.60-2.51(m, 4H), 2.35(t,J=7.5Hz,2H),2.05(dtd,J=13.1,5.4,2.6Hz,1H),1.81-1.72(m,2H),1.57-1.41(m,4H),1.32(m,6H).

[0157] Example 12: (2S,4R)-1-((S)-2-(9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)nonanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (11) [ka] Benzyl 9-(4-(3-amino-6-chloropyridazine-4-yl)piperazine-1-yl)nonanoate 4-bromo-6-chloropyridazine-3-amine (208 mg, 1 mmol) was dissolved in MeCN (5 mL), to which benzyl 9-(piperazin-1-yl)nonanoate (400 mg, 1.2 mmol) and DIEA (650 mg, 5 mmol) were added. The reaction mixture was stirred overnight at 100°C in a sealed tube. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (180 mg, 39% yield). LCMS (m / z): 460 [M+H] + .

[0158] 9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazine-1-yl)nonanoic acid Benzyl 9-(4-(3-amino-6-chloropyridazin-4-yl)piperazin-1-yl)nonanoate (180 mg, 0.4 mmol) was dissolved in dioxane / H2O (10 mL / 1 mL), to which (2-hydroxyphenyl)boronic acid (73 mg, 0.53 mmol), Xphos-Pd-G3 (34 mg, 0.04 mmol), and K2CO3 (110 mg, 0.8 mmol) were added. The reaction mixture was stirred overnight at 90°C under N2 protection. The reaction mixture was cooled and concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (54 mg, 32% yield). LCMS (m / z): 428 [M+H] + .

[0159] (2S,4R)-1-((S)-2-(9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)nonanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide A mixture of (2S,4R)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (8 mg, 0.017 mmol) and 9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)nonanoic acid (9 mg, 0.017 mmol) was mixed in DMF (0.5 mL), to which HATU (9.5 mg, 0.025 mmol) and DIPEA (0.01 mL, 0.05 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 7.8 mg, yield 55%). LCMS (m / z): 854 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 10.03(s,1H),9.05(s,1H),8.43(d,J=7.8Hz,1H),7.84(d,J=9.3Hz,1H),7.74(d,J=7.8Hz,1H),7.67(s,1H),7 .59-7.26(m,7H),7.14-6.96(m,2H),5.09-4.84(m,2H),4.58(d,J=9.3Hz,1H),4.48(t,J=8.1Hz,1H),4.39-4.3 0(m,1H),3.92-3.78(m,4H),3.23-3.12(m,4H),2.51(s,3H),2.37-2.27(m,1H),2.22-1.94(m,3H),1.90-1.81( m,1H),1.79-1.67(m,2H),1.64-1.47(m,3H),1.44(d,J=7.0Hz,3H),1.41-1.17(m,10H),0.99(d,J=7.1Hz,9H).

[0160] Example 13: (2S,4R)-1-((S)-2-(9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (12) [ka] Benzyl 9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononanoate A mixture of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (77 mg, 0.28 mmol) and 9-(benzyloxy)-9-oxononanoic acid (56 mg, 0.2 mmol) in DMF (2 mL) was mixed with HATU (114 mg, 0.3 mmol) and DIPEA (0.11 mL, 0.6 mmol). The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 67 mg, yield 63%). LCMS (m / z): 531 [M+H] + .

[0161] 9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononanoic acid Pd / C (10 mg, 10% w / t) was added to a solution of benzyl 9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononanoate (67 mg, 0.13 mmol) in ethyl acetate (5 mL). The reaction mixture was stirred under H2 at room temperature for 5 hours. After completion, the mixture was filtered and then concentrated to obtain the target compound (white solid, 54 mg, 94% yield). LCMS (m / z): 442 [M+H] + .

[0162] (2S,4R)-1-((S)-2-(9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononanamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide A mixture of (2S,4R)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (8 mg, 0.017 mmol) and 9-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)-9-oxononanoic acid (10 mg, 0.017 mmol) was added to DMF (0.5 mL), to which HATU (10 mg, 0.025 mmol) and DIPEA (0.01 mL, 0.05 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), and the organic phase was washed with brine (20 mL x 3). Na2SO4 The mixture was dried, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 11.6 mg, 79% yield). LCMS (m / z): 868 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 9.05(s,1H),8.43(d,J=7.7Hz,1H),7.84(d,J=9.3Hz,1H),7.67-7.31(m,9H),7.20-6.91(m,2H) ,5.07-4.85(m,2H),4.57(d,J=9.3Hz,1H),4.48(t,J=8.0Hz,1H),4.38-4.30(m,1H),3.44-3.17( m,9H),2.51(s,3H),2.41(t,J=7.5Hz,2H),2.35-2.26(m,1H),2.22-2.12(m,1H),2.12-2.02(m,1 H),1.89-1.80(m,1H),1.62-1.48(m,5H),1.43(d,J=7.0Hz,3H),1.37-1.25(m,7H),0.99(s,9H).

[0163] Example 14: N-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)hexyl)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetamide(13) [ka] HATU, DIEA, DMF, rt, o / n 6-Chloro-4-(piperazine-1-yl)pyridazine-3-amine To a solution of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)piperazine-1-carboxylate (157 mg, 0.5 mmol) in DCM (5 mL), TFA (2 mL) was added. The reaction mixture was stirred in rt for 2 hours. The reaction mixture was concentrated to obtain the desired product (100 mg, 61%) as the TFA salt. LCMS (m / z): 214 [M+H] + .

[0164] tert-butyl(6-(4-(3-amino-6-chloropyridazine-4-yl)piperazine-1-yl)hexyl)carbamate To a solution of 6-chloro-4-(piperazin-1-yl)pyridazin-3-amine (100 mg, TFA salt, 0.3 mmol) in DMF (3 mL), tert-butyl(6-bromohexyl)carbamate (110 mg, 0.39 mmol) and K2CO3 (83 mg, 0.6 mmol) were added. The reaction mixture was stirred at 60°C for 72 hours, then cooled and concentrated. The residue was purified by silica gel column chromatography to obtain the desired product (95 mg, 77% yield). LCMS (m / z): 413 [M+H] + .

[0165] tert-butyl(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)hexyl)carbamate To a solution of tert-butyl(6-(4-(3-amino-6-chloropyridazine-4-yl)piperazin-1-yl)hexyl)carbamate (95 mg, 0.23 mmol) in dioxane / H2O (10 mL / 1 mL), (2-hydroxyphenyl)boronic acid (42 mg, 0.3 mmol), Xphos-Pd-G3 (20 mg, 0.023 mmol), and K2CO3 (64 mg, 0.46 mmol) were added. The reaction mixture was stirred overnight at 90°C under N2 protection. The reaction mixture was cooled and concentrated. The residue was purified by preparative HPLC to obtain the desired product (60 mg, 55% yield). LCMS (m / z): 471 [M+H] + .

[0166] 2-(6-amino-5-(4-(6-aminohexyl)piperazine-1-yl)pyridazine-3-yl)phenol To a solution of tert-butyl(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)hexyl)carbamate (60 mg, 0.13 mmol) in DCM (5 mL), TFA (2 mL) was added. The reaction mixture was stirred in rt for 2 hours. The reaction mixture was concentrated to obtain the desired product (50 mg, 79%) as the TFA salt. LCMS (m / z): 371 [M+H] + .

[0167] N-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)hexyl)-2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetamide A mixture of 2-(6-amino-5-(4-(6-aminohexyl)piperazine-1-yl)pyridazin-3-yl)phenol (25 mg, TFA salt, 0.05 mmol) and 2-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-4-yl)oxy)acetic acid (17 mg, 0.05 mmol) was added to DMF (0.5 mL), to which HATU (29 mg, 0.075 mmol) and DIPEA (0.05 mL, 0.25 mmol) were added. The reaction mixture was stirred overnight in rt. After completion, the mixture was extracted with EA (50 mL x 3), the organic phase was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated to remove the solvent, and the residue was purified by preparative HPLC to obtain the target compound (white solid, 13.1 mg, yield 38%). LCMS(m / z):685[M+H] + . 1 1H NMR (500MHz, DMSO-d6)δ 11.12(s,1H),9.98(s,1H),7.98(t,J=5.7Hz,1H),7.86-7.77(m,1H),7.68(d ,J=7.7Hz,1H),7.61(s,1H),7.55-7.33(m,5H),7.07-6.95(m,2H),5.16-5.07 (m,1H),4.78(s,2H),3.26-3.07(m,8H),2.99-2.81(m,2H),2.17-1.93(m,2H) ,1.76-1.57(m,2H),1.55-1.42(m,2H),1.41-1.30(m,4H),1.30-1.16(m,4H).

[0168] Example 15: Cell-CRBN binding assay BRD4 BD2The MCS-eGFP-P2A-mCherry was subcloned into a modified mammalian pcDNA5 / FRT vector (resistant to ampicillin and hygromycin B) containing MCS-eGFP-P2A-mCherry. Stable cell lines expressing the eGFP-protein fusion and mCherry reporter were constructed using the Flip-In® 293 system. Plasmid (0.3 μg) and pOG44 (4.7 μg) DNA were pre-incubated for 20 minutes in 100 μl of Opti-MEM I (Gibco®, Life Technologies) medium containing 0.05 mg / ml Lipofectamine® 2000 (Invitrogen), and then added to Flip-In® 293 cells in a 6-well plate format (Falcon, 353046) containing 1.9 ml of DMEM medium (Gibco®, Life Technologies) per well. The cells were grown after 48 hours and placed in DMEM medium containing 50 μg / ml hygromycin B (REF 10687010, Invitrogen) as a selective marker in a 10 cm³ solution. 2 The cells were transferred to plates (Corning, 430165). After 2-3 passage cycles, cells expressing eGFP and mCherry were enriched using FACS (FACSAria II, BD).

[0169] BRD4 including mCherry reporter BD2Cells stably expressing -GFP were seeded at 30-50% confluence in 384-well plates (3764, Corning) containing FluoroBrite DMEM medium (Gibco®, A18967) with 50 μl of 10% FBS per well the day before compound treatment. The compound and 100 nM dBET6 were dispensed using a D300e digital dispenser (HP) normalized to 0.5% DMSO and incubated with the cells for 5 hours. The assay plates were immediately imaged using an Acumen eX3 / HCl (TTPLabtech) High Content Imager with a 2 μm x 1 μm grid per well format, using 488 nm and 561 nm lasers. The resulting images were analyzed using CellProfiler (Carpenter, et al., Genome Biol. 7: R100 PIMD 17076895 (2006)).

[0170] The results are shown in Figures 1A to 1C. IC of Compound 1 50 The IC of compound 2 is 0.00003047 (Figure 1A); 50 The IC of compound 3 is 0.00002086 (Figure 1B); 50 The value is 0.0000001623 (Figure 1C). The results indicate that compounds with a PEG-based linker (Figures 1A and 1B) had lower permeability than compounds consisting only of carbon (alkylene) (Figure 1C).

[0171] Example 16: PBRM1 PB5 GFP / RFP degradation assay Cell degradation assay PBRM1 PB5 was subcloned into a modified mammalian pcDNA5 / FRT vector (resistant to ampicillin and hygromycin B) containing MCS-eGFP-P2A-mCherry. Stable cell lines expressing the eGFP-protein fusion and mCherry reporter were constructed using the Flip-In® 293 system. Plasmid (0.3 μg) and pOG44 (4.7 μg) DNA were pre-incubated for 20 minutes in 100 μl of Opti-MEM I (Gibco®, Life Technologies) medium containing 0.05 mg / ml Lipofectamine 2000 (Invitrogen), and then added to Flip-In® 293 cells in a 6-well plate format (Falcon, 353046) containing 1.9 ml of DMEM medium (Gibco®, Life Technologies) per well. The cells were grown after 48 hours and placed in DMEM medium containing 50 μg / ml hygromycin B (REF 10687010, Invitrogen) as a selective marker in a 10 cm³ solution. 2 The cells were transferred to plates (Corning, 430165). After 2-3 passage cycles, cells expressing eGFP and mCherry were enriched using FACS (FACSAria II, BD).

[0172] Cells were seeded at 30–50% confluence in 24, 48, or 96-well plates (3524, 3548, 3596, and Costar, respectively) the day before compound treatment. The titrated compounds were trypsinized and resuspended in DMEM medium, incubated with cells for 5 hours, and then transferred to 96-well plates (353910, Falcon) for analysis using a flow cytometer (guava easyCyte HT, Millipore). Signals were acquired from a minimum of 3000 events per well, and eGFP and mCherry fluorescence were monitored. Data were analyzed using FlowJo® (FlowJo, LLC). After removing outliers for forward and side scattering, which frequently occur with cell fragments, over 90% of the total cells remained. Subsequently, after removing outliers for eGFP and mCherry signals, 88–90% of the total cells remained, creating the set used for quantification. The eGFP protein abundance relative to mCherry was then quantified as a 10-fold amplification ratio for individual cells using the formula: 10 x eGFP / mCherry. Next, the median ratio was calculated for each set and normalized to the median DMSO ratio.

[0173] The results are shown in Figure 2. These results indicate that the carbon-only (i.e., alkylene) linker maintained strong decomposition of PBRM1-PB5.

[0174] Example 17: Imaging-based PBRM1 PB5 GFP / RFP degradation assay Cells stably expressing PBRM1 PB5 from Example 16 were seeded at 30-50% confluence in 384-well plates (3764, Corning) containing FluoroBrite DMEM medium (Gibco, A18967) with 50 μL of 10% FBS per well the day before compound treatment. The compound and 100 nM dBET6 were dispensed using a D300e digital dispenser (HP) normalized to 0.5% DMSO and incubated with the cells for 5 hours. The assay plates were immediately imaged with 488 nm and 561 nm lasers using an Acumen eX3 / HCl (TTPLabtech) High Content Imager with a 2 μm x 1 μm grid per well format. The obtained images were analyzed using CellProfiler (Carpenter et al., Genome Biol. 7:R100 PIMD 17076895 (2006)). A series of image analysis steps ("image analysis pipeline") was constructed.

[0175] The CellProfiler pipeline steps were as follows: First, the red and green channels were aligned and trimmed to target the center of each well (to avoid analyzing heavily aggregated cells at the edges), and the background illumination function was calculated separately for both the red and green channels of each well and subtracted to compensate for illumination variations across the 384-well plate due to various sources of error. Next, an additional step was applied to the green channel to suppress the analysis of large autofluorescence artifacts and enhance the analysis of cell-specific fluorescence by selecting objects with a given size, 30 A.U., and a given shape and speckle. Then, cells that were mCherry-positive were identified in the red channel by filtering objects between 8 and 60 pixels in diameter and using intensity to distinguish aggregated objects. Next, the green channel was split into GFP-positive and GFP-negative regions, and objects were classified as GFP-positive if at least 40% of them overlapped with the GFP-positive region. Finally, the ratio of GFP-positive cells to mCherry-positive cells (GFP / mCherry ratio) for each well was calculated, and the green and red images were rescaled for visualization. The GFP / mCherry ratio was normalized to DMSO visualized in GraphPad Prism 7.

[0176] The results for compounds 11, 12, and 13 after 3 hours of incubation are shown in Figures 3H to 3J. The VHL ligand-based degrading compound 12 was able to induce potent degradation of PBRM1 PB5, while compound 11, lacking ketone oxygen in the PBRM1 ligand, was less effective in degrading PBRM1 PB5. These results indicate that a hydrogen bond acceptor is required at this position for binding to the PBRM1 ligand. The CRBN-based degrading compound 13, containing an aliphatic linker of oxoacetamide and thalidomide scaffold, exhibits potent degradation of PBRM1 PB5, but also shows the "hook effect," a known phenomenon in heterobifunctional degrading agents where high compound concentrations hinder effective complex formation and reduce proteolysis. In contrast, the other CRBN-based degrading agents (compounds 3-8) containing an aliphatic linker and lacking the oxoacetamide feature did not exhibit the hook effect at 10 μM concentrations, indicating that the oxoacetamide feature in this configuration is suboptimal.

[0177] Example 18: PBRM1 PB5 Reporter Assay The assay described in Example 16 was repeated using compounds 3-8 and the control ("negative compound" (G)).

[0178] The results are shown in Figures 3A to 3G. Figures 3A to 3F show the DCs of compounds 3 to 8, respectively. 50 The values ​​are shown below. These are also shown in the table below. [Table 1] The compounds in Table 1 exhibited complete degradation of PBRM1 PB5 in the range of 100 nM to 10 μM, demonstrating a large window of degradation activity. These compounds were able to induce potent degradation of PBRM1 PB5 at 10 μM without a "hook effect."

[0179] Example 19: Western blot for cytoregradation of Kelly cells PBRM1 protein Kelly cells were treated with the indicated compound and incubated for 6 or 24 hours. Samples were electrophoresed on 4–20% or Any kD™ SDS-PAGE gels (Bio-Rad) and transferred to PVDF membranes using an iBlot 2.0 dry blotting system (Thermo-Fisher Scientific). The membranes were blocked with LI-COR blocking solution (LI-COR) and incubated overnight with the primary antibody, followed by three washes with LI-COR blocking solution and incubation in the dark for 1 hour with the secondary antibody. After three final washes, the membranes were imaged using a LI-COR fluorescence imaging station (LI-COR). Antibodies used: 1:500 dilution of anti-PBRM1 (Cell Signaling, clone D3F70), 1:10,000 dilution of anti-GAPDH (G8795, Sigma), and 1:10,000 dilution of IRDye 680 Donkey anti-mouse (926-68072, LI-COR).

[0180] The results are shown in Figure 4. Both the 6-hour and 24-hour treatments showed almost complete degradation of endogenous PBRM1 at a concentration of 10 μM, and a visible decrease in protein abundance was obtained at 1 μM after 24 hours, but there was no effect on the protein levels of the reference protein GAPDH.

[0181] All patent and non-patent publications represent the level of skill of those skilled in the art to which the present invention relates. All such publications (including their specific portions referenced) are incorporated herein by reference to the same extent that each individual publication is specifically and individually indicated as being incorporated by reference.

[0182] While the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the invention. Therefore, it should be understood that numerous modifications can be made to the exemplary embodiments and other arrangements can be devised without departing from the spirit and scope of the invention as defined by the appended claims. The present invention may provide the following embodiments. [1] Formula I:

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[10] formula:

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[11] formula:

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[10] , or represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[12] formula:

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[11] , or represented by a pharmaceutically acceptable salt or stereoisomer thereof.

[13] If the linker is -O-, -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, - C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N( R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O) 2 -, -OS(O)-, -S(O)O-, -S(O)-, -OS(O) 2 -, -S(O) 2 O-, -N(R')S(O) 2 -, -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, C 3 ~C 12 Carbocyclene, 3-12 member heterocyclene, 5-12 member heteroarylene, or any combination thereof (wherein R' is H or C) 1 ~C 6 An alkylene chain that can be interrupted by at least one alkyl group and / or terminated by at least one (at either or both ends), wherein the interrupting group and one or both terminal groups may be the same or different, according to any one of the above [1] to

[12] .

[14] The linker is -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C (NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R ')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O) 2 -, -OS(O)-, -S(O)O-, -S(O)-, -OS(O) 2 -, -S(O) 2 O-, -N(R')S(O) 2 -, -S(O) 2 N(R')-, -N(R')S(O)-, -S(O)N(R')-, -N(R')S(O) 2 N(R')-, -N(R')S(O)N(R')-, C 3~12 Carbocyclene, 3-12 member heterocyclene, 5-12 member heteroarylene, or any combination thereof (wherein R' is H or C) 1 ~C 6 A polyethylene glycol chain that can be terminated at least one (either or both ends) of alkyl groups, wherein one or both terminal groups may be the same or different, according to any one of the above [1] to

[12] .

[15] The compound according to

[13] above, wherein the linker is an alkylene linker having 1 to 10 alkylene units.

[16] The aforementioned degron is given by formula D1:

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[15] .

[17] The following formula:

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[16] above, or represented by one of its pharmaceutically acceptable salts, isotopic derivatives, or stereoisomers.

[18] The following formula:

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[19]

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[20] A pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds described in [1] to

[18] above, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[21] A method for treating a disease or disorder mediated by PB1, comprising the step of administering a therapeutically effective amount of any one of the compounds described in [1] to

[19] above, or a pharmaceutically acceptable salt or stereoisomer thereof, to a subject in need.

[22] The method according to

[21] above, wherein the disease is cancer.

[23] The method according to

[22] above, wherein the cancer is melanoma.

Claims

1. Formula I: 【Chemistry 1】 or a compound represented by a pharmaceutically acceptable salt or stereoisomer thereof, The PB1-targeting ligand is 【Chemistry 2】 Represented by; where the linker is selected from the group consisting of -O-, -S-, -N(R'), -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(NOR'), -C(O)N(R'), -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N(R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R'), -C(NR'), -N(R')C(NR'), -C(NR')N(R'), -N(R')C(NR')N(R'), -OB(Me)O-, -S(O) ２ -, -OS(O)-, -S(O)O-, -S(O)-, -OS(O) ２ -, -S(O) ２ O-, -N(R')S(O) ２ -, -S(O) ２ N(R'), -N(R')S(O)-, -S(O)N(R'), -N(R')S(O) ２ N(R'), -N(R')S(O)N(R'), C ３ ~C １２ carbocyclene, 3- to 12-membered heterocycle, 5- to 12-membered heteroarylene or any combination thereof (wherein R' is H or C １ ~C ６ alkyl), and is an alkylene chain or a polyethylene glycol chain that can be interrupted by at least one of them and / or terminated by at least one of them (either or both ends), and the interrupting group and the one or both end groups may be the same or different; The aforementioned degron is given by formula D2, D3, D4, or D5: 【Transformation 3】 【Chemistry 4】 (In the formula, Y' represents a bond, NH, O, or CH) ２ (is); 【Transformation 5】 (In the formula, Z is a C5-6 carboncyclic group or a heterocyclic group.) A compound represented by However, the compound of formula I: 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 Except in the case of

2. The compound according to claim 1, wherein the linker is an alkylene linker having 1 to 10 alkylene units.

3. The linker is -O-, -S-, -N(R')-, -C≡C-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O- , -C(NOR')-, -C(O)N(R')-, -C(O)N(R')C(O)-, -C(O)N(R')C(O)N(R')-, -N (R')C(O)-, -N(R')C(O)N(R')-, -N(R')C(O)O-, -OC(O)N(R')-, -C(NR')-, -N(R')C(NR')-, -C(NR')N(R')-, -N(R')C(NR')N(R')-, -OB(Me)O-, -S(O) The compound according to claim 1, wherein the interrupting group and one or both terminal groups are the same or different, wherein the alkylene chain is interrupted by at least one of C3-C12 carbocylene, 3-12 member heterocyclene, 5-12 member heteroarylene or any combination thereof (wherein R' is H or C1-C6 alkyl).

4. formula: 【Transformation 6】 The compound according to claim 1, or represented by a pharmaceutically acceptable salt or stereoisomer thereof.

5. One of the following formulas: 【Transformation 7】 【Transformation 8】 【Chemistry 9】 The compound according to claim 1, or represented by one of its pharmaceutically acceptable salts or stereoisomers. 【Request Item 6】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 or its pharmaceutically acceptable salt or stereoisomer The compound according to claim 1.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition for treating a disease or disorder mediated by PB1, comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer described in any one of claims 1 to 6.

9. The pharmaceutical composition according to claim 8, wherein the disease is cancer.

10. The pharmaceutical composition according to claim 9, wherein the cancer is melanoma.

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