Chemical targeting of SWI / SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) and its use in diffuse intrinsic pontine glioma (DIPG)

Abstract

The present disclosure relates to bifunctional compounds, compositions and methods for treating diseases or conditions mediated by the abnormal activity of SMARCA4 or SMARCA2 and SMARCA4.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 297,505, filed January 7, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Diffuse intrinsic pontine gliomas (DIPGs) and diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard treatment therapies (Hoffman et al., J Clin Oncol 36:1963-1972(2018)). The primary genetic driver is a series of recurrent amino acid substitutions in the genes encoding histone H3 (H3.3 and H3.1), where lysine 27 is mutated to methionine (H3K27M) (Schwartzentruber et al., Nature 482:226-23l(2012);Wu et al., Nat Genet 44:251-253(2012)). The H3K27 oncohistone does not contain a direct enzymatic function and is therefore not conducive to the development of new drugs. Summary of the Invention [Means for solving the problem]

[0003] The first aspect of the present disclosure is a compound of formula (I): [ka] A bifunctional compound having a structure represented by or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein [ka] represents a targeting moiety that binds to SWI / SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) or SMARCA2 and SMARCA4, degron represents a moiety that binds to an E3 ubiquitin ligase, and L represents a linker that covalently attaches the targeting moiety to the degron: R1 and R4 are each independently H or halogen; R2 is H or NH2; R3 is H, NH2, NO2, OH, CN, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C3-C6)carbocyclyl, 4- to 6-membered heterocyclyl, (C1-C6)alkyl-(C3-C6)carbocyclyl, or (C1-C6)alkyl-4- to 6-membered heterocyclyl, wherein said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl is selected from one or more of the same or different R 1a groups, where each R 1a are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxyl, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl; X is C(O), C(O)NH, [ka] and the wavy line ( [ka] ) is the point of attachment to the pyridine ring, and the wavy line-asterisk ( [ka] ) is the point of attachment to the linker.

[0004] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier.

[0005] In another aspect of the present disclosure, a method of making a bifunctional compound is provided.

[0006] A further aspect of the present disclosure relates to a method of treating a disease or disorder characterized by or mediated by abnormal activity of SMARCA4 or SMARCA2 and SMARCA4 (SMARCA2 / 4), comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0007] In some embodiments, the disease or disorder is cancer, hi some embodiments, the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt's lymphoma, childhood medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial carcinoma, and melanoma.

[0008] Another aspect of the present disclosure is directed to a method of treating diffuse midline glioma harboring an H3K27M mutation, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a bifunctional compound of formula I', I'', or II'', or a pharmaceutically acceptable salt or stereoisomer thereof.

[0009] In some embodiments, the diffuse midline glioma with an H3K27M mutation is a diffuse intrinsic pontine glioma (DIPG).

[0010] Without intending to be bound by any particular theory of operation, the bifunctional compounds disclosed herein can serve as a set of new chemical tools for SMARCA4 or SMARCA2 and SMARCA4 knockdown, and can provide effective treatment of SMARCA4 or SMARCA2 / 4-mediated diseases and disorders, such as cancer. Applicant has surprisingly and unexpectedly discovered that DIPG cells are sensitive to SMARCA4 depletion. Degrading SMARCA4, the catalytic ATPase subunit of the SWItch / sucrose non-fermenting (SWI / SNF) complex, also known as Brg / Brm-associated (BAF) complex, effectively disrupts the function of the SWI / SNF or BAF complex. Thus, the disclosed bifunctional compounds can provide effective treatment of DIPG and other diffuse midline gliomas with H3K27M mutations. [Brief description of the drawings]

[0011] [Figure 1A] Western blot showing degradation of SWI / SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) (also known herein as Brahma-related gene 1 (BRG1) or BRG) in NOMO-1 cells by bifunctional compounds 1-3 and DMSO (negative control).

[0012] [Figure 1B] Western blot showing SMARCA4 (BRG) degradation in NOMO-1 cells with bifunctional compounds 4-6 and DMSO negative control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings set forth to facilitate understanding of this disclosure.

[0014] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, etc.

[0015] Unless otherwise specified, the term "about" means within 10%, e.g., within 5%, 2%, or 1% of the particular value that is modified by the term "about."

[0016] The transitional phrase "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes elements, steps, or ingredients not specified in the claim. The transitional phrase "consisting essentially of" limits the claim to certain materials or steps, "and which do not materially affect the basic and novel characteristics" of the claimed invention.

[0017] To the extent that the following terms are used herein with respect to and to further describe the compounds of the present disclosure, the following definitions apply.

[0018] As used herein, the term "alkyl" refers to a saturated, straight or branched chain monovalent hydrocarbon radical. Unless otherwise stated for any one or more groups, in one embodiment, an alkyl radical is a C1-C 18 In other embodiments, the alkyl radical is a C0-C6, C0-C5, C0-C3, C1-C 12, C1-C8, C1-C6, C1-C5, C1-C4 or C1-C3 group (wherein 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.

[0019] As used herein, the term "alkylene" refers to a straight or branched divalent hydrocarbon chain that links the remainder of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain may be attached to the remainder of the molecule through a single bond or to the radical group through a single bond. Unless otherwise stated for any one or more groups, in some embodiments, an alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene). In other embodiments, an alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene). In other embodiments, an alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene). In other embodiments, an alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene). In other embodiments, an alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene). In other embodiments, an alkylene group contains 1 carbon atom (C1 alkylene).

[0020] As used herein, the term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl includes radicals having "cis" and "trans" orientations, alternatively "E" and "Z" orientations. Unless otherwise specified for any one or more groups, in one example, an alkenyl radical is any of C2 to C6 18 In another embodiment, the alkenyl radical is a C2-C 12 , C2~C 10 , C2-C8, C2-C6 or C2-C3 groups. Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.

[0021] The term "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbyl groups covalently linked by an oxygen. Thus, the substituent of an alkyl that makes it an ether is an alkoxyl or resembles an alkoxyl, and can be represented, for example, by one of -O-alkyl, -O-alkenyl, and -O-alkynyl.

[0022] As used herein, the term "alkoxylenes" refers to compounds having the general formula (-OC), where n represents an integer (e.g., 1, 2, 3, 4, 5, 6, or 7). n H 2n"alkoxylene" refers to a saturated monovalent aliphatic radical of the formula (-), including both straight-chain and branched-chain radicals. The alkoxylene chain may be attached to the remainder of the molecule through a single bond or to the radical group through a single bond. Unless otherwise stated for any one or more groups, in some embodiments, the alkoxylene group contains 1 to 3 carbon atoms (-O-C1-C3 alkoxylene). In other embodiments, the alkoxylene group contains 1 to 5 carbon atoms (-O-C1-C5 alkoxylene).

[0023] As used herein, the term "cyclic group," used alone or as part of a larger moiety, broadly refers to any group including saturated, partially saturated, or aromatic ring systems, e.g., carbocyclic (cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl, heterocycloalkenyl), aryl, and heteroaryl groups. A cyclic group can have one or more (e.g., fused) ring systems. Thus, for example, unless otherwise stated for any one or more groups, a cyclic group can contain one or more carbocyclic, heterocyclic, aryl, or heteroaryl groups.

[0024] As used herein, the term "carbocycle" (also "carbocyclyl"), used alone or as part of a larger moiety, refers to a group that is alone or part of a larger moiety (e.g., an alkyl carbocyclic group) containing saturated, partially unsaturated, or aromatic ring systems having from 3 to 20 carbon atoms. The term carbocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. Unless otherwise stated for any one or more groups, in one embodiment, a carbocyclyl refers to a ring system containing from 3 to 15 carbon atoms (C3-C4). 15 In one embodiment, the carbocyclyl contains 3 to 12 carbon atoms (C 12 In another embodiment, carbocyclyl is C3-C8, C3-C 10 Or C5~C 10In another embodiment, the carbocyclyl, as a monocyclic ring, includes C3-C8, C3-C6, or C5-C6. In some embodiments, the carbocyclyl, as a bicyclic ring, includes C7-C 12 In another embodiment, the carbocyclyl, as a spiro system, is a C5-C 12 Includes. Representative examples of monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-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. Representative examples of spirocarbocyclyl 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 monocyclic, bicyclic, or spirocarbocycles). 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 heterocycles), where the radical or point of attachment is on the carbocyclic ring.

[0025] Thus, the term carbocycle as used herein means R c is an alkylene chain; c The term carbocyclyl, as used herein, also encompasses carbocyclylalkyl groups, which refer to the group R c is an alkylene chain of the formula --O--Rc Also included are carbocyclylalkoxy groups, which refer to groups attached through the oxygen atom of a -carbocyclyl.

[0026] As used herein, the term "aryl" (e.g., "aralkyl" where a terminal carbon atom on the alkyl group is the point of attachment, e.g., a benzyl group), "aralkoxy" where an oxygen atom is the point of attachment, or "aroxyalkyl" where the point of attachment is on an aryl group) used alone or as part of a larger moiety refers to a group that includes a monocyclic, bicyclic, or tricyclic, carbocyclic ring system, including fused rings, in which at least one ring in the system is aromatic. In some embodiments, an aralkoxy group is a benzoxy group. The term "aryl" may be used interchangeably with the term "aryl ring." Unless otherwise stated for any one or more groups, in one embodiment, aryl includes groups having 6 to 18 carbon atoms. In another embodiment, aryl includes groups having 6 to 10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, naphthyridinyl, and the like, which may be substituted or independently substituted with one or more substituents described herein. A particular aryl is phenyl. In some embodiments, an aryl group comprises an aryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocyclic or heterocyclic), where the radical or point of attachment is on the aryl ring. The structure of any aryl group that may have differently positioned double bonds is considered to encompass any and all such resonance structures.

[0027] Thus, the term aryl, as disclosed above, refers to R c is an alkylene chain such as methylene or ethylene; c-aryl groups, such as aralkyl groups (e.g., benzyl). In some embodiments, the aralkyl group is an optionally substituted benzyl group. The term aryl, as used herein, refers to a group of R c is an alkylene chain such as methylene or ethylene; c Also included are aralkoxy groups, which refer to groups bonded through the oxygen atom of an -aryl.

[0028] As used herein, the term "heterocyclyl" refers to "carbocyclyl" used alone or as part of a larger moiety and includes saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., O, N, N(O), S, S(O), or S(O)2). The term heterocyclyl includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. Unless otherwise stated for any one or more groups, in some embodiments, heterocyclyl refers to a 3-15 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a 3-12 membered heterocyclyl ring system. In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3-12 membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaryl ring system, such as a 5-14 membered heteroaryl ring system. The term heterocyclyl also includes C3-C8 heterocycloalkyl, which are saturated or partially unsaturated monocyclic, bicyclic or spirocyclic ring systems containing 3 to 8 carbons and one or more (1, 2, 3 or 4) heteroatoms.

[0029] Unless otherwise stated for any one or more groups, in some embodiments, a heterocyclyl group contains 3-12 ring atoms, including monocyclic, bicyclic, tricyclic, and spirocyclic systems, where the ring atoms are carbon and 1-5 ring atoms are heteroatoms such as nitrogen, sulfur, or oxygen. In some embodiments, a heterocyclyl contains a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, and oxygen. In some embodiments, a heterocyclyl contains a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, and oxygen. In some embodiments, a heterocyclyl contains a 3-membered monocyclic ring. In some embodiments, a heterocyclyl contains a 4-membered monocyclic ring. In some embodiments, a heterocyclyl contains a 5- to 6-membered monocyclic ring. In some embodiments, a heterocyclyl contains 0-3 double bonds. In any of the foregoing embodiments, a heterocyclyl contains 1, 2, 3, or 4 heteroatoms. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO2) and any nitrogen heteroatom may be optionally quaternized (e.g., [NR4] + Cl - , [NR4] + OH -Representative examples of heterocyclyl include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl. , thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 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, thiazinyl, thiophenyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H -pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperazinonyl, 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]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclyls containing a sulfur or oxygen atom and 1 to 3 nitrogen atoms are thiazolyl including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl including oxazol-2-yl, and oxadiazolyl including 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered heterocyclyls containing 2 to 4 nitrogen atoms include imidazolyls such as imidazol-2-yl; triazolyls such as 1,3,4-triazol-5-yl, 1,2,3-triazol-5-yl, and 1,2,4-triazol-5-yl; and tetrazolyls such as 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyls are benzoxazol-2-yl, benzthiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclyls contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, especially pyridazin-3-yl, and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide and pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and 1,3,4-triazin-2-yl groups are further examples of heterocyclyl groups. In some embodiments, a heterocyclic group comprises a heterocycle fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocycles or heterocycles), where the radical or point of attachment is on the heterocycle, and in some embodiments, the point of attachment is a heteroatom contained in the heterocycle.

[0030] Thus, the term heterocycle, as used herein, includes N-heterocyclyl groups, which refer to heterocyclyl groups containing at least one nitrogen, where the attachment point of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl. The term heterocycle, as used herein, also includes C-heterocyclyl groups, which refer to heterocyclyl groups containing at least one heteroatom, where the attachment point of the heterocyclyl group to the rest of the molecule is through a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl radicals include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The term heterocycle, as disclosed above, refers to R c is an alkylene chain; c The term heterocycle as used herein also encompasses heterocyclylalkyl groups, which refer to the group R -heterocyclyl. c is an alkylene chain of the formula --O--R c Also included are heterocyclylalkoxy groups, which refer to radicals attached through the oxygen atom of a -heterocyclyl.

[0031] As used herein, the term "heteroaryl," used alone or as part of a larger moiety (e.g., "heteroarylalkyl" (also "heteroaralkyl") or "heteroarylalkoxy" (also "heteroaralkoxy"), refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, in which at least one ring is aromatic and contains at least one heteroatom. Unless otherwise stated for any one or more groups, in one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups in which one or more ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl. , pyrimidyl, imidazopyridyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, deazapurinyl, benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazo Heteroaryl groups include 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The term "heteroaryl" also includes groups in which a heteroaryl is fused to one or more cyclic (e.g., carbocyclyl or heterocyclyl) rings, where the radical or point of attachment is on the heteroaryl ring.Non-limiting examples include indolyl, indolizinyl, isoindolyl, benzothienyl, benzothiophenyl, methylenedioxyphenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzodioxazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic, bicyclic, or tricyclic. In some embodiments, a heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., 1, 2, or 3) different cyclic groups (e.g., carbocyclic or heterocyclic rings), where the radical or point of attachment is on the heteroaryl ring, and in some embodiments, the point of attachment is a heteroatom contained in the heterocyclic ring. The structure of any heteroaryl group that can have differently positioned double bonds is intended to encompass any and all such resonance structures.

[0032] Thus, the term heteroaryl encompasses N-heteroaryl groups, as used herein, which refer to heteroaryl groups as defined above that contain at least one nitrogen, and the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The term heteroaryl, as used herein, also encompasses C-heteroaryl groups, which refer to heteroaryl groups as defined above, and the point of attachment of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The term heteroaryl refers to any of R, ... c is an alkylene chain as defined above; c The term heteroaryl, as used herein, also encompasses heteroarylalkyl groups, which refer to the group R -heteroaryl. c is an alkylene group as defined above;c Also included are heteroaralkoxy (or heteroarylalkoxy) groups, which refer to groups attached through the oxygen atom of a -heteroaryl.

[0033] Thus, unless otherwise disclosed for any particular group(s), representative examples of substituents include alkyl, substituted alkyl (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), alkoxy (e.g., C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C1), substituted ... ), haloalkyl (e.g., CF3), alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkenyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), substituted alkynyl (e.g., C2-C6, C2-C5, C2-C4, C2-C3, C2), cyclic (e.g., C3-C 12 , C5-C6), substituted cyclic (e.g., C3-C 12 , C5-C6), carbocyclic (e.g., C3-C 12 , C5-C6), substituted carbocyclic (e.g., C3-C 12 , C5-C6), heterocyclic (e.g., C3-C 12 , C5-C6), substituted heterocyclic (e.g., C3-C 12 , C5-C6), aryl (e.g., benzyl and phenyl), substituted aryl (e.g., substituted benzyl or phenyl), heteroaryl (e.g., pyridyl or pyrimidyl), substituted heteroaryl (e.g., substituted pyridyl or pyrimidyl), aralkyl (e.g., benzyl), substituted aralkyl (e.g., substituted benzyl), halo, hydroxyl, aryloxy (e.g., C6-C 12 , C6), substituted aryloxy (e.g., C6-C 12 , C6), alkylthio (e.g., C1-C6), substituted alkylthio (e.g., C1-C6), arylthio (e.g., C6-C 12 , C6), substituted arylthio (e.g., C6-C 12, C6), cyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, thio, substituted thio, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfinamide, substituted sulfinamide, sulfonamide, substituted sulfonamide, urea, substituted urea, carbamate, substituted carbamate, amino acid, and peptide groups.

[0034] The term "binding", when referring to interactions between a targeting ligand and a targeting protein (in this disclosure SWI / SNF-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) or SMARCA2 and SMARCA4), typically refers to a molecular interaction that is preferential (also referred to herein as "selective") in that binding of the targeting ligand to other proteins present in the cell is substantially less and may not be functionally significant. The terms "selective" and "selectivity" refer to the ability of a bifunctional compound to discriminate between molecular targets.

[0035] The term "binding" when referring to an interaction between a degron and an E3 ubiquitin ligase typically refers to an intermolecular interaction that may or may not exhibit an affinity level equal to or exceeding that between a targeting ligand and a target protein, but is nevertheless sufficient to achieve recruitment of the ligase to the target protein, which in this disclosure is SMARCA4 or SMARCA2 and SMARCA4, for selective degradation.

[0036] Generally, the bifunctional compound has the formula (I): [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof, During the ceremony, [ka] represents a targeting moiety that binds to SWI / SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) or both SMARCA2 and SMARCA4, degron represents a moiety that binds to an E3 ubiquitin ligase, and L represents a linker that covalently attaches the targeting moiety to the degron, wherein: R1 and R4 are each independently H or halogen; R2 is H or NH2; R3 is H, NH2, NO2, OH, CN, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C3-C6)carbocyclyl, 4- to 6-membered heterocyclyl, (C1-C6)alkyl-(C3-C6)carbocyclyl, or (C1-C6)alkyl-4- to 6-membered heterocyclyl, wherein said alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl is selected from one or more of the same or different R 1a groups, where each R 1a are independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(C1-C3)alkoxy, halogen, amino, hydroxyl, (C1-C6)haloalkyl, NH-(C1-C6)alkyl, N((C1-C6)alkyl)2, (C3-C6)carbocyclyl, or 4- to 6-membered heterocyclyl;

[0037] X is C(O), C(O)NH, [ka] and the wavy line ( [ka] ) is the point of attachment to the pyridine ring, and the wavy line-asterisk ( [ka] ) is the point of attachment to the linker.

[0038] In some embodiments, R3 is H, NH2, or CH2OH.

[0039] In some embodiments, R1 is halogen and R2, R3, R4 are H.

[0040] In some embodiments, R1 is halogen, R2 and R4 are H, and R3 is CH2OH.

[0041] In some embodiments, R 1 is Cl or F.

[0042] In some embodiments, R1 and R3 are H, R2 is NH2, and R4 is a halogen.

[0043] In some embodiments, R4 is Cl.

[0044] In some embodiments, X is C(O), C(O)NH, [ka] It is.

[0045] In some embodiments, X is [ka] In some embodiments, R1 is halogen, R3 is H, NH2, or methoxy, and X is [ka] isn't it.

[0046] In some embodiments, the bifunctional compounds of the present disclosure have the structures I-1 to I-17: [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0047] Linker The linker ("L") provides a covalent bond between the targeting ligand and the degron. The structure of the linker is: [ka] In some embodiments, the linker comprises an alkylene chain (e.g., having 1-20 alkylene units). In some embodiments, the linker comprises an uninterrupted C2-C 15 In other embodiments, the linker comprises an alkylene chain. In other 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 12It may include an alkylene chain which may be interrupted and / or terminated (at either or both ends) by at least one of a carbocyclene, a 3- to 12-membered heterocyclene, a 5- to 12-membered heteroarylene, or any combination thereof, where R' is H or a C1-C6 alkyl, and the interrupting group and one or both terminating groups may be the same or different.

[0048] In some embodiments, the linker is a C2-C 15 It may contain an alkylene chain, and the nitrogen is also attached to the degron.

[0049] In some embodiments, the linker is [ka] The alkylene chain includes an alkylene chain having 2 to 10 alkylene units interrupted and / or terminated by:

[0050] "Carbocyclene" refers to a divalent carbocyclic radical, which is optionally substituted.

[0051] "Heterocyclene" refers to an optionally substituted divalent heterocyclyl radical.

[0052] "Heteroarylene" refers to an optionally substituted divalent heteroaryl group.

[0053] Representative examples of alkylene linkers that may be suitable for use in the present disclosure include the following: [ka] In the formula, n is an integer from 1 to 12 (the "of" being inclusive), for example, 1 to 12, 1 to 11, 1 to 10, 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 -5, 3-4, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-10, 5-9, 5-8, 5-7, 5-6, 6-10, 6-9, 6-8, 6-7, 7-10, 7-9, 7-8, 8-10, 8-9, 9-10 and 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, examples of which include: [ka] Alkylene chains terminated with various functional groups (as described above), examples of which are: [ka] [ka] Alkylene chains interrupted by various functional groups (as described above), examples of which are: [ka] Alkylene chains interrupted or terminated by heterocyclene groups, e.g. [ka] (wherein m and n are independently an integer of 0 to 10), examples of which include compounds of the formula: [ka] Alkylene chains interrupted by amide, heterocyclene and / or aryl groups, such as: [ka] [ka] Heterocyclenes, aryl groups, and alkylene chains interrupted by heteroatoms, examples of which include: [ka] and Alkylene chains interrupted by heteroatoms, such as N, O or B, e.g. [ka] In the formula, each n is independently 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, 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, 3, 4, 5, 6, 7, 8, 9 and 10; R is H or C1 to C4 alkyl, examples of which are [ka] is

[0054] In some embodiments, the linker comprises a C6 carbocyclene, a 6-membered heterocyclene, or a phenyl group. In some embodiments, the 6-membered heterocyclene is [ka] It is.

[0055] 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 It may comprise a polyethylene glycol chain which may terminate (at either or both termini) with at least one of a carbocyclene, a 3- to 12-membered heterocyclene, a 5- to 12-membered heteroarylene, or any combination thereof, where R' is H or a C1-C6 alkyl, and one or both end groups may be the same or different.

[0056] In some embodiments, the linker comprises a polyethylene glycol chain having 2-8 PEG units. [ka] It terminates at one or both ends.

[0057] In some embodiments, the linker comprises 1 to 6 consecutive PEG units.

[0058] Representative examples of linkers containing polyethylene glycol chains include: [ka] Examples include: In the formula, n is an integer from 1 to 10. Examples include [ka] Examples include:

[0059] In some embodiments, the polyethylene glycol linker may be terminated with a functional group, examples of which are as follows: [ka]

[0060] In some embodiments, the linker has the structure: [ka] It is represented by one of the following:

[0061] Degron The ubiquitin-proteasome pathway (UPP) is a key cellular pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These ligases include over 500 different proteins and are divided into multiple classes defined by the structural elements of their E3 functional activity.

[0062] In some embodiments, the degron binds to an E3 ligase that is cereblon. (CRBN).

[0063] Representative examples of such degrons are structures (D1a)-(D1d). [ka] It is represented by one of: In the formula, X1 is CH2 or C(O), and X2 is a bond, CH2, NH, or O.

[0064] Further degrons that bind cereblon that may be suitable for use in the present disclosure are disclosed in U.S. Patent No. 9,770,512, as well as U.S. Patent Application Publication Nos. 2018 / 0015087, 2018 / 0009779, 2016 / 0243247, 2016 / 0235731, 2016 / 0235730, and 2016 / 0176916, and International Patent Publication Nos. WO2017 / 197055, WO2017 / 197051, WO2017 / 197036, WO2017 / 197056, and WO2017 / 197046.

[0065] In some embodiments, the degron binds to von Hippel-Lindau (VHL) E3 ubiquitin ligase.

[0066] Representative examples of such degrons include structures (D1-a)-(D1-f): [ka] wherein Y' is a bond, N, O or C, and R' is H or methyl; [ka] In the formula, Z is a C5-C6 carbocyclic group or a C5-C6 heterocyclic group; [ka] where Y″ is a bond, N, O or C, and R″ is F or CN. or Or a stereoisomer thereof.

[0067] In some embodiments, Z is [ka] It is.

[0068] Still other degrons that bind to VHL and may be suitable for use in the present disclosure are disclosed in U.S. Patent Application Publication No. 2017 / 0121321 A1.

[0069] In some embodiments, the bifunctional compound of the present invention has the structures (1) to (27): [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0070] The bifunctional compound of formula (I) may be in the form of free acid or free base, or pharmaceutically acceptable salt.The pharmaceutically acceptable salt of the compound of the present disclosure can be formed, for example, by reacting a suitable free base of the compound of the present disclosure with a suitable pharmaceutically acceptable acid in a suitable solvent under standard conditions well known in the art.See, for example, Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977).

[0071] As used herein, the term "pharmaceutically acceptable" in the context of salts refers to a salt of a compound that does not abrogate the biological activity or properties of the compound, is relatively non-toxic, i.e., the compound in salt form, and can be administered to a subject without causing undesirable biological effects (such as dizziness or stomach upset) or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The term "pharmaceutically acceptable salt" refers to the product obtained by reacting a compound of the present invention with a suitable acid or base. Examples of pharmaceutically acceptable salts of the 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 pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with 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, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, or p-toluenesulfonate, etc. Certain compounds of the present invention can form pharma- ceutically acceptable salts with various organic bases, such as lysine, arginine, guanidine, diethanolamine, or metformin.

[0072] The bifunctional compounds of formula (I) may have at least one chiral center and therefore may be in the form of stereoisomers, which as used herein includes all isomers of the individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror isomers (enantiomers containing the (R-) or (S-) configuration of the compound), mixtures of mirror isomers of the compounds (physical mixtures of enantiomers, and racemates or racemic mixtures), geometric (cis / trans or E / Z, R / S) isomers of the compounds, and isomers of compounds with two or more chiral centers that are not mirror images of each other (diastereoisomers). The chiral centers of the compounds may undergo epimerization in vivo; therefore, for these compounds, administration of the compound in its (R-) form is considered equivalent to administration of the compound in its (S-) form. Thus, the compounds of the disclosure can be prepared and used in the form of individual isomers, substantially free of other isomers, or in the form of mixtures of various isomers, e.g., racemic mixtures of stereoisomers.

[0073] In some embodiments, the bifunctional compound of formula (I) is an isotopic derivative in that it has at least one desired isotopic substitution of an atom in an amount that is greater than the natural abundance of the isotope, i.e., enriched. In one embodiment, the compound contains deuterium or multiple deuterium atoms. As used herein, the term "compound" encompasses isotopic derivatives. Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances.

[0074] Additionally, the bifunctional compounds of formula (I) encompass N-oxides of the compounds, crystalline forms (also known as polymorphs), active metabolites of the compounds having the same type of activity, tautomers, and unsolvated and solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the conjugates presented herein are also considered to be disclosed herein.

[0075] Synthesis method Another aspect of the present disclosure is directed to a method for making the bifunctional compound of formula (I) or its pharma- ceutically acceptable salt or stereoisomer.Generally, the compound or its pharma- ceutically acceptable salt or stereoisomer can be prepared by any process known to be applicable to the preparation of chemically related compounds.The compounds of the present disclosure will be better understood in conjunction with the synthetic schemes described in various examples, which illustrate the non-limiting methods by which the compounds of the present disclosure can be prepared.

[0076] Pharmaceutical Compositions Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a therapeutically effective amount of a bifunctional compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable carrier. The term "pharma- ceutically acceptable carrier" as known in the art refers to a pharma- ceutically acceptable material, composition or vehicle suitable for administering the compounds of the present disclosure to a mammal. Suitable carriers include, for example, liquids (both aqueous and non-aqueous, and combinations thereof), solids, encapsulating materials, gases, and combinations thereof (e.g., semi-solids), and gases, which function to carry or transport the compound from one organ or part of the body to another organ or part of the body. A carrier is "acceptable" in the sense of being physiologically inert and compatible with the other ingredients of the formulation and not harmful to the subject or patient. Depending on the type of formulation, the composition may include one or more pharma- ceutically acceptable excipients.

[0077] In general, the bifunctional compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers can be formulated into a given type of composition according to conventional pharmaceutical practices such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping and compression processes (see, for example, Remington: The Science and Practice of Pharmacy (20th ed.), ed. AR Gennaro, Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York). The type of formulation depends on the mode of administration, which may include enteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g., subcutaneous (sc), intravenous (iv), intramuscular (im), and intrasternal injection, or infusion techniques, intraocular, intraarterial, intramedullary, intrathecal, intracerebroventricular, transdermal, intradermal, intravaginal, intraperitoneal, mucosal, nasal, intratracheal instillation, bronchial instillation, and inhalation), and topical (e.g., transdermal). In general, the most appropriate route of administration will depend on a variety of factors, including, for example, the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). For example, parenteral (e.g., intravenous) administration may also be advantageous in that the compound may be administered relatively quickly, such as in the case of single-dose treatments and / or acute conditions.

[0078] In some embodiments, the bifunctional compounds are formulated for oral or intravenous administration (eg, systemic intravenous injection).

[0079] Thus, the bifunctional compounds of the present disclosure 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., propellants for aerosol compositions). The compounds can also be formulated for rapid, moderate, or sustained release.

[0080] Oral solid dosage forms include capsules, tablets, pills, powders and granules.In such solid dosage forms, the active compound is mixed with a carrier such as sodium citrate or dicalcium phosphate, and additional carriers or excipients, such as a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) wetting agents such as glycerol, d) crosslinked polymers (e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinked carbo Disintegrating agents such as sodium hydroxymethylcellulose (croscarmellose sodium), sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings. They may further comprise an emulsifier.

[0081] In some embodiments, the bifunctional compound of the present disclosure can be formulated into hard or soft gelatin capsules.Representative excipients that can be used include pregelatinized starch, magnesium stearate, mannitol, sodium stearyl fumarate, anhydrous lactose, microcrystalline cellulose and croscarmellose sodium.Gelatin shells can include gelatin, titanium dioxide, iron oxide and coloring agents.

[0082] Liquid dosage forms for oral administration include solutions, suspensions, emulsions, microemulsions, syrups and elixirs.In addition to the compound, liquid dosage forms may contain aqueous or non-aqueous carriers (depending on the solubility of the compound) commonly used in the art, 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 fatty acid esters of sorbitan, and mixtures thereof.Oral compositions may also contain excipients such as wetting agents, suspending agents, coloring agents, sweeteners, flavoring agents, and aromatic agents.

[0083] Injectable preparations may include sterile aqueous or oily suspensions. They may be formulated according to standard techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any mild fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable preparations may be sterilized, for example, by filtration through a bacteria-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 medium prior to use. The effect of the compound may be prolonged by delaying its absorption, which may be achieved by the use of liquid suspensions with poor water solubility or crystalline or amorphous materials. Prolonged absorption of a compound from a parenterally administered formulation may also be accomplished by suspending the compound in an oil vehicle.

[0084] In certain embodiments, the bifunctional compounds of formula (I) can be administered locally rather than systemically, for example, by injecting the conjugate directly into an organ, often in a depot or sustained release preparation. In certain embodiments, long-acting formulations are administered by infusion (e.g., subcutaneously or intramuscularly) or intramuscular injection. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). The release rate of the compound can be controlled by varying the ratio of compound to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues. Furthermore, in other embodiments, the compound is delivered in a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and taken up selectively by the organ.

[0085] The bifunctional compounds can be formulated for buccal or sublingual administration and examples include tablets, lozenges and gels.

[0086] The bifunctional compound may be formulated for administration by inhalation. Various forms suitable for administration by inhalation include aerosol, mist or powder. The pharmaceutical composition may be delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In some embodiments, the dosage unit of the pressurized aerosol may be determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges, for example, containing gelatin for use in an inhaler or insufflator, may be formulated to contain a powder mixture of the compound and a suitable powder base, for example, lactose or starch.

[0087] The bifunctional compound of formula (I) can be formulated for topical administration, which refers to intradermal administration by applying the formulation to the epidermis as used herein.These types of compositions are typically in the form of ointments, pastes, creams, lotions, gels, solutions and sprays.

[0088] Representative 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 buffer solutions (e.g., hypotonic or buffered saline). For example, 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 non-ionic surfactants, such as polyoxy-40-stearate.

[0089] In some embodiments, topical formulations may also include excipients, examples of which are penetration enhancers. These agents can transport pharmacologically active compounds through the stratum corneum, preferably to the epidermis or dermis with little or no systemic absorption. A wide variety of compounds have been evaluated for their effectiveness in enhancing the penetration rate of drugs through the skin. For example, see Percutaneous Penetration Enhancers, Maibach HI and Smith HE (eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which reviews 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). Representative examples of penetration enhancers include triglycerides (e.g., soybean oil), aloe compositions (e.g., aloe vera gel), ethyl alcohol, isopropyl alcohol, octriphenyl polyethylene glycol, oleic acid, polyethylene glycol 400, propylene glycol, N-decyl methyl sulfoxide, fatty acid esters (e.g., isopropyl myristate, methyl laurate, glycerol monooleate and propylene glycol monooleate), and N-methylpyrrolidone.

[0090] Representative examples of further excipients that may be included in topical and other types of formulations (to the extent that they are compatible) include preservatives, antioxidants, moisturizers, 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 citric acid.Suitable moisturizers include glycerin, sorbitol, polyethylene glycol, urea, and propylene glycol.Suitable buffers include citrate buffer, hydrochloric acid buffer, and lactate buffer.Suitable solubilizers include quaternary ammonium chloride, cyclodextrin, benzyl benzoate, lecithin, and polysorbates. Suitable skin protectants include vitamin E oil, allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

[0091] Transdermal formulations typically use transdermal delivery devices and transdermal delivery patches, where the compound is formulated in a lipophilic emulsion or buffered aqueous solution, dissolved and / or dispersed in a polymer or adhesive. Patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceuticals. Transdermal delivery of compounds can be achieved by iontophoretic patches. Transdermal patches can provide controlled delivery of compounds, where the absorption rate is slowed by using a rate-controlling membrane or by trapping the compound within a polymer matrix or gel. Absorption enhancers can be used to increase absorption, examples of which include pharma- ceutically acceptable absorbent solvents that aid passage through the skin.

[0092] Ophthalmic preparations include eye drops.

[0093] Formulations for rectal administration include enemas, rectal gels, rectal foams, rectal aerosols, and retention enemas, which may contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, etc. Compositions for rectal or vaginal administration can also be formulated as suppositories, which can be prepared by mixing the compound with suitable non-irritating carriers and excipients, such as cocoa butter, mixtures of fatty acid glycerides, polyethylene glycol, suppository waxes, and combinations thereof, all of which are solid at ambient temperature but liquid at body temperature, and therefore will melt in the rectum or vaginal cavity and release the compound.

[0094] Dosage As used herein, the term "therapeutically effective amount" refers to an amount of a bifunctional compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof; or a composition comprising a bifunctional compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof, effective to bring about a desired therapeutic response in a particular patient suffering from a disease or disorder characterized by or mediated by the abnormal activity of SMARCA4 or SMARCA2 and SMARCA4. Thus, the term "therapeutically effective amount" includes an amount of a bifunctional compound of the present disclosure or a pharma- ceutically acceptable salt or stereoisomer thereof, when administered, that is sufficient to induce a positive degeneration of the disease or disorder being treated, or inhibit or even prevent the onset or progression of the disease or disorder, or to alleviate to some extent one or more of the symptoms of the disease or disorder being treated in a subject, or simply kill or inhibit the proliferation of disease (e.g., cancer) cells, or reduce the amount of SMARCA4 or SMARCA2 and SMARCA4 in disease cells.

[0095] The total daily dosage of bifunctional compound and its usage can be determined according to standard medical practice, for example by attending physician using good medical judgment.The specific therapeutically effective dose for any specific subject can depend on various factors, including the disease or disorder to be treated and its severity (e.g., its current condition); the subject's age, weight, general health condition, sex and diet; the administration time, administration route and excretion rate of the specific compound used; duration of treatment; the drug used in combination with or simultaneously with the bifunctional compound; and similar factors known in the medical field (for example, see 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). The bifunctional compounds of formula (I) and their pharma- ceutically acceptable salts and stereoisomers may be effective over a wide dosage range. In some embodiments, the total daily dosage (e.g., for adults) may range from about 0.001 to about 1600 mg, 0.01 to about 1600 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 about 400 mg / day, about 1 to about 50 mg / day, and about 5 to about 40 mg / day, and in other embodiments, about 10 to about 30 mg / day. Individual doses may be formulated to contain the desired dosage depending on the number of times the compound is administered per day. By way of example, capsules may be formulated with about 1 to about 200 mg of the bifunctional compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100, 150, and 200 mg). In some embodiments, individual doses may be formulated to contain a desired dosage depending on the number of times the compound is to be administered per day.

[0096] How to use In some aspects, the disclosure relates to a method of treating a disease or disorder associated with abnormal (e.g., dysfunctional or dysregulated) activity of SMARCA4 or SMARCA2 and SMARCA4, the method involving administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of formula (I) or a pharma- ceutical acceptable salt or stereoisomer thereof.

[0097] The disease or disorder is characterized by or mediated by abnormal activity of SMARCA4 or SMARCA2 and SMARCA4 (e.g., elevated levels of SMARCA4 or SMARCA2 and SMARCA4, or otherwise functionally abnormal SMARCA4 or SMARCA2 and SMARCA4, compared to non-pathological conditions). A "disease" is generally considered to be a state of health of a subject in which the subject is unable to maintain homeostasis and the subject's health will continue to deteriorate unless the disease is ameliorated. In contrast, a "disorder" in a subject is a state of health in which the subject is able to maintain homeostasis, but the subject's health is less favorable than if the disorder does not exist. If left untreated, the disorder does not necessarily cause further deterioration of the animal's health.

[0098] The term "subject" (or "patient") as used herein includes all members of the animal kingdom susceptible to or afflicted with the indicated disease or disorder. In some embodiments, the subject is a mammal, such as a human or a non-human mammal. The method is also applicable to companion animals such as dogs and cats, as well as domestic animals such as cows, horses, sheep, goats, pigs, and other farm animals, and wild animals. A subject "in need" of treatment according to the present disclosure may be "suffering or suspected of suffering from" a particular disease or disorder, may have been positively diagnosed, or otherwise exhibits a sufficient number of risk factors, or a sufficient number or combination of signs or symptoms, such that a medical professional may diagnose or suspect that the subject suffers from the disease or disorder. Thus, subjects suffering from and suspected of suffering from a particular disease or disorder are not necessarily two distinct populations.

[0099] In some embodiments, the bifunctional compounds of formula (I) may be useful in the treatment of cell proliferative diseases and disorders (e.g., cancer or benign neoplasms). As used herein, the term "cell proliferative disease or disorder" refers to conditions characterized by unregulated or abnormal cell proliferation or both, including non-cancerous conditions such as neoplasms, pre-cancerous conditions, benign tumors, and cancers.

[0100] In other embodiments, the method relates to treating a subject with cancer.In general, the bifunctional compounds of the present disclosure can be effective in treating carcinomas (solid tumors, including both primary and metastatic tumors), sarcomas, melanomas, and hematological cancers (cancers that affect the blood, including lymphocytes, bone marrow, and / or lymph nodes), such as leukemia, lymphoma, and multiple myeloma.Included are adult tumors / cancers and pediatric tumors / cancers.Cancers can be vascularized or not yet substantially vascularized or non-vascularized tumors.

[0101] Representative examples of cancer include adrenal cortical carcinoma, AIDS-related cancers (e.g., Kaposi's and AIDS-related lymphomas), appendix cancer, childhood cancers (e.g., childhood cerebellar astrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, brain cancer (e.g., gliomas and glioblastomas, e.g., brain stem glioma, gestational trophoblastic tumor glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant tumor glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway 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 bone marrow cancer, Myeloproliferative disorders, colorectal cancer (e.g., colon cancer, rectal cancer), lymphoid neoplasms, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastrointestinal cancer (e.g., gastric cancer, small intestine cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST)), bile duct cancer, germ cell tumors, ovarian germ cell tumors, head and neck cancer, neuroendocrine tumors, Hodgkin's lymphoma, AnnArbor Class III and Class IV pediatric non-Hodgkin's lymphoma, ROS1-positive refractory non-Hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma, hypopharyngeal carcinoma, intraocular melanoma, eye cancer, pancreatic islet cell tumors (endocrine pancreas), kidney cancer (e.g., Wilms' tumor, renal cell carcinoma), liver cancer, lung cancer (e.g., non-small cell lung cancer and large cell lung cancer), ALK-positive anaplastic large cell lymphoma, ALK-positive advanced malignant solid neoplasms, Waldenström's macroglobulinemia, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma of the neck of unknown primary site, multiple endocrine neoplasia (MEN), myelodysplastic syndromes, myelodysplastic / myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer (e.g., oral cancer, lip cancer, oral cancer) , tongue cancer, oropharyngeal cancer, throat cancer, pharyngeal cancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor), pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, metastatic anaplastic thyroid cancer, anaplastic thyroid cancer, papillary thyroid cancer, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleural embryonal tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, uterine cancer (e.g., endometrial cancer, uterine sarcoma, endometrial cancer), squamous cell carcinoma, testicular cancer, thymoma, thymic carcinoma, thyroid cancer, juvenile xanthogranuloma, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, urethral cancer, gestational trophoblastic tumor, vaginal cancer, vulvar cancer, hepatoblastoma, rod body tumor, and Wilms' tumor.

[0102] Sarcomas that may be treatable with the bifunctional compounds of the present disclosure include both soft tissue and bone cancers as well, representative examples of which include osteosarcoma or osteogenic sarcoma (bone) (e.g., Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelioma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (fatty tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), mesenchymal or mixed mesodermal tumor (mixed connective tissue types), and histiocytic sarcoma (immune cancer).

[0103] In some embodiments, the methods of the disclosure involve treatment of a subject having a cell proliferative disease or disorder of the blood system, liver, brain, lung, colon, pancreas, prostate, ovaries, breast, skin, and endometrium.

[0104] As used herein, "cell proliferative diseases or disorders of the blood system" includes lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid papulosis, polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Thus, representative examples of hematological cancers include multiple myeloma, lymphomas (T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplastic large cell lymphoma (e.g., B-cell non-Hodgkin's lymphoma selected from 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's lymphoma / leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, ALK+ anaplastic large cell lymphoma (ALK+ anaplastic large cell lymphoma), ... and relapsed B-cell non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin, e.g., small lymphocytic lymphoma, childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, and leukemias, myeloid neoplasms and mast cell neoplasms, including leukemia, marginal zone lymphoma, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, metastatic pancreatic adenocarcinoma, refractory B-cell non-Hodgkin's lymphoma, and relapsed B-cell non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin, e.g., small lymphocytic lymphoma, childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia (e.g., acute monocytic leukemia), chronic lymphocytic leukemia, small lymphocytic leukemia, chronic myeloid leukemia, and mast cell leukemia.

[0105] As used herein, "hepatic cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the liver.Hepatic cell proliferation disorder can include liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma and hepatoblastoma), precancerous or precancerous conditions of the liver, benign growth or lesion of the liver, and malignant growth or lesion of the liver, as well as metastatic lesions in tissues and organs in the body other than the liver.Hepatic cell proliferation disorder can include liver hyperplasia, metaplasia, and dysplasia.

[0106] As used herein, "brain cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the brain.Brain cell proliferation disorder can include brain cancer (e.g., glioma, glioblastoma, meningioma, pituitary adenoma, vestibular schwannoma, and primitive neuroectodermal tumor (medulloblastoma)), brain precancerous or precancerous condition, brain benign growth or lesion, and brain malignant growth or lesion, as well as metastatic lesion in body tissues and organs other than the brain.Brain cell proliferation disorder can include brain hyperplasia, metaplasia, and dysplasia.

[0107] As used herein, "cell proliferative disease or disorder of the lung" includes all forms of cell proliferative disorders that affect germ cells. Cell proliferative disorders of the lung include lung cancer, precancerous and precancerous conditions of the lung, benign growths or lesions of the lung, hyperplasia, metaplasia, and dysplasia of the lung, and metastatic lesions in tissues and organs of the body other than the lung. 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"), adenocarcinoma, small cell carcinoma, large cell carcinoma, squamous cell carcinoma, and mesothelioma. Lung cancer can include "scar carcinoma", bronchioveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer also includes lung neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell types).In some embodiments, the compounds of the present disclosure can be used to treat non-metastatic or metastatic lung cancer (e.g., NSCLC, ALK-positive NSCLC, NSCLC with ROS1 fusion gene, lung adenocarcinoma, and squamous cell lung cancer).

[0108] As used herein, "cell proliferative diseases or disorders of the colon" include all forms of cell proliferative disorders affecting colon 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 colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma, and squamous cell carcinoma. Colon cancer may be associated with genetic syndromes, such as hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, MYH-associated polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis. Cell proliferative disorders of the colon may also be characterized by colonic hyperplasia, metaplasia, or dysplasia.

[0109] As used herein, "cell proliferation disease or disorder of pancreas" includes all forms of cell proliferation disorder that affect pancreatic cells.Cell proliferation disorder of pancreas can include pancreatic cancer, precancerous or precancerous conditions of pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign growth or lesion of pancreas, and malignant growth or lesion of pancreas, as well as metastatic lesions in tissues and organs of the body other than pancreas.Pancreatic cancer includes all forms of cancer of pancreas, including ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatic blastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma, as well as pancreatic neoplasms with histological and ultrastructural heterogeneity (e.g., mixed cell).

[0110] As used herein, "prostate cell proliferation disease or disorder" includes all forms of cell proliferation disorder that affect the prostate.Prostate cell proliferation disorder can include prostate cancer, prostate precancerous or precancerous conditions, prostate benign growth or lesion, prostate malignant growth or lesion, and metastatic lesion in body tissues and organs other than the prostate.Prostate cell proliferation disorder can include prostate hyperplasia, metaplasia, and dysplasia.

[0111] As used herein, "cell proliferative disease or disorder of the ovary" includes all forms of cell proliferative disorders that affect cells of the ovary. Cell proliferative disorders of the ovary may include precancerous or precancerous conditions of the ovary, benign growths or lesions of the ovary, ovarian cancer, and metastatic lesions in tissues and organs of the body other than the ovary. Cell proliferative disorders of the ovary may include ovarian hyperplasia, metaplasia, and dysplasia.

[0112] As used herein, "cell proliferative disease or disorder of the breast" includes all forms of cell proliferative disorders affecting breast cells. Cell proliferative disorders of the breast can include breast cancer, precancerous or precancerous conditions of the breast, benign growths or lesions of the breast, and metastatic lesions in body tissues and organs other than the breast. Cell proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0113] As used herein, "cell proliferative diseases or disorders of the skin" include all forms of cell proliferative disorders affecting skin cells. Cell proliferative disorders of the skin may include precancerous or precancerous conditions of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma or other malignant growths or lesions of the skin, and metastatic lesions in tissues and organs of the body other than the skin. Cell proliferative disorders of the skin may include hyperplasia, metaplasia, and dysplasia of the skin.

[0114] As used herein, "endometrial cell proliferative disease or disorder" includes all forms of cell proliferative disorder that affect endometrial cells.Endometrial cell proliferative disorder can include endometrial precancerous or precancerous conditions, endometrial benign growths or lesions, endometrial cancer, and metastatic lesions in body tissues and organs other than endometrium.Endometrial cell proliferative disorder can include endometrial hyperplasia, metaplasia, and dysplasia.

[0115] In some embodiments, the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, renal cancer, leukemia, non-small cell lung cancer, Burkitt's lymphoma, childhood medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial carcinoma, and melanoma.

[0116] In some aspects, the present disclosure is directed to a method of treating diffuse midline gliomas with H3K27M mutations, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof. In another aspect, the present disclosure is directed to a method of treating diffuse midline gliomas with H3K27M mutations, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of any of formulas I', I" and II".

[0117] In some embodiments, the method of treating diffuse midline glioma harboring an H3K27M mutation comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I' [ka] or a pharma- ceutically acceptable salt thereof: In the formula, A is [ka] [ka] and E is [ka] and X 1 and X 2 are each independently O, NR 3 and S; or X 1 Or X 2 combines with L to form a heterocyclyl or heteroaryl; or X 1 and X 2 both of which combine with L to form a heterocyclyl or heteroaryl; X 3 , O, NR 3 , or S; L comprises an alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene chain containing 1 to 35 carbon atoms, e.g., 1 to 35 -CH2- moieties, or a combination thereof; optionally, when L comprises an alkylene containing 1 to 35 -CH2- moieties, at least one but not more than 10 -CH2- moieties of L are independently selected from -C(=O)-, -C(=O)-NR 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 4 -C(=O)-NR 3 -, -OC(=O)-NR 4 -, -NR 4 -C(=O)-O-, -O-, -S-, and -NR 4 -, provided that the number of -CH2- moieties in L is equal to or greater than the number of -C(=O)-, -C(=O)-NR 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 4 -C(=O)-NR3-, OC(=O)-NR 4 -, -NR 4 -C(=O)-O-, -O-, -S-, and -NR 3 more than the total number of - moieties, except that L is -C(=O)-, -C(=O)-NR 4 -, -NR 4 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 4 -C(=O)-NR 3 -, -OC(=O)-NR 4 -, -NR 4 -C(=O)-O-, -O-, -S-, and -NR 4 provided that there is at least one -CH2- between each - moiety; R 1 and R 2are each independently selected from H, alkyl, halo, hydroxyl, hydroxyalkyl, carboxyl, acyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, heteroaralkyl, sulfonamido, aryl, heteroaryl, heterocyclyl, and aralkyl; R 3 and R 4 are each independently selected from H and alkyl; n is an integer of 1 to 5, preferably 1.

[0118] In some embodiments, the bifunctional compound of formula I' is selected from: [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0119] Compounds of formula I' are described in PCT / US2021 / 017626, the contents of which are incorporated herein by reference.

[0120] In some embodiments, the method of treating diffuse midline glioma harboring an H3K27M mutation comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I" or II" [ka] Bifunctional compounds of; or a pharma- ceutically acceptable salt thereof, X is a bond, aryl, or heteroaryl; L is an alkylene, alkenylene, or alkynylene chain containing 1 to 35 carbon atoms, e.g., 1 to 35 -CH2- moieties. Optionally: At least one but not more than ten -CH- moieties in L are independently -C(=O)-, -C(=O)-NR 3 -, -NR 3 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 3 -C(=O)-NR 3 -, -OC(=O)-NR 3 -, -NR 3 -C(=O)-O-, -O-, -S-, and -NR 3 moieties, provided that the number of -CH2- moieties in L is equal to or greater than the number of -C(=O)-, -C(=O)-NR 3 -, -NR 3 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 3 -C(=O)-NR 3 -, -OC(=O)-NR 3 -, -NR 3 -C(=O)-O-, -O-, -S-, and -NR 3 - More than the total number of parts However, L is -C(=O)-, -C(=O)-NR 3 -, -NR 3 -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR 3 -C(=O)-NR 3 -, -OC(=O)-NR 3 -, -NR 3 -C(=O)-O-, -O-, -S-, and -NR 3 at least one -CH2- is present between each of the - moieties; ZL is -CH2-L, -O-CH2-L, or -NR 3 -CH2-L; R 1 , R 2 , and R 3 are each independently selected from H and alkyl.

[0121] Thus, in some embodiments, the bifunctional compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0122] Compounds of formula I'' and II'' are described in International Patent Application No. PCT / US2020 / 039638, the contents of which are incorporated herein by reference in their entirety.

[0123] Compounds of Formula I', I'', and II'' can be formulated and administered consistent with the teachings herein in conjunction with compounds of Formula I for the purpose of treating diffuse midline gliomas harboring H3K27M mutations.

[0124] In some embodiments, the diffuse midline glioma with an H3K27M mutation is a diffuse intrinsic pontine glioma (DIPG).

[0125] The bifunctional compounds may be administered to patients, such as cancer patients, as monotherapy or in combination therapy. The therapy may be "front / first line" as an initial treatment for patients who have not previously received an anti-cancer treatment regimen, either alone or in combination with other treatments; or "second line" as a treatment for patients who have previously received an anti-cancer treatment regimen, either alone or in combination with other treatments; or "third line", "fourth line", etc., treatment, either alone or in combination with other treatments. The therapy may also be administered to patients who have previously received unsuccessful or partially successful treatments, except for patients who have become intolerant to a particular treatment. The therapy may also be administered as an adjuvant treatment, i.e., to prevent recurrence of cancer in patients who currently have no detectable disease or after surgical removal of a tumor. Thus, in some embodiments, the bifunctional compounds may be administered to patients who have received another therapy, such as chemotherapy, radioimmunotherapy, surgical therapy, immunotherapy, radiation therapy, targeted therapy, or any combination thereof. The disclosed methods can involve administration of a bifunctional compound or 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 dosing frequency can range from once a day to approximately once every 8 weeks. In some embodiments, the dosing frequency varies from about once a day for 1, 2, 3, 4, 5, or 6 weeks, and in other embodiments involves a 28-day cycle that includes daily dosing for 3 weeks (21 days) followed by a 7-day "off" period. In other embodiments, the bifunctional compound can be administered twice a day (BID) over a period of 2 1 / 2 days (a total of 5 doses), or once a day (QD) over a period of 2 days (a total of 2 doses). In other embodiments, the bifunctional compound can be administered once a day (QD) over a period of 5 days.

[0126] Combination therapy The bifunctional compounds and their pharma- ceutically acceptable salts and stereoisomers can be used in combination or simultaneously with at least one other active agent, e.g., an anti-cancer agent or regimen, in the treatment of diseases and disorders. In this context, the terms "in combination" and "concurrently" mean that the agents are administered simultaneously, including substantially simultaneous administration, by the same or separate dosage forms, by the same or separate modes of administration, or sequentially, e.g., as part of the same treatment regimen, or by consecutive treatment regimens. Thus, when given sequentially, at the start of administration of the second compound, the first of the two compounds is still detectable at effective concentrations at the treatment site, as the case may be. The order and time intervals can be determined so that they can act together (e.g., synergistically) to provide a greater benefit than if they were administered otherwise. For example, the therapeutic agents can be administered simultaneously or at different times, sequentially, in any order; however, if not administered simultaneously, they can be administered close enough in time to provide the desired therapeutic effect, which may be in a synergistic form. Thus, these terms are not limited to administering the active agents exactly at the same time.

[0127] In some embodiments, the treatment regimen may include administration of the bifunctional compound in combination with one or more additional therapeutic agents or pharmaceutical agents known for use in treating a disease or condition (e.g., cancer). The dosage of the additional anti-cancer therapeutic agent may be the same as or lower than the known or recommended dose. See Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis Of Therapeutics, 10th ed., McGraw-Hill, New York, 2001; Physician's Desk Reference 60th ed., 2006. For example, anti-cancer agents that may be suitable for use in combination with the bifunctional compound are known in the art. See, for example, U.S. Pat. No. 9,101,622 (section 5.2 thereof) and U.S. Pat. No. 9,345,705 B2 (columns 12-18 thereof). Representative examples of additional active agents and treatment regimens include radiation therapy, chemotherapeutic agents (e.g., antimitotic agents, angiogenesis inhibitors, antihormonal agents, autophagy inhibitors, alkylating agents, intercalating antibiotics, growth factor inhibitors, antiandrogens, signal transduction pathway inhibitors, microtubule inhibitors, platinum coordination complexes, HDAC inhibitors, proteasome inhibitors, and topoisomerase inhibitors), immunomodulatory agents, therapeutic antibodies (e.g., monospecific and bifunctional antibodies), and CAR-T therapy.

[0128] In some embodiments, the bifunctional compound and the additional (e.g., anti-cancer) therapeutic agent may be administered less than 5 minutes apart, less than 30 minutes apart, less than 1 hour apart, about 1 hour apart, about 1 to about 2 hours apart, about 2 to about 3 hours apart, about 3 to about 4 hours apart, about 4 to about 5 hours apart, about 5 to about 6 hours apart, about 6 to about 7 hours apart, about 7 to about 8 hours apart, about 8 to about 9 hours apart, about 9 to about 10 hours apart, about 10 to about 11 hours apart, about 11 to about 12 hours apart, about 12 to 18 hours apart, 18 to 24 hours apart, 24 to 36 hours apart, 36 to 48 hours apart, 48 to 52 hours apart, 52 to 60 hours apart, 60 to 72 hours apart, 72 to 84 hours apart, 84 to 96 hours apart, or 96 to 120 hours apart. Two or more (eg, anti-cancer) therapeutic agents may be administered during a single patient visit.

[0129] In some embodiments involving cancer therapy, the bifunctional compound and the additional anti-cancer or therapeutic agent are administered in a cyclical manner. Cyclic therapy includes administering one anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one or both of the anti-cancer therapeutic agents, to avoid or reduce the side effects of one or both of the anti-cancer therapeutic agents, and / or to improve the efficacy of the therapy. In one example, cyclic therapy includes administering a first anti-cancer therapeutic agent for a period of time, followed by administering a second anti-cancer therapeutic agent for a period of time, optionally followed by administering a third anti-cancer therapeutic agent for a period of time, etc., and repeating this sequential administration, i.e., cycle, to reduce the occurrence of resistance to one anti-cancer therapeutic agent, to avoid or reduce the side effects of one anti-cancer therapeutic agent, and / or to improve the efficacy of the anti-cancer therapeutic agent.

[0130] In some embodiments, the additional therapeutic agent or pharmaceutical agent is a B-lymphoma Mo-MLV insertion region 1 homolog (BMI1) inhibitor. In some embodiments, the BMI1 inhibitor is PTC028, PTC209, PTC596, or QW24.

[0131] Medicine Kit The bifunctional compounds of the present invention and / or compositions comprising them can be assembled into kits or pharmaceutical systems.The kits or pharmaceutical systems according to this aspect of the present disclosure can include a carrier or package such as a box, carton, tube, etc., in which one or more containers, such as vials, tubes, ampoules, or bottles, that contain the bifunctional compounds of the present disclosure or pharmaceutical compositions thereof are tightly enclosed.The kits or pharmaceutical systems of the present disclosure can also include printed instructions for using the compounds and compositions.

[0132] These and other aspects of the present disclosure will be further understood in light of the following examples, which are intended to illustrate particular embodiments of the disclosure, but are not intended to limit its scope, which is defined by the claims. EXAMPLES

[0133] These and other aspects of the present disclosure will be further understood in light of the following examples, which are intended to illustrate particular embodiments of the disclosure, but are not intended to limit its scope, which is defined by the claims.

[0134] Synthesis of intermediates int-1 to int-3. [ka] Phenyl(3-chlorophenyl)carbamate

[0135] To a solution of 2-chloropyridin-4-amine (1 g, 7.78 mmol) and pyridine (0.63 mL, 7.78 mmol) in DCM (40 mL) was added phenyl chloroformate (1.03 mL, 8.17 mmol) dropwise. The reaction was stirred at room temperature for 16 hours (h). The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate and water. The mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc / hexanes) to give phenyl (3-chlorophenyl)carbamate as a white solid (4.26 g, quant.).

[0136] MS(ESI)m / z249.2[M+H] + . [ka] 4-(3-(2-chloropyridin-4-yl)ureido)picolinic acid methyl ester

[0137] To a solution of phenyl (3-chlorophenyl)carbamate (350 mg, 1.41 mmol) and methyl 4-aminopicolinate (195 mg, 1.28 mmol) in THF was added N,N-diisopropylethylamine (DIPEA) (0.446 mL, 2.56 mmol) and the resulting mixture was microwaved for 45 min at 110° C. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (DCM / MeOH) to give methyl 4-(3-(2-chloropyridin-4-yl)ureido)picolinate as a yellow solid (157 mg, 33% yield).

[0138] MS(ESI)m / z307.06[M+H] + . [ka] 4-(3-(2-chloropyridin-4-yl)ureido)picolinic acid (int-1)

[0139] To a solution of methyl 4-(3-(2-chloropyridin-4-yl)ureido)picolinate (130 mg, 0.43 mmol) in MeOH was added 2 M LiOH (0.43 mL, 0.86 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give int-1 as a yellow solid (125 mg, 100% yield).

[0140] MS(ESI)m / z293.04[M+H] + . [ka] 3-((4-(3-(2-chloropyridin-4-yl)ureido)pyridin-2-yl)ethynyl)benzoic acid (int-2)

[0141] Compound int-2 was synthesized according to the procedure of Papillon et al., J. Med. Chem. 61(22):10155-10172(2018). [ka]

[0142] To a solution of (4-amino-6-chloropyridin-3-yl)methanol (1 g, 6.31 mmol) in DMF was added tert-butyldimethylsilyl chloride (1.05 g, 6.94 mmol) and imidazole (1.07 g, 15.8 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo and the resulting residue was extracted with ethyl acetate and water. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (Hex / EtOAc) to give 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-amine as a white solid (1.63 g, 95% yield).

[0143] MS(ESI)m / z273.3[M+H] + . [ka] Phenyl(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-yl)carbamate

[0144] To a solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-amine (1 g, 7.78 mmol) and pyridine (0.63 mL, 7.78 mmol) in DCM (40 mL) was added phenyl chloroformate (1.03 mL, 8.17 mmol) dropwise. The reaction was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and then diluted with ethyl acetate and water. The mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc / hexanes) to give 2,(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-yl)carbamate as a white solid (4.26 g, quantitative).

[0145] MS(ESI)m / z393.2[M+H] + . [ka] Methyl 3-((4-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-yl)ureido)pyridin-2-yl)ethynyl)benzoate

[0146] To a solution of (5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-yl)carbamate (173 mg, 0.44 mmol) and DIPEA (0.14 mL, 0.8 mmol) in THF (3 mL) was added methyl 3-((4-aminopyridin-2-yl)ethynyl)benzoate (100 mg, 0.40 mmol). The reaction mixture was microwaved at 110° C. for 50 min and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc / hexanes) to give methyl 3-((4-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-yl)ureido)pyridin-2-yl)ethynyl)benzoate as a white solid (26 mg, 12% yield). [ka] 3-((4-(3-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)ureido)pyridin-2-yl)ethynyl)benzoic acid (int-3)

[0147] To a solution of methyl 3-((4-(3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridin-4-yl)ureido)pyridin-2-yl)ethynyl)benzoate (26 mg, 0.05 mmol) in methanol (0.15 mL) was added 2 M lithium hydroxide in water (0.05 mL, 0.1 mmol). The reaction was stirred at room temperature for 16 h. The crude reaction mixture was concentrated in vacuo to afford int-3 as a white solid (21 mg, quantitative).

[0148] Example 2: Synthesis of 1-(2-chloropyridin-4-yl)-3-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazine-1-carbonyl)pyridin-4-yl)urea (YL-dS2-23,1).

[0149] General Procedure To a solution of int-1, int-2, or int-3 (1 equiv.) in dimethylformamide (DMF) (0.2 M), triethylamine (TEA) (3 equiv.) and HATU (2 equiv.) were added, and the mixture was stirred at room temperature for 15 min, followed by the addition of IMiD amine (1 equiv.). The resulting reaction mixture was stirred at room temperature for 16 h. The crude mixture was concentrated in vacuo and purified by silica gel chromatography (DCM / MeOH) followed by high performance liquid chromatography (HPLC) to afford the products (5–20% yields). [ka]

[0150] Compound 1 was synthesized according to the general procedure above using int-1 (10 mg, 0.034 mmol) and 1M-C2-piperidin-1-amine (13.2 mg, 0.034 mmol) and isolated as a yellow powder (2.4 mg, 11% yield).

[0151] MS(ESI)m / z660.47[M+H] + .

[0152] Example 3: Synthesis of 4-(3-(2-chloropyridin-4-yl)ureido)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)picolinamide (YL-dS2-24,2). [ka]

[0153] Compound 2 was synthesized in a similar manner to compound 1 in Example 2 from int-1 (10 mg, 0.034 mmol) and IM-C8-1-amine (13.6 mg, 0.034 mmol) and isolated as a yellow powder (3.2 mg, 14% yield).

[0154] MS(ESI)m / z675.44[M+H] + .

[0155] Example 4: Synthesis of 4-(3-(2-chloropyridin-4-yl)ureido)-N-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)picolinamide (YL-dS2-25,3). [ka]

[0156] Compound 3 was synthesized from int-1 (10 mg, 0.034 mmol) and IM-C10-1-amine (14.6 mg, 0.034 mmol) in a manner similar to compound 1 in Example 2 and was isolated as a yellow powder (2.1 mg, 9% yield).

[0157] MS(ESI)m / z703.44[M+H] + .

[0158] Example 5: Synthesis of 1-(2-chloropyridin-4-yl)-3-(2-((3-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)piperazine-1-carbonyl)phenyl)ethynyl)pyridin-4-yl)urea (YL-dS2-27, 4). [ka]

[0159] Compound 4 was synthesized in a similar manner to compound 1 in Example 2 from int-2 (10 mg, 0.025 mmol) and IM-C2-piperidin-1-amine (12.4 mg, 0.025 mmol) and isolated as a yellow powder (1.8 mg, 10% yield).

[0160] MS(ESI)m / z760.48[M+H] + .

[0161] Example 6: Synthesis of 3-(2-(4-(3-(2-chloropyridin-4-yl)ureido)pyridin-2-yl)ethyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)benzamide (YL-dS2-28,5). [ka]

[0162] To a stirred solution of compound 19 (Example 15) (100 mg, 0.139 mmol) in DCM / MeOH (10 mL, 1:1), Pd / C (20 mg, 5 mol%) was added and the resulting mixture was stirred under H2 atmosphere for 7 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give a crude residue, which was purified by Prep-HPLC to give compound 5 as a yellow solid (45.12 mg, 44.9% yield).

[0163] MS(ESI)m / z722.24[M+H] + .

[0164] Example 7: Synthesis of 4-((4-(3-(2-chloropyridin-4-yl)ureido)pyridin-2-yl)ethynyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)benzamide (YL-dS2-29,6). [ka]

[0165] Compound 6 was synthesized in a similar manner to compound 1 in Example 2 from the para isomer of int-2 (16 mg, 0.041 mmol) and IM-C4-1-amine (14.1 mg, 0.041 mmol) and isolated as a yellow powder (6 mg, 21% yield).

[0166] MS(ESI)m / z719.16[M+H] + .

[0167] Example 8: Synthesis of 4-(3-(2-chloropyridin-4-yl)ureido)-N-(12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)picolinamide (YL-dS2-30,7). [ka]

[0168] Compound 7 was synthesized in a similar manner to compound 1 in Example 2 from int-1 (10 mg, 0.034 mmol) and IM-C12-1-amine (15.5 mg, 0.034 mmol) and isolated as a yellow powder (2 mg, 8% yield).

[0169] MS(ESI)m / z730.3[M+H] + .

[0170] Example 9: Synthesis of 3-((4-(3-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)ureido)pyridin-2-yl)ethynyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)benzamide (YL-dS2-31,8). [ka]

[0171] Compound 8 was synthesized from int-3 (10 mg, 0.019 mmol) and IM-C4-1-amine (6.54 mg, 0.019 mmol) in a similar manner to compound 1 in Example 2 and was isolated as a yellow powder (2 mg, 8% yield).

[0172] MS(ESI)m / z730.3[M+H] + .

[0173] Example 10: Synthesis of 1-(2-chloropyridin-4-yl)-3-(2-((3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carbonyl)phenyl)ethynyl)pyridin-4-yl)urea (YL-dS2-32,9). [ka]

[0174] Compound 9 was synthesized in a similar manner to compound 1 in Example 2 from int-2 (100 mg, 0.25 mmol) and 1M-piperidin-1-amine (85.6 mg, 0.25 mmol) and isolated as a yellow powder (68.4 mg, 38% yield).

[0175] MS(ESI)m / z717.19[M+H] + .

[0176] Example 11: Synthesis of 4-(3-(2-chloropyridin-4-yl)ureido)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)picolinamide (YL-dS2-33,10). [ka]

[0177] Compound 10 was synthesized from int-1 (10 mg, 0.034 mmol) and IM-C4-1-amine (11.8 mg, 0.034 mmol) in a manner similar to compound 1 in Example 2 and was isolated as a yellow powder (1.6 mg, 8% yield).

[0178] MS(ESI)m / z620.17[M+H] + .

[0179] Example 12: Synthesis of 1-(2-chloropyridin-4-yl)-3-(2-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazine-1-carbonyl)phenethyl)pyridin-4-yl)urea (YL-dS2-34,11). [ka]

[0180] To a stirred solution of compound 9 (10 mg, 0.014 mmol) in DCM / MeOH (10 mL, 1:1) was added Pd / C (1.5 mg, 10 mol%) and the resulting mixture was stirred under H2 atmosphere for 8 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give a crude residue which was purified by HPLC to give compound 11 as a yellow solid (1.8 mg, 18% yield).

[0181] MS(ESI)m / z722.24[M+H] + .

[0182] Example 13: Synthesis of 3-(2-(4-(3-(2-chloro-5-(hydroxymethyl)pyridin-4-yl)ureido)pyridin-2-yl)ethyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)benzamide (YL-dS2-35,12). [ka]

[0183] To a stirred solution of compound 8 (10 mg, 0.013 mmol) in DCM / MeOH (10 mL, 1:1) was added Pd / C (1.5 mg, 10 mol%) and the resulting mixture was stirred under H2 atmosphere for 8 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give a crude residue which was purified by HPLC to give compound 12 as a yellow solid (2 mg, 19% yield).

[0184] MS(ESI)m / z753.25[M+H] + .

[0185] Example 14: Synthesis of 4-(3-(2-chloropyridin-4-yl)ureido)-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)benzyl)picolinamide (YL-dS2-36,13). [ka]

[0186] Compound 14 was synthesized in a similar manner to compound 1 in Example 2 from int-1 (10 mg, 0.034 mmol) and 1M-benzyl-C1-amine (13.4 mg, 0.034 mmol) and isolated as a yellow powder (1.3 mg, 6% yield).

[0187] MS(ESI)m / z667.18[M+H] + .

[0188] Example 15: Synthesis of 3-((4-(3-(2-chloropyridin-4-yl)ureido)pyridin-2-yl)ethynyl)-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)benzamide (DL-dS2-4, 19). [ka]

[0189] Compound 19 was synthesized from int-2 (10 mg, 0.034 mmol) and IM-C4-1-amine (11.8 mg, 0.034 mmol) in a manner similar to compound 1 in Example 2, and was isolated as a yellow powder.

[0190] Example 16: Cellular degradation of SMARCA4 in NOMO-1 cells using bifunctional compounds 1-6.

[0191] For each test condition, one million cells were seeded into wells of a 6-well plate. After overnight incubation at 37°C in 5% CO2, the cells were treated with either DMSO or various doses of the indicated bifunctional compounds and returned to the incubator for the indicated treatment times. Treated cells were collected by transferring the cell suspension from the 6-well plate wells to a microcentrifuge tube and spinning down the samples at 3000 rpm for 3 minutes. The supernatant was discarded and all samples were washed with phosphate-buffered saline (PBS) to remove any residual compound from the cells. Cells were lysed using radioimmunoprecipitation assay (RIPA) buffer, sonicated on ice for 3 seconds at 25% amplification, and allowed to stand for 15-30 minutes. The lysates were then spun down at 15000 rpm for 10 minutes and the supernatant was collected. Protein concentration was measured using the Pierce™ Bicinchoninic Acid (BCA) Protein Assay Kit from ThermoFisher Scientific according to the manufacturer's instructions. Equal amounts of protein were separated by Western blotting using 4-12% Bis-Tris NuPAGE™ gels (Thermo-Fisher Scientific) before transfer and immunoblotting overnight using primary antibodies against the indicated proteins. Secondary antibodies were horseradish peroxidase (HRP)-conjugated anti-rabbit or anti-mouse (Santa Cruz Biotechnology®) and incubated for 1 h at room temperature before exposure to enhanced chemiluminescence reagent (GE Amersham).

[0192] The results are shown in Figures 1A-1B, which show that BRG (SMARCA4) was significantly degraded after low micromolar treatment of bifunctional compounds 5 and 6 for 24 hours in NOMO1 cells.

[0193] Example 17: Cell proliferation assay in MV411 (human myelomonocytic leukemia) and MOLM13 (acute monocytic leukemia) cells with bifunctional compounds 16-15.

[0194] 2000 cells were seeded in 50 μL of RPMI medium in each well of a white solid-bottom 384-well plate. The plate was spun down briefly and the seeded cells were pinned with 100 nM of bifunctional compounds at serial 3-fold diluted concentrations using a JANUS® Liquid Handling Workstation. The plate was incubated at 37° C. in 5% CO2 for the indicated treatment times (48 hours). After compound treatment, 15 μL of a 1:2 solution of ATPlite™, serially diluted in PBS, was added to each well of the 384-well plate. The plate was placed on a plate shaker for 1 minute, incubated at room temperature for 9 minutes, and the resulting luminescence signal was read using an EnVision® plate reader. Cell viability was calculated by normalizing the luminescence signal of SMARC compound-treated cells to that of vehicle-treated cells.

[0195] The results are shown in Table 1 below. Table 1. IC in MV411 and MOLM13 cells 50 value. [Table 1]

[0196] The results in Table 1 show the IC of cell viability in MV411 and MOLM13 cells after treatment with bifunctional compounds of various linkers and linker positions at 48 h. 50 values ​​were shown, with bifunctional compound 19 exhibiting submicromolar activity for both cell lines.

[0197] All patent and non-patent publications are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All these publications, including any specific portions thereof referred to, are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0198] Although the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is thus to be understood that numerous modifications can be made to the illustrative embodiments and other arrangements can be devised without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt or stereoisomer thereof, wherein 【Chemistry 2】 represents a targeting moiety that binds to SWI / SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) or SMARCA2 and SMARCA4; degron represents a moiety that binds to an E3 ubiquitin ligase; and L represents a linker that covalently attaches the targeting moiety to the degron, where: R １ and R ４ are each independently H or halogen; R ２ is H or NH ２ and R ３ , H, NH ２ , NO ２ , OH, CN, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) aminoalkyl, (C ３ ~C ６ ) carbocyclyl, 4- to 6-membered heterocyclyl, (C １ ~C ６ ) alkyl-(C ３ ~C ６ ) carbocyclyl, or (C １ ~C ６ ) alkyl-4 to 6-membered heterocyclyl, wherein the alkyl, hydroxyalkyl, aminoalkyl, carbocyclyl, or heterocyclyl is selected from one or more of the same or different R １ａ groups, where each R １ａ are independently １ ~C ６ ) alkyl, (C １ ~C ６ ) alkoxy, (C １ ~C ６ ) alkyl-(C １ ~C ３ ) alkoxy, halogen, amino, hydroxyl, (C １ ~C ６ ) haloalkyl, NH-(C １ ~C ６ ) alkyl, N((C １ ~C ６ ) alkyl) ２ , (C ３ ~C ６ ) carbocyclyl, or 4- to 6-membered heterocyclyl; X is C(O), C(O)NH, 【Chemistry 3】 and the wavy line ( 【Chemistry 4】 ) is the point of attachment to the pyridine ring, and the wavy line-asterisk ( 【Chemistry 5】 ) is the point of attachment to the linker.

2. R ３ H, NH ２ , or C.H. ２ 2. The bifunctional compound of claim 1, wherein said difunctional compound is OH.

3. R １ is a halogen, R ２ , R ３ , R ４ The bifunctional compound of claim 1 , wherein

4. R １ is a halogen, R ２ and R ４ is H, and R ３ CH ２ 2. The bifunctional compound of claim 1, wherein said difunctional compound is OH.

5. R １ 5. The bifunctional compound according to claim 3, wherein is Cl or F.

6. R １ and R ３ is H, and R ２ NH ２ and R ４ The bifunctional compound of claim 1 , wherein is a halogen.

7. R ４ The bifunctional compound according to claim 6, wherein is Cl.

8. X is C(O), C(O)NH, 【Chemistry 6】 2. The bifunctional compound according to claim 1, wherein

9. X is 【Chemistry 7】 The bifunctional compound according to claim 7, wherein

10. R １ is a halogen, R ３ H, NH ２ or methoxy, where X is 【Chemistry 8】 The bifunctional compound of claim 1 , which is not

11. Structures I-1 to I-17: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

12. The linker is an uninterrupted C ２ ~C １５ The bifunctional compound of claim 1 comprising an alkylene chain.

13. 13. The bifunctional compound of claim 12, wherein the alkylene chain comprises from 2 to 10 consecutive alkylene units.

14. The bifunctional compound of claim 1, wherein the linker comprises 1 to 6 uninterrupted PEG units.

15. 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 and R′ is H or C. １ ~C ６ 2. The bifunctional compound of claim 1, wherein the alkylene groups are the same or different.

16. The linker is C ６ 2. The bifunctional compound of claim 1, comprising a carbocyclene, a six-membered heterocyclene, or a phenyl group.

17. The 6-membered heterocyclene is 【Chemistry 12】 17. The bifunctional compound of claim 16, wherein

18. The linker has the structure: 【Chemistry 13】 2. The bifunctional compound according to claim 1, which is any one of:

19. The degron has the structures (D1a) to (D1d): 【Chemistry 14】 wherein X is represented by any one of the following formulas: １ CH ２ or C(O), X ２ The bifunctional compound of claim 1 , wherein is a bond, NH, or O.

20. The bifunctional compound of claim 1 , wherein the degron binds to VHL.

21. The degron has the structures (D2-a) to (D2-f): 【Chemistry 15】 【Chemistry 16】 wherein Y' is a bond, N, O or C, and R' is H or methyl; 【Chemistry 17】 Z is C ５ -C ６ Carbocyclic group or C ５ -C ６ is a heterocyclic group; 【Chemistry 18】 21. The bifunctional compound of claim 20, represented by: Y" is a bond, N, O or C; and R" is F or CN, or a stereoisomer thereof.

22. Z 【Chemistry 19】 22. The bifunctional compound of claim 21, wherein

23. Structures (1) to (27): 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

24. A pharmaceutical composition comprising a therapeutically effective amount of the bifunctional compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt or stereoisomer thereof, and a pharma- ceutically acceptable carrier.

25. A method for treating a disease or disorder characterized by or mediated by abnormal activity of SMARCA4 or SMARCA2 and SMARCA4, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt or stereoisomer thereof.

26. 26. The method of claim 25, wherein the disease or disorder is cancer.

27. 27. The method of claim 26, wherein the cancer is selected from synovial sarcoma, lung cancer, ovarian cancer, brain cancer, kidney cancer, leukemia, non-small cell lung cancer, Burkitt's lymphoma, childhood medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, renal cell carcinoma, endometrial carcinoma and melanoma.

28. 24. A method for treating diffuse midline glioma harboring an H3K27M mutation, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt or stereoisomer thereof.

29. 1. A method of treating diffuse midline glioma harboring an H3K27M mutation, comprising administering to a subject in need thereof a therapeutically effective amount of a bifunctional compound of formula I′, I″ or II″, or a pharma- ceutically acceptable salt or stereoisomer thereof: 【Chemistry 26】 During the ceremony, A is, 【Chemical 27】 and E is, 【Chemistry 28】 and X １ and X ２ are each independently O, NR ３ and S; or X １ Or X ２ is combined with L to form a heterocyclyl or heteroaryl; or X １ and X ２ both of which are joined with L to form a heterocyclyl or heteroaryl; X ３ , O, NR ３ or S; L is 1 to 35 carbon atoms, for example 1 to 35 -CH ２ -alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, or heteroarylene chains, or combinations thereof, containing a - moiety, and optionally L is 1 to 35 -CH ２ When L contains an alkylene group containing a - moiety, at least one but not more than 10 -CH ２ The - moiety is independently -C(=O)-, -C(=O)-NR ４ --, --NR ４ -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR ４ -C(=O)-NR ３ - -OC(=O)-NR ４ --, --NR ４ —C(═O)—O—, —O—, —S—, and —NR ４ -, provided that the number of -CH2- moieties in L is equal to or greater than the number of -C(=O)-, -C(=O)-NR ４ --, --NR ４ -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR ４ -C(=O)-NR ３ -, OC(=O)-NR ４ --, --NR ４ —C(═O)—O—, —O—, —S—, and —NR ３ more than the total number of - moieties, provided that L is -C(=O)-, -C(=O)-NR ４ --, --NR ４ -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR ４ -C(=O)-NR ３ -, -OC(=O)-NR ４ --, --NR ４ —C(═O)—O—, —O—, —S—, and —NR ４ At least one -CH between each of the - moieties ２ - provided that - is present; R １ and R ２ are each independently selected from H, alkyl, halo, hydroxyl, hydroxyalkyl, carboxyl, acyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, heteroaralkyl, sulfonamido, aryl, heteroaryl, heterocyclyl, and aralkyl; R ３ and R ４ are each independently selected from H and alkyl; n is 1 to 5, preferably 1; 【Chemical Formula 29】 Including, X is a bond, aryl, or heteroaryl; L is 1 to 35 carbon atoms, for example, 1 to 35 -CH ２ an alkylene, alkenylene, or alkynylene chain containing the - moiety; Optionally: At least one but not more than 10 of L is -CH ２ The - moiety is independently -C(=O)-, -C(=O)-NR ３ --, --NR ３ -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR ３ -C(=O)-NR ３ -, -OC(=O)-NR ３ --, --NR ３ —C(═O)—O—, —O—, —S—, and —NR ３ - moiety, with the proviso that L is -CH ２ The number of - portions is -C(=O)-, -C(=O)-NR of L. ３ --, --NR ３ -C(=O)-, -C(=O)-O-, -OC(=O)-, -NR ３ -C(=O)-NR ３ -, -OC(=O)-NR ３ --, --NR ３ —C(═O)—O—, —O—, —S—, and —NR ３ - more than the sum of the parts, However, L is -C(=O)-, -C(=O)-NR ３ -, -NR3-C(=O)-, -C(=O)-O-, -OC(=O)-, -NR ３ -C(=O)-NR ３ -, -OC(=O)-NR ３ --, --NR ３ —C(═O)—O—, —O—, —S—, and —NR ３ At least one -CH between each of the - moieties ２ - is present; Z-L is -CH ２ -L, -O-CH ２ -L, or -NR ３ -CH ２ -L; R １ , R ２ , and R ３ are each independently selected from H and alkyl.

30. The bifunctional compound is 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 or a pharma- ceutically acceptable salt or stereoisomer thereof.

31. 30. The method of claim 29, wherein the H3K27M mutated diffuse midline glioma is diffuse intrinsic pontine glioma (DIPG).

32. 30. The method of claim 29, further comprising administering to the subject a therapeutically effective amount of an additional pharmaceutical agent in combination with the bifunctional compound, or a pharma- ceutically acceptable salt or stereoisomer thereof.

33. 33. The method of claim 32, wherein the additional pharmaceutical agent is a B-lymphoma Mo-MLV insertion region 1 homologue (BMI1) inhibitor.

34. 34. The method of claim 33, wherein the BMI1 inhibitor is PTC028, PTC209, PTC596, or QW24.

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