Compounds and pharmaceutical compositions that degrade SWI / SNF-related matrix-associated actin-dependent regulators of chromatin subfamily A.

Abstract

A compound of formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is disclosed, which is useful for regulating or degrading proteins expressed from one or more SWI / SNF-related matrix-associated actin-dependent regulators (SMARCAs) of one or more chromatin subfamily A (e.g., SMARCA2 and / or SMARCA4). TIFF2026522333000130.tif33170

Description

[Technical Field]

[0001] Cross-reference of related applications This application asserts the interests under Section 119(e) of U.S. Provisional Application No. 63 / 508,803, filed on 16 June 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure provides compounds useful as regulators of targeted ubiquitination, including pharmaceutically acceptable salts thereof. The compounds disclosed herein bind to and degrade proteins expressed from one or more SWI / SNF-related matrix-associated actin-dependent regulators ("SMARCA") of chromatin subfamily A. Also disclosed are pharmaceutical compositions containing the compounds and methods of using the compounds for the treatment of various SMARCA-mediated diseases or disorders.

[0003] Conventional technology The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates major regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and when defective or imbalanced, it can lead to the pathogenesis of various diseases. The covalent binding of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0004] There are over 600 E3 ubiquitin ligases that promote the ubiquitination of different proteins in vivo, and these can be divided into four families: HECT domain E3, U-box E3, monomeric ring E3, and multi-subunit E3. For example, Li et al. “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.” PLOS One 2008, (3) 1487, Berndsen et al. “New insights into ubiquitin E3 ligase mechanism” Nat.Struct.Mol.Biol.2014, 21:301, Deshaies et al. “RING domain E3 ubiquitin ligases” Ann.Rev.Biochem.2009, 78:399, Sprattetal. “RBRE3 ubiquitin ligases: new structures, new insights, new questions” Biochem.2014, 458:421, and Wang et al., “Roles of F-box proteins in cancer” Nat.Rev.Cancer.2014, See 14:233.

[0005] UPP plays a crucial role in the degradation of short-lived and regulatory proteins essential for various fundamental cellular processes, including cell cycle regulation, regulation of cell surface receptors and ion channels, and antigen presentation. The pathway is involved in the pathogenesis of multiple forms of malignancy, several genetic disorders (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and muscle wasting. Many diseases are associated with abnormal UPP, which adversely affects the cell cycle and division, cellular responses to stress and extracellular regulators, neuronal network morphogenesis, regulation of cell surface receptors, ion channels, secretory pathways, DNA repair, and organelle biomogenesis.

[0006] Abnormalities in this process are now considered to be involved in the pathogenesis of several diseases, both hereditary and acquired. These diseases can be classified into two main groups: (a) diseases resulting from the loss of function of a particular protein and the subsequent stabilization of that protein, and (b) diseases resulting from the acquisition of function, i.e., abnormalities or accelerated degradation of protein targets.

[0007] UPPs are used to induce selective proteolysis, including the use of fusion proteins for artificially ubiquitinating target proteins and synthetic small molecule probes for inducing proteasome-dependent degradation. Compounds acting as molecular glues can induce or stabilize protein-protein interactions between target proteins and E3 ubiquitin ligase ligands, leading to protein ubiquitination and subsequent proteasome-mediated degradation via recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the potential for transient control of protein expression. Such compounds can induce inactivation of the target protein upon addition to cells or administration to animals or humans, and can be useful as biochemical reagents, bringing about a new paradigm for disease treatment by removing pathogenic or oncogenic proteins. See, for example, Crews, Chem. & Biol. 2010, 17 (6):551 and Schneekloth and Crews, Chem Bio Chem., 2005, 6 (1):40.

[0008] There is a continuing need in this technology for effective treatments for diseases, particularly hyperplasia and cancer. However, nonspecific effects, as well as the inability to target and fully regulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anticancer drugs. Therefore, small molecule therapeutics that utilize E3 ligase-mediated proteolysis to target cancer-related proteins, such as one or more SWESNF-related matrix-associated actin-dependent regulators ("SMARCA") and / or polybromo-1 ("PB1") proteins of chromatin subfamily A, are promising therapeutic agents. Thus, there remains a need to find compounds that act as degradation factors for proteins expressed from the SMARCA gene, which are useful as therapeutic agents. [Overview of the project]

[0009] Compounds and pharmaceutically acceptable salts thereof that are expressed from the SMARCA gene and are useful as inducers of target ubiquitination of proteins that are subsequently degraded and / or inhibited by the monovalent compounds described herein, pharmaceutical compositions comprising such compounds or pharmaceutically acceptable salts thereof, and methods of using such compounds, their pharmaceutically acceptable salts, and their pharmaceutical compositions are disclosed. The advantage of the compounds provided herein is that a wide range of pharmacological activities are possible that coincide with the degradation / inhibition of proteins expressed from the SMARCA gene. Additionally, the present disclosure provides methods of using an effective amount of a compound described herein for the treatment or amelioration of a disease state, such as cancer, e.g., lung cancer, in a subject that needs it.

[0010] In some embodiments, the disclosed compounds are of formula I:

Chemical formula

[0011] In some embodiments, the compounds described herein modulate a protein expressed from the SMARCA gene. In some embodiments, the compounds described herein degrade a protein expressed from the SMARCA gene. In some embodiments, the protein that is modulated or degraded is expressed from SMARCA gene member 2 (SMARCA2). In some embodiments, the protein that is modulated or degraded is expressed by SMARCA gene member 4 (SMARCA4).

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0013] In some embodiments, the present disclosure provides a method for regulating or degrading a protein expressed from a SMARCA gene, comprising contacting the protein with an effective amount of a compound of formula I or any subformula thereof, under conditions in which the protein expressed from the SMARCA gene binds to the compound and is regulated or degraded. In some embodiments, the protein to be regulated or degraded is a protein expressed from the SMARCA2 gene. In some embodiments, the protein to be regulated or degraded is a protein expressed from the SMARCA4 gene.

[0014] In some embodiments, the Disclosure provides a method for regulating or degrading a protein expressed from the SMARCA gene in a subject, comprising administering to the subject a pharmaceutical composition comprising an effective amount of the compound of formula I or any subformula thereof, or a pharmaceutically acceptable excipient, and an effective amount of the compound of formula I or any subformula thereof, under conditions in which the protein expressed from the SMARCA gene binds to the compound and is regulated or degraded. In some embodiments, the protein regulated or degraded in the subject is a protein expressed from the SMARCA2 gene. In some embodiments, the protein regulated or degraded in the subject is a protein expressed from the SMARCA4 gene.

[0015] In some embodiments, the Disclosure provides a method for carrying out treatment of hyperplasia in a subject requiring treatment, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula I or any subformula thereof, or a pharmaceutically acceptable excipient, and an effective amount of a compound of formula I or any subformula thereof.

[0016] In some embodiments, the Disclosure provides a method for carrying out the treatment of cancer in a subject requiring treatment, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula I or any subformula thereof, or a pharmaceutically acceptable excipient, and an effective amount of a compound of formula I or any subformula thereof. [Modes for carrying out the invention]

[0017] This disclosure provides compounds, pharmaceutical compositions comprising such compounds, and methods for treating diseases, disorders, or conditions mediated at least partially by SMARCA2 or SMARCA4 transcription factors using such compounds and compositions. However, before detailing the disclosure, the following terms are defined. Unless otherwise defined, terms used herein have their generally accepted scientific meanings.

[0018] The terms used herein are intended solely to describe specific embodiments and are not intended to limit the disclosure. Where used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms unless the context clearly indicates otherwise.

[0019] A dash ("-") without a space between two letters or symbols is used to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and the chemical group may be shown with or without one or more dashes without losing their usual meaning. A dashed or wavy line drawn across a line in the structure indicates a specific bonding point of the group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0020] "C u-vThe prefix "C" indicates that the following group has u to v carbon atoms. For example, "C 1-6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0021] The term "approximately," when used before a numerical expression that includes a range, such as temperature, time, quantity, or concentration, indicates an approximation that may vary by (+) or (-) 10%, 5%, 1%, or any sub-range or sub-value between them. In one embodiment, the term "approximately," when used in relation to a dosage, means that the dosage may vary by ±10%.

[0022] "Comprising" or "comprises" is intended to mean that the composition and method include the listed elements but do not exclude other elements.

[0023] When used to define compositions and methods, “essentially consisting of” means excluding any other elements having any essential importance to the combination of interest. Thus, a composition essentially consisting of elements as defined herein would not exclude any other materials or steps that do not substantially affect the essential and novel features of the claimed disclosure.

[0024] "Consists of" means excluding other components and elements that are not in trace amounts of substantial method steps. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0025] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1-20 Alkyl), 1 to 12 carbon atoms (i.e., C 1-12 Alkyl), 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e., C1-4 Alkyl compounds include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbon atoms may be included; therefore, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0026] In some cases, certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, and divalent heteroaryl groups may also be called "alkylene" or "alkylenyl" groups (e.g., methyleneyl, ethyleneyl, and propyrenyl), or "arylene" or "aryrenyl" groups (e.g., phenylenyl or naphthyrenyl, or quinolinyl in the case of heteroarylenes). Also, unless otherwise specified, when a combination of multiple groups is referred to as a single part (e.g., arylalkyl or aralkyl) in this specification, the last group mentioned includes the atom to which that part is bonded to the rest of the molecule.

[0027] "Alkenyl" contains at least one (e.g., 1 to 3 or 1) carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2-20 Alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 Alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyls), or 2-4 carbon atoms (i.e., C2-4 This refers to an alkyl group having an alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0028] "Alkynnyl" contains at least one (e.g., 1 to 3 or 1) carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2-6 carbon atoms (i.e., C 2-6 Alkynyl) or 2-4 carbon atoms (i.e., C 2-4 This refers to an alkyl group having an alkynyl bond. The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0029] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0030] "Alkylthio" refers to the "alkyl-S-" group. "Alkylsulfinyl" refers to the "alkyl-S(O)-" group. "Alkylsulfonyl" refers to the "alkyl-S(O)2-" group. "Alkylsulfonylalkyl" refers to the -alkyl-S(O)2-alkyl group.

[0031] "Ashiru" is -C(O)R y It refers to the base, R yThe acyl is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0032] "Amide" is -C(O)NR y R z The "C-amide" group and -NR refer to the group. y C(O)R z The term "N-amide" refers to both the group and the R group. y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein, or R y and R z These combine to form a cycloalkyl or heterocycline, each of which may be unsubstituted or substituted as defined herein.

[0033] "Amino" is -NR y R z It refers to the base, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0034] "Amidino" is -C(NR y )(NR z 2) refers to R y and R zThese are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0035] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) system including a condensed system. As used herein, aryl refers to a ring carbon atom (i.e., C) with 6 to 20 carbon atoms. 6-20 aryl), 6-12 carbocyclic atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 It contains an aryl group. Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, the aryl group does not include, and does not overlap in any way with, the heteroaryl groups as defined below. When one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl regardless of the bonding site. When one or more aryl groups are fused with a heterocyclyl group, the resulting ring system is heterocyclyl regardless of the bonding site. When one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is cycloalkyl regardless of the bonding site.

[0036] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group and -NR refer to the group. y C(O)OR z The term "N-carbamoyl" refers to both the group and the R group. y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0037] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)ORx It refers to both, R x These are alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0038] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures, including condensed ring systems, bridged ring systems, and spirocyclic systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 This includes carbocyclic fused ring systems having carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyls have 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-14 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3-6 They have cycloalkyl groups. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring, which may condense with an aryl ring regardless of its bonding to the rest of the molecule. Additionally, cycloalkyls also include "spirocycloalkyls" where there are two substitution positions on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0039] "Imino" is -C(NR y )R z It refers to the base, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0040] "Imido" is -C(O)NR y C(O)R z It refers to the base, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0041] "Halogen" or "halo" refers to atoms belonging to Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0042] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens. For example, if a residue is substituted with multiple halogens, it can be referred to using a prefix corresponding to the number of halogenated groups. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, and these halo groups do not necessarily have to be the same halogen. Examples of haloalkyls include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0043] A "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms (for example, 1 to 6 or 1 to 3) are replaced by halogens.

[0044] "Hydroxyalkyl" refers to an alkyl group defined above in which one or more hydrogen atoms (for example, 1 to 6 or 1 to 3) are replaced by a hydroxyl group.

[0045] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atoms, are independently replaced by the same or different heteroatomic groups, provided that the bonds with the rest of the molecule are mediated through carbon atoms. The term "heteroalkyl" includes unbranched or branched saturated chains containing carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Examples of heteroatomic groups include -NR y Examples include -, -O-, -S-, -S(O)-, -S(O)2-, etc., but are not limited to these, R y The elements are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2 CH2NRy CH3, etc., R y Examples include hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl (each of which may be unsubstituted or substituted as defined herein). As used herein, a heteroalkyl comprises 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0046] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or multiple fused ring, where one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring group having 1 to 20 ring carbon atoms (i.e., C 1-20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 Heteroaryls), or 3 to 8 carbon ring atoms (i.e., C 3-8A heteroaryl compound, and independently comprising 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl compound may include a 5 to 10-membered ring system, a 5 to 7-membered ring system, or a 5 to 6-membered ring system, each independently comprising 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, sinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and isoquinolyl. Examples include isoxazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl; heteroaryls can be bonded via any of the rings in the fused system. Any aromatic ring having a single or multiple fused ring containing at least one heteroatom is considered a heteroaryl, whether or not it is bonded to the rest of the molecule (i.e., via any one of the fused rings).Heteroaryl does not include aryl as defined above and does not overlap with it.

[0047] "Heterocyclyl" (used interchangeably with "heterocycloalkyl") independently refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro heterocyclyl groups. Heterocyclyl may be monocyclic or polycyclic, and the polycycle may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O - ) moieties. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl regardless of the bond (i.e., it can be bonded through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, and this ring may be fused to a cycloalkyl, aryl, or heteroaryl ring regardless of its bond to the rest of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl), or independently 3 to 6 ring carbon atoms selected from nitrogen, sulfur, or oxygen (i.e., C 3-6It has a heterocyclyl group and contains 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolinyl Examples include lyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanyl, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl," which has two substitution positions on the same carbon atom. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, and heterocyclyls can be bonded via any of the rings in the condensation system. In some embodiments, the heterocycloalkyl may be substituted with oxo groups on the heteroatom (e.g., S=O, S(=O)2).

[0048] "Oxime" refers to a -CR y (=NOH) group, where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0049] "Oxo" refers to a moiety =O.

[0050] "Sulfonyl" refers to a -S(O)2R y group, where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0051] "Sulfinyl" refers to a -S(O)R y group, where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein. Examples of sulfinyl include methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0052] "Sulfonamide" refers to -SO2NR y R z and -NR y SO2R z groups, where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be unsubstituted or substituted as defined herein.

[0053] The terms "optional" or "optionally" mean that the event or situation described thereafter may or may not occur, and include the cases in which such event or situation occurs and the cases in which it does not occur. Furthermore, the terms "unsubstituted or substituted" mean that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a given atom or group may or may not be replaced by non-hydrogen parts.

[0054] As used herein, the term “substituted” means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl), at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond with a non-hydrogen atom, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidino, aryl, aralkyl, azide, Carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imide, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3 is included, but is not limited to these, and each R y These are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0055] In certain embodiments, "substituted" means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently substituted for deuterium, halo, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(O)R h , -NR g C(O)NR g R h , -NR g C(O)OR h , -NR g S(O) 1-2 R h , -C(O)R g , -C(O)OR g -OC(O)OR g -OC(O)R g -C(O)NR g R h -OC(O)NR g R h , -OR g , -SR g ,-S(O)R g -S(O)2R g , -OS(O) 1-2 R g , -S(O) 1-2 Ure g , -NR g S(O) 1-2 NR g R h ,=NSO2R g 、=NOR g , -S(O) 1-2 NR g R h The group comprises any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups listed above, which are replaced by -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" also means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are -C(O)R g , -C(O)OR g -C(O)NR g R h-CH2SO2R g , or -CH2SO2NR g R h It means any of the above bases which are replaced by R. g and R h These are, whether identical or different, independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond with amino, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or R g and R h Two of these groups, together with the atoms to which they are bonded, form one of the above groups: an unsubstituted or oxo, halo, or alkyl-substituted heterocyclyl ring, or an unsubstituted or oxo, halo, amino, hydroxy, or alkoxy-substituted alkyl ring.

[0056] Polymers or similar non-tertiary structures obtained by defining substituents with an infinitely increasing number of substituents (e.g., substituted aryls having a substituted alkyl, where the substituted alkyl itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to [(substituted aryl)substituted aryl]substituted aryls. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as defined herein.

[0057] In certain embodiments, the phrase "one or more" as used herein refers to 1 to 5 items. In certain embodiments, the phrase "one or more" as used herein refers to 1 to 3 items.

[0058] Any compound or structure given herein is also intended to represent both an unlabeled and an isotope-labeled form of the compound. These forms of the compound may also be called “isotope-enriched analogs.” An isotope-labeled compound has the structure shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include, respectively: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18F, 36 Cl, 123 I, and 125 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Various isotope-labeled compounds of this disclosure include, for example, 3 H and 14 These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including metabolic studies, reaction kinetic studies, and drug or substrate tissue distribution assays, or in radiotherapy for patients.

[0059] The term “isotope-enriched analog” includes “deuterated analogs” of the compounds described herein, where one or more hydrogen atoms (e.g., hydrogen atoms on carbon atoms) are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol.Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0060] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have DMPK (improved drug metabolism and pharmacokinetic) properties with respect to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits arising from better metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, or 1114C-labeled compounds may be useful in PET or SPECT or other imaging studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the scheme or in the examples and preparations described below, by substituting readily available isotope-labeling reagents with non-isotope-labeling reagents. In this context, deuterium is understood to be a substituent in the compounds described herein.

[0061] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise specified, where a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0062] In many cases, the compounds of this disclosure can form acids and / or base salts due to the presence of an amino group and / or a carboxyl group, or a similar group.

[0063] Provided herein are pharmaceutically acceptable salts, isotopic enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. “pharmaceutically acceptable” or “physiologically acceptable” means compounds, salts, compositions, dosage forms, and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0064] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, merely as examples, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), and di(substituted alkenyl)amines ( These include, but are not limited to, HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono, di, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono, di, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of preferred amines, merely illustrative, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0065] The term “solvate” refers to a complex formed by a combination of solvent molecules and solute molecules or ions. The solvent may be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term “solvate” includes “hydrates” (i.e., complexes formed by a combination of water molecules and solute molecules or ions), hemihydrates, channel hydrates, and the like. Some examples of solvents include, but are not limited to, acetonitrile, methanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, and water. In general, solvated forms are equivalent to non-solvated forms and are included within the scope of this disclosure.

[0066] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imido acid tautomer. Regardless of which tautomers are shown and regardless of the nature of the equilibrium between the tautomers, a person skilled in the art will understand that the compound contains both an amide and an imido acid tautomer. Therefore, an amide-containing compound will be understood to also contain its imido acid tautomer. Similarly, an imido acid-containing compound will be understood to contain its amide tautomer.

[0067] Compounds, or pharmaceutically acceptable salts thereof, may contain a chiral center and thus, from the viewpoint of absolute stereochemistry, may result in enantiomers, diastereomers, and other stereoisomeric forms, which in the case of amino acids, can be defined as (R)- or (S)- or (D)- or (L)-. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or they may be resolved using conventional techniques such as chromatography and / or classification crystallization. Prior art for preparing / isolating individual enantiomers includes chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). If a compound described herein contains an olefin double bond or other geometrically asymmetric center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0068] A "stereoisomer" refers to a compound that consists of the same atoms bonded together by the same bonds, but has different three-dimensional structures that are not interchangeable. This disclosure intends various stereoisomers, or mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other but whose molecules cannot be superimposed.

[0069] A "diastereomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other.

[0070] The relative centers of the compounds shown herein are illustrated using a "thick bond" style (thick or parallel lines), and absolute stereochemistry is represented using wedge bonds (thick or parallel lines).

[0071] "Prodrug" means any compound that, when administered to a target mammal, releases an active parent drug in vivo according to the structures described herein. Prodrugs of the compounds described herein are prepared by modifying the functional groups present in the compounds described herein such that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in the compound in such a way that the modification is cleaved to the parent compound either by routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy group, amino group, carboxyl group, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate a free hydroxy group, amino group, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc. of the hydroxy functional groups of the compounds described herein. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series, “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0072] "Subject" refers to a mammal. A mammal can be a human or non-human mammalian organism. "Patient" refers to a human subject.

[0073] "To treat" or "to cure" a disease or disorder in a subject means: 1) to prevent the onset of a disease or disorder in a subject who is predisposed to the disease or disorder or who has not yet shown symptoms; 2) to inhibit or halt the progression of a disease or disorder; or 3) to improve or cause regression of a disease or disorder.

[0074] "Effective dose" means the amount of the compound described herein that is sufficient to treat a disease or disorder affecting a subject, or to prevent such disease or disorder from occurring in the subject or patient.

[0075] "Administration" refers to any form of administration to a subject recognized in the art, including oral (including forced oral administration), pulmonary, transdermal, sublingual, injection (e.g., intravenous, intramuscular), and transmucosal (e.g., vaginal, nasal). The route of administration is selected by the attending physician and is based on factors such as the patient's age, weight and overall health, as well as the severity of their condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally.

[0076] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting them for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-conjugated enzymes, cause ubiquitin to bind to lysine on target proteins, which then target specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin-conjugated enzymes, are responsible for the transfer of ubiquitin to targeted proteins. Generally, ubiquitin ligases are involved in polyubiquitination, where a second ubiquitin binds to a first ubiquitin, and a third ubiquitin binds to a second ubiquitin. Polyubiquitination labels proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted by the proteasome for degradation, but instead can be modified in their cellular location or function by binding to other proteins that have domains capable of binding to ubiquitin, for example. A further complicating factor is that different lysines on ubiquitin can be targeted by E3 to construct chains. The most common lysine is Lys48 on ubiquitin chains, which is used to construct polyubiquitin that is recognized by the proteasome.

[0077] compound In one embodiment, this disclosure relates to formula I: [ka] A compound of, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein, Each of m, n, and p is independently 0, 1, or 2. R 1 However, hydroxy, halo, cyano, C 1-4 It is an alkoxy or -N(R)2, R 2 However, -N(R)2, Each R independently produces hydrogen and C 1-4 Alkyl, or C 3-6 It is a cycloalkyl group, and each alkyl or cycloalkyl group is either unsubstituted or has 1 to 3 Z groups. 1 Replaced by, Each R 3 However, independently, Halo, Cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 8 Z 1 It is arbitrarily replaced with, Each R 4 However, independently, Halo, Cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 8 Z 1 It is arbitrarily replaced with, Each R 5 However, independently, Halo, Cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 8 Z 1 It is arbitrarily replaced with, R 6 However, hydrogen, C 1-3 Alkyl or halo, (i)L 1 However, linked, linear, or branched C 1-3 It is either alkylene, C(O), or -O-. L 2 However, linked, linear, or branched C 1-3 It is either alkylene, C(O), or -O-. (ii) or L 1 However, it is a bond, L 2 However, if it is a bond, R 2 and R 4 The R atoms cyclize together with the atoms they are bonded to, forming a heterocycline. X 1 However, CH, CR 5 It is either , or N, X 2 However, CH, CR 5 It is either , or N, X 3 However, CH, CR 5 It is either , or N, and X 1 , X 2 , and X 3 One or fewer of these is N, Ring A is a 4-11 member heterocyclyl or 5-10 member heteroaryl containing at least one nitrogen atom. each Z 1However, independently, Halo, Cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z 1a It is arbitrarily replaced with, Each R 11 However, independently, hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z 1aIt is arbitrarily replaced with, each Z 1a However, independently, hydroxy, halo, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2, -OR 13 , -C(O)R 13 , -C(O)OR 13 , -S(O) 0-2 R 13 , -NR 13 S(O) 0-2 R 13 , -S(O) 0-2 N(R 13 )2, -NR 13 S(O) 0-2 N(R 13 )2, -NR 13 C(O)N(R 13 )2, -C(O)N(R 13 )2, -NR 13 C(O)R 13 ,-OC(O)N(R 13 )2, or -NR 13 C(O)OR 13 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z 1b It is arbitrarily replaced with, Each R 13 However, independently, hydrogen, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 They are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z 1b It is arbitrarily replaced with, each Z 1b However, independently, halo, cyano, hydroxy, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkinyl, -LC 1-6 Haloalkyl, -LC 3-10 It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl, Each L independently produces -O-, -NH-, -S-, -S(O)-, -S(O)2-, and -N(C 1-6 Alkyl)-,-N(C 2-6 Alkenyl)-, -N(C 2-6 Alkinyl)-, -N(C 1-6 Haloalkyl)-,-N(C) 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 Alkyl)-,-C(O)N(C 2-6 Alkenyl)-,-C(O)N(C 2-6 Alkinyl)-,-C(O)N(C 1-6 Haloalkyl)-,-C(O)N(C 3-10 These are cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-, Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are further independently of 1-5 hydroxy, halo, cyano, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 The present invention provides compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl compounds.

[0078] In some embodiments, Formula II: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0079] In some embodiments, formula IIA: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0080] In some embodiments, Formula III: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0081] In some embodiments, formula IIIA: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0082] In some embodiments, formula IV: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0083] In some embodiments, formula IVA: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0084] In some embodiments, formula V: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0085] In some embodiments, formula VA: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where L 1 , L 2 , m, n, p, R 3 , R 4 , R 5 , R 6 , and ring A are as defined herein.

[0086] In some embodiments, R 1 It is hydroxyl.

[0087] In some embodiments, R 2R is -N(R)2. In some embodiments, R 2 is -NH2. In some embodiments, R 1 is hydroxyl, and R 2 It is -NH2.

[0088] In some embodiments, ring A is a 4- to 8-membered monocyclic heterocycline containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R 4 It is optionally substituted with. In some embodiments, ring A is a 4- to 7-membered monocyclic heterocycline containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R 4 It can be arbitrarily replaced with.

[0089] In some embodiments, ring A is [ka] And q and r are independently 1, 2, or 3, where the sum of q and r is 6 or less, and X is N or CH. [ka] L 1 This represents the connection point with L, and (*) indicates L 2 The bond point with is represented, and ring A has 1 or 2 R 4 It can be arbitrarily replaced with.

[0090] In some embodiments, ring A is [ka] Selected from, each ring A has 1 or 2 R 4 It is arbitrarily replaced with, [ka] L 1 This represents the connection point with L, and (*) indicates L 2 This represents the connection point.

[0091] In some embodiments, ring A is a 7-11 member spirocyclic heterocycline containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R 4 It is optionally substituted with. In some embodiments, ring A is a 7-10 membered spirocyclic heterocycline containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R 4 It can be arbitrarily replaced with.

[0092] In some embodiments, ring A is [ka] And q and r are independently 1, 2, or 3, where the sum of q, r, s, and t is 8 or less, and X is N or CH. [ka] L 1 This represents the connection point with L, and (*) indicates L 2 The bond point with is represented, and ring A has 1 or 2 R 4 It can be arbitrarily replaced with.

[0093] In some embodiments, ring A is [ka] Selected from, each ring A has 1 or 2 R 4 It is arbitrarily replaced with, [ka] L 1 This represents the connection point with L, and (*) indicates L 2 This represents the connection point.

[0094] In some embodiments, ring A is a 7-11 membered condensed bicyclic heterocycline containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R 4 It is optionally substituted with. In some embodiments, ring A is a 7- to 9-membered condensed bicyclic heterocycline containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R4 It can be arbitrarily replaced with.

[0095] In some embodiments, ring A is [ka] And u, v, w, and x are each independently 0, 1, 2, or 3, where the sum of u, v, w, and x is 7 or less, and X is N or CH. [ka] L 1 This represents the connection point with L, and (*) indicates L 2 The bond point with is represented, and ring A has 1 or 2 R 4 It can be arbitrarily replaced with.

[0096] In some embodiments, ring A is [ka] Selected from, each ring A has 1 or 2 R 4 It is arbitrarily replaced with, [ka] L 1 This represents the connection point with L, and (*) indicates L 2 This represents the connection point.

[0097] In some embodiments, ring A is a 7-11 membered cross-linked heterocyclyl containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R 4 It is optionally substituted with. In some embodiments, ring A is a 7- to 9-membered bridged heterocyclyl containing 1 or 2 nitrogen atoms, and ring A contains 1 or 2 R 4 It can be arbitrarily replaced with.

[0098] In some embodiments, ring A is [ka] The equation is such that z is 1 or 2, a, b, c, and d are each independently 0, 1, or 2, where the sum of z, a, b, c, and d is 7 or less, and X is N or CH. [ka] L 1 This represents the connection point with L, and (*) indicates L 2 The bond point with is represented, and ring A has 1 or 2 R 4 It can be arbitrarily replaced with.

[0099] In some embodiments, ring A is [ka] Selected from, each ring A has 1 or 2 R 4 It is arbitrarily replaced with, [ka] L 1 This represents the connection point with L, and (*) indicates L 2 This represents the connection point.

[0100] In some embodiments, ring A is a 5- to 10-membered heteroaryl, and ring A has 1 or 2 R 4 It can be arbitrarily replaced with.

[0101] In some embodiments, ring A is [ka] Ring A has 1 or 2 R 4 It is arbitrarily replaced with, [ka] L 1 This represents the connection point with L, and (*) indicates L 2 This represents the connection point.

[0102] In some embodiments, L 1 C is a bonded, linear, or branched C1-3 It is an alkylene, C(O), or -O-. In some embodiments, L 1 is a bond, C(O), -O-, or -CH(CH3)-. In some embodiments, L 1 It is a combination.

[0103] In some embodiments, L 2 C is a bonded, linear, or branched C 1-3 It is an alkylene, C(O), or -O-. In some embodiments, L 2 is a bond or -O-. In some embodiments, L 2 It is a combination.

[0104] In some embodiments, (i)L 1 C is a bonded, linear, or branched C 1-3 It is either alkylene, C(O), or -O-, L 2 C is a bonded, linear, or branched C 1-3 It is either alkylene, C(O), or -O-, and R 2 Each R is independently a hydrogen, C 1-4 Alkyl, or C 3-6 It is a cycloalkyl group, and each alkyl or cycloalkyl group is either unsubstituted or has 1 to 3 Z groups. 1 Replaced by each R 4 These are independently Halo, Cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR 11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently contain 1 to 8 Z 1 It can be arbitrarily replaced with.

[0105] In some embodiments, L 1 is a bond, L 2 It is a bond, R 2 Each R is independently a hydrogen, C 1-4 Alkyl, or C 3-6 It is a cycloalkyl group, and each alkyl or cycloalkyl group is either unsubstituted or has 1 to 3 Z groups. 1 Replaced by each R 4 These are independently Halo, Cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2, -OR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O) 0-2 R 11 , -NR 11 S(O) 0-2 R 11 , -S(O) 0-2 N(R 11 )2, -NR 11 S(O) 0-2 N(R 11 )2, -NR 11 C(O)N(R 11 )2, -C(O)N(R 11 )2, -NR11 C(O)R 11 ,-OC(O)N(R 11 )2, or -NR 11 C(O)OR 11 And each C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules independently contain 1 to 8 Z 1 It is optionally replaced by L. In some embodiments, 1 is a bond, L 2 is a bond. In some embodiments, L 1 is a bond, L 2 is -O-. In some embodiments, L 1 It is -O- and L 2 It is a combination.

[0106] In some embodiments, L 1 is a bond, L 2 It is a bond, R 2 and R 4 The R atoms cyclize together with the atoms they are bonded to to form a heterocycline. In some embodiments, L 1 is a bond, L 2 It is a bond, R 2 and R 4 The R atoms cyclize with the atoms they are bonded to to form a heterocycline containing 2-3 nitrogen atoms. In some embodiments, L 1 is a bond, L 2 It is a bond, R 2 and R 4 The R atoms cyclize together with the atoms they are bonded to to form a 9-10 membered heterocycline containing 2-3 nitrogen atoms.

[0107] In some embodiments, L 1 is a bond, L 2 It is a bond, R 2 and R 4The R atoms cyclize together with the atoms they are bonded to to form a 10-membered heterocycline containing three nitrogen atoms.

[0108] In some embodiments, L 1 is a bond, L 2 It is a bond, R 2 and R 4 The R atoms cyclize together with the atoms they are bonded to to form a nine-membered heterocycline containing two nitrogen atoms.

[0109] In some embodiments, formula IA: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where m, n, p, R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , and X 3 This is as defined herein.

[0110] In some embodiments, formula IB: [ka] A compound of formula I represented by , or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided, where m, n, R 3 , R 5 , R 6 , X 1 , X 2 , and X 3 This is as defined herein.

[0111] Several embodiments, each R 4 Independently, C 1-6 It is alkyl. In some embodiments, each R 4 Independently, C 1-3 It is alkyl. In some embodiments, each R4 R is independently methyl, ethyl, or isopropyl. In some embodiments, each R 4 is methyl. In some embodiments, each R 4 is ethyl. In some embodiments, each R 4 It is isopropyl.

[0112] In some embodiments, p is 0.

[0113] In some embodiments, p is 1, and R 4 is methyl. In some embodiments, p is 1 and R 4 is ethyl. In some embodiments, p is 1 and R 4 It is isopropyl.

[0114] In some embodiments, p is 2, and each R 4 It is methyl.

[0115] Several embodiments, each R 3 In some embodiments, each R is a halo. 3 It is fluoro.

[0116] In some embodiments, n is 0.

[0117] In some embodiments, n is 1, and R 3 is fluoro. In some embodiments, n is 2, and each R 3 It is fluoro.

[0118] Several embodiments, each R 5 In some embodiments, each R is independently a halo or a cyano. 5 is fluoro. In some embodiments, each R 5 It is cyano.

[0119] In some embodiments, m is 0.

[0120] In some embodiments, m is 1, and R 5 is fluoro. In some embodiments, m is 1 and R 5 It is cyano.

[0121] In some embodiments, m is 0, n is 1, and p is 1. In some embodiments, m is 1, n is 0, and p is 0. In some embodiments, m is 1, n is 0, and p is 1. In some embodiments, m is 0, n is 2, and p is 1.

[0122] In some embodiments, m is 0, n is 0, and p is 1 or 2. In some embodiments, m is 0, n is 0, and p is 1. In some embodiments, m is 0, n is 0, and p is 2.

[0123] In some embodiments, m, n, and p are 0.

[0124] In some embodiments, R 6 is hydrogen, methyl, or fluoro. In some embodiments, R 6 It is methyl or fluoro.

[0125] In some embodiments, R 6 It is hydrogen.

[0126] In some embodiments, R 6 C 1-3 It is alkyl. In some embodiments, R 6 It is methyl.

[0127] In some embodiments, R 6 is a halo. In some embodiments, R 6 It is fluoro.

[0128] Some embodiments provide compounds selected from Table 1 or Table 2, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof.

[0129] Table 1 shows representative and non-limiting examples of compounds within the range of Formula I above, each of which includes its pharmaceutically acceptable salts, solvates, hydrates, or tautomers. TIFF2026522333000032.tif232170TIFF2026522333000033.tif232170TIFF20265223330 00034.tif223170TIFF2026522333000035.tif248170TIFF2026522333000036.tif248170 TIFF2026522333000037.tif245170TIFF2026522333000038.tif244170TIFF20265223330 00039.tif250170TIFF2026522333000040.tif225170TIFF2026522333000041.tif157170

[0130] Table 2 shows representative and non-limiting examples of compounds within the range of Formula I above, each of which includes its pharmaceutically acceptable salts, solvates, hydrates, or tautomers. TIFF2026522333000042.tif188170TIFF2026522333000043.tif219170TIFF2026522333 000044.tif206170TIFF2026522333000045.tif226170TIFF2026522333000046.tif21017 0TIFF2026522333000047.tif211170TIFF2026522333000048.tif220170TIFF2026522333 000049.tif214170TIFF2026522333000050.tif223170TIFF2026522333000051.tif32170

[0131] In some embodiments, the disclosure provides compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, that degrade SMARCA2 by 5%, 10%, or 20% or more at a concentration of 1 μM.

[0132] In some embodiments, the disclosure provides compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, that degrade SMARCA4 by 5%, 10%, or 20% or more at a concentration of 1 μM.

[0133] In some embodiments, the Disclosure provides a method for regulating or degrading a protein expressed from the SMARCA2 gene, comprising contacting the protein with an effective amount of a compound described herein. In some embodiments, the Disclosure provides a method for regulating or degrading a protein expressed from the SMARCA2 gene, comprising contacting the protein with an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, under conditions in which the protein expressed from the SMARCA2 gene is regulated or degraded.

[0134] In some embodiments, the Disclosure provides a method for regulating or degrading a protein expressed from the SMARCA4 gene, comprising contacting the protein with an effective amount of a compound described herein. In some embodiments, the Disclosure provides a method for regulating or degrading a protein expressed from the SMARCA4 gene, comprising contacting the protein with an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, under conditions in which the protein expressed from the SMARCA4 gene is regulated or degraded.

[0135] In some embodiments, a method is provided for regulating or degrading a protein expressed from the SMARCA2 gene in a subject, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutical composition described herein. In some embodiments, a method is provided for regulating or degrading a protein expressed from the SMARCA2 gene in a subject, comprising administering to the subject an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, and a pharmaceutically acceptable excipient.

[0136] In some embodiments, a method is provided for regulating or degrading a protein expressed from the SMARCA4 gene in a subject, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutical composition described herein. In some embodiments, a method is provided for regulating or degrading a protein expressed from the SMARCA4 gene in a subject, comprising administering to the subject an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, and a pharmaceutically acceptable excipient.

[0137] In some embodiments, a method is provided for carrying out the treatment of cancer in a subject that requires treatment, comprising administering to the subject an effective amount of a compound or a pharmaceutical composition described herein. In some embodiments, a method is provided for carrying out the treatment of cancer in a subject that requires treatment, comprising selecting a subject having cancer that is at least partially mediated by SMARCA2, and administering to the subject an effective amount of a pharmaceutical composition comprising a compound of formula I, II, III, IV, or V, or any subformula thereof, or a pharmaceutically acceptable excipient, and an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof.

[0138] In some embodiments, a method is provided for carrying out the treatment of cancer in a subject that requires treatment, comprising: selecting a subject having cancer that is at least partially mediated by SMARCA4; and administering to the subject an effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, or a pharmaceutically acceptable excipient, and an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof.

[0139] In some embodiments, a method is provided for carrying out treatment of hyperplasia in a subject requiring treatment, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof, or a pharmaceutically acceptable excipient, and an effective amount of a compound of formula I, II, III, IV, or V, or any subformula thereof.

[0140] General synthesis methods The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through routine optimization procedures.

[0141] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Protecting groups suitable for various functional groups, as well as favorable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, Third Edition, Wiley, New York, 1999, and the references cited therein.

[0142] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), and Emka-Chemce (St. Louis, Missouri, USA). Other starting materials can be found in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 2016), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 2001), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 2019), and March's Advanced Organic Chemistry, (John Wiley, and Sons, 8) th It can be prepared by the procedures described in standard references such as Edition, 2019, and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or by obvious modifications thereof.

[0143] Synthesis of Representative Compounds The general synthesis of the compounds described herein is shown in the following reaction schemes. Schemes 1, 2, and 3 show general methods for preparing the compounds of formula I. In schemes 1, 2, and 3, substituent L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3Rings A, m, n, and p are as defined throughout this specification. PG is a protecting group (including, but not limited to, Boc).

[0144] [ka] In some embodiments, compounds of formula I and its subformulas are prepared as shown in Scheme 1. In Scheme 1, the first step is to prepare conventional SN AR The reaction involves combining at least stoichiometric amounts of ring A, compound 2A, with compound 1A in an inert diluent such as tetrahydrofuran, dioxane, DMSO, or DMF, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, or potassium carbonate. The reaction is typically maintained at 25°C to 100°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be carried out to obtain compound 3A.

[0145] In the next step, a conventional Suzuki coupling reaction is carried out, combining at least a stoichiometric amount of arylboronic acid, compound 4A, with compound 3A in an inert diluent such as tetrahydrofuran, dioxane, toluene, or dimethoxyethane, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, or potassium carbonate. The reaction is typically maintained at 10°C to 65°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be performed to obtain compound 5A.

[0146] In the next step, the conventional SN ARThe reaction is carried out, and at least a stoichiometric amount of 5A from the previous step is combined with 6A in an inert diluent such as tetrahydrofuran, dioxane, DMSO, or DMF, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, or potassium carbonate. The reaction is typically maintained at 25°C to 100°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be carried out to obtain compound 7A.

[0147] In the final step, the Suzuki-Miyaura cross-coupling reaction is carried out, combining at least stoichiometric amounts of potassium vinyl trifluoroborate, compound 8A, with compound 7A under conventional coupling reaction conditions well known in the art, typically including the use of a palladium catalyst (e.g., palladium(II) bis(triphenylphosphine) dichloride, palladium diacetate, etc.) in the presence of a suitable base (e.g., diisopropylethylamine, potassium phosphate, sodium carbonate, cesium carbonate, etc.). The coupling reaction is typically carried out in an inert solvent such as toluene, N,N-dimethylformamide, benzene, dioxane, or dimethoxyethane. The reaction is typically carried out at about 10°C to about 110°C for a time sufficient to substantially complete the reaction, as manifested by thin-layer chromatography, for example. Once the reaction is complete, after conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be performed to obtain the compound of formula I.

[0148] [ka] In some embodiments, a compound of formula I (wherein L) 1 is a bond, L 2 It is a bond, R 2 and R 4The R in compound 11A is cyclized with the atoms bonded to it to form a heterocycline, and ring A is piperidine. The compound and its subformula are prepared as shown in Scheme 2. In Scheme 2, the first step is a conventional Sonogashira coupling reaction, in which at least a stoichiometric amount of a protected aminoalkyne, compound 11A, is combined with compound 10A under conventional reaction conditions well known in the art, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, or cesium carbonate, and including the use of palladium(II) bis(triphenylphosphine) dichloride and copper(I) iodide as catalysts. The reaction is typically carried out in an inert solvent such as toluene or N,N-dimethylformamide. The reaction is typically carried out at about 25°C to about 110°C for a sufficient time for the reaction to be substantially completed, as can be manifested, for example, by thin-layer chromatography. Once the reaction is complete, compound 12A can be obtained by performing isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) after conventional workup of the reaction solution.

[0149] In the next step, a cyclization reaction is carried out by treating at least a stoichiometric equivalent of compound 12A with a suitable base, such as potassium tert-butoxide or cesium carbonate, in an inert diluent such as tetrahydrofuran, dioxane, toluene, or dimethoxyethane. The reaction is typically maintained at 10°C to 50°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be performed to obtain compound 13A.

[0150] In the next step, protecting groups such as t-butoxycarbonyl (Boc) are removed under conventional conditions, depending on the specific protecting group used. The Boc group is merely an example; other conventional amino protecting groups such as benzyl, 9-fluorenyl methoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), and p-nitrobenzyloxycarbonyl can also be used. Once the reaction is complete, compound 14A can be obtained by performing isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) after conventional workup of the reaction solution.

[0151] In the next step, a cyclization reaction is carried out by combining at least a stoichiometric equivalent of compound 14A with an aldehyde in an inert aqueous diluent such as a tetrahydrofuran:water mixture, typically in the presence of a suitable base such as potassium hydroxide or sodium hydroxide. The reaction is typically maintained at 50°C to 90°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be performed to obtain compound 15A.

[0152] In the next step, a conventional Suzuki coupling reaction is carried out, combining at least stoichiometric equivalents of an arylboronic acid, compound 4A, with compound 15A in an inert diluent such as tetrahydrofuran, dioxane, toluene, or dimethoxyethane, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, or potassium carbonate. The reaction is typically maintained at 10°C to 65°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be performed to obtain compound 16A.

[0153] In the next step, the conventional SN ARThe reaction is carried out, and at least stoichiometric equivalents of compound 16A are combined with dibromoheteroaryl compound 6A in an inert diluent such as tetrahydrofuran, dioxane, DMSO, or DMF, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, or potassium carbonate. The reaction is typically maintained at 25°C to 100°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be performed to obtain compound 17A.

[0154] In the final step, a Suzuki-Miyaura cross-coupling reaction is carried out, combining at least a stoichiometric amount of potassium vinyl trifluoroborate, compound 7A, with compound 17A under conventional coupling reaction conditions well known in the art, typically including the use of a palladium catalyst (e.g., palladium(II) bis(triphenylphosphine) dichloride, palladium diacetate, etc.) in the presence of a suitable base (e.g., diisopropylethylamine, potassium phosphate, sodium carbonate, cesium carbonate, etc.). The coupling reaction is typically carried out in an inert solvent such as toluene, N,N-dimethylformamide, benzene, dioxane, or dimethoxyethane. The reaction is typically carried out at about 10°C to about 110°C for a sufficient time to substantially complete the reaction, as manifested by thin-layer chromatography, for example. Once the reaction is complete, compound 18A can be obtained by carrying out isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) after conventional workup of the reaction solution.

[0155] [ka] In some embodiments, a compound of formula I (wherein L) 1 is a bond, L 2 It is a bond, R 2 and R 4The R in compound 10A is cyclized with the atoms bonded to it to form a heterocycline, and ring A is piperazine. Its subformula is prepared as shown in Scheme 3. In Scheme 3, the first step is a conventional Buchwald-Hartwig reaction using at least a stoichiometric amount of a suitable heterocycloalkyl acid, compound 18A, combined with compound 10A under conventional reaction conditions well known to those skilled in the art, including the use of Pd2(dba)3 as a catalyst in the presence of a suitable base, such as sodium tert-butoxide. The reaction is typically carried out in an inert solvent, such as toluene or N,N-dimethylformamide. The reaction is typically carried out at about 25°C to about 110°C for a time sufficient to allow the reaction to be substantially completed, as demonstrated by thin-layer chromatography, for example. Once the reaction is complete, compound 19A can be obtained by carrying out isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) after conventional workup of the reaction solution.

[0156] In the next step, protecting groups such as t-butoxycarbonyl (Boc) are removed under conventional conditions, depending on the specific protecting group used. The Boc group is merely an example; other conventional amino protecting groups such as benzyl, 9-fluorenyl methoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), and p-nitrobenzyloxycarbonyl can also be used. Once the reaction is complete, compound 20A can be obtained by performing isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) after conventional workup of the reaction solution.

[0157] In the next step, at least a stoichiometric amount of compound 20A is treated with a suitable reducing agent, such as lithium aluminum hydride or borane, in an inert diluent, such as THF, MeCN, or toluene. The reaction is typically maintained at 0°C to 30°C until it is substantially complete. After conventional workup of the reaction solution, isolation / purification processes such as crystallization, chromatography, or high-performance liquid chromatography (HPLC) can be carried out to obtain compound 21A.

[0158] Next, compound 21A was subjected to Suzuki coupling with an arylboronic acid and SN coupling with a dibromoheteroaryl compound, as described in Scheme 2 above, using similar reagents and reaction conditions. AR The compound was subjected to the reaction, and finally to a Suzuki-Miyaura cross-coupling reaction with vinyl trifluoroborate, yielding compound 22A.

[0159] Other starting materials used herein are either well known in the art, commercially available, or can be prepared by conventional synthetic methods.

[0160] method In one embodiment, the compounds and compositions described herein are useful for methods of treating SMARCA2 or SMARCA4-dependent diseases or disorders, or diseases or disorders mediated at least partially by SMARCA2 or SMARCA4. The method comprises administering to a subject suffering from a SMARCA2 or SMARCA4-dependent disease or disorder an effective amount of the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0161] In one embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is provided for use in the treatment of SMARCA2 or SMARCA4-dependent diseases or disorders.

[0162] In one embodiment, the method relates to a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising such compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for use in the manufacture of a drug for reducing the level of protein expressed from the SMARCA2 or SMARCA4 gene, wherein such reduction of protein level treats or improves a disease or disorder.

[0163] In one embodiment, the method described herein includes the use of a prodrug of a compound described herein.

[0164] In one embodiment, the method relates to a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for use as described herein, or to a pharmaceutical composition comprising such compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein the degradation of proteins expressed from the SMARCA2 or SMARCA4 gene at a 1 μM concentration of the compound described herein is in the range of about 25% to 99%. The degradation of proteins expressed from the SMARCA2 or SMARCA4 gene is measured by assays described in the biological examples. In some embodiments, the degradation of proteins expressed from the SMARCA2 or SMARCA4 gene is about 25% to about 50%, about 45% to about 70%, about 65% to about 90%, or about 75% to about 99%. In some embodiments, the degradation of proteins expressed from the SMARCA2 or SMARCA4 gene is approximately 25% to 35%, 35% to 45%, 45% to 55%, 55% to 65%, 65% to 75%, 75% to 85%, and 85% to 99%. In some embodiments, the degradation of proteins expressed from the SMARCA2 or SMARCA4 gene exceeds 60%. In some embodiments, the degradation of proteins expressed from the SMARCA2 or SMARCA4 gene exceeds 70%. In some embodiments, the degradation of proteins expressed from the SMARCA2 or SMARCA4 gene exceeds 80%. In some embodiments, the degradation of proteins expressed from the SMARCA2 or SMARCA4 gene exceeds 90%.

[0165] The compounds and compositions described herein are useful for the treatment of SMARCA2 or SMARCA4-dependent diseases or disorders, such as liposarcoma, glioblastoma, bladder cancer, adrenocortical carcinoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile cancer, anal cancer, thyroid cancer, or vaginal cancer, or Epstein-Barr virus-associated nasopharyngeal cancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma, or diffuse large B-cell lymphoma. Cancers may also be selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, bile duct cancer, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancer, cancers with an immune response deficiency, immunogenic cancers, and Ewing's sarcoma. In one embodiment, SMARCA2 or SMARCA4-dependent diseases or disorders may be selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumors (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the SMARCA2 or SMARCA4-dependent disease or disorder is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite-stable colorectal cancer (mssCRC).

[0166] The compounds of this disclosure can be administered in amounts effective to treat or prevent a disorder in a subject, and / or prevent its onset.

[0167] Generally, a method of using the compounds of this disclosure involves administering a therapeutically effective amount of the compound described herein to a subject requiring its use.

[0168] In certain embodiments, the compounds described herein are useful for treating proliferative disorders (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In certain embodiments, according to the therapeutic methods of the Disclosure, contact with cells of the compounds or compositions described herein modulates the levels of target cellular proteins, such as pathogenic and oncoplastic proteins, or inhibits their proliferation or causes them to degrade. In other embodiments, the compounds are useful for treating cancer.

[0169] Accordingly, another aspect of this disclosure provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound or composition described herein to a subject in need of it. In certain embodiments, a method for treating cancer is provided, comprising administering a therapeutically effective amount of a compound, or a pharmaceutical composition containing a compound, to a subject in need of it, in the amount and for the duration necessary to achieve the desired result. In some embodiments, the compounds of this disclosure are administered orally or intravenously. In certain embodiments of this disclosure, “therapeutically effective amount” of a compound or pharmaceutical composition means an amount effective to kill or inhibit the growth of tumor cells. According to the methods of this disclosure, compounds and compositions may be administered in any amount and by any route of administration that is effective to kill or inhibit the growth of tumor cells. Accordingly, as used herein, the expression “an amount effective to kill or inhibit the growth of tumor cells” means an amount of drug sufficient to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general health of the subject, the severity of the disease, the specific anticancer agent, and its mode of administration. In certain embodiments of this disclosure, the “therapeutic effective amount” of a compound or pharmaceutical composition described herein is an amount effective in reducing the level of a target protein. In certain embodiments of this disclosure, the “therapeutic effective amount” of a compound or pharmaceutical composition is an amount effective in killing skin cells or inhibiting the proliferation of skin cells.

[0170] In certain embodiments, the method comprises administering a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to, humans or other mammals requiring it). In certain embodiments, the compounds or compositions described herein are useful for the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, gastric cancer, brain tumor, liver cancer, or esophageal cancer).

[0171] In certain embodiments, the compounds or compositions described herein are useful for the treatment of cancers and other proliferative disorders, including but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the compounds or compositions described herein are active against solid tumors.

[0172] Another aspect of the present disclosure relates to a method for treating or reducing the severity of a disease or condition associated with proliferative disorders in a patient, the method comprising the step of administering to the patient a compound of formula I, or a composition containing such compound.

[0173] It will be understood that, according to the methods of this disclosure, compounds and compositions may be administered in any amount and via any route of administration that is effective for treating cancer and / or disorders associated with cell overgrowth. For example, when using a compound to treat cancer, the expression “effective amount” as used herein refers to an amount of the drug sufficient to inhibit proliferation or sufficient to mitigate the effects of cancer. The exact amount required will vary from subject to subject, depending on the species, age, and general health of the subject, the severity of the disease, the specific anticancer agent, and its mode of administration.

[0174] This disclosure provides a method for treating proliferative disorders in subjects requiring treatment, by administering a therapeutically effective amount of the compounds disclosed, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, to subjects requiring treatment of proliferative disorders. The proliferative disorders may be cancer or precancerous conditions. This disclosure further provides the use of the compounds disclosed, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, for preparing agents useful for the treatment of proliferative disorders.

[0175] The disclosure also provides a method of protecting a subject in need of such treatment from proliferative disorders by administering a therapeutically effective amount of the compound disclosed, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, or tautomer thereof, to the subject in need of such treatment. The proliferative disorder may be cancer or a precancerous condition. The disclosure also provides the use of the compound disclosed, or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, or tautomer thereof, for the preparation of agents useful for the prevention of proliferative disorders.

[0176] As used herein, the term “proliferative disorder” refers to a condition in which uncontrolled or abnormal proliferation of cells, or both, may lead to the development of an undesirable condition or disease, which may or may not be cancerous. Illustrative proliferative disorders in this disclosure include a variety of conditions in which cell division becomes uncontrolled. Illustrative proliferative disorders include, but are not limited to, tumors, benign tumors, malignant tumors, precancerous conditions, carcinomas in situ, encapsulated tumors, metastatic tumors, humoral tumors, solid tumors, immunological tumors, hematological tumors, cancer, carcinomas, leukemia, lymphoma, sarcoma, and rapidly dividing cells. As used herein, the term “rapidly dividing cells” is defined as any cells that divide at a rate faster than or equal to the rate expected or observed between adjacent or juxtaposed cells within the same tissue. Proliferative disorders include precancerous or precancerous conditions. Proliferative disorders include cancer. Methods provided herein are used to treat or alleviate the symptoms of cancer. The term “cancer” includes not only solid tumors but also hematological malignancies and / or malignant tumors. "Precancerous cells" or "precancerous cells" are cells that exhibit proliferative disorders that are precancerous or in a precancerous state. "Cancer cells" or "cancerous cells" are cells that exhibit proliferative disorders that are cancerous. Any reproducible measurement method can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological classification or grading of tissue specimens (e.g., biopsy specimens). Cancer cells or precancerous cells can be identified using appropriate molecular markers.

[0177] In certain embodiments, provided herein is a method for treating a non-cancerous condition or disorder, comprising administering a therapeutically effective amount of a compound or composition described herein. Exemplary non-cancerous conditions or disorders that may be treatable with the compounds described herein include: rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative conditions; acromegaly; rheumatic spondylitis; osteoarthritis; gout, other arthritis; sepsis; septic shock; endotoxin shock; gram-negative bacterial sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pneumonia; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute and chronic kidney disease; irritable bowel syndrome; fever; restenosis; cerebral malaria; stroke and ischemic injury; neurological trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease Diseases; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; herniated, ruptured, or prolapsed disc syndrome; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption disorders such as osteoporosis; graft-versus-host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as herpes zoster, herpes simplex virus type 1 or 2, influenza virus, and cytomegalovirus; as well as diabetes mellitus.

[0178] In certain embodiments, provided herein is a method for treating cancer, comprising administering a therapeutically effective amount of a compound or composition described herein. Exemplary cancers include adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendiceal cancer, pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma, bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, and ependymoma. Medulloblastoma, supratentorial primordial neuroectodermal tumor, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal cancer, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid tumors, mycosis fungoides, Sézary syndrome, endometrial cancer, esophagus Cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, head and neck cancer, hepatocellular carcinoma (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, pancreatic islet cell tumor (pancreatic endocrine part), Kaposi's sarcoma, kidney cancer, kidney cancer, kidney cancer, laryngeal cancer, acute Lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-associated lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenström macroglobulinemia, medulloblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous cell carcinoma of the neck, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oral cancer, oral cavity cancerCancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial carcinoma, low-grade ovarian tumor, pancreatic cancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell tumor / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureteral cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma family tumors, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer This includes, but is not limited to, cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), Merkel cell carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (gastric) cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis, ureter, and other urinary organs, gestational trophoblastic neoplasm, urethral cancer, endometrial cancer, uterine sarcoma, endometrial cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0179] "Hematological proliferative disorders" are proliferative disorders involving cells of the blood system. Hematological proliferative disorders can include lymphoma, leukemia, myeloid neoplasm, mast cell tumor, myelodysplasia, benign monoclonal immunoglobulinemia, lymphomatoid granulomatosis, lymphomatoid papule, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown cause, and essential thrombocythemia. Hematological proliferative disorders can include hyperplasia, dysplasia, and metaplasia of cells of the blood system. The compositions of this disclosure may be used to treat cancers selected from the group consisting of hematological malignancies or hematological proliferative disorders of this disclosure. The hematological malignancies described herein may include multiple myeloma, lymphoma (including Hodgkin lymphoma, non-Hodgkin lymphoma, pediatric lymphoma, and lymphomas of lymphoid and cutaneous origin), leukemia (including pediatric leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms, and mast cell neoplasms.

[0180] "Lung proliferative disorders" are proliferative disorders affecting lung cells. Lung proliferative disorders can include any form of proliferative disorder affecting lung cells. Lung proliferative disorders can include lung cancer, precancerous or precancerous conditions of the lung, benign tumors or lesions of the lung, malignant tumors or lesions of the lung, and metastatic lesions of tissues and organs in the body other than the lungs. The compositions of this disclosure may be used to treat lung cancer or lung proliferative disorders. Lung cancer can include any form of cancer of the lung. Lung cancer can include malignant lung tumors, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer can include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous carcinoma, and mesothelioma. Lung cancer can include "scar carcinoma," bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung tumors with histological and suprastructural heterogeneity (e.g., mixed cell type).

[0181] Lung proliferative disorders can include any form of proliferative disorder affecting lung cells. Lung proliferative disorders can include lung cancer and precancerous conditions of the lung. Lung proliferative disorders can include lung hyperplasia, metaplasia, and dysplasia. Lung proliferative disorders can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Lung proliferative disorders can include replacement of columnar epithelium with stratified squamous epithelium and mucosal dysplasia. People who have inhaled harmful environmental factors such as tobacco smoke and asbestos may be at increased risk of developing lung proliferative disorders. Past lung diseases that may cause lung proliferative disorders can include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatic diseases, sarcoidosis, interstitial pneumonia, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granuloma, asbestosis, alveolitis fibrosis, and Hodgkin's disease.

[0182] "Colonial proliferative disorder" is a proliferative disorder affecting the cells of the colon. In one embodiment, colonial proliferative disorder is colon cancer. In one embodiment, the compositions of the present disclosure may be used to treat colon cancer or colonial proliferative disorder. Colon cancer can include any form of colon cancer. Colon cancer can include sporadic and hereditary colon cancer. Colon cancer can include malignant colon tumors, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma. Colon cancer can be associated with hereditary syndromes selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcott syndrome, and juvenile polyposis. Colon cancer can be caused by a genetic syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcott syndrome, and juvenile polyposis.

[0183] Colonic proliferative disorders can include any form of proliferative disorder affecting colonic cells. Colonic proliferative disorders can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Colonic proliferative disorders can include adenomas. Colonic proliferative disorders can be characterized by colonic hyperplasia, metaplasia, and dysplasia. Past colonic diseases that may lead to colonic proliferative disorders can include past colonic cancer. Current diseases that may increase the risk of developing colonic proliferative disorders can include Crohn's disease and ulcerative colitis. Colonic proliferative disorders can be associated with mutations in genes selected from the group consisting of p53, ras, FAP, and DCC. Individuals may be at higher risk of developing colonic proliferative disorders due to the presence of mutations in genes selected from the group consisting of p53, ras, FAP, and DCC.

[0184] "Pancreatic proliferative disorders" are proliferative disorders affecting the cells of the pancreas. Pancreatic proliferative disorders can include any form of proliferative disorder affecting pancreatic cells. Pancreatic proliferative disorders can include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign tumors or lesions of the pancreas, malignant tumors or lesions of the pancreas, and metastatic lesions to other tissues and organs of the body. Pancreatic cancer includes all forms of pancreatic cancer. Pancreatic cancer can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclastoid giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreaticblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma. Pancreatic cancer can also include pancreatic tumors with histological and ultrastructural heterogeneity (e.g., mixed cell type).

[0185] "Proliferative disorders of the prostate" are proliferative disorders affecting the cells of the prostate gland. Proliferative disorders of the prostate can include any form of proliferative disorder that affects prostate cells. Proliferative disorders of the prostate can include prostate cancer, precancerous or precancerous conditions of the prostate, benign tumors or lesions of the prostate, malignant tumors or lesions of the prostate, and metastatic lesions to other tissues and organs of the body. Proliferative disorders of the prostate can include prostatic hyperplasia, metaplasia, and dysplasia.

[0186] "Skin proliferative disorders" are proliferative disorders affecting skin cells. Skin proliferative disorders can include any form of proliferative disorder affecting skin cells. Skin proliferative disorders can include precancerous or precancerous conditions of the skin, benign tumors or lesions of the skin, melanoma, malignant melanoma, other malignant tumors or lesions of the skin, and metastatic lesions to tissues and organs other than the skin. Skin proliferative disorders can include skin hyperplasia, metaplasia, and dysplasia.

[0187] "Ovarian proliferative disorders" are proliferative disorders affecting ovarian cells. Ovarian proliferative disorders can include any form of proliferative disorder that affects ovarian cells. Ovarian proliferative disorders can include precancerous or precancerous conditions of the ovary, benign tumors or lesions of the ovary, ovarian cancer, malignant tumors or lesions of the ovary, and metastatic lesions of other tissues and organs in the body. Skin proliferative disorders can include hyperplasia, metaplasia, and dysplasia of ovarian cells.

[0188] "Mammary proliferative disorders" are proliferative disorders affecting the cells of the breast. Mammary proliferative disorders can include any form of proliferative disorder that affects breast cells. Mammary proliferative disorders can include breast cancer, precancerous or precancerous conditions of the breast, benign tumors or lesions of the breast, malignant tumors or lesions of the breast, and metastatic lesions to other tissues and organs of the body. Mammary proliferative disorders can include breast hyperplasia, metaplasia, and dysplasia.

[0189] Cancers being treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, with tumors (T) assigned stages TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; local lymph nodes (N) assigned stages NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and distant metastases (M) assigned stages MX, M0, or M1. Cancers being treated can also be staged according to the American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. Cancers being treated may be graded according to the AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3, or Grade 4. Cancers being treated may be staged according to the AJCC pathological classification (pN) as pNX, pN0, PN0(I-), PN0(I+), PN0(mol-), PN0(mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0190] Cancers to be treated may include tumors determined to have a diameter of approximately 2 centimeters or less. Cancers to be treated may include tumors determined to have a diameter of approximately 2 to 5 centimeters. Cancers to be treated may include tumors determined to have a diameter of approximately 3 centimeters or more. Cancers to be treated may include tumors determined to have a diameter of more than 5 centimeters. Cancers to be treated can be classified into well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated types based on their microscopic appearance. Cancers to be treated can be classified into types based on their microscopic appearance relating to mitotic number (e.g., the amount of cell division) or nuclear pleomorphism (e.g., cellular changes). Cancers to be treated can be classified into types relating to necrotic areas (e.g., areas of dead or degenerated cells) based on their microscopic appearance. Cancers to be treated can be classified into types having one or more chromosomes with karyotype abnormalities, chromosomal number abnormalities, or appearance abnormalities. Cancers to be treated can be classified into types having aneuploidy, triploidy, tetraploidy, or ploidy abnormalities. Cancers treated can be classified as those having chromosomal translocations, deletions or duplications of entire chromosomes, or deletions, duplications, or amplification regions of parts of chromosomes.

[0191] Cancers to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. Cancers to be treated can be classified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthetic stage of cell division (e.g., S phase of cell division). Cancers to be treated can be classified as having a low S phase fraction or a high S phase fraction.

[0192] As used herein, “normal cells” are cells that cannot be classified as part of “proliferative disorders.” Normal cells lack uncontrolled proliferation or abnormal proliferation, or both, which can lead to the development of an undesirable condition or disease. In one embodiment, normal cells have a normally functioning cell cycle checkpoint control mechanism.

[0193] Those skilled in the art may refer to general references for detailed descriptions of known techniques or equivalent techniques discussed herein. These references include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005), Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000), Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY, Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, NY, and Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). Of course, these references can also be referenced when creating or using aspects of this disclosure.

[0194] In certain embodiments, the compounds of this disclosure are useful for treating proliferative disorders (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In certain embodiments, according to the therapeutic methods of this disclosure, contact with cells of the compounds or compositions described herein modulates the levels of target cellular proteins, such as pathogenic proteins and oncogeneic proteins, or inhibits their proliferation. In other embodiments, the compounds are useful for treating cancer.

[0195] In certain embodiments, the method comprises administering a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to, humans or animals) that requires it. In certain embodiments, the compound is useful in the treatment of cancer (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colon and rectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, gastric cancer, brain tumor, liver cancer, or esophageal cancer).

[0196] In certain embodiments, the methods provided herein further include the administration of an anticancer agent. In certain embodiments, the anticancer agent is useful for the treatment of cancer and other proliferative disorders, including but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the anticancer agent is active against solid tumors.

[0197] Furthermore, this disclosure provides pharmaceutically acceptable derivatives of the compound, and methods for treating a subject using these compounds, their pharmaceutically acceptable compositions, or any of these in combination with one or more additional therapeutic agents.

[0198] In certain embodiments, the additional therapeutic agent is another therapeutic or anticancer agent. For example, other therapeutic or anticancer agents that may be used in combination with the compounds disclosed herein include surgery, radiotherapy, endocrine therapy, biological reaction modifiers (such as interferon, interleukin, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, agents to reduce any side effects (such as antiemetics), as well as alkylating agents (mechloretamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluoro Other approved chemotherapy drugs include, but are not limited to, uracil, cytarabine, gemcitabine, spindle toxins (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol). For a more comprehensive discussion of cancer treatments, please refer to The Merck Manual, Twentieth Ed. 2020, which is incorporated herein by reference in its entirety. For a list of FDA-approved oncology drugs, please also refer to the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website (www.fda.gov / cder / cancer / druglistframe).

[0199] In certain embodiments, a pharmaceutical composition comprising the compounds disclosed herein further comprises one or more additional therapeutic active ingredients (e.g., chemotherapeutic agents and / or palliative agents). For the purposes of this disclosure, the term “palliative” refers to treatment that focuses on reducing the symptoms of a disease and / or the side effects of a treatment regimen, but is not curative. For example, palliative treatments include analgesics, antiemetics, and anti-nausea drugs. In addition, chemotherapy, radiotherapy, and surgery can all be used palliatively (i.e., to alleviate symptoms without curing, for example, to shrink a tumor and reduce cancer pressure, bleeding, pain, and other symptoms).

[0200] Administration, pharmaceutical composition The administration of the disclosed compounds and pharmaceutical compositions can be achieved by any mode of administration of the therapeutic agent. These modes include systemic or topical administration, such as oral, nasal, extra-gastrointestinal, transdermal, subcutaneous, vaginal, oral, rectal, or topical administration.

[0201] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, and sometimes in unit doses, consistent with conventional pharmaceutical practices. Similarly, they may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, all of which may be administered using forms well known to those skilled in the art of pharmaceuticals.

[0202] Exemplary pharmaceutical compositions include the compounds of the Disclosure and pharmaceutically acceptable carriers, for example, a) diluents, for example, purified water, triglyceride oils, for example, hydrogenated or partially hydrogenated vegetable oils, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, for example, EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, c) Binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, e.g., glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g., acacia, tragacanth or sodium alginate, wax, and / or polyvinylpyrrolidone; d) Disintegrants, e.g., starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) Absorbents, colorants, flavorings, and sweeteners; f) Emulsifiers or dispersants, e.g., Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, Vitamin E TGPS or other acceptable emulsifiers;Furthermore / or g) tablets and gelatin capsules containing agents that promote the absorption of compounds, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, and PEG200.

[0203] Liquids, particularly injectable compositions, can be prepared by means of dissolution, dispersion, etc. For example, the disclosed compounds may be dissolved or mixed in a pharmaceutically acceptable solvent such as water, saline, aqueous dextrose, glycerol, or ethanol to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins may be used to solubilize the disclosed compounds.

[0204] The disclosed compounds can also be formulated as suppositories that can be prepared from lipid emulsions or suspensions using polyalkylene glycols such as propylene glycol as a carrier.

[0205] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. The liposomes can be formed from various phospholipids, including cholesterol, stearylamine, or phosphatidylcholine.

[0206] In some embodiments, a film of lipid components is hydrated with an aqueous solution of the drug to form a lipid layer that encapsulates the drug, as described in U.S. Patent No. 5,262,564, which is incorporated entirely herein by reference.

[0207] The disclosed compounds can also be delivered by using monoclonal antibodies as individual carriers to which the disclosed compounds are conjugated. The disclosed compounds can also be conjugated to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamidophenol, polyhydroxyethyl aspartamidephenol, or polyoxyethylene polylysine, which are substituted with palmitoyl residues. Furthermore, the disclosed compounds can be conjugated to a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In one embodiment, the disclosed compounds are not covalently bonded to polymers such as polycarboxylic acid polymers or polyacrylates.

[0208] Parenteral administration is generally performed by subcutaneous, intramuscular, or intravenous injection and infusion. Injectable drugs can be prepared in conventional forms, either as a liquid solution or suspension, or as a solid form suitable for dissolving in a liquid before injection.

[0209] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier may further comprise excipients, diluents, or surfactants.

[0210] Each composition can be prepared according to conventional mixing, granulation, or coating methods, and the pharmaceutical compositions may contain the disclosed compounds in amounts of about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume.

[0211] In one embodiment, the Disclosure provides a kit comprising two or more distinct pharmaceutical compositions, at least one of which comprises a compound of the Disclosure. In one embodiment, the kit includes means for holding the compositions separately, such as containers, divided bottles, or divided foil packets. An example of such a kit is typically a blister pack used for packaging tablets, capsules, and the like.

[0212] The kits of this disclosure may be used to administer different dosage forms, such as oral and parenteral administration, to administer separate compositions at different dosing intervals, or to titrate separate compositions with respect to each other. To assist compliance, the kits of this disclosure typically include instructions for administration.

[0213] The pharmaceutically acceptable dosage forms of the compounds of this disclosure may be produced by any of the methods well known in the art, such as conventional mixing, sieving, dissolution, melting, granulation, dragee production, tableting, suspension, extrusion, spray drying, excipient formation, emulsification, (nano / micro)encapsulation, encapsulation, or freeze-drying processes. As described above, the compositions of this disclosure may contain one or more physiologically acceptable inert components that facilitate the processing of the active molecule into a preparation for pharmaceutical use.

[0214] As described above, the compositions generally consist of the compounds of the present disclosure in combination with at least one pharmaceutically acceptable excipient. The acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic effect of the claimed compound. Such excipients may be any solid, liquid, semi-solid, or gaseous excipient in the case of an aerosol composition, which are generally available to those skilled in the art.

[0215] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, and dried skim milk powder. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, plant, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). In some embodiments, liquid carriers, particularly for injectable solutions, include water, physiological saline, aqueous dextrose, and glycol.

[0216] Compressed gases may be used to disperse the compounds of this disclosure in aerosol form. Suitable inert gases for this purpose include nitrogen and carbon dioxide. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 18th ed., 1990).

[0217] The compositions of the present disclosure may, as necessary, be provided in packs or dispenser devices containing one or more unit dosage forms containing the active ingredient. Such packs or devices may consist of, for example, metal or plastic foil such as blister packs, or glass and rubber stoppers such as vials. The packs or dispenser devices may be accompanied by instructions for administration. Furthermore, compositions containing the compounds of the present disclosure, formulated in a suitable pharmaceutical carrier, may be prepared, placed in appropriate containers, and labeled for the treatment of the indicated symptoms.

[0218] The amount of compound in a formulation can vary within the entire range adopted by those skilled in the art. Typically, a formulation contains about 0.01 to 99.99% by weight (wt%) of the compound in this disclosure, based on the total formulation, with the remainder being one or more preferred pharmaceutically acceptable excipients. In one embodiment, the compound is present at a level of about 1 to 80% by weight. Representative pharmaceutically acceptable formulations are described below.

[0219] Formulation Examples The following are representative pharmaceutical preparations containing the compounds of this disclosure.

[0220] Formulation Example 1 - Tablet Formulation Mix the following ingredients thoroughly and compress them into scored tablets. TIFF2026522333000055.tif36170

[0221] Formulation Example 2 - Capsule Formulation Mix the following ingredients thoroughly and fill them into hard-shell gelatin capsules. TIFF2026522333000056.tif30170

[0222] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration. TIFF2026522333000057.tif71170

[0223] Formulation Example 4 - Injectable Formulation TIFF2026522333000058.tif36170

[0224] Formulation Example 5 - Suppository Formulation A suppository weighing 2.5 g is prepared by mixing the compound of this disclosure with Witepsol® H-15 (saturated vegetable fatty acid triglyceride; Riches-Nelson, Inc., New York), and has the following composition: TIFF2026522333000059.tif18170

[0225] Dosage Dosage regimens utilizing the disclosed compounds are selected according to various factors, including the patient's type, breed, age, weight, sex, and condition, the severity of the condition being treated, the route of administration, the patient's renal or hepatic function, and the specific disclosed compound being used. A physician or veterinarian skilled in the art can easily determine and prescribe the effective dose of the drug necessary to prevent, suppress, or halt the progression of the condition.

[0226] The effective dose of the compound, when used for the indicated effect, ranges from about 0.5 mg to about 5000 mg of the disclosed compound, as needed to treat the condition. Compositions for use in vivo or in vitro may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or in a range from any of the amounts in the dosage list to another. In one embodiment, the composition is in the form of a scored tablet. [Examples]

[0227] This disclosure will be further understood by reference to the following embodiments, which are intended purely as examples of the disclosure. The scope of this disclosure is not limited by the illustrated embodiments, which are intended only as examples of a single aspect of the disclosure. All functionally equivalent methods are within the scope of this disclosure. Various modifications of this disclosure, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are included within the scope of the accompanying claims.

[0228] In this specification and the following examples, all temperatures are expressed in degrees Celsius. The following abbreviations have the meanings set forth below. Unless otherwise defined, these abbreviations have meanings known to those skilled in the art. TIFF2026522333000060.tif249170TIFF2026522333000061.tif151170

[0229] LC-MS method (general method) The experiment was conducted using Xbridge-C. 18 The analysis was performed using a 2.1 × 50 mm column (5 μm particles) LC column. LC / MS: The gradient was 5%B at 0.40 min, 5–95%B from 0.40 to 3.40 min, with 95%B held for 0.45 min, followed by 95–5%B at 0.01 min, with a flow rate of 0.8 ml / min. Mobile phase A was H2O + 10 mM NH4HCO3, and mobile phase B was acetonitrile. The LC column temperature was 40°C. Detection methods included diode array (DAD) and evaporative light scattering (ELSD) detection, as well as positive electrospray ionization. The MS range was 100–1000.

[0230] Example 1 Preparation of o-{6-amino-5-[4-(2-vinyl-4-pyrimidinyl)-1,4-diazepan-1-yl]-3-pyridazinyl}phenol (compound 58): [ka] Step 1: [ka] To a solution of tert-butyl 1,4-diazepan-1-carboxylate (800.69 mg, 4.00 mmol, 784.99 μL, 1 equivalent) and 4-bromo-6-chloropyridazine-3-amine (1 g, 4.80 mmol, 1.2 equivalents) in EtOH (10 mL), DIEA (5.17 g, 39.98 mmol, 6.96 mL, 10 equivalents) was added. The mixture was stirred at 100 °C for 12 hours. The reaction product was concentrated under reduced pressure to obtain tert-butyl 4-(3-amino-6-chloropyridazine-4-yl)-1,4-diazepan-1-carboxylate. m / z (ESI + ) 328.2 (M+H) + .

[0231] Step 2: [ka] A mixture of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)-1,4-diazepane-1-carboxylate (0.4 g, 1.22 mmol, 1 equivalent), (2-hydroxyphenyl)boronic acid (252.46 mg, 1.83 mmol, 1.5 equivalents), Pd(dppf)2Cl2 (89.28 mg, 122.02 μmol, 0.1 equivalent), and Cs2CO3 (2.39 g, 7.32 mmol, 6 equivalents) in dioxane (10 mL) and H2O (4 mL) was degassed and purged with N2. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction product was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 0% to 100% ethyl acetate in petroleum ether) to obtain tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-carboxylate. m / z (ESI + ):328.1 (M-100+H) + .

[0232] Step 3: [ka] To a solution of tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-carboxylate (0.5 g, 1.30 mmol, 1 equivalent) in DCM (4 mL), TFA (2 mL) was added. The mixture was stirred at 25°C for 3 hours. The reaction product was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 0% to 100% ethyl acetate in petroleum ether) to obtain 2-(6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl)phenol. 1H NMR (400 MHz, d6-DMSO) δ ppm 8.97 (br s, 2 H), 7.57 (d, J = 7.6 Hz), 7.41 - 7.37 (m, 2 H), 7.05 - 6.96 (m, 4H), 3.85 (br s, 2H), 3.64 (br s, 2H), 3.36 (br s, 2H), 3.27 (br s, 2H), 2.10 (br s, 2H).

[0233] Step 4: [ka] To a solution of 2-(6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl)phenol (650 mg, 2.28 mmol, 1 equivalent) and 2,4-dibromopyrimidine (812.82 mg, 3.42 mmol, 1.5 equivalents) in DMF (6 mL), DIEA (1.47 g, 11.39 mmol, 1.98 mL, 5 equivalents) and DMAP (27.83 mg, 227.80 μmol, 0.1 equivalent) were added. The mixture was stirred at 25°C for 12 hours. Water (20 mL) was added at 0°C, and the reaction mixture was filtered. The filtered cake was subjected to preparative HPLC (column: Waters Xbridge Prep OBD C). 18 The sample was purified using a 150×40mm×10μm mobile phase (water (NH3H2O ​​+ NH4HCO3) - ACN) for 8 minutes to obtain 2-(6-amino-5-(4-(2-bromopyrimidine-4-yl)-1,4-diazepan-1-yl)pyridazine-3-yl)phenol. 1H NMR (400 MHz, d6-DMSO) δ 14.15 (br s, 1H), 7.97 ( s, 1H), 7.86 ( d, J = 7.2 Hz, 1H), 7.51 (s, 1H), 7.28 - 7.17 (m, 1H), 6.88 (J = 2.4, 7.6 Hz, 2H), 6.80 (d, J = 6.4 Hz, 1H), 6.19 (s, 2H), 4.00 (s, 1H), 3.86 (s, 1H), 3.77 (s, 1H), 3.67 (s, 1H), 3.48 - 3.41 (m, 2H), 3.28 (s, 2H), 2.06 (d, J = 4.8 Hz, 2H).

[0234] Step 5: [ka] A mixture of 2-(6-amino-5-(4-(2-bromopyrimidine-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (50 mg, 113.04 μmol, 1 equivalent), trifluoro(vinyl)-14-borane, potassium salt (30.28 mg, 226.08 μmol, 2 equivalents), Pd(dppf)Cl2 (8.27 mg, 11.30 μmol, 0.1 equivalent), and Cs2CO3 (110.49 mg, 339.13 μmol, 3 equivalents) in dioxane (1 mL) and water (0.5 mL) was degassed and then heated to 80°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated to obtain the residue. The residue was purified by preparative HPLC (neutral conditions) to obtain o-{6-amino-5-[4-(2-vinyl-4-pyrimidinyl)-1,4-diazepan-1-yl]-3-pyridazinyl}phenol. 1H NMR (400 MHz, CD3OD) δ 8.07 (d, J = 6.4 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.48 (s, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.95 - 6.82 (m, 2H), 6.72 - 6.57 (m, 2H), 6.54 - 6.43 (m, 1H), 5.63 (dd, J = 1.6, 10.4 Hz, 1H), 4.26 - 3.76 (m, 4H), 3.59 (t, J = 5.2 Hz, 2H), 3.42 (d, J = 4.4 Hz, 2H), 2.15 (d, J = 3.6 Hz, 2H).

[0235] Example 2 Preparation of o-(6-amino-5-{1-[1-(2-vinyl-4-pyridyl)ethyl]-4-pyrazolyl}-3-pyridazinyl)phenol (compound 2): [ka] Step 1: [ka] To a mixture of 1-(2-chloropyridine-4-yl)ethane-1-one (2.0 g, 12.8 mmol, 1.0 equivalent) in THF (40 mL), NaBH4 (486.3 mg, 12.8 mmol, 1.0 equivalent) was gradually added under N2 conditions at 0°C. After addition, the mixture was stirred at 20°C for 2 hours. 1N HCl (5 mL) was added at 0°C. H2O (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(2-chloropyridine-4-yl)ethane-1-ol. 1H NMR (400 MHz, d6-DMSO) δ 8.33 (d, J = 5.2 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.38 - 7.36 (m, J = 0.8, 5.2 Hz, 1H), 5.54 (d, J = 4.8 Hz, 1H), 4.82 - 4.67 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H).

[0236] Step 2: [ka] To a solution of 1-(2-chloropyridine-4-yl)ethane-1-ol (1.5 g, 9.52 mmol, 1.0 equivalent) and PPh3 (4.9 g, 19.0 mmol, 2.0 equivalents) in DCM (20 mL), NBS (2.5 g, 14.2 mmol, 1.5 equivalents) was gradually added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was partitioned between DCM (10 mL) and H2O (20 mL). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 20%-50% ethyl acetate in petroleum ether) to obtain 4-(1-bromoethyl)-2-chloropyridine. 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (d, J = 4.8 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 5.44 (q, J = 6.8 Hz, 1H), 1.96 (d, J = 6.8 Hz, 3H).

[0237] Step 3: [ka] A mixture of 4-bromo-6-chloropyridazine-3-amine (1.0 g, 4.8 mmol, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.4 g, 7.2 mmol, 1.5 equivalent), Cs2CO3 (4.6 g, 14.3 mmol, 3.0 equivalent), and Pd(dppf)Cl2 (351.0 mg, 479.7 μmol, 0.1 equivalent) in dioxane (20 mL) and H2O (10 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered, and the filtered cake was dried to obtain 6-chloro-4-(1H-pyrazole-4-yl)pyridazine-3-amine. 1 H NMR (400 MHz, d6-DMSO) δ 13.36 (s, 1H), 8.47 - 8.03 (m, 2H), 7.61 (s, 1H), 6.37 (s, 2H).

[0238] Step 4: [ka] A mixture of 6-chloro-4-(1H-pyrazole-4-yl)pyridazine-3-amine (500.0 mg, 2.5 mmol, 1.0 equivalent), [2-(methoxymethoxy)phenyl]boronic acid (697.7 mg, 3.8 mmol, 1.5 equivalent), Pd(dppf)Cl2 (187.0 mg, 255.6 μmol, 0.1 equivalent), and Cs2CO3 (2.5 g, 7.6 mmol, 3.0 equivalent) in dioxane (20 mL) and H2O (10 mL) was degassed and purged three times with N2. The mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (20 mL) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 15%-50% methanol in ethyl acetate) to obtain 6-(2-(methoxymethoxy)phenyl)-4-(1H-pyrazole-4-yl)pyridazine-3-amine. m / z (ESI + ):298.0 (M+H)+ .

[0239] Step 5: [ka] A mixture of 6-(2-(methoxymethoxy)phenyl)-4-(1H-pyrazole-4-yl)pyridazine-3-amine (60.0 mg, 201.8 μmol, 1.0 equivalent), 4-(1-bromoethyl)-2-chloropyridine (133.4 mg, 605.4 μmol, 3.0 equivalents), and Cs2CO3 (197.2 mg, 605.4 μmol, 3.0 equivalents) in DMF (1 mL) was stirred at 100°C for 2 hours. The reaction mixture was partitioned between ethyl acetate (2 mL) and H2O (2 mL). The organic phase was separated, washed with brine (2 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, ethyl acetate, 20%-50% methanol) to obtain 4-(1-(1-(2-chloropyridine-4-yl)ethyl)-1H-pyrazole-4-yl)-6-(2-(methoxymethoxy)phenyl)pyridazine-3-amine. 1 H NMR (400 MHz, d6-DMSO) δ 8.51 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.65 (dd, J = 1.6, 7.6 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.29 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.26 (s, 2H), 5.76 (q, J = 6.8 Hz, 1H), 5.22 (s, 2H), 3.31 - 3.31 (m, 3H), 1.86 (d, J = 7.2 Hz, 3H).

[0240] Step 6: [ka] A mixture of 4-(1-(1-(2-chloropyridine-4-yl)ethyl)-1H-pyrazole-4-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine (30.0 mg, 68.6 μmol, 1.0 equivalent) in HCO2H (0.5 mL) was stirred at 20°C for 2 hours. The reaction mixture was partitioned between ethyl acetate (1 mL) and H2O (1 mL). The organic phase was separated, washed with brine (0.5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(6-amino-5-(1-(1-(2-chloropyridine-4-yl)ethyl)-1H-pyrazole-4-yl)pyridazin-3-yl)phenol. m / z (ESI + ):393.0 (M+H) + .

[0241] Step 7 [ka] A mixture of 2-(6-amino-5-(1-(1-(2-chloropyridine-4-yl)ethyl)-1H-pyrazole-4-yl)pyridazin-3-yl)phenol (20.0 mg, 50.9 μmol, 1.0 equivalent), potassium trifluoro(vinyl) borate (20.4 mg, 152.7 μmol, 3.0 equivalent), Pd(dppf)Cl2 (3.7 mg, 5.0 μmol, 0.1 equivalent), and Cs2CO3 (49.7 mg, 152.7 μmol, 3.0 equivalent) in dioxane (1 mL) and H2O (0.5 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (1 mL) and H2O (1 mL). The organic phase was separated, washed with brine (1 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (instrument: Gilson 281 semi-preparative HPLC system; mobile phase: A: FA / H2O = 0.075% v / v; B: ACN; column: Phenomenex Gemini-NX C 18The sample was purified using a 75mm × 30mm × 3μm filter (flow rate: 25mL / min) to obtain o-(6-amino-5-{1-[1-(2-vinyl-4-pyridyl)ethyl]-4-pyrazolyl}-3-pyridazinyl)phenol. 1 H NMR (400 MHz, CD3OD) δ 8.48 - 8.44 (m, 2H), 8.13 (s, 2H), 7.86 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 4.8 Hz, 1H), 6.98 - 6.91 (m, 2H), 6.82 (dd, J = 10.8, 17.6 Hz, 1H), 6.19 (d, J = 18.0 Hz, 1H), 5.76 (q, J = 7.6 Hz, 1H), 5.53 (d, J = 11.2 Hz, 1H), 1.99 (d, J = 7.2 Hz, 3H).

[0242] Example 3 Preparation of o-{6-amino-5-[3-(2-vinyl-4-pyridyloxy)-1-azetidinyl]-3-pyridazinyl}phenol (compound 4): [ka] Step 1: [ka] A mixture of 4-bromo-6-chloropyridazine-3-amine (5 g, 23.99 mmol, 1 equivalent), azetidine-3-ol (2.63 g, 23.99 mmol, 1 equivalent, HCl salt), and DIEA (31.00 g, 239.87 mmol, 41.78 mL, 10 equivalents) in DMF (50 mL) was degassed and purged three times with N2. The mixture was stirred at 120°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, 0%-10% methanol in ethyl acetate) to obtain 1-(3-amino-6-chloropyridazine-4-yl)azetidine-3-ol. 1H NMR (400 MHz, d6-DMSO) δ 6.32 (s, 1H), 5.73 (s, 2H), 5.68 (d, J = 6.4 Hz, 1H), 4.52 - 4.46 (m, 1H), 4.35 - 4.28 (m, 2H), 3.73 (dd, J = 4.8, 9.2 Hz, 2H).

[0243] Step 2: [ka] A mixture of 1-(3-amino-6-chloropyridazin-4-yl)azetidine-3-ol (4.4 g, 21.93 mmol, 1 equivalent), [2-(methoxymethoxy)phenyl]boronic acid (4.39 g, 24.12 mmol, 1.1 equivalent), Pd(dppf)Cl2 (1.60 g, 2.19 mmol, 0.1 equivalent), and Cs2CO3 (42.87 g, 131.59 mmol, 6 equivalents) in dioxane (45 mL) and water (22.5 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 5 hours under an N2 atmosphere. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The mixed organic layer was washed with brine (2 × 50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was ground in ACN (20 mL) at 20°C for 30 minutes to obtain 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetidine-3-ol. 1 H NMR (400 MHz, d6-DMSO) δ 7.59 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.65 (s, 1H), 5.68 (s, 1H), 5.61 (s, 2H), 5.20 (s, 2H), 4.50 (d, J = 6.0 Hz, 1H), 4.28 (t, J = 7.2 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H), 3.38 - 3.36 (m, 3H).

[0244] Step 3: [ka] To a solution of 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetidine-3-ol (1 g, 3.31 mmol, 1 equivalent) in DMF (10 mL), NaH (661.47 mg, 16.54 mmol, 60% purity, 5 equivalents) was added gradually under N2 at 0°C. After 10 minutes, 2-bromo-4-fluoropyridine (582.10 mg, 3.31 mmol, 1 equivalent) in DMF (5 mL) was added dropwise to the solution under N2 at 0°C. The mixture was stirred at 20°C for 1 hour. A saturated NH4Cl solution (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The mixed organic layer was washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was ground with ACN (5 mL) at 20°C for 30 minutes to obtain 4-(3-((2-bromopyridine-4-yl)oxy)azetidine-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazine-3-amine). 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (d, J = 6.0 Hz, 1H), 7.59 (dd, J = 1.6, 7.6 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.21 - 7.15 (m, 2H), 7.08 (dt, J = 1.2, 7.6 Hz, 1H), 7.01 (dd, J = 2.4, 5.6 Hz, 1H), 6.73 (s, 1H), 5.66 (s, 2H), 5.23 (td, J = 2.8, 6.4 Hz, 1H), 5.19 (s, 2H), 4.49 (dd, J = 6.4, 9.6 Hz, 2H), 4.08 - 4.01 (m, 2H), 3.33 (s, 3H).

[0245] Step 4: [ka] A mixture of 4-(3-((2-bromopyridine-4-yl)oxy)azetidine-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine (140 mg, 305.47 μmol, 1 equivalent) in HCO2H (1.4 mL) was stirred at 20°C for 5 hours. The reaction mixture was quenched at 20°C by adding NaHCO3 (5 mL) and extracted with ethyl acetate (3 × 2 mL). The mixed organic layer was washed with brine (2 × 2 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC to obtain 2-(6-amino-5-(3-((2-bromopyridine-4-yl)oxy)azetidine-1-yl)pyridazin-3-yl)phenol. 1 H NMR (400 MHz, d6-DMSO) δ 14.62 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.92 (dd, J = 1.6, 8.4 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.06 - 7.01 (m, 2H), 6.88 - 6.83 (m, 2H), 5.97 (s, 2H), 5.27 (dt, J = 3.6, 6.4 Hz, 1H), 4.65 (dd, J = 6.4, 9.6 Hz, 2H), 4.22 (dd, J = 3.2, 9.6 Hz, 2H).

[0246] Step 5: [ka] A mixture of 2-(6-amino-5-(3-((2-bromopyridine-4-yl)oxy)azetidine-1-yl)pyridazin-3-yl)phenol (20 mg, 48.28 μmol, 1 equivalent), difluoro-[(Z)-vinylboranylidene-fluoranyl]potassium (19.40 mg, 144.84 μmol, 3 equivalents), Cs2CO3 (47.19 mg, 144.84 μmol, 3 equivalents), and Pd(dppf)Cl2 (3.53 mg, 4.83 μmol, 0.1 equivalent) in dioxane (0.2 mL) and H2O (0.1 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC to obtain o-{6-amino-5-[3-(2-vinyl-4-pyridyloxy)-1-azetidinyl]-3-pyridazinyl}phenol. 1 H NMR (400 MHz, d6-DMSO) δ 8.41 (d, J = 5.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.06 - 7.02 (m, 2H), 6.87 (d, J = 7.6 Hz, 2H), 6.85 - 6.81 (m, 2H), 6.81 - 6.73 (m, 1H), 6.27 (dd, J = 1.6, 17.6 Hz, 1H), 5.99 (s, 2H), 5.48 (dd, J = 1.6, 10.8 Hz, 1H), 5.25 (td, J = 3.2, 6.4 Hz, 1H), 4.68 (dd, J = 6.4, 9.2 Hz, 2H), 4.26 - 4.18 (m, 2H).

[0247] Example 4 Preparation of o-[(R)-5-methyl-6-(2-vinyl-4-pyridyl)-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraazafluoren-3-yl]phenol and o-[(S)-5-methyl-6-(2-vinyl-4-pyridyl)-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraazafluoren-3-yl]phenol: [ka] Step 1: [ka] To a solution of 4-bromo-6-chloropyridazine-3-amine (36 g, 172.7 mmol, 1.0 equivalent) in DMF (200 mL), tert-butyl N-buta-3-inylcarbamate (43.8 g, 259.1 mmol, 1.5 equivalents), CuI (3.3 g, 17.3 mmol, 0.1 equivalent), triethylamine (174.7 g, 1.7 mol, 120.2 mL, 10.0 equivalents), and Pd(PPh3)4 (10.0 g, 8.6 mmol, 0.05 equivalents) were added, and the resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (600 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 10% to 50% ethyl acetate in petroleum ether) to obtain tert-butyl(4-(3-amino-6-chloropyridazine-4-yl)buta-3-in-1-yl)carbamate. 1 H NMR (400 MHz, d6-DMSO) δ 7.49 (s, 1H), 6.85 (br s, 2H), 3.26 - 3.15 (m, 2H), 2.63 (t, J = 6.4 Hz, 2H), 1.39 (s, 9H).

[0248] Step 2: [ka] To a solution of tert-butyl(4-(3-amino-6-chloropyridazine-4-yl)buta-3-in-1-yl)carbamate (23 g, 77.5 mmol, 1.0 equivalent) in THF (150 mL), t-BuOK (1 M in THF, 93.0 mL, 1.2 equivalents) was added at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (80 mL) at 0°C. The mixture was diluted with H2O (300 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 12.5-50% ethyl acetate in petroleum ether) to obtain tert-butyl(2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethyl)carbamate. 1 H NMR (400 MHz, d6-DMSO) δ 12.47 (s, 1H), 7.86 (s, 1H), 7.01 (t, J = 5.2 Hz, 1H), 6.32 (s, 1H), 3.39 - 3.35 (m, 2H), 2.95 (t, J = 6.8 Hz, 2H), 1.36 (s, 9H).

[0249] Step 3: [ka] A solution of tert-butyl(2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethyl)carbamate (10 g, 33.7 mmol, 1.0 equivalent) in HCl / dioxane (150 mL) was stirred at 25°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to obtain 2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethane-1-amine, which was used directly in the next step without further purification. 1 H NMR (400 MHz, d6-DMSO) δ 12.68 (s, 1H), 8.16 (s, 2H), 3.29 - 3.13 (m, 4H).

[0250] Step 4: [ka] To a solution of 2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethane-1-amine (4.5 g, 22.9 mmol, 1.0 equivalent) in H2O (30 mL), acetaldehyde (5.0 g, 45.8 mmol, 6.4 mL, 40% purity, 2.0 equivalents) and NaOH (1 M, 45.8 mL, 2.0 equivalents) were added at 25°C. The mixture was stirred at 70°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove H2O. The crude product was ground with ACN to obtain 3-chloro-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine. 1 H NMR (400 MHz, d6-DMSO) δ 7.50 (s, 1H), 4.03 (d, J = 6.8 Hz, 1H), 3.51 - 3.36 (m, 2H), 3.17 (s, 3H), 2.91 - 2.79 (m, 2H), 1.35 (d, J = 6.8Hz, 3H).

[0251] Step 5: [ka] A mixture of 3-chloro-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine (1 g, 4.49 mmol, 1 equivalent), Boc2O (2.45 g, 11.23 mmol, 2.58 mL, 2.5 equivalents), and DIEA (1.74 g, 13.47 mmol, 2.35 mL, 3 equivalents) in THF (10 mL) was degassed and purged three times with N2. The mixture was stirred under an N2 atmosphere at 25°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, 1% to 50% ethyl acetate in petroleum ether) to obtain di-tert-butyl3-chloro-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate. 1H NMR (400 MHz, CDCl3) δ 7.56 - 7.43 (m, 1H), 5.30 - 4.20 (m, 2H), 3.30 - 3.02 (m, 3H), 1.70 (s, 10H), 1.51 (s, 10H), 1.46 (d, J = 6.8 Hz, 4H).

[0252] Step 6: [ka] A mixture of di-tert-butyl 3-chloro-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate (1 g, 2.36 mmol, 1 equivalent), [2-(methoxymethoxy)phenyl]boronic acid (645.47 mg, 3.55 mmol, 1.5 equivalents), BrettPhos Pd G3 (214.35 mg, 236.46 μmol, 0.1 equivalent), and K2CO3 (653.62 mg, 4.73 mmol, 2 equivalents) in dioxane (30 mL) and water (7 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. Three additional reaction products were prepared as described above, and all reaction mixtures were combined for workup. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over Na₂SO₄ and concentrated under vacuum to obtain di-tert-butyl 3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate, which was used directly without further purification.

[0253] Step 7: [ka] To a solution of di-tert-butyl 3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate (1 g, 1.91 mmol, 1 equivalent) in DCM (10 mL), TFA (5 mL) was added at 20°C and the mixture was stirred for 10 minutes. The reaction mixture was concentrated and ground with MTBE (5 mL) for 30 minutes to obtain 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-3-yl)phenol. 1 H NMR (400 MHz, d6-DMSO) δ 10.44 - 10.24 (m, 1H), 9.97 - 9.78 (m, 1H), 8.71 (s, 1H), 7.75 - 7.62 (m, 1H), 7.48 - 7.36 (m, 1H), 7.19 - 7.11 (m, 1H), 7.08 - 7.01 (m, 1H), 4.84 - 4.79 (m, 1H), 3.72 - 3.20 (m, 4H), 1.76 (d, J = 6.4 Hz, 3H).

[0254] Step 8: [ka] A mixture of 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol (2.2 g, 7.85 mmol, 1 equivalent), TEA (5.56 g, 54.94 mmol, 7.65 mL, 7 equivalents), Boc2O (5.99 g, 27.47 mmol, 6.31 mL, 3.5 equivalents), and DMAP (95.88 mg, 784.81 μmol, 0.1 equivalent) in DMF (20 mL) was degassed and purged three times with N2. The mixture was stirred under an N2 atmosphere at 40°C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, 5% to 25% ethyl acetate in petroleum ether) to obtain di-tert-butyl 3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate. m / z (ESI + ): 581.5 (M+H) + .

[0255] Step 9: [ka] Di-tert-butyl 3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate (4g, 6.89 mmol) was processed using SFC (Instrument: Waters SFC350 preparative SFC system; Column: DAIEL CHIRALPAK). Separation by AD (250mm x 50mm, 10μm; mobile phase: CO2 A and EtOH B (0.1% NH4.OH); gradient: B% = 14.00% uniform concentration elution mode; flow rate: 180.00g / min; detection wavelength: 220 and 254nm; column temperature: 40℃) yielded di-tert-butyl 3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate, isomer 1( 1 H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.87 - 7.83 (m, 1H), 7.59 - 7.51 (m, 1H), 7.49 - 7.43 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.44 - 5.29 (m, 1H), 4.41 (d, J = 3.2 Hz, 1H), 3.27 - 2.92 (m, 3H), 1.72 (s, 9H), 1.54 - 1.51 (m, 12H), 1.28 (s, 9H)), and di-tert-butyl 3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate, isomer 2( 1¹H NMR (400 MHz, CD3OD) yielded the following δ values: 8.02 (s, 1H), 7.87 - 7.83 (m, 1H), 7.59 - 7.51 (m, 1H), 7.49 - 7.43 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 5.44 - 5.29 (m, 1H), 4.41 (d, J = 3.2 Hz, 1H), 3.27 - 2.92 (m, 3H), 1.72 (s, 9H), 1.54 - 1.51 (m, 12H), 1.28 (s, 9H).

[0256] Step 10: [ka] To a solution of one enantiomer of di-tert-butyl 3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylate (1.3 g, 2.24 mmol, 1 equivalent) in DCM (13 mL), TFA (1.28 g, 11.19 mmol, 831.51 μL, 5 equivalents) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was ground with methyl tert-butyl ether (10 mL) for 30 minutes to obtain 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol trifluroacetate. 1 H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 7.68 - 7.63 (m, 1H), 7.55 - 7.45 (m, 1H), 7.15 - 7.05 (m, 2H), 4.99 (d, J = 6.8 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.72 - 3.62 (m, 1H), 3.46 - 3.39 (m, 2H), 1.90 - 1.84 (m, 3H).

[0257] Step 11: [ka] A mixture of 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol (100.0 mg, 356.7 μmol, 1.0 equivalent), 2-bromo-4-fluoropyridine (62.7 mg, 356.7 μmol, 1.0 equivalent), and DIEA (461.0 mg, 3.5 mmol, 621.3 μL, 10.0 equivalent) in DMA (1 mL) was stirred at 135°C for 12 hours. The reaction mixture was quenched by adding H2O (20 mL) at 20°C, then filtered, and the filtered cake was dried under reduced pressure to obtain 2-(6-(2-bromopyridine-4-yl)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-3-yl)phenol, which was used in the next step without further purification.

[0258] Step 12: [ka] A mixture of 2-(6-(2-bromopyridine-4-yl)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol (30.0 mg, 68.7 μmol, 1.0 equivalent), potassium trifluoro(vinyl)boranoid (27.6 mg, 206.2 μmol, 3.0 equivalent), Cs2CO3 (67.2 mg, 206.2 μmol, 3.0 equivalent), and Pd(dppf)Cl2 (5.0 mg, 6.8 μmol, 0.1 equivalent) in dioxane (1 mL) and H2O (0.5 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was partitioned between ethyl acetate (2 mL) and H2O (1 mL). The organic phase was separated, washed with brine (1 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (instrument: Gilson 281 semi-preparative HPLC system; mobile phase: A: formic acid / H2O = 0.075% v / v; B: ACN; column: Phenomenex Gemini-NX C 18 The sample was purified using a 75mm × 30mm × 3μm filter (flow rate: 25mL / min) to obtain o-[5-methyl-6-(2-vinyl-4-pyridyl)-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraazafluoren-3-yl]phenol. 1H NMR (400 MHz, CD3OD) δ 8.47 - 8.38 (m, 1H), 8.14 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.34 - 7.26 (m, 1H), 7.22 (d, J = 6.0 Hz, 1H), 7.05 - 6.94 (m, 2H), 6.82 (dd, J = 11.2, 17.6 Hz, 1H), 6.35 (d, J = 18.0 Hz, 1H), 5.83 (d, J = 11.2 Hz, 1H), 5.66 (q, J = 6.4 Hz, 1H), 4.55 (dd, J = 4.0, 14.0 Hz, 1H), 3.89 - 3.72 (m, 1H), 3.22 - 3.10 (m, 1H), 3.09 - 2.96 (m, 1H), 1.72 (d, J = 6.4 Hz, 3H).

[0259] Example 5 Compound 68およびCompound 69のPreparation:

change

change

[0260] Step 2: [ka] A mixture of (2-hydroxyphenyl)boronic acid (699.69 mg, 5.07 mmol, 3 equivalents), tert-butyl 8-((3-amino-6-chloropyridazine-4-yl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylate (600 mg, 1.69 mmol, 1 equivalent), Pd(dppf)Cl2 (123.73 mg, 169.09 μmol, 0.1 equivalent), and Cs2CO3 (3.31 g, 10.15 mmol, 6 equivalents) in dioxane (20 mL) and H2O (10 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (2 × 10 mL). The mixed organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 20% to 50% ethyl acetate in petroleum ether) to obtain tert-butyl 8-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylate. 1 H NMR (400 MHz, d6-DMSO) δ 14.33 (s, 1H), 8.02 - 7.93 (m, 1H), 7.71 - 7.60 (m, 1H), 7.29 - 7.22 (m, 1H), 6.94 - 6.84 (m, 2H), 6.66 - 6.46 (m, 2H), 5.12 - 4.95 (m, 1H), 3.93 - 3.46 (m, 2H), 3.44 - 3.35 (m, 1H), 3.28 - 3.03 (m, 1H), 2.46 - 2.31 (m, 2H), 1.98 - 1.78 (m, 2H), 1.59 - 1.48 (m, 1H), 1.45 - 1.38 (m, 9H).

[0261] Step 3: [ka] A solution of tert-butyl 8-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylate (500 mg, 1.21 mmol, 1 equivalent) and TFA (7.68 g, 67.31 mmol, 5.00 mL, 55.53 equivalents) in DCM (5 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain a residue. The residue was ground using MTBE (20 mL) at 25°C for 1 hour to obtain 2-(5-((3-azabicyclo[3.2.1]octane-8-yl)oxy)-6-aminopyridazin-3-yl)phenol as the TFA salt. 1 H NMR (400 MHz, CDCl3) δ 9.23 - 8.81 (m, 1H), 9.33 - 8.75 (m, 1H), 8.55 - 8.18 (m, 1H), 7.50 - 7.29 (m, 2H), 7.09 - 6.92 (m, 2H), 5.31 - 4.85 (m, 1H), 3.50 (t, J = 10.0 Hz, 2H), 3.37 - 3.17 (m, 2H), 2.98 (m, 1H), 2.65 - 2.53 (m, 2H), 2.18 - 1.74 (m, 4H).

[0262] Step 4: [ka] A mixture of 2-(5-((3-azabicyclo[3.2.1]octan-8-yl)oxy)-6-aminopyridazine-3-yl)phenol (50 mg, 160.07 μmol, 1 equivalent), 2-bromo-4-fluoropyridine (28.17 mg, 160.07 μmol, 1 equivalent), and DIEA (206.88 mg, 1.60 mmol, 278.81 μL, 10 equivalents) in DMA (1 mL) was stirred at 120 °C for 16 hours. The reaction mixture was quenched with ice water (5 mL) and stirred at 20 °C for 30 minutes. The mixture was filtered, and the filtered cake was dried to obtain 2-(6-amino-5-((3-(2-bromopyridine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)oxy)pyridazine-3-yl)phenol. 1H NMR (400 MHz, d6-DMSO) δ 14.41 - 14.27 (m, 1H), 8.06 - 7.94 (m, 1H), 7.93 - 7.85 (m, 1H), 7.80 - 7.62 (m, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.00 - 6.74 (m, 4H), 6.65 - 6.41 (m, 2H), 5.24 - 5.01 (m, 1H), 3.87 - 3.71 (m, 0.5H), 3.56 - 3.39 (m, 1H), 3.30 - 3.13 (m, 2.5H), 2.57 (s, 2H), 2.09 - 2.00 (m, 0.6H), 1.95 - 1.86 (m, 1.5H), 1.67 - 1.47 (m, 2H).

[0263] Step 5: [ka] A mixture of 2-(6-amino-5-((3-(2-bromopyridine-4-yl)-3-azabicyclo[3.2.1]octan-8-yl)oxy)pyridazin-3-yl)phenol (20 mg, 42.70 μmol, 1 equivalent), Pd(dppf)Cl2 (3.12 mg, 4.27 μmol, 0.1 equivalent), difluoro-[(Z)-vinylboranylidene-fluoranyl]potassium (17.16 mg, 128.11 μmol, 3 equivalents), and Cs2CO3 (41.74 mg, 128.11 μmol, 3 equivalents) in dioxane (1 mL) and H2O (0.5 mL) was degassed and purged three times with N2. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (1 mL) and extracted with ethyl acetate (2 × 1 mL). The mixed organic layer was washed with brine (1 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (instrument: Gilson 281 semi-preparative HPLC system; mobile phase: A: formic acid / H2O = 0.075% v / v; B: ACN; column: Phenomenex Gemini-NX C 18Purified by (75×30mm×3μm; flow rate: 25mL / min), o-(5-{3-(2-vinyl-4-pyridyl)-3-azabicyclo[3.2.1]octa-8-yloxy}-6-amino-3-pyridazinyl)phenol (first elution peak), 1 H NMR (400 MHz, d6-DMSO) δ 14.30 (m, 1H), 8.17 (s, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.28 - 7.21 (m, 1H), 6.93 - 6.85 (m, 3H), 6.76 - 6.62 (m, 2H), 6.52 (s, 2H), 6.23 - 6.13 (m, 1H), 5.35 (d, J = 12.4 Hz, 1H), 5.20 (s, 1H), 3.79 (d, J = 10.0 Hz, 2H), 3.19 (s, 2H), 2.60 (s, 2H), 2.09 - 2.00 (m, 2H), 1.55 (d, J = 7.6 Hz, 2H), and o-(5-{3-(2-vinyl-4-pyridyl)-3-azabicyclo[3.2.1]octa-8-yloxy}-6-amino-3-pyridazinyl)phenol (second elution peak), 1 H NMR (400 MHz, d6-DMSO) δ 14.67 - 14.07 (m, 1H), 8.16 (s, 1H), 8.10 (d, J = 5.6 Hz, 1H), 8.06 - 8.00 (m, 1H), 7.74 (s, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.97 - 6.83 (m, 3H), 6.74 - 6.62 (m, 2H), 6.54 (s, 2H), 6.16 (d, J = 17.2 Hz, 1H), 5.33 (d, J = 10.8 Hz, 1H), 5.07 (s, 1H), 3.54 - 3.52 (m, 2H), 3.49 (s, 2H), 2.64 - 2.62 (m, 2H) 1.96 - 1.89 (m, 2H), 1.63 (d, J = 7.6 Hz, 2H) were obtained.

[0264] Each of the compounds shown in Table 3 was prepared according to the procedure described above. TIFF2026522333000101.tif214170TIFF2026522333000102.tif228170TIFF20265223330 00103.tif243170TIFF2026522333000104.tif219170TIFF2026522333000105.tif222170 TIFF2026522333000106.tif248170TIFF2026522333000107.tif233170TIFF20265223330 00108.tif248170TIFF2026522333000109.tif228170TIFF2026522333000110.tif145170

[0265] Biological examples SMARCA2 and SMARCA4 degradation assays The degradation of proteins expressed from the SMARCA2 and SMARCA4 genes was monitored using engineered HiBiT-fused HeLa cell lines from Promega. In summary, SMARCA2-HiBiT or SMARCA4-HiBiT HeLa cells were seeded at 8,000 cells / well in 384-well white opaque plates (Greiner) and incubated overnight at 37°C to allow cell adhesion. After overnight incubation, the test compound was added in a 10-step dilution series (typically 10 μM to 300 pM) using a TECAN D300e digital dispenser, followed by incubation of the plate at 37°C for 24 hours. After 24 hours post-treatment, protein levels were quantified by adding HiBiT lysis buffer, LgBiT protein, and HiBiT substrate according to the manufacturer's specifications. The plate was incubated on an orbital plate shaker at room temperature for 10 minutes. The resulting luminescence values ​​were read using a ClarioStar plate reader, and dose-response curves and degradation DCs were obtained. 50 This was used to construct the calculations for (GraphPad Prism).

[0266] Table 4 provides data from the assay. The activity of the tested compounds is shown in Table 4 below: A=DC 50 <0.050μM; B=0.05μM <DC 50 <0.50 μM; C = <0.5 μM <DC 50 <5.0μM; D=DC 50 >5.0 μM. Degradation activity of SMARCA2 and SMARCA4 at 1 μM: +++ = >70%; ++ = 30-70%; + = <30%. TIFF2026522333000111.tif225170TIFF2026522333000112.tif196170

[0267] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0268] The disclosures described herein as illustrative can be suitably implemented without any elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, while the terms and expressions used herein are for illustrative purposes only and not limiting, and there is no intention to exclude any equivalent or part thereof of the illustrated and described features, it should be recognized that various modifications are possible within the claims.

[0269] All publications, patent applications, patents, and other references referred to herein are expressly incorporated by reference to the same extent that each is incorporated by reference individually. In case of any conflict, this specification, including its definitions, shall prevail.

[0270] While this disclosure has been described in conjunction with the embodiments described above, it should be understood that the foregoing description and examples are illustrative and not intended to limit the scope of this disclosure. Other aspects, advantages, and modifications within the scope of this disclosure will be apparent to those skilled in the art to whom this disclosure relates.

Claims

1. Formula I: 【Chemistry 1】 A compound of, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein, Each of m, n, and p is independently 0, 1, or 2. R １ However, hydroxy, halo, cyano, C １－４ Alkoxy, or -N(R) ２ And, R ２ However, -N(R) ２ And, Each R independently produces hydrogen and C. １－４ Alkyl, or C ３－６ It is a cycloalkyl group, where each alkyl or cycloalkyl group is unsubstituted or has 1 to 3 Z groups. １ Replaced by, Each R ３ is, independently, halo, cyano, -NO ２ , -SF ５ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １１ ), -OR ２ , -C(O)R １１ , -C(O)OR １１ , -S(O) １１ R ０－２ , -NR １１ S(O) １１ R ０－２ , -S(O) １１ N(R ０－２ ), -NR １１ S(O) ２ N(R １１ ), -NR ０－２ S(O) １１ N(R ２ , -NR １１ C(O)N(R １１ ), -C(O)N(R ２ ), -NR １１ C(O)R ２ , -OC(O)N(R １１ ), or -NR １１ C(O)OR １１ ), and each C ２ alkyl, C １１ alkenyl, C １１ alkynyl, C １－６ cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with 1 to 8 Z ２－６ s, ２－６ and ３－１０ １ １ is as defined below Each R ４ However, independently, Halo, Cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R) １１ ) ２ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -S(O) ０－２ R １１ , -NR １１ S(O) ０－２ R １１ , -S(O) ０－２ N(R) １１ ) ２ , -NR １１ S(O) ０－２ N(R) １１ ) ２ , -NR １１ C(O)N(R) １１ ) ２ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ And each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 8 Z groups. １ It is arbitrarily replaced with, Each R ５ is, independently, halo, cyano, -NO ２ , -SF ５ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R １１ ), -OR ２ , -C(O)R １１ , -C(O)OR １１ , -S(O) １１ R ０－２ , -NR １１ S(O) １１ R ０－２ , -S(O) １１ N(R ０－２ ), -NR １１ S(O) ２ N(R １１ ), -NR ０－２ S(O) １１ N(R ２ ), -NR １１ C(O)N(R １１ ), -C(O)N(R ２ ), -NR １１ C(O)R ２ , -OC(O)N(R １１ ), -NR １１ C(O)OR １１ ), or -NR ２ C(O)OR １１ and each C １１ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently optionally substituted with 1 to 8 Z ３－１０ １ １ and R ６ However, hydrogen, C １－３ Alkyl or halo, (i) L １ However, bonded, linear, or branched C １－３ It is either alkylene, C(O), or -O-. L ２ However, bonded, linear, or branched C １－３ It is either alkylene, C(O), or -O-. (ii) or L １ However, it is a bond, L ２ However, if it is a bond, R ２ and R ４ The R atoms cyclize together with the atoms they are bonded to, forming a heterocycline. X １ However, CH, CR ５ It is either , or N, X ２ However, CH, CR ５ It is either , or N, X ３ However, CH, CR ５ It is either N or X １ , X ２ , and X ３ One or fewer of these is N, Ring A is a 4-11 member heterocyclyl or 5-10 member heteroaryl containing at least one nitrogen atom. Each Z １ However, independently, Halo, Cyano, -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R) １１ ) ２ , -OR １１ , -C(O)R １１ , -C(O)OR １１ , -S(O) ０－２ R １１ , -NR １１ S(O) ０－２ R １１ , -S(O) ０－２ N(R) １１ ) ２ , -NR １１ S(O) ０－２ N(R) １１ ) ２ , -NR １１ C(O)N(R) １１ ) ２ , -C(O)N(R １１ ) ２ , -NR １１ C(O)R １１ , -OC(O)N(R １１ ) ２ , or -NR １１ C(O)OR １１ And each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z groups. １ａ It is arbitrarily replaced with, Each R １１ However, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ The compounds are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z groups. １ａ It is arbitrarily replaced with, Each Z １ａ However, independently, hydroxy, halo, cyano, and -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R) １３ ) ２ , -OR １３ , -C(O)R １３ , -C(O)OR １３ , -S(O) ０－２ R １３ , -NR １３ S(O) ０－２ R １３ , -S(O) ０－２ N(R) １３ ) ２ , -NR １３ S(O) ０－２ N(R) １３ ) ２ , -NR １３ C(O)N(R) １３ ) ２ , -C(O)N(R １３ ) ２ , -NR １３ C(O)R １３ , -OC(O)N(R １３ ) ２ , or -NR １３ C(O)OR １３ And each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z groups. １ｂ It is arbitrarily replaced with, Each R １３ However, independently, hydrogen, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ The compounds are cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, or heteroaryl groups independently contain 1 to 5 Z groups. １ｂ It is arbitrarily replaced with, Each Z １ｂ However, independently, halo, cyano, hydroxy, -SH, -NH ２ , -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-C １－６ Alkyl, -L-C ２－６ Alkenyl, -L-C ２－６ Alkinyl, -L-C １－６ Haloalkyl, -L-C ３－１０ It is a cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl, Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O) ２ -, -N(C １－６ Alkyl)-,-N(C ２－６ Alkenyl)-,-N(C) ２－６ Alkinyl)-,-N(C) １－６ Haloalkyl)-,-N(C) ３－１０ Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C １－６ Alkyl)-,-C(O)N(C ２－６ Alkenyl)-,-C(O)N(C ２－６ Alkinyl)-,-C(O)N(C １－６ Haloalkyl)-,-C(O)N(C ３－１０ Cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ２ It is NH-, Z １ｂ and each C of L １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may also independently contain 1 to 5 hydroxy, halo, cyano, -SH, and -NH groups. ２ , -NO ２ , -SF ５ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, C ３－１０ Compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl groups.

2. Formula IIA: 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

3. Formula IIIA: 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

4. Formula IVA: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

5. Formula VA: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

6. Ring A is a 4- to 7-membered monocyclic heterocycline containing one or two nitrogen atoms, and ring A contains one or two R ４ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which is optionally substituted by.

7. Ring A is 【Transformation 6】 Selected from, Each ring A has 1 to 2 R ４ It is arbitrarily replaced with, 【Transformation 7】 However, L １ This represents the connection point with L, where (*) is L ２ The compound according to claim 6, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, representing a bonding site with .

8. Ring A is a 7-10 membered spirocyclic heterocycline containing one or two nitrogen atoms, and ring A contains one or two R ４ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which is optionally substituted by.

9. Ring A is 【Transformation 8】 Selected from, Each ring A has 1 to 2 R ４ It is arbitrarily replaced with, 【Chemistry 9】 However, L １ This represents the connection point with L, where (*) is L ２ The compound according to claim 8, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, representing a bonding site with .

10. Ring A is a 7- to 9-membered condensed bicyclic heterocycline containing one or two nitrogen atoms, and ring A contains one or two R ４ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which is optionally substituted by.

11. Ring A is 【Chemistry 10】 Selected from, Each ring A has 1 to 2 R ４ It is arbitrarily replaced with, 【Chemistry 11】 However, L １ This represents the connection point with L, where (*) is L ２ The compound according to claim 10, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, representing a bonding site with.

12. Ring A is a 7-9 membered bridged heterocyclyl containing one or two nitrogen atoms, and ring A contains one or two R ４ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which is optionally substituted by.

13. Ring A is 【Chemistry 12】 Selected from, Each ring A has 1 to 2 R ４ It is arbitrarily replaced with, 【Chemistry 13】 However, L １ This represents the connection point with L, where (*) is L ２ The compound according to claim 12, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, representing a bonding site with.

14. Ring A is a 5- to 10-membered heteroaryl, and ring A has 1 or 2 R ４ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which is optionally substituted by.

15. Ring A is 【Chemistry 14】 And ring A has 1 to 2 R ４ It is arbitrarily replaced with, 【Chemistry 15】 However, L １ This represents the connection point with L, where (*) is L ２ A compound according to claim 14, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, representing a bonding site with.

16. L １ However, the bond is C(O), -O-, or -CH(CH ３ ) - the compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

17. L １ However, the compound according to claim 16, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is a bond.

18. L ２ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which is a bond.

19. Formula IA: 【Chemistry 16】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

20. Formula IB: 【Chemistry 17】 The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

21. Each R ４ However, independently, C １－６ A compound according to any one of claims 1 to 19, which is alkyl, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

22. Each R ４ The compound according to claim 21, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein the compound is methyl.

23. Each R ３ However, independently, a halo is a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

24. Each R ３ The compound according to claim 23, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, which is fluoro.

25. Each R ５ However, the compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is independently halo or cyano.

26. A compound according to any one of claims 1 to 19 or 21 to 22, wherein m is 0, n is 0, and p is 1 or 2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

27. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein m, n, and p are 0.

28. R ６ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein the compound is hydrogen.

29. R ６ The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein the compound is methyl or fluoro.

30. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

31. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

32. A method for regulating or degrading a protein expressed from the SMARCA2 gene, comprising contacting the protein with an effective amount of a compound described in any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

33. A method for regulating or degrading a protein expressed from the SMARCA4 gene, comprising contacting the protein with an effective amount of a compound described in any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

34. A method for regulating or degrading a protein expressed from the SMARCA2 gene in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

35. A method for regulating or degrading a protein expressed from the SMARCA4 gene in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

36. A method for regulating or degrading a protein expressed from the SMARCA2 gene in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 31.

37. A method for regulating or degrading a protein expressed from the SMARCA4 gene in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 31.

38. A method for treating cancer in a subject requiring treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

39. A method for treating cancer in a subject requiring treatment, comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 31.

40. A method for treating hyperplasia in a subject requiring treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

41. A method for treating hyperplasia in a subject requiring treatment, comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 31.

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