Compounds and pharmaceutical compositions that degrade SWI / SNF-RELATED MATRIX-ASSOCIATED ACTIN-DEPENDENT REGULATOR OF CHROMATIN SUBFAMILY A

Abstract

Disclosed are compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, useful for regulating or degrading proteins expressed from one or more SWI / SNF-related matrix-associated actin-dependent regulators of chromatin subfamily A (SMARCA) (e.g., SMARCA2 and / or SMARCA4). TIFF2025525340000430.tif52170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 352,936, filed June 16, 2022, the contents of which are incorporated herein by reference in their entirety.

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

[0003] The ubiquitin-proteasome pathway (UPP) is a critical pathway that controls key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and when defective or imbalanced, it contributes to the pathogenesis of various diseases. Covalent attachment 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 various proteins in vivo, and these ligases can be classified into four families: HECT domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. 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. al., “Roles of F-box proteins in See “Nat. Rev. Cancer” 2014, 14:233.

[0005] The UPP plays a key role in the degradation of short-lived, regulated proteins that are important in various fundamental cellular processes, including cell cycle regulation, cell surface receptor and ion channel regulation, and antigen presentation. The pathway is involved in the pathogenesis of several malignant tumor types, several genetic disorders (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and the pathology of muscle wasting. Many diseases are associated with abnormal UPP, adversely affecting cell cycle and division, cellular responses to stress and extracellular regulators, neuronal network morphogenesis, cell surface receptor regulation, ion channels, secretory pathways, DNA repair, and organelle biogenesis.

[0006] In recent years, abnormalities in this process have been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) diseases resulting from loss-of-function and the resulting stabilization of specific proteins, and (b) diseases resulting from gain-of-function, i.e., diseases resulting from the aberrant or accelerated degradation of protein targets.

[0007] UPPs are used to induce selective protein degradation, including in fusion proteins to artificially ubiquitinate target proteins and in synthetic small molecule probes to induce proteasome-dependent degradation. Compounds acting as molecular adhesives can induce or stabilize protein-protein interactions between target proteins and E3 ubiquitin ligase ligands, leading to their recruitment to E3 ubiquitin ligases and subsequent ubiquitination, leading to protein ubiquitination and subsequent proteasome-mediated degradation. These drug-like molecules offer the potential for temporal control over protein expression. Such compounds, when added to cells or administered to animals or humans, can induce the inactivation of target proteins, making them useful as biochemical reagents and potentially opening up new paradigms for disease treatment by eliminating pathogenic or oncogenic proteins. See, e.g., Crews, Chem. & Biol. 2010, 17(6):551; Schneekloth and Crews, Chem Bio Chem., 2005, 6(1):40.

[0008] There is an ongoing need in the art for effective treatments for diseases, particularly hyperplasia and cancer. However, nonspecific activity and the difficulty of targeting and regulating the entirety of a particular class of proteins, such as transcription factors, remain obstacles to the development of effective anticancer drugs. Therefore, small molecule therapeutics that exploit E3 ligase-mediated proteolysis to target cancer-related proteins, such as one or more of SWESNF-related matrix-associated actin-dependent regulator of chromatin subfamily A (SMARCA) and / or polybromo-1 (PB1), hold promise as potential therapeutics. Therefore, there remains a need to identify compounds that are degraders of proteins expressed by the SMARCA gene and are useful as therapeutic agents. Summary of the Invention

[0009] Disclosed herein are compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing the compounds and their pharmaceutically acceptable salts, and methods of using the compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions, which are useful as inducers of targeted ubiquitination of proteins expressed from the SMARCA gene, which are subsequently degraded and / or inhibited by the monovalent compounds described herein. An advantage of the compounds provided herein is the potential for a wide range of pharmacological activity, which is consistent with the degradation / inhibition of proteins expressed from the SMARCA gene. Furthermore, the present disclosure provides methods of using an effective amount of the compounds described herein to treat or ameliorate disease conditions, such as cancer, for example, lung cancer, in subjects in need thereof.

[0010] In some embodiments, compounds of the present disclosure have the following formula I: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, L 1 , L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2 , Z, and ring A are as defined herein.

[0011] In some embodiments, compounds of the present disclosure have the following formula IA: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L, L 1 , L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are as defined herein.

[0012] In some embodiments, compounds of the present disclosure have the following formula I': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 1 , L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are as defined herein.

[0013] In some embodiments, the compounds described herein regulate proteins expressed by the SMARCA gene. In some embodiments, the compounds described herein degrade proteins expressed by the SMARCA gene. In some embodiments, the regulated or degraded protein is expressed by SMARCA gene member 2 (SMARCA2). In some embodiments, the regulated or degraded protein is expressed by SMARCA gene member 4 (SMARCA4).

[0014] 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 I', or any subformula thereof, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0015] In some embodiments, the present disclosure provides a method for regulating or degrading a protein expressed from a SMARCA gene, the method comprising contacting the protein expressed from the SMARCA gene with an effective amount of a compound of Formula I or I', or any subformula thereof, under conditions such that the protein is bound to and regulated or degraded by the compound. 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.

[0016] In some embodiments, the present disclosure provides a method for regulating or degrading a protein expressed from a SMARCA gene in a subject, the method comprising administering to the subject an effective amount of a compound of Formula I or I', or any subformula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I or I', or any subformula thereof, under conditions such that the protein expressed from the SMARCA gene is bound to and regulated or degraded by the compound. 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.

[0017] In some embodiments, the present disclosure provides a method for treating hyperplasia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or I', or any subformula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I or I', or any subformula thereof.

[0018] In some embodiments, the disclosure provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or I', or any subformula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I or I', or any subformula thereof. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present disclosure provides compounds for treating diseases, disorders, or conditions mediated at least in part by SMARCA2 or SMARCA4 transcription factors, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions.However, before providing a detailed description of the present disclosure, the following terms will first be defined.If not defined, terms used herein have their generally accepted scientific meanings.

[0020] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0021] A dash (-) that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash before or after a chemical group is for convenience. A chemical group may be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dashed line drawn through a line in a structure indicates a particular point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which chemical groups are described or named.

[0022] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0023] The term "about" when used before a numerical designation, e.g., temperature, time, amount, concentration, etc., including ranges, indicates approximations that can vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue therebetween. In one embodiment, the term "about" when used in reference to a dose means that the dose can vary by + / - 10%.

[0024] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but do not exclude others.

[0025] "Consisting essentially of," when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the purposes described. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed disclosure.

[0026] "Consisting of" shall mean excluding more than trace amounts of other ingredients and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0027] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 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., C 1-4alkyl). Examples of alkyl groups 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 carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be included. Thus, 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). "Propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0028] Certain commonly used alternative chemical names may also be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, and divalent heteroaryl groups may also be referred to as "alkylene" or "alkylenyl" groups (e.g., methylenyl, ethylenyl, and propylenyl), "arylene" or "arylenyl" groups (e.g., phenylenyl or napthylenyl, or quinolinyl for heteroarylene), respectively. Also, unless explicitly indicated otherwise, when a combination of groups is referred to herein as a single moiety, e.g., arylalkyl or aralkyl, the last-mentioned group contains the atom through which the moiety is attached to the remainder of the molecule.

[0029] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0030] "Alkynyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 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 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0031] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy is an example.

[0032] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-". "Alkylsulfonylalkyl" refers to -alkyl-S(O)2-alkyl.

[0033] "Acyl" means -C(O)R y refers to a group, wherein R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0034] "Amide" means -C(O)NR y R z The "C-amido" group refers to the -NR group y C(O)R z Refers to the base "N-amido" groups, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein, or R y and R z together form a cycloalkyl or heterocyclyl, each of which can be unsubstituted or substituted as defined herein.

[0035] "Amino" means -NR y R z refers to a group, wherein R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0036] "Amidino" means -C(NR y )(NR z 2), where R y and R zis independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0037] "Aryl" refers to an aromatic carbocyclic group having one ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl regardless of the point of attachment. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl regardless of the point of attachment. When one or more aryl groups are fused with a cycloalkyl, the resulting ring system is a cycloalkyl regardless of the point of attachment.

[0038] "Carbamoyl" means -OC(O)NR y R z The group refers to the "O-carbamoyl" group and the -NR y C(O)OR z "N-carbamoyl" refers to both the "N-carbamoyl" group and the "N-carbamoyl" group, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0039] "Carboxyl ester" or "ester" means -OC(O)R x and -C(O)OR xIn the formula, R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0040] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having one or more rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cyclic groups having at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 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 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). 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, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aryl ring, regardless of attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl" when there are two positions of substitution on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0041] "Imino" means -C(NR y )R z refers to a group, wherein R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0042] "Imide" is -C(O)NR y C(O)R z refers to a group, wherein R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0043] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, for example, fluoro, chloro, bromo, or iodo.

[0044] "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 halogen. For example, if a residue is substituted with two or more halogens, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (di) or three (tri) halo groups, which are not necessarily the same halogens. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0045] "Haloalkoxy" refers to an alkoxy group, as defined above, where one or more (e.g., 1 to 6 or 1-3) hydrogen atoms are replaced by halogens.

[0046] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxy groups.

[0047] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom, are each independently replaced with the same or different heteroatom group, provided that the point of attachment to the remainder of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. As an example, one, two, or three carbon atoms can be independently replaced with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(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 CH2CH2NR yCH3, etc., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein. As used herein, heteroalkyl contains 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.

[0048] "Heteroaryl" refers to an aromatic group having one ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic 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 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8Heteroaryl) and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In particular examples, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, Included are isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, 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, where the heteroaryl may be attached through either ring of the fused system. Any aromatic ring having one or more fused rings containing at least one heteroatom is considered heteroaryl, regardless of attachment to the rest of the molecule (i.e., through any one of the fused rings).Heteroaryl does not encompass or overlap with aryl, as defined above.

[0049] "Heterocyclyl" is used interchangeably with "heterocycloalkyl" and refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently 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 spiroheterocyclyl groups. A heterocyclyl may be a single ring or multiple rings, where the multiple rings may be fused, bridged, or spiro, and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. - ) moiety. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl regardless of attachment (i.e., it may be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom regardless of attachment to the rest of the molecule, and the ring may be fused to a cycloalkyl, aryl, or heteroaryl ring. As used herein, heterocyclyl refers to a ring of 2 to 20 ring carbon atoms (i.e., C) having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. 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 3 to 6 ring carbon atoms (i.e., C 3-6Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, and octahydroisoquinolyl.

[0033] Examples of heterocyclyl include aryl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two positions for substitution on the same carbon atom. Examples of spiro-heterocyclyl 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 fused 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, where the heterocyclyl can be attached via either ring of the fused system. In some embodiments, heterocycloalkyl can be substituted with an oxo group on the heteroatom (e.g., S=O, S(=O)2).

[0050] "Oxime" means -CR y (=NOH) group, where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0051] "Oxo" refers to the =O moiety.

[0052] "Sulfonyl" means -S(O)R y refers to a group, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0053] "Sulfinyl" means -S(O)R y refers to a group, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0054] "Sulfonamide" means -SO2NR y R z groups and -NR y SO2R z refers to a group, wherein R y and R z is each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which can be unsubstituted or substituted as defined herein.

[0055] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur. Also, the term "unsubstituted or substituted" refers to whether or not any one or more (e.g., 1-5 or 1-3) hydrogen atoms on a specified atom or group may or may not be replaced with a non-hydrogen moiety.

[0056] As used herein, the term "substituted" refers to a group in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom has been substituted with, for example, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH, =NNH, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanato, -S(O)OH, -S(O)OH, sulfonamide, thiol, thioxo, N-oxide or -Si(R y )3, wherein each R y means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and / or heteroalkyl), which is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0057] In certain embodiments, "substituted" includes replacing one or more (e.g., 1-5 or 1-3) hydrogen atoms independently with deuterium, halo, cyano, nitro, azido, 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 OR g , -NR g S(O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(O) 1-2 NR g R h , -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups substituted with -C(O)R. g , -C(O)OR g , -C(O)NR g R h , -CH2SO2Rg , or -CH2SO2NR g R h It also means any of the above groups substituted with R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" refers to one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms being replaced by a bond to 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 which, together with the atoms to which they are attached, form an unsubstituted heterocyclyl ring, or form a heterocyclyl ring substituted with oxo, halo, or unsubstituted alkyl, or form a heterocyclyl ring substituted with alkyl substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0058] Polymers or similar amorphous structures arrived at by defining a substituent with an infinite number of additional substituents (e.g., a substituted aryl with a substituted alkyl, which itself is substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be encompassed herein. Unless otherwise specified, the maximum number of consecutive substituents in a compound 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 aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorine atoms, or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are known to those of skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein.

[0059] In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 5. In certain embodiments, as used herein, the phrase "one or more" refers to 1 to 3.

[0060] Any compound or structure provided herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These compound forms may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have 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 may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H and 14 A radioactive isotope, such as C, is incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques including drug or substrate tissue distribution assays, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for radiotherapy of patients.

[0061] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens, e.g., hydrogens on carbon atoms, are replaced by deuterium. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds may be synthesized by means known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0062] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties, which relate to absorption, distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may confer certain therapeutic benefits, such as increased metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F, 3 H, or 11Compounds labeled with C can be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures and preparations disclosed in the schemes or examples described below by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It is understood that deuterium in this context is considered a substituent in the compounds described herein.

[0063] The concentration of such heavy isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0064] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0065] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances useful in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0066] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness 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, when a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying 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, according to standard procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize 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, phosphoric acid, and the like. 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, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, primary amines, secondary amines, 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(alkoxy)), alkenylamines (i.e., N(alkenyl)), di(substituted alkenyl)amines (i.e., N(substituted alkenyl)), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)), mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)), mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)). Specific examples of suitable amines include, by way of example, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0067] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imidinoic acid tautomers. Regardless of which tautomer is shown and the nature of the equilibrium between tautomers, it is understood by those skilled in the art that the compound includes both amide tautomers and imidinoic acid tautomers. Therefore, amide-containing compounds are understood to include their imidinoic acid tautomers. Similarly, imidinoic acid-containing compounds are understood to include their amide tautomers.

[0068] The compounds, or their pharmaceutically acceptable salts, contain asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-) isomers, (R) and (S) isomers, or (D) and (L) isomers can be prepared using chiral synthons or chiral reagents or resolved using standard techniques, such as chromatography and / or fractional crystallization. Standard techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0069] "Stereoisomers" refer to compounds composed of the same molecules joined by the same bonds but with different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers or mixtures thereof, and includes "enantiomers." Enantiomers refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0070] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0071] Relative centers of compounds depicted herein are depicted using a "bold bond" style (bold or parallel lines), and absolute stereochemistry is indicated using a wedge bond (bold or parallel lines).

[0072] "Prodrug" refers to any compound that releases an active parent drug according to the structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein in such a way that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications can be cleaved to the parent compound in routine manipulation or in vivo. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxy, amino, 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), and the like of hydroxy functional groups in 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 ACS 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 by reference herein in its entirety.

[0073] "Subject" refers to a mammal. The mammal may be a human or a non-human mammal. "Patient" refers to a human subject.

[0074] "Treating" or "treatment" of a disease or disorder in a subject refers to 1) preventing the occurrence of the disease or disorder in a subject who is predisposed to or who does not yet exhibit symptoms of the disease or disorder; 2) inhibiting or halting the development of the disease or disorder; or 3) ameliorating or causing regression of the disease or disorder.

[0075] An "effective amount" refers to an amount of a compound described herein sufficient to treat a disease or disorder from which a subject suffers or to prevent such disease or disorder from occurring in the subject or patient.

[0076] "Administration" refers to any mode of administration to a subject known in the art, including oral (including oral gavage), pulmonary, transdermal, sublingual, injection (e.g., intravenous, intramuscular), transmucosal (e.g., vaginal, nasal, etc.), etc. The route of administration is selected by the attending physician and is based on factors such as the age, weight, and general health of the patient, as well as the severity of the condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally.

[0077] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, targeting the substrate proteins for degradation. For example, E3 ubiquitin, alone or in combination with E2 ubiquitin conjugating enzymes, attaches ubiquitin to lysines on target proteins, subsequently targeting specific protein substrates for proteasomal degradation. Thus, E3 ubiquitin ligases, either alone or in complex with E2 ubiquitin conjugating enzymes, are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, such as attaching a second ubiquitin to a first ubiquitin, and then attaching a third ubiquitin to the second ubiquitin, etc. Polyubiquitination marks proteins for degradation by the proteasome. However, some ubiquitination events are limited to monoubiquitination, in which a single ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation but may instead alter their cellular location or function, for example, by binding to other proteins that contain domains capable of binding ubiquitin. To further complicate matters, various lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to form polyubiquitin, which is then recognized by the proteasome.

[0078] compound In one embodiment, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C 1-4 alkoxy, or -N(R)2; Y is N, C or CH; Y1 is N, C or CH, X 1 , CH, CR 6 or N, X 2 , CH, CR 6 or N, in which case X 1 or X 2 at least one of is N, T is -N(R)2; Ring A is C 4-8 Cycloalkyl, C 6-10 aryl, 4-11 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-3 heteroatoms selected from O, N, NR, and S, and the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each independently is unsubstituted or contains 1-4 R 1 is replaced by L is a bond, —CH— or —O—; L 1 is -RC=CR- or -C≡C-, L 2 teeth, [ka] is selected from where t is 0 or 1, and p is 0, 1, 2, or 3, in which case the dashed line [ka] L 2 ~L 1 The wavy line indicates the connection point of [ka] L 2 indicates the point of attachment of ~Z, Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8cycloalkyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-4 heteroatoms selected from NR, N, O, and S, and the heterocycloalkyl or heteroaryl each independently is unsubstituted or has 1-4 R 2 and each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with 1 to 3 R 3 is replaced by Each R is independently hydrogen, C 1-4 Alkyl, or C 3-6 cycloalkyl, where each alkyl or cycloalkyl is unsubstituted or has 1 to 3 R 4 is replaced by, or When two R groups are attached to the same nitrogen, they form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or contains 1 to 4 R 4 is replaced by R x and R y are independently hydrogen, C 1-4 C substituted with alkyl or 1-3 halo 1-4 is haloalkyl, or R x and R y C, along with the atoms to which they are attached. 3-6 Forms a cycloalkyl, which is unsubstituted or has 1 to 4 R 4 is replaced by Each R 1 are independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted with 1-3 halo 1-4 Haloalkyl, unsubstituted or substituted with 1-3 halo 1-4 C having 1 to 3 heteroatoms selected from alkoxy, O, N, NR and / or S 5-6heteroaryl, 4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R; Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy-substituted C 1-4 C having 1 to 3 heteroatoms selected from alkyl, O, N, and NR 5-6 Heteroaryl, or C 3-6 is cycloalkyl, Each R 3 are independently oxo, cyano, hydroxy, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Haloalkyl, C 1-6 Aryl, C substituted with 1-3 phenyl 1-4 Alkyl, or C 3-6 is cycloalkyl, Each R 4 are independently -N(R), cyano, halo, or hydroxyl; Each R 5 D, Halo, C 1-3 Haloalkyl, or C 1-4 is an alkoxy, Each R 6 is N(R), SR, halo, cyano, unsubstituted or substituted with 1-3 halo, C 1-4 Alkoxy, unsubstituted C 1-4 Alkyl, C 1-2 Alkoxy-substituted C 1-4 Alkyl or hydroxy substituted C 1-4 is alkyl, m is 0, 1 or 2, and n is 0, 1, 2, or 3, However, the compound [ka] But the following part: [ka] and L 2 is -C(O)NH-, a bond, -CH2-, or -(CH2)2-, Z is heterocyclyl (wherein the heterocyclyl is unsubstituted or substituted), -C 1-6 Alkylene-NH2, or -C 1-6 Instead of alkylene-OH, The compound is as follows: 2-(6-amino-5-(8-(2-(3-((2-hydroxyethyl)(methyl)amino)prop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(2-hydroxyethoxyprop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(diethylamino)prop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-(3-(piperidin-3-yloxy)prop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, N-[3-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-pyridyl]prop-2-ynyl]piperidine-4-carboxamide, 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1-ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[9-[2-[3-(azepan-l-yl)prop-l-ynyl]-4-pyridyl]-3,9-diazaspiro[5.5]undecan-3-yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[2-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridyl]-2,8-diazaspiro[4.5]decan-8-yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[6-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]pyridazin-3-yl]phenol, 2-(6-amino-5-(8-(2-(((1r,4r)-4-aminocyclohexyl)ethynyl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol, or It is not 2-[6-amino-5-[8-[2-[(E)-3-(azepan-1-yl)prop-1-enyl]-4-pyridyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol.

[0079] In one embodiment, the present disclosure provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C 1-4alkoxy, or -N(R)2; Y is N, C or CH; Y 1 is N, C or CH, T is -N(R)2; Ring A is C 4-8 Cycloalkyl, C 6-10 aryl, 4-11 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-3 heteroatoms selected from O, N, NR, and S, and the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each independently is unsubstituted or contains 1-4 R 1 is replaced by L is a bond, —CH— or —O—; L 1 is -RC=CR- or -C≡C-, L 2 teeth, [ka] is selected from where t is 0 or 1, and p is 0, 1, 2, or 3, in which case the dashed line [ka] L 2 ~L 1 The wavy line indicates the connection point of [ka] L 2 indicates the point of attachment of ~Z, Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8cycloalkyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-4 heteroatoms selected from NR, N, O, and S, and the heterocycloalkyl or heteroaryl each independently is unsubstituted or has 1-4 R 2 and each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with 1 to 3 R 3 is replaced by Each R is independently hydrogen, C 1-4 Alkyl, or C 3-6 cycloalkyl, where each alkyl or cycloalkyl is unsubstituted or has 1 to 3 R 4 is replaced by, or When two R groups are attached to the same nitrogen, they form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or contains 1 to 4 R 4 is replaced by R x and R y are independently hydrogen, C 1-4 C substituted with alkyl or 1-3 halo 1-4 is haloalkyl, or R x and R y C, along with the atoms to which they are attached. 3-6 Forms a cycloalkyl, which is unsubstituted or has 1 to 4 R 4 is replaced by Each R 1 are independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted with 1-3 halo 1-4 Haloalkyl, unsubstituted or substituted with 1-3 halo 1-4 C having 1 to 3 heteroatoms selected from alkoxy, O, N, NR and / or S 5-6heteroaryl, 4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R; Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy-substituted C 1-4 C having 1 to 3 heteroatoms selected from alkyl, O, N, and NR 5-6 Heteroaryl, or C 3-6 is cycloalkyl, Each R 3 are independently oxo, cyano, hydroxy, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Haloalkyl, C 1-6 Aryl, C substituted with 1-3 phenyl 1-4 Alkyl, or C 3-6 is cycloalkyl, Each R 4 are independently -N(R), cyano, halo, or hydroxyl; Each R 5 D, Halo, C 1-3 Haloalkyl, or C 1-4 is an alkoxy; Each R 6 is N(R), SR, halo, cyano, unsubstituted or substituted with 1-3 halo, C 1-4 Alkoxy, unsubstituted C 1-4 Alkyl, C 1-2 Alkoxy-substituted C 1-4 Alkyl or hydroxy substituted C 1-4 is alkyl, m is 0, 1 or 2, and n is 0, 1, 2, or 3, However, the compound is not 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1-ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol.

[0080] In one embodiment, the present disclosure provides a compound of formula I': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C 1-4 alkoxy, or -N(R)2; Y is N, C or CH; Y 1 is N, C or CH, T is -N(R)2; Ring A is C 4-8 Cycloalkyl, C 6-10 aryl, 4-11 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-3 heteroatoms selected from O, N, NR, and S, and the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each independently is unsubstituted or contains 1-4 R 1 is replaced by L 1 is -RC=CR- or -C≡C-, L 2 teeth, [ka] is selected from where t is 0 or 1, and p is 0, 1, 2, or 3, in which case the dashed line [ka] L 2 ~L 1 The wavy line indicates the connection point of [ka] L 2 indicates the point of attachment of ~Z, Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-4 heteroatoms selected from NR, N, O, and S, and the heterocycloalkyl or heteroaryl each independently is unsubstituted or has 1-4 R 2 and each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with 1 to 3 R 3 is replaced by Each R is independently hydrogen, C 1-4 Alkyl, or C 3-6 cycloalkyl, where each alkyl or cycloalkyl is unsubstituted or has 1 to 3 R 4 is replaced by, or When two R groups are attached to the same nitrogen, they form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or contains 1 to 4 R 4 is replaced by R x and R y are independently hydrogen, C 1-4 C substituted with alkyl or 1-3 halo 1-4 is haloalkyl, or R x and R y C, along with the atoms to which they are attached. 3-6 Forms a cycloalkyl, which is unsubstituted or has 1 to 4 R 4 is replaced by Each R 1are independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted with 1-3 halo 1-4 Haloalkyl, unsubstituted or substituted with 1-3 halo 1-4 C having 1 to 3 heteroatoms selected from alkoxy, O, N, NR and / or S 5-6 heteroaryl, 4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R; Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy-substituted C 1-4 C having 1 to 3 heteroatoms selected from alkyl, O, N, and NR 5-6 Heteroaryl, or C 3-6 is cycloalkyl, Each R 3 are independently oxo, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Haloalkyl, or C 3-6 is cycloalkyl, Each R 4 are independently -N(R), cyano, halo, or hydroxyl; Each R 5 D, Halo, C 1-3 Haloalkyl, or C 1-4 is an alkoxy; Each R 6 is N(R)2, SR, cyano, unsubstituted or substituted with 1-3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy-substituted C1-4 Alkyl or hydroxy substituted C 1-4 is alkyl, m is 0, 1 or 2, and n is 0, 1, 2, or 3, However, the compound is not 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1-ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenol.

[0081] In one embodiment, the present disclosure provides a compound of formula I': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein: X is hydroxy, halo, cyano, C 1-4 alkoxy, or -N(R)2; Y is N, C or CH; Y 1 is N, C or CH, T is -N(R)2; Ring A is C 4-8 Cycloalkyl, C 6-10 aryl, 4-11 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-3 heteroatoms selected from O, N, NR, and S, and the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl each independently is unsubstituted or contains 1-4 R 1 is replaced by L 1 is -RC=CR- or -C≡C-, L 2 teeth, [ka] is selected from where t is 0 or 1, and p is 0, 1, 2, or 3, in which case the dashed line [ka] L 2 ~L 1 The wavy line indicates the connection point of [ka] L 2 indicates the point of attachment of ~Z, Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the heterocycloalkyl or heteroaryl each has 1-4 heteroatoms selected from NR, N, O, and S, and the heterocycloalkyl or heteroaryl each independently is unsubstituted or has 1-4 R 2 and each alkyl, alkoxy, or cycloalkyl is independently unsubstituted or substituted with 1 to 3 R 3 is replaced by Each R is independently hydrogen, C 1-4 Alkyl, or C 3-6 cycloalkyl, where each alkyl or cycloalkyl is unsubstituted or has 1 to 3 R 4 is replaced by, or When two R groups are attached to the same nitrogen, they form a 4- to 7-membered heterocycloalkyl, which is unsubstituted or contains 1 to 4 R 4 is replaced by R x and R y are independently hydrogen, C 1-4 C substituted with alkyl or 1-3 halo 1-4 is haloalkyl, or R x and R y C, along with the atoms to which they are attached. 3-6Forms a cycloalkyl, which is unsubstituted or has 1 to 4 R 4 is replaced by Each R 1 are independently cyano, halo, hydroxyl, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted with 1-3 halo 1-4 Haloalkyl, unsubstituted or substituted with 1-3 halo 1-4 C having 1 to 3 heteroatoms selected from alkoxy, O, N, NR and / or S 5-6 heteroaryl, 4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R; Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy-substituted C 1-4 C having 1 to 3 heteroatoms selected from alkyl, O, N, and NR 5-6 Heteroaryl, or C 3-6 is cycloalkyl, Each R 3 are independently oxo, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 Haloalkyl, or C 3-6 is cycloalkyl, Each R 4 are independently -N(R), cyano, halo, or hydroxyl; Each R 5 D, Halo, C 1-3 Haloalkyl, or C 1-4 is an alkoxy, Each R 6is N(R)2, SR, cyano, unsubstituted or substituted with 1-3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy-substituted C 1-4 Alkyl or hydroxy substituted C 1-4 is alkyl, m is 0, 1 or 2, and n is 0, 1, 2, or 3.

[0082] In some embodiments, the compound of formula I is represented by formula II: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2 , Z, and ring A are each independently as defined herein.

[0083] In some embodiments, the compound of Formula II is represented by Formula II-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0084] In some embodiments, the compound of Formula II is represented by Formula II-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0085] In some embodiments, the compound of Formula II is represented by Formula II-3: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0086] In some embodiments, the compound of Formula I, represented by Formula IIa: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, m, n, p, R, R x , R y , R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2 , Z, and ring A are each independently as defined herein.

[0087] In some embodiments, the compound of Formula I is represented by Formula IIb: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, m, n, p, R, R x , R y , R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2 , Z, and ring A are each independently as defined herein.

[0088] In some embodiments, the compound of Formula I is represented by Formula IIc: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, m, n, p, R x , R y , R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2 , Z, and ring A are each independently as defined herein.

[0089] In some embodiments, the compound of formula IIc is represented by formula IIc-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, m, n, p, R x , R y , R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0090] In some embodiments, the compound of formula IIc is represented by formula IIc-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, m, n, p, R x , R y , R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0091] In some embodiments, the compound of formula IIc is represented by formula IIc-3: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, m, n, p, R x , R y , R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0092] In some embodiments, the compound of Formula I is represented by formula III-E: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, L 1 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2 , Z, and ring A are each independently as defined herein.

[0093] In some embodiments, the compound of Formula I represented by formula IIIb-E: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L, m, n, p, R x , R y , R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2 , Z, and ring A are each independently as defined herein.

[0094] In some embodiments, the compound of formula I' is represented by formula II': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0095] In some embodiments, the compound of formula II' is represented by formula IIa': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R, R 5 , R 6 , R x , R y ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0096] In some embodiments, the compound of formula IIa' is represented by formula IIa'-1: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, R, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0097] In some embodiments, the compound of formula IIa' is represented by formula IIa'-2: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, R, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0098] In some embodiments, the compound of formula II' is represented by formula IIb': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R, R 5 , R 6 , R x , R y ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0099] In some embodiments, the compound of formula II' is represented by formula IIc': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R 5 , R 6 , Rx , R y ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0100] In some embodiments, the compound of formula II' is represented by formula IId': [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R 5 , R 6 , R x , R y ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0101] In some embodiments, the compound of formula I' is represented by formula III'-E: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0102] In some embodiments, the compound of formula III'-E is represented by formula IIIa'-E: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R, R 5 , R 6 , R x , R y ,T,X,Y,Y 1, Z, and ring A are each independently as defined herein.

[0103] In some embodiments, the compound of formula III'-E is represented by formula IIIb'-E: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R 5 , R 6 , R x , R y ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0104] In some embodiments, the compound of formula I' is represented by formula III'-Z: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0105] In some embodiments, the compound of formula III'-Z is represented by formula IIIa'-Z: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R, R 5 , R 6 , R x , R y ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0106] In some embodiments, the compound of formula III'-Z is represented by formula IIIb'-Z: [ka] or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof is provided; In the formula, m, n, p, R 5 , R 6 , R x , R y ,T,X,Y,Y 1 , Z, and ring A are each independently as defined herein.

[0107] In some embodiments of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, [ka] is a monocyclic 4-11 membered nitrogen-containing heterocycloalkyl. [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to L or pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 wherein each R 1 are independently halo or C 1-4 It is alkyl.

[0108] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, [ka] is a monocyclic 4-11 membered nitrogen-containing heterocycloalkyl. [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to the pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 and each R 1 are independently halo or C 1-4 It is alkyl.

[0109] In some embodiments of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, [ka] is a fused bicyclic 4-11 membered nitrogen-containing heterocycloalkyl. [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to L or pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 Each R is replaced by 1 are independently halo or C 1-4 It is alkyl.

[0110] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, [ka] is a fused bicyclic 4-11 membered nitrogen-containing heterocycloalkyl. [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to the pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 and each R 1 are independently halo or C 1-4 It is alkyl.

[0111] In some embodiments of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, [ka] is a spirocyclic 4-11 membered nitrogen-containing heterocycloalkyl. [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to L or pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 wherein each R 1 are independently halo or C 1-4 It is alkyl.

[0112] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, [ka] is a spirocyclic 4-11 membered nitrogen-containing heterocycloalkyl. [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to the pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 and each R 1 are independently halo or C 1-4 It is alkyl.

[0113] In some embodiments of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, [ka] is a bridged 4-11 membered nitrogen-containing heterocycloalkyl. In some embodiments, [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to L or pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 and each R 1 are independently halo or C 1-4 It is alkyl.

[0114] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, [ka] is a bridged 4-11 membered nitrogen-containing heterocycloalkyl. In some embodiments, [ka] teeth, [ka] is selected from In the formula, dashed lines [ka] indicates the point of attachment of ring A to the pyrimidine, and the wavy line [ka] indicates the point of attachment of ring A to the pyridazine, and each ring A is independently unsubstituted or has 1 to 4 R 1 and each R 1 are independently halo or C 1-4 It is alkyl.

[0115] In some embodiments of the compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a 4-10 membered nitrogen-containing heterocycloalkyl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, hydroxy, cyano, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0116] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a 4-10 membered nitrogen-containing heterocycloalkyl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0117] In some embodiments of the compounds of Formula I or Formula I', or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 4-10 membered oxygen- and nitrogen-containing heterocycloalkyl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0118] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 4-10 membered oxygen- and nitrogen-containing heterocycloalkyl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0119] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 4-10 membered sulfur- and nitrogen-containing heterocycloalkyl. [ka] and wherein Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0120] In some embodiments of the compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is a 4-10 membered oxygen-containing heterocycloalkyl. [ka] is selected from wherein Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0121] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 4-10 membered oxygen-containing heterocycloalkyl. [ka] and wherein Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0122] In some embodiments of the compounds of Formula I or Formula I', or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 5-10 membered nitrogen-containing heteroaryl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0123] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 5-10 membered nitrogen-containing heteroaryl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0124] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 5-10 membered oxygen- and nitrogen-containing heteroaryl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0125] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 5-10 membered sulfur- and nitrogen-containing heteroaryl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0126] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is a 5-10 membered oxygen-containing heteroaryl. [ka] is selected from wherein each Z is independently unsubstituted or 1 to 4 R 2 Each R is replaced by 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C1-4 Alkyl, C substituted with 1-3 halo groups 1-4 haloalkyl, C with 1 to 3 heteroatoms selected from O, N, and NR 5-6 Heteroaryl, or C 3-6 It is cycloalkyl.

[0127] In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is C 1-10 In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is -N(R). In some embodiments of the compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, Z is -C 1-10 In some embodiments of the compounds of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is -OH.

[0128] In some embodiments, compounds of Formula I are provided, wherein X is hydroxy.

[0129] In some embodiments, compounds of Formula I are provided, wherein T is -NH2.

[0130] In some embodiments, compounds of formula I are provided, wherein Y is N. In some embodiments, compounds of formula I are provided, wherein Y is N. 1 is N. In some embodiments, compounds of Formula I are provided, wherein Y and Y 1 Both are N.

[0131] In some embodiments, compounds of Formula I are provided, wherein L 2 teeth, [ka] where t is 0 or 1, p is 1, 2 or 3, and the dashed line [ka] L 2 From L 1 The wavy line indicates the attachment point to [ka] L 2 indicates the point of attachment from L to Z. In some embodiments, compounds of Formula I are provided, wherein L 2 teeth, [ka] and the dashed line [ka] L 2 From L 1 The wavy line indicates the attachment point to [ka] L 2 indicates the point of attachment from to Z.

[0132] Representative, non-limiting examples of compounds within the scope of Formula I above are set forth in Table 1, each of which includes a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof. TIFF2025525340000106.tif236170TIFF2025525340000107.tif241170TIFF2025525340000108.t if241170TIFF2025525340000109.tif246170TIFF2025525340000110.tif251170TIFF20255253400 00111.tif236170TIFF2025525340000112.tif251170TIFF2025525340000113.tif251170TIFF202 5525340000114.tif251170TIFF2025525340000115.tif246170TIFF2025525340000116.tif241170 TIFF2025525340000117.tif237170TIFF2025525340000118.tif253170TIFF2025525340000119.t if237170TIFF2025525340000120.tif251170TIFF2025525340000121.tif244170TIFF20255253400 00122.tif223170TIFF2025525340000123.tif209170TIFF2025525340000124.tif233170TIFF202 5525340000125.tif237170TIFF2025525340000126.tif219170TIFF2025525340000127.tif131170

[0133] Also provided herein are the following compounds falling within the scope of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof: TIFF2025525340000128.tif239170TIFF2025525340000129.tif249170TIFF202 5525340000130.tif249170TIFF2025525340000131.tif249170TIFF20255253400 00132.tif249170TIFF2025525340000133.tif249170TIFF2025525340000134.t if249170TIFF2025525340000135.tif249170TIFF2025525340000136.tif131170

[0134] Representative, non-limiting examples of compounds within the scope of Formula I or Formula I' above are listed in Table 1A, each of which includes a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof. TIFF2025525340000137.tif106170TIFF2025525340000138.tif249170TIFF2025525340000139.tif250170TIFF2025525340000140.tif244170TIFF2025525340000141.tif246170TIFF2025525340000142.tif226170TIFF2025525340000143.tif224170TIFF2025525340000144.tif233170TIFF2025525340000145.tif241170TIFF2025525340000146.tif233170TIFF2025525340000147.tif228170TIFF2025525340000148.tif239170TIFF2025525340000149.tif253170TIFF2025525340000150.tif253170TIFF2025525340000151.tif229170TIFF2025525340000152.tif236170TIFF2025525340000153.tif251170TIFF2025525340000154.tif250170TIFF2025525340000155.tif244170TIFF2025525340000156.tif230170TIFF2025525340000157.tif239170TIFF2025525340000158.tif216170TIFF2025525340000159.tif253170TIFF2025525340000160.tif234170TIFF2025525340000161.tif252170TIFF2025525340000162.tif247170TIFF2025525340000163.tif241170TIFF2025525340000164.tif228170TIFF2025525340000165.tif251170TIFF2025525340000166.tif245170TIFF2025525340000167.tif227170TIFF2025525340000168.tif230170TIFF2025525340000169.tif230170TIFF2025525340000170.tif227170TIFF2025525340000171.tif233170TIFF2025525340000172.tif239170TIFF2025525 340000173.tif232170TIFF2025525340000174.tif252170TIFF2025525340000175.tif223170TIFF2025525340000176.tif131170.

[0135] Representative, non-limiting examples of compounds within the scope of Formula I or Formula I' above are set forth in Table 2. Each of these compounds includes pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof. TIFF2025525340000177.tif245170TIFF2025525340000178.tif246170TIFF2025525340000179.tif248170TIFF2025525340000180.tif252170TIFF2025525340000181.tif246170TIFF2025525340000182.tif246170TIFF2025525340000183.tif235170TIFF2025525340000184.tif233170TIFF2025525340000185.tif238170TIFF2025525340000186.tif246170TIFF2025525340000187.tif246170TIFF2025525340000188.tif247170TIFF2025525340000189.tif250170TIFF2025525340000190.tif252170TIFF2025525340000191.tif252170TIFF2025525340000192.tif252170TIFF2025525340000193.tif248170TIFF2025525340000194.tif241170TIFF2025525340000195.tif252170TIFF2025525340000196.tif252170TIFF2025525340000197.tif235170TIFF2025525340000198.tif235170TIFF2025525340000199.tif248170TIFF2025525340000200.tif241170TIFF2025525340000201.tif252170TIFF2025525340000202.tif232170TIFF2025525340000203.tif247170TIFF2025525340000204.tif234170TIFF2025525340000205.tif241170TIFF2025525340000206.tif250170TIFF2025525340000207.tif234170TIFF2025525340000208.tif252170TIFF2025525340000209.tif246170TIFF2025525340000210.tif229170TIFF2025525340000211.tif235170TIFF202552534000 0212.tif242170TIFF2025525340000213.tif247170TIFF2025525340000214.tif247170TIFF2025525 340000215.tif242170TIFF2025525340000216.tif247170TIFF2025525340000217.tif243170TIFF20 25525340000218.tif240170TIFF2025525340000219.tif243170TIFF2025525340000220.tif228170.

[0136] In some embodiments, the disclosure provides a method for regulating or degrading a protein expressed from the SMARCA2 gene, the method comprising contacting the protein with an effective amount of a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'-Z or IIIb'-Z under conditions whereby the protein expressed from the SMARCA2 gene is regulated or degraded.

[0137] In some embodiments, the present disclosure provides a method for regulating or degrading a protein expressed from the SMARCA4 gene, the method comprising contacting the protein with an effective amount of a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'-Z or IIIb'-Z under conditions in which the protein expressed from the SMARCA4 gene is regulated or degraded.

[0138] In some embodiments, there is provided a method of regulating or degrading a protein expressed from the SMARCA2 gene in a subject, the method comprising administering to the subject a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'- and administering to a subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'-Z or IIIb'-Z.

[0139] In some embodiments, there is provided a method of regulating or degrading a protein expressed from the SMARCA4 gene in a subject, the method comprising administering to the subject a compound of formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'- and administering to a subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'-Z or IIIb'-Z.

[0140] In some embodiments, there is provided a method of treating cancer in a subject in need thereof, the method comprising selecting a subject whose cancer is at least partially regulated by SMARCA2, and administering to the subject a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'- and administering to a subject a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'-Z or IIIb'-Z.

[0141] In some embodiments, there is provided a method of treating cancer in a subject in need thereof, the method comprising selecting a subject whose cancer is at least partially regulated by SMARCA4, and administering to the subject a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'- and administering to a subject a compound of Formula I, IA, II, II-1, II-2, II-3, IIa, IIb, IIc, IIc-1, IIc-2, IIc-3, III-E, IIIb-E, I', II', IIa', IIa'-1, IIa'-2, IIb', IIc', IId', III'-E, IIIa'-E, IIIb'-E, III'-Z, IIIa'-Z or IIIb'-Z.

[0142] General synthesis method 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 is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0143] Furthermore, as will be apparent to those skilled in the art, standard protecting groups may be required to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are known in the art. For example, many protecting groups are described in TW Greene and PG M Butts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and the references cited therein.

[0144] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or simple 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). Others are described in, for example, 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), March's Advanced Organic Chemistry, (John Wiley and Sons, 8 th Organic synthesis of hydroxybenzoates can be prepared by procedures described in standard reference works, such as The Organic Synthesis of hydroxybenzoates (VCH Publishers Inc., 1989), or simple modifications thereof.

[0145] Synthesis of representative compounds The general synthesis of the compounds described herein is depicted in the following reaction schemes. Schemes 1, 2, 3, 4, 5, and 6 show general methods for preparing compounds of formula I and I'. In Schemes 1, 2, 3, 4, 5, and 6, the substituents L, L 1 , L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , X 1 , X 2, Z, and ring A are as defined throughout the specification. PG is a protecting group (including but not limited to, Boc, etc.). LG is a suitable coupling partner (including but not limited to, hydrogen when performing Sonogashira coupling, or boronic acid or ester when performing Suzuki coupling). [ka]

[0146] Scheme 1 In some embodiments, compounds of Formula I' and subformulas thereof are prepared as shown in Scheme 1. In Scheme 1, the first step is a standard SN AR In this reaction, at least a stoichiometric amount of protected ring A, compound 2, is mixed with compound 1, typically in the presence of a suitable base, such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, or the like, in an inert diluent, such as tetrahydrofuran, dioxane, DMSO, DMF, or the like. The reaction is typically maintained at 25° C. to 100° C. until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), or the like, to afford compound 3.

[0147] In the next step, a standard Suzuki coupling reaction is carried out in which at least a stoichiometric amount of arylboronic acid, compound 4, is mixed with compound 3, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, or the like, in an inert diluent, such as tetrahydrofuran, dioxane, toluene, or dimethoxyethane. The reaction is typically maintained at 10°C to 65°C until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), to afford compound 5.

[0148] In the next step, the protecting group, e.g., t-butoxycarbonyl (t-BOC), is removed under standard conditions depending on the specific protecting group employed. The t-BOC group is merely exemplary; other standard amino protecting groups, e.g., benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc., can also be employed. After standard workup of the reaction solution upon completion of the reaction, an isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), etc., can then be carried out.

[0149] In the next step, standard SN AR The reaction is carried out by combining at least a stoichiometric amount of the deprotected product of the previous step with 2,4-dibromopyrimidine, compound 6, typically in the presence of a suitable base, e.g., diisopropylethylamine, triethylamine, pyridine, potassium carbonate, or the like, in an inert diluent, e.g., tetrahydrofuran, dioxane, DMSO, DMF, or the like. The reaction is typically maintained at 25°C to 100°C until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), or the like, to afford compound 7.

[0150] In the final step, a standard coupling reaction, including but not limited to Sonogashira coupling, Suzuki coupling, etc., is carried out in which at least a stoichiometric amount of an appropriate coupling partner, compound 8, is mixed with compound 7 under standard coupling reaction conditions known in the art, including the use of a palladium catalyst (e.g., palladium(II) bis(triphenylphosphine) dichloride, palladium diacetate, etc.), a cocatalyst (e.g., copper(I) iodide, etc.), and typically in the presence of a suitable base (e.g., diisopropylethylamine, triethylamine, pyridine, cesium carbonate, etc.). The coupling reaction is typically carried out in an inert solvent, such as toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, etc. The reaction is typically carried out at about 10°C to about 110°C for a period of time sufficient for the reaction to be substantially complete, as evidenced, for example, by thin layer chromatography. Upon completion of the reaction, standard workup of the reaction solution is followed by an isolation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide the compound of formula I'. [ka]

[0151] Scheme 2 In some embodiments, compounds of Formula I' and subformulas thereof are prepared as shown in Scheme 2. In Scheme 2, the first step is a standard Sonogashira coupling reaction employing at least a stoichiometric amount of a protected propargylamine, compound 9, mixed with compound 7 under standard reaction conditions known in the art, including the use of palladium(II) bis(triphenylphosphine) dichloride or copper(I) iodide as catalysts in the presence of a suitable base, such as, for example, diisopropylethylamine, triethylamine, pyridine, or cesium carbonate. The reaction is typically carried out in an inert solvent, such as, for example, toluene or N,N-dimethylformamide. The reaction is typically carried out at about 25°C to about 110°C for a period of time sufficient for substantial completion of the reaction, as evidenced, for example, by thin layer chromatography. Following standard testing of the reaction solution upon completion, an isolation / purification process, such as, for example, crystallization, chromatography, or high-performance liquid chromatography (HPLC), is carried out to provide compound 10.

[0152] In the next step, the protecting group, e.g., t-butoxycarbonyl (t-BOC), is removed under standard conditions depending on the specific protecting group employed. The t-BOC group is merely exemplary; other standard amino protecting groups, e.g., benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc., can also be employed. After standard workup of the reaction solution upon completion, a subsequent isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), etc., provides compound 11.

[0153] In the final step, at least a stoichiometric amount of the appropriate carboxylic acid, compound 12, is mixed with compound 11 under standard amide bond-forming reaction conditions known in the art, including the use of N,N-dicyclohexylcarbodiimide (DCC) as a carboxyl group activating agent. Other activating agents are known in the art. The reaction is typically carried out in an inert solvent, such as, for example, chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically carried out at about 0°C to about 30°C for a period of time sufficient for substantial completion of the reaction, as evidenced, for example, by thin layer chromatography. Standard testing of the reaction solution upon completion, followed by an isolation / purification process, such as, for example, crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., provides the compound of Formula I'. [ka]

[0154] Scheme 3 In some embodiments, compounds of Formula I' and subformulas thereof are prepared as shown in Scheme 3. In Scheme 3, the first step is a standard Suzuki coupling reaction in which at least a stoichiometric amount of protected aminovinylboronic acid, compound 13, is combined with compound 7, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, or the like, in an inert diluent, such as tetrahydrofuran, dioxane, toluene, or dimethoxyethane. The reaction is typically maintained at 10°C to 65°C until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), to afford compound 14.

[0155] In the next step, the protecting group, e.g., t-butoxycarbonyl (t-BOC), is removed under standard conditions depending on the specific protecting group employed. The t-BOC group is merely exemplary; other standard amino protecting groups, e.g., benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc., can also be employed. After standard workup of the reaction solution upon completion, a subsequent isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), etc., provides compound 15. In the final step, at least a stoichiometric amount of the appropriate carboxylic acid, compound 12, is combined with compound 15 under standard amide bond-forming reaction conditions known in the art, including the use of N,N-dicyclohexylcarbodiimide (DCC) as a carboxyl group activating agent. Other activating agents are known in the art. The reaction is typically carried out in an inert solvent, such as, for example, chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically carried out at about 0°C to about 30°C for a period of time sufficient for substantial completion of the reaction, as evidenced, for example, by thin layer chromatography. Standard testing of the reaction solution upon completion, followed by an isolation / purification process, such as, for example, crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., provides the compound of Formula I'. [ka]

[0156] Scheme 4 In some embodiments, compounds of Formula I and subformulas thereof are prepared as shown in Scheme 4. In Scheme 4, the first step is a standard SN ARIn this reaction, at least a stoichiometric amount of protected ring A, compound 2A, is mixed with compound 1, typically in the presence of a suitable base, such as sodium hydride, potassium carbonate, cesium carbonate, or the like, in an inert diluent, such as tetrahydrofuran, dioxane, DMSO, DMF, or the like. The reaction is typically maintained at 25° C. to 100° C. until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), or the like, to provide compound 3A.

[0157] In the next step, a standard Suzuki coupling reaction is carried out in which at least a stoichiometric amount of arylboronic acid, compound 4, is mixed with compound 3A, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, or the like, in an inert diluent, such as tetrahydrofuran, dioxane, toluene, or dimethoxyethane. The reaction is typically maintained at 10°C to 65°C until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, such as crystallization, chromatography, or high-performance liquid chromatography (HPLC), to yield compound 5A.

[0158] In the next step, the protecting group, e.g., t-butoxycarbonyl (t-BOC), is removed under standard conditions depending on the specific protecting group employed. The t-BOC group is merely exemplary; other standard amino protecting groups, e.g., benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc., can also be employed. After standard workup of the reaction solution upon completion of the reaction, an isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), etc., can then be carried out.

[0159] In the next step, standard SN ARA reaction is carried out in which at least a stoichiometric amount of the deprotected product of the previous step is combined with 2,4-dibromopyrimidine, compound 6, typically in the presence of a suitable base, e.g., diisopropylethylamine, triethylamine, pyridine, potassium carbonate, or the like, in an inert diluent, e.g., tetrahydrofuran, dioxane, DMSO, DMF, or the like. The reaction is typically maintained at 25°C to 100°C until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), or the like, to provide compound 7A.

[0160] In the final step, a standard coupling reaction, including but not limited to Sonogashira coupling, Suzuki coupling, etc., is carried out in which at least a stoichiometric amount of an appropriate coupling partner, compound 8, is mixed with compound 7 under standard coupling reaction conditions known in the art, including the use of a palladium catalyst (e.g., palladium(II) bis(triphenylphosphine) dichloride, palladium diacetate, etc.), a cocatalyst (e.g., copper(I) iodide, etc.), and typically in the presence of a suitable base (e.g., diisopropylethylamine, triethylamine, pyridine, cesium carbonate, etc.). The coupling reaction is typically carried out in an inert solvent, such as toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, etc. The reaction is typically carried out at about 10°C to about 110°C for a period of time sufficient for substantial completion of the reaction, as evidenced by, for example, thin layer chromatography. Following standard examination of the reaction solution upon completion, an isolation / purification process, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., is carried out to obtain the compound of Formula I. [ka]

[0161] Scheme 5 In some embodiments, compounds of Formula I and subformulas thereof are prepared as shown in Scheme 5. In Scheme 5, the first step is a standard Sonogashira coupling reaction employing at least a stoichiometric amount of protected propargylamine, compound 9, mixed with compound 7A under standard reaction conditions known in the art, typically involving the use of palladium(II) bis(triphenylphosphine) dichloride or copper(I) iodide as catalysts in the presence of a suitable base, such as, for example, diisopropylethylamine, triethylamine, pyridine, or cesium carbonate. The reaction is typically carried out in an inert solvent, such as, for example, toluene or N,N-dimethylformamide. The reaction is typically carried out at about 25° C. to about 110° C. for a period of time sufficient for substantial completion of the reaction, as evidenced, for example, by thin layer chromatography. Following standard testing of the reaction solution upon completion, an isolation / purification process, such as, for example, crystallization, chromatography, or high-performance liquid chromatography (HPLC), is performed to provide compound 10A.

[0162] In the next step, the protecting group, e.g., t-butoxycarbonyl (t-BOC), is removed under standard conditions depending on the specific protecting group employed. The t-BOC group is merely exemplary; other standard amino protecting groups, e.g., benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc., can also be employed. After standard workup of the reaction solution upon completion, a subsequent isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), etc., provides compound 11A.

[0163] In the final step, at least a stoichiometric amount of the appropriate carboxylic acid, compound 12, is mixed with compound 11A under standard amide bond-forming reaction conditions known in the art, including the use of N,N-dicyclohexylcarbodiimide (DCC) as a carboxyl group activating agent. Other activating agents are known in the art. The reaction is typically carried out in an inert solvent, such as, for example, chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically carried out at about 0°C to about 30°C for a period of time sufficient for substantial completion of the reaction, as evidenced, for example, by thin layer chromatography. After standard testing of the reaction solution upon completion, a subsequent isolation / purification process, such as, for example, crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., is carried out to provide the compound of Formula I. [ka]

[0164] Scheme 6 In some embodiments, compounds of Formula I and subformulas thereof are prepared as shown in Scheme 3'. In Scheme 3', the first step is a standard Suzuki coupling reaction in which at least a stoichiometric amount of protected aminovinylboronic acid, compound 13, is combined with compound 7A, typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base, such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, or the like, in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, or the like. The reaction is typically maintained at 10°C to 65°C until substantially complete. Standard workup of the reaction solution is followed by an isolation / purification process, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), or the like, to afford compound 14A.

[0165] In the next step, the protecting group, e.g., t-butoxycarbonyl (t-BOC), is removed under standard conditions depending on the specific protecting group employed. The t-BOC group is merely exemplary; other standard amino protecting groups, e.g., benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc., can also be employed. After standard workup of the reaction solution upon completion, a subsequent isolation / purification process, e.g., crystallization, chromatography, high performance liquid chromatography (HPLC), etc., provides compound 15A.

[0166] In the final step, at least a stoichiometric amount of the appropriate carboxylic acid, compound 12, is mixed with compound 15A under standard amide bond-forming reaction conditions known in the art, including the use of N,N-dicyclohexylcarbodiimide (DCC) as a carboxyl group activating agent. Other activating agents are known in the art. The reaction is typically carried out in an inert solvent, such as, for example, chloroform, methylene chloride, toluene, N,N-dimethylformamide, and the like. The reaction is typically carried out at about 0°C to about 30°C for a period of time sufficient for substantial completion of the reaction, as evidenced, for example, by thin layer chromatography. After standard testing of the reaction solution upon completion, a subsequent isolation / purification process, such as, for example, crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., is carried out to provide the compound of Formula I.

[0167] Other starting materials used herein are known in the art, commercially available, or can be prepared by standard synthetic methods.

[0168] method In one embodiment, the compounds and compositions described herein are useful in a method for treating a SMARCA2-dependent disease or disorder, or a disease or disorder mediated at least in part by SMARCA2. The method comprises administering to a subject suffering from a SMARCA2-dependent disease or disorder an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0169] In one embodiment, there is provided a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or the compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for use in the treatment of a SMARCA2-dependent disease or disorder.

[0170] In one embodiment, the method relates to a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, or the compound or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, used in the manufacture of a medicament for reducing the level of a protein expressed from the SMARCA2 gene, wherein reducing the level of such protein treats or ameliorates the disease or disorder.

[0171] In one embodiment, the methods described herein include the use of a prodrug of a compound described herein.

[0172] In one embodiment, the method relates to a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for the uses described herein, wherein at a concentration of 1 μM of a compound described herein, degradation of the protein expressed from the SMARCA2 gene ranges from about 25% to about 99%. Degradation of the protein expressed from the SMARCA2 gene is measured by the assay described in the Biological Examples. In some embodiments, degradation of the protein expressed from the SMARCA2 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, degradation of the protein expressed from the SMARCA2 gene is about 25% to about 35%, about 35% to about 45%, about 45% to about 55%, about 55% to about 65%, about 65% to about 75%, about 75% to about 85%, or about 85% to about 99%. In some embodiments, degradation of the protein expressed from the SMARCA2 gene is greater than 60%. In some embodiments, degradation of the protein expressed from the SMARCA2 gene is greater than 70%. In some embodiments, degradation of the protein expressed from the SMARCA2 gene is greater than 80%. In some embodiments, degradation of the protein expressed from the SMARCA2 gene is greater than 90%.

[0173] The compounds and compositions described herein are useful for treating SMARCA2-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 carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma, or diffuse large B-cell lymphoma. The cancer may 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, renal 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, immune-deficient cancer, immunogenic cancer, and Ewing's sarcoma. In one embodiment, the SMARCA2-dependent disease or disorder is a disease or disorder selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, and gastrointestinal stromal tumor (GIST). In another embodiment, the cancer is a disease or disorder selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite-stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, the SMARCA2-dependent disease or disorder is a disease or disorder selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite-stable colorectal cancer (mssCRC).

[0174] The compounds of the present disclosure can be administered in an amount effective to treat or prevent a disorder and / or prevent its onset in a subject.

[0175] In general, the methods of using the compounds of the present application involve administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0176] In certain embodiments, the compounds described herein are useful for treating proliferative disorders (e.g., cancer, benign neoplasms, inflammatory diseases, and autoimmune diseases). In certain embodiments, the therapeutic methods of the present application modulate the levels of cellular proteins of a subject, such as pathogenic and oncogenic proteins, or inhibit their proliferation, or degrade the proteins by contacting the cells with a compound or composition described herein. In other embodiments, the compounds are useful for treating cancer.

[0177] Thus, in another aspect of the present application, a method for treating cancer is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition described herein. In certain embodiments, a method for treating cancer is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutical composition comprising the compound, in an amount and for a time necessary to achieve the desired result. In some embodiments, the compound of the present application is administered orally or intravenously. In certain embodiments of the present application, a "therapeutically effective amount" of a compound or pharmaceutical composition is an amount effective to kill tumor cells or inhibit tumor cell growth. The compounds and compositions according to the methods of the present application can be administered in any amount and using any route effective to kill tumor cells or inhibit tumor cell growth. Thus, as used herein, an "amount effective to kill tumor cells or inhibit tumor cell growth" refers to an amount of agent sufficient to kill tumor cells or inhibit tumor cell growth. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular anti-cancer agent, its mode of administration, etc. In certain embodiments of the present application, a "therapeutically effective amount" of a compound or pharmaceutical composition described herein is an amount effective to reduce the level of a target protein. In certain embodiments of the present application, a "therapeutically effective amount" of a compound or pharmaceutical composition is an amount effective to kill skin cells or inhibit the proliferation of skin cells.

[0178] In certain embodiments, the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof to a subject (including, but not limited to, a human or other mammal in need thereof). In certain embodiments, the compounds or compositions described herein are useful for treating 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's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain tumor, liver cancer or esophageal cancer).

[0179] In certain embodiments, the compounds or compositions described herein are useful for treating 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's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the compounds or compositions described herein are effective against solid tumors.

[0180] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and provides methods of treating subjects using these compounds, pharmaceutical compositions thereof, or any of these in combination with one or more additional therapeutic agents.

[0181] Another aspect of the present application relates to a method of treating or lessening the severity of a disease or condition associated with a proliferative disorder in a patient, the method comprising administering to the patient a compound of formula I, or a composition comprising said compound.

[0182] The compounds and compositions of the present application can be administered in any amount and by any route of administration that is effective for treating cancer and / or disorders related to cell hyperproliferation.For example, when a compound is used to treat cancer, the term "effective amount" as used herein refers to the amount of agent that is effective for inhibiting proliferation or the amount that is sufficient to reduce the effects of cancer.The exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the specific anti-cancer agent, its mode of administration, etc.

[0183] The present application provides a method for treating a proliferative disorder in a subject in need thereof by administering a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable 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 present application further provides the use of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for the preparation of a medicament useful for treating a proliferative disorder.

[0184] The present application also provides a method for preventing a proliferative disorder in a subject in need of such treatment by administering a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, to the subject in need of such treatment. The proliferative disorder can be cancer or a precancerous condition. The present application also provides the use of a compound of the present application, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, for the preparation of a medicament useful for preventing a proliferative disorder.

[0185] As used herein, the term "proliferative disorder" refers to a condition in which uncontrolled or abnormal cell proliferation, or both, can lead to the development of an undesirable condition or disease, whether cancerous or not. Exemplary proliferative disorders of the present application encompass a variety of conditions in which cell division is uncontrolled. Exemplary proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematologic tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cells" is defined as any cell that divides at a rate that exceeds or is faster than the rate expected or observed among adjacent or juxtaposed cells within the same tissue. Proliferative disorders include precancerous or precancerous conditions. Proliferative disorders include cancer. The methods provided herein are used to treat or alleviate the symptoms of cancer. The term "cancer" includes solid tumors, as well as hematological and / or malignant tumors. A "precancerous cell" or "precancerous cell" is a cell that represents a precancerous state or a proliferative disorder that is a precancerous state. A "cancer cell" or "cancerous cell" is a cell that represents a proliferative disorder that is cancer. Any reproducible means of measurement may be used to identify cancer or precancerous cells. Cancer or precancerous cells can be identified by histological classification or grading of a tissue sample (e.g., a biopsy sample). Cancer or precancerous cells can be identified through the use of appropriate molecular markers.

[0186] Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxin shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; 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; neurotrauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic kidney disease. 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; tendonitis; tenosynovitis; herniated, ruptured, or prolapsed disc syndromes; osteopetrosis; thrombosis; restenosis; silicosis; pulmonary sarcoidosis; bone resorption diseases such as osteoporosis; graft-versus-host reaction; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral diseases such as shingles, herpes simplex type I or II, influenza virus, and cytomegalovirus; and diabetes mellitus.

[0187] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), bile duct cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, glioma of the visual pathway and hypothalamus, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal, cancer of the nervous system, lymphoma of the nervous system, cancer of the central nervous system, lymphoma of the central nervous system, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasms, mycosis fungoides, Sézary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet (pancreatic) cell tumor, Kaposi's sarcoma, renal cancer, kidney cancer, renal cell carcinoma, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma , primary central nervous system lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) 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 carcinoma, neuroblastoma, oral cancer, oral cavity cancercancer), oropharyngeal cancer, ovarian cancer, epithelial ovarian cancer, ovarian tumors of low malignant potential, pancreatic cancer, islet cell pancreatic cancer, cancer of the paranasal sinuses and nasal cavity, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumors, plasma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma, Kaposi's sarcoma, soft tissue sarcomas, and uterus These include uterine sarcoma, non-melanoma skin cancer, melanoma skin cancer, Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma, thymoma and cancer of the thymus, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary system, gestational trophoblastic neoplasia, urethral cancer, endometrial cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0188] A "blood system proliferative disorder" is a proliferative disorder involving cells of the blood system. Blood system proliferative disorders can include lymphoma, leukemia, myeloid tumors, mast cell tumors, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myelogenous leukemia, primary myelofibrosis, and essential thrombocythemia. Blood system proliferative disorders can include hyperplasia, dysplasia, and metaplasia of blood system cells. The compositions of the present application can be used to treat a cancer selected from the group consisting of the blood cancers of the present application or the blood proliferative disorders of the present application. Hematological cancers of the present application may include multiple myeloma, lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, and lymphocytic lymphomas and lymphomas of cutaneous origin), leukemias (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid tumors, and mast cell tumors.

[0189] A "pulmonary proliferative disorder" is a proliferative disorder involving lung cells. Pulmonary proliferative disorders can include all forms of proliferative disorders affecting lung cells. Pulmonary proliferative disorders can include lung cancer, precancerous or precancerous conditions of the lung, benign lung growths or lesions, and malignant lung growths or lesions, as well as metastatic lesions in bodily tissues and organs other than the lung. The compositions of the present application can be used to treat lung cancer or a pulmonary proliferative disorder. Lung cancer can include all forms of lung cancer. 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 histologic and ultrastructural heterogeneity (e.g., mixed cell types).

[0190] Pulmonary proliferative disorders may include all forms of proliferative disorders affecting lung cells. Pulmonary proliferative disorders may include lung cancer and precancerous lung conditions. Pulmonary proliferative disorders may include pulmonary hyperplasia, metaplasia, and dysplasia. Pulmonary proliferative disorders may include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Pulmonary proliferative disorders may include replacement of columnar epithelium with stratified squamous epithelium and mucosal dysplasia. For example, individuals exposed to inhalation of harmful environmental factors such as tobacco smoke and asbestos may be at increased risk of developing pulmonary proliferative disorders. Pre-existing lung diseases that predispose individuals to developing proliferative disorders of the lung include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatic diseases, sarcoidosis, interstitial pneumonia, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granulomatosis, asbestosis, fibrosing alveolitis, and Hodgkin's disease.

[0191] A "proliferative disorder of the colon" is a proliferative disorder involving colon cells. In one embodiment, the proliferative disorder of the colon is colon cancer. In one embodiment, the compositions of the present application can be used to treat colon cancer or a proliferative disorder of the colon. Colon cancer can include all forms 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 carcinoma. Colon cancer can be associated with hereditary non-adenomatous colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis. Colon cancer can be caused by hereditary nonadenomatous colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot syndrome, and juvenile polyposis.

[0192] Colonic proliferative disorders may include all forms of proliferative disorders affecting colon cells. Colonic proliferative disorders may include colon cancer, colonic precancerous conditions, colonic adenomatous polyps, and colonic metachronous lesions. Colonic proliferative disorders may include adenomas. Colonic proliferative disorders may be characterized by colonic hyperplasia, metaplasia, and dysplasia. Past colonic diseases that predispose individuals to developing colonic proliferative disorders include past colon cancer. Current diseases that predispose individuals to developing colonic proliferative disorders include Crohn's disease and ulcerative colitis. Colonic proliferative disorders may be associated with mutations in genes selected from the group consisting of p53, ras, FAP, and DCC. Individuals may be at increased 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.

[0193] A "pancreatic proliferative disorder" is a proliferative disorder involving pancreatic cells. Pancreatic proliferative disorders can include all forms of proliferative disorders affecting pancreatic cells. Pancreatic proliferative disorders can include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia and pancreatic dysplasia, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, as well as metastatic lesions in tissues and organs of the body other than the pancreas. Pancreatic cancer includes all forms of pancreatic cancer. Pancreatic cancer can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary tumor, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma. Pancreatic cancer can also include tumors of the pancreas that have histologic and ultrastructural heterogeneity (eg, mixed cell types).

[0194] A "proliferative disorder of the prostate" is a proliferative disorder involving cells of the prostate. Proliferative disorders of the prostate may include all forms of proliferative disorders affecting prostate cells. Proliferative disorders of the prostate may include prostate cancer, precancerous or precancerous conditions of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, as well as metastatic lesions in tissues and organs of the body other than the prostate. Proliferative disorders of the prostate may include hyperplasia, metaplasia, and dysplasia of the prostate.

[0195] A "skin proliferative disorder" is a proliferative disorder involving skin cells. Skin proliferative disorders can include all forms of proliferative disorders affecting skin cells. Skin proliferative disorders can include precancerous or precancerous conditions of the skin, benign skin growths or lesions, and melanoma, malignant melanoma, and other malignant skin growths or lesions, as well as metastatic lesions in body tissues and organs other than the skin. Skin proliferative disorders can include skin hyperplasia, metaplasia, and dysplasia.

[0196] An "ovarian proliferative disorder" is a proliferative disorder involving cells of the ovary. Ovarian proliferative disorders can include all forms of proliferative disorders affecting ovarian cells. Ovarian proliferative disorders can include precancerous or precancerous conditions of the ovary, benign ovarian growths or lesions, ovarian cancer, malignant ovarian growths or lesions, and metastatic lesions in tissues and organs of the body other than the ovaries. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of ovarian cells.

[0197] A "proliferative disorder of the breast" is a proliferative disorder involving cells of the breast. Proliferative disorders of the breast can include all forms of proliferative disorders affecting breast cells. Proliferative disorders of the breast can include breast cancer, precancerous or precancerous conditions of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, as well as metastatic lesions in tissues and organs of the body other than the breast. Proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0198] The cancer to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) is assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d, the regional lymph nodes (N) are assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c, and the distant metastases (M) can be assigned a stage of MX, M0, or M1. The cancer to be treated can 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. The cancer to be treated may be assigned a grade according to the AJCC classification as grade GX (e.g., grade not assessable), grade 1, grade 2, grade 3, or grade 4. The cancer to be 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.

[0199] The cancer to be treated may include tumors determined to be about 2 centimeters or less in diameter. The cancer to be treated may include tumors determined to be about 2 to about 5 centimeters in diameter. The cancer to be treated may include tumors determined to be about 3 centimeters or more in diameter. The cancer to be treated may include tumors determined to be more than 5 centimeters in diameter. The cancer to be treated may be classified by microscopy as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated. The cancer to be treated may be classified by microscopy with respect to mitotic rate (e.g., amount of cell division) or nuclear pleomorphism (e.g., cellular changes). The cancer to be treated may be classified by microscopy as being associated with areas of necrosis (e.g., areas of dead or degenerating cells). The cancer to be treated may be classified as having an abnormal karyotype, an abnormal chromosome number, or one or more chromosomes that are abnormal in appearance. The cancer to be treated may be classified as aneuploid, triploid, tetraploid, or having altered ploidy. The cancers to be treated may be classified as having a chromosomal translocation, or as having a deletion or duplication of an entire chromosome, or as having a region of deletion, duplication, or amplification of part of a chromosome.

[0200] The cancer to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. The cancer to be treated is typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., S phase of cell division). The cancer to be treated is typed as having a low S phase fraction or a high S phase fraction.

[0201] As used herein, a "normal cell" is a cell that cannot be classified as part of a "proliferative disorder." A normal cell lacks uncontrolled or aberrant growth, or both, that can lead to the development of an undesirable condition or disease. In one embodiment, a normal cell has normally functioning cell cycle checkpoint control mechanisms.

[0202] Those skilled in the art can refer to general reference texts for detailed descriptions of known techniques described herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd 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; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). These texts can, of course, also be referenced when making or using embodiments of the present application.

[0203] In certain embodiments, the compounds of the present application are useful for treating proliferative disorders (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In certain embodiments, the therapeutic methods of the present application regulate the levels of cellular proteins of a subject, such as the levels of pathogenic and oncogenic proteins, or inhibit their proliferation by contacting the cells with a compound or composition described herein. In other embodiments, the compounds are useful for treating cancer.

[0204] In certain embodiments, the method comprises administering a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof to a subject (including but not limited to, a human or an animal) in need thereof. In certain embodiments, the compound is useful for treating 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's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain tumor, liver cancer or esophageal cancer).

[0205] In certain embodiments, the anti-cancer agent is useful in 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's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. In certain embodiments, the anti-cancer agent is effective against solid tumors.

[0206] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and provides methods of treating subjects using these compounds, pharmaceutical compositions thereof, or any of these in combination with one or more additional therapeutic agents.

[0207] For example, other therapies or anti-cancer agents that may be combined with the compounds disclosed herein include surgery, radiation therapy, endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents that attenuate some adverse effects (e.g., antiemetics), and alkylating agents (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists, and pyrimidine antagonists, to name a few, but are not limited to. Other approved chemotherapeutic agents include agonists (6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine), spindle poisons (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 overview of cancer therapy, see The Merck Manual, Twentieth Edition, 2020, the entire contents of which are incorporated herein by reference. Also see the National Cancer Institute (NCI) website (www.nci.nih.gov) and the Food and Drug Administration (FDA) website for a list of FDA-approved oncology drugs (www.fda.gov / cder / cancer / druglistframe).

[0208] In certain embodiments, pharmaceutical compositions comprising compounds disclosed herein further comprise one or more additional therapeutically active ingredients (e.g., chemotherapeutic agents and / or palliative agents). For purposes of this application, the term "palliative" refers to treatment that focuses on alleviating symptoms of a disease and / or side effects of a therapeutic regimen, but is not curative. For example, palliative treatments include painkillers, antiemetics, and anti-disease drugs. In addition, chemotherapy, radiation therapy, and surgery can all be used palliatively (i.e., to reduce symptoms rather than cure, e.g., to shrink tumors, reduce pressure, bleeding, pain, and other symptoms of cancer, etc.).

[0209] Administration, Pharmaceutical Compositions Administration of the compounds and pharmaceutical compositions of the present disclosure can be achieved via any mode of administration for therapeutic agents, including systemic or local administration, such as, for example, oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0210] Depending on the intended mode of administration, the compositions of the present disclosure may be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., and may be in unit doses, consistent with standard pharmaceutical practice. Similarly, they may be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms known to those of ordinary skill in the pharmaceutical arts.

[0211] Exemplary pharmaceutical compositions include a compound of the present disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, such as purified water, a triglyceride oil, such as a hydrogenated or partially hydrogenated vegetable oil, or a mixture thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil, such as EPA or DHA, or an ester thereof, or a triglyceride or mixture thereof, an omega-3 fatty acid or a derivative thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, its magnesium salts or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; and for tablets, c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars, for example, glucose and beta-lactose, corn sweeteners, natural and synthetic gums, for example, acacia, tragacanth or sodium alginate, waxes, and / or polyvinylpyrrolidone, as needed; d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavors and sweeteners; f) emulsifiers or dispersing agents, for example, Tween Tablets and gelatin capsules containing 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that improves compound absorption, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200, etc.

[0212] Liquid, particularly injectable compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. For example, proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0213] The compounds of the present disclosure may also be formulated as suppositories which may be prepared from fatty emulsions or suspensions, using, for example, polyalkylene glycols, such as propylene glycol, as the carrier.

[0214] The compounds of the present disclosure can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids containing cholesterol, stearylamine, or phosphatidylcholines.

[0215] 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 US Pat. No. 5,262,564.

[0216] The disclosed compounds can be delivered using monoclonal antibodies as individual carriers to which the disclosed compounds are bound. The disclosed compounds can also be coupled to soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be coupled to certain biodegradable polymers useful for controlled drug release, such as polylactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic hydrogel block copolymers. In one embodiment, the disclosed compounds are not covalently coupled to polymers, such as polycarboxylic acid polymers or polyacrylates.

[0217] Parenteral injections are generally used for subcutaneous, intramuscular, or intravenous injections and infusions. Injections can be prepared in standard forms, either as liquid solutions or suspensions, or in solid forms suitable for dissolving in liquid prior to injection.

[0218] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

[0219] The compositions can be prepared according to standard mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of a compound of the present disclosure by weight or volume.

[0220] In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present disclosure. In one embodiment, the kit includes a means for keeping the pharmaceutical compositions separate, such as, for example, a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, typically used for packaging tablets, capsules, and the like.

[0221] The kits of the present disclosure can be used to administer different dosage forms, e.g., oral and parenteral, can be used to administer the separate compositions at different dosage intervals, or can be used to titrate the separate compositions relative to one another. To aid in compliance, the kits of the present disclosure typically include directions for administration.

[0222] Pharmaceutical dosage forms of the compounds of the present disclosure can be prepared by any method known in the art, such as, for example, standard mixing, sieving, dissolving, melting, granulating, dragee-making, tablet-forming, suspending, extruding, spray-drying, gelling, emulsifying, (nano / micro)encapsulating, entrapment, or lyophilization processes. As noted above, the compositions of the present disclosure can contain one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into a preparation for pharmaceutical use.

[0223] As described above, the composition generally comprises a compound of the present disclosure combined with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic benefits of the claimed compound. Such excipients may be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

[0224] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0225] Compressed gases can be used to disperse the compounds of the present disclosure in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, etc. 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).

[0226] The compositions of the present disclosure may be in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient, if desired. Such a pack or device may, for example, comprise a blister pack or a metal or plastic foil such as glass, and a rubber stopper, for example, in the case of a vial. The pack or dispenser device may also be accompanied by instructions for administration. Compositions containing the compounds of the present disclosure, which may be formulated in a compatible pharmaceutical carrier, can also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0227] The amount of compound in a formulation can vary within the full range accepted by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01 to 99.99% by weight of the compound of the present disclosure based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80% by weight. Representative pharmaceutical formulations are described below.

[0228] Formulation example The following are representative pharmaceutical formulations containing compounds of the present disclosure.

[0229] Formulation Example 1 - Tablet formulation The following ingredients are intimately mixed and compressed into single scored tablets: TIFF2025525340000227.tif41170

[0230] Formulation example 2 - Capsule formulation The following ingredients are intimately mixed and loaded into a hard-shell gelatin capsule: TIFF2025525340000228.tif29170

[0231] Formulation Example 3 - Suspension formulation The following ingredients are mixed to form a suspension for oral administration: TIFF2025525340000229.tif63170

[0232] Formulation Example 4 - Injectable formulation The following ingredients are mixed to form an injectable formulation: TIFF2025525340000230.tif29170

[0233] Formulation Example 5 - Suppositories Suppositories weighing 2.5 g total are prepared by mixing a compound of the present disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and have the following composition: TIFF2025525340000231.tif20170

[0234] Administration Dosage regimens utilizing the present compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the patient's renal or hepatic function; and the particular disclosed compound being employed. Physicians and veterinarians of ordinary skill in the art can readily determine and prescribe the effective amount required to prevent, reverse, or arrest the progression of the condition.

[0235] The effective dosage of the disclosed compounds, when used for the indicated effects, ranges from about 0.5 mg to about 5,000 mg of the disclosed compounds as needed to treat the condition. For in vivo or in vitro use, the composition can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed compounds, or a range of amounts from one to another listed in the dosage list. In one embodiment, the composition is in the form of a tablet that can be divided. [Example]

[0236] The present disclosure will be further understood by reference to the following examples, which are intended to be purely exemplary of the present disclosure. The present disclosure is not limited in scope by the exemplary embodiments, which are intended only as illustrations of one aspect of the present disclosure. Any functionally equivalent methods are also within the scope of the present disclosure. In addition to what is described herein, various modifications of the present disclosure will be apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are within the scope of the appended claims.

[0237] In this specification and in the examples that follow, all temperatures are in degrees Celsius. Additionally, the following abbreviations have the following meanings: If not defined, these abbreviations have their art-recognized meaning. TIFF2025525340000232.tif245170TIFF2025525340000233.tif81170

[0238] LC-MS method (general method) Method A: Luna® 5 μm C 18 (2) Experiments were performed using a 100 Å, 250 x 21.2 mm, AXIA™ Packed LC column (00G-4252-P0-AX) at a flow rate of 20 mL / min and a mass spectrometer using ESI as the ionization source. Solvent A was 4.0 mL of TFA in 4 L of water, and solvent B was 4.0 mL of TFA in 4 L of acetonitrile. The gradient consisted of 10 to 100% solvent B over 20 min, and the LC column temperature was 40 °C. UV absorbance was collected at 220 nm and 254 nm. Example 1 Preparation of N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)-1,5-dimethyl-1H-pyrazole-3-carboxamide (Compound P-12) [ka] Step 1: [ka]

[0239] To a solution of 4-bromo-6-chloropyridazin-3-amine (1 g, 4.80 mmol, 1 equiv.) in EtOH (10 mL) was added DIEA (1.86 g, 14.39 mmol, 2.51 mL, 3 equiv.) and tert-butyl piperazine-1-carboxylate (1.34 g, 7.20 mmol, 1.5 equiv.). The mixture was stirred at 80° C. for 12 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (20 mL), washed with water, dried over magnesium sulfate, and the solvent was evaporated in vacuo to give tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)piperazine-1-carboxylate. Step 2: [ka]

[0240] A mixture of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)piperazine-1-carboxylate (1.3 g, 4.14 mmol, 1 equiv.), (2-hydroxyphenyl)boronic acid (857.16 mg, 6.21 mmol, 1.5 equiv.), Pd(dppf)Cl (303.15 mg, 414.30 μmol, 0.1 equiv.), and CsCO (8.10 g, 24.86 mmol, 6 equiv.) in dioxane (14 mL) and HO (1.4 mL) was degassed and purged with N. The mixture was stirred at 80 °C under a N atmosphere for 12 h. The reaction was extracted with ethyl acetate (5 mL), and the organic phase was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 0-100% ethyl acetate in petroleum ether) to give tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazine-1-carboxylate. 1 H NMR(400MHz,d6-DMSO)δ7.92(dd,J=8.25,1.25Hz,1H)7.55(s,1H)7.18~7.29(m,1H)6.82~6.95(m,2H)6.38(s,2H)3.55(br s,5H)2.99~3.08(m,4H)1.43(s,9H). Step 3: [ka]

[0241] To a solution of tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazine-1-carboxylate (1 g, 2.69 mmol, 1 equiv) in DCM (8 mL) was added TFA (4 mL). The mixture was stirred at 25° C. for 12 h. The reaction was concentrated under reduced pressure to give a residue which was triturated with MTBE to give 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol. 1H NMR(400MHz,d6-DMSO)δ9.34~9.61(m,2H)8.27~8.48(m,1H)7.79(br d,J=7.50Hz,1H)7.61(s,1H)7.31(br t,J=7.50Hz,1H)7.05~7.22(m,2H)6.99(br d,J=8.13Hz,1H)6.93(br t,J=7.44Hz,1H)3.37(br s,7H). Step 4: [ka]

[0242] To a solution of 4-bromo-2-(methylthio)pyrimidine (5 g, 24.38 mmol, 1 equiv.) in MeCN (20 mL), DCM (20 mL), and HO (20 mL) at 0 °C was added NaIO (10.41 g, 48.76 mmol, 2 equiv.). RuCl (0.1 g, 0.02 equiv.) was added, and the reaction was warmed to 25 °C and stirred for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic phase was separated, washed with saturated NaSO (50 mL), and dried over sodium sulfate. The organic phase was concentrated to give a residue that was purified by column chromatography to give 4-bromo-2-(methylsulfonyl)pyrimidine. Step 5: [ka]

[0243] Di-tert-butyl prop-2-yn-1-yliminodicarbonate (2.16 g, 8.44 mmol, 1 equiv.) was added to a solution of LiHMDS (10 mL, 1.2 equiv., 1N) in THF (30 mL) at -78°C and stirred for 1 h. A solution of 4-bromo-2-(methylsulfonyl)pyrimidine (2 g, 8.44 mmol, 1 equiv.) in DCM (10 mL) was added dropwise. The mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (30 mL), diluted with water (50 mL), and extracted with MTBE (50 mL). The organic phase was separated, dried over sodium sulfate, and concentrated to give a residue. The residue was purified by column chromatography to give di-tert-butyl (3-(4-bromopyrimidin-2-yl)prop-2-yn-1-yl)iminodicarbonate. 1 H NMR (400MHz, CDCl3) δ8.44(d,J=6.4Hz,1H),7.45(d,J=6.4Hz,1H),4.66(s,2H),1.54(s,18H). Step 6: [ka]

[0244] A solution of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (802 mg, 2.08 mmol, 1 equiv.), di-tert-butyl (3-(4-bromopyrimidin-2-yl)prop-2-yn-1-yl)iminodicarbonate (650 mg, 2.08 mmol, 1 equiv.), and DIEA (807 mg, 6.25 mmol, 3 equiv.) in DMF (5.0 mL) was stirred at room temperature overnight. 1 M citric acid solution was added to the reaction mixture until the pH reached approximately 4. The precipitate was filtered, washed with ethyl acetate and dried to give tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)(tert-butoxycarbonyl)carbamate. Step 7: [ka]

[0245] To a solution of tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)(tert-butoxycarbonyl)carbamate (162 mg, 322 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo to give 2-(6-amino-5-(4-(2-(3-aminoprop-1-yn-1-yl)pyrimidin-4-yl)piperazin-1-yl)pyridazin-3-yl)phenol. Step 8: [ka]

[0246] A solution of 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (3.3 mg, 23.8 μmol) and HATU (9.1 mg, 24 μmol) in DMF (0.3 mL) was stirred at room temperature for 2 minutes. A solution of 2-(6-amino-5-(4-(2-(3-aminoprop-1-yn-1-yl)pyrimidin-4-yl)piperazin-1-yl)pyridazin-3-yl)phenol (15 mg, 24 μmol) and DIEA (12.3 mg, 95.2 μmol, 4 equiv.) in DMF (0.2 mL) was added. The solution was stirred at room temperature for 5 hours. The solution was purified by preparative HPLC (column: Phenomenex Luna C). 18 Purification was performed using a 100 × 40 mm × 5 m column column; mobile phase: (0.1% formic acid in water to 0.1% formic acid in ACN; B%: 5% to 50%, 8 min). Fractions were combined and lyophilized to give N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazin-1-yl)pyrimidin-2-yl)prop-2-yn-1-yl)-1,5-dimethyl-1H-pyrazole-3-carboxamide. Example 2 Preparation of N-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound P-119) [ka] Step 1: [ka]

[0247] To a solution of 4-bromo-6-chloropyridazin-3-amine (1 g, 4.80 mmol, 1 equiv.) in EtOH (10 mL) was added DIEA (1.86 g, 14.39 mmol, 2.51 mL, 3 equiv.) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.53 g, 7.20 mmol, 1.5 equiv.). The mixture was stirred at 100 °C for 12 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE to give tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. m / z (ESI + ):340.2(M+H) + . Step 2: [ka]

[0248] A mixture of tert-butyl 3-(3-amino-6-chloropyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.4 g, 7.06 mmol, 1 equiv.), (2-hydroxyphenyl)boronic acid (1.46 g, 10.59 mmol, 1.5 equiv.), Pd(dppf)Cl (516.78 mg, 706.26 μmol, 0.1 equiv.), and CsCO (13.81 g, 42.38 mmol, 6 equiv.) in dioxane (20 mL) and HO (2 mL) was degassed and purged under N. The mixture was stirred at 80 °C under N for 12 h. The reaction was extracted with ethyl acetate (5 mL), and the organic phase was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, 0-100% ethyl acetate in petroleum ether) to give tert-butyl 3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. m / z (ESI + )298.2.2(M-100+H) + . Step 3: [ka]

[0249] To a solution of tert-butyl 3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (0.92 g, 2.31 mmol, 1 equiv.) in DCM (6 mL) was added TFA (3 mL). The mixture was stirred at 25° C. for 12 hours. The reaction was concentrated under reduced pressure to give a residue that was triturated with MTBE to give 2-(6-amino-5-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol as the TFA salt. 1H NMR(400MHz,d6-DMSO)δ9.15(br s,2H)7.69(br d,J=7.25Hz,1H)7.57(s,1H)7.36(br t,J=7.63Hz,1H)6.76~7.09(m,4H)4.18(br s,2H)3.69(br d,J=12.63Hz,2H)3.25(br d,J=13.13Hz,2H)2.23(br d,J=7.75Hz,2H)1.90~2.02(m,2H). Step 4: [ka]

[0250] To a solution of 2-(6-amino-5-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol trifluoroacetic acid (250 mg, 608 μmol, 1.0 equiv.) in DMF (4 mL) was added DIEA (259 mg, 2.01 mmol, 3.3 equiv.) and 2,4-dibromopyrimidine (145 mg, 608 μmol, 1 equiv.). The reaction was stirred at room temperature for 16 hours. The solution was purified by preparative HPLC (column: Phenomenex LunaC). 18 The mixture was purified using a 100 mm × 40 mm × 5 μm column (mobile phase: 0.1% formic acid in water to 0.1% formic acid in ACN; B%: 20% to 80%, 8 min). The fractions were combined and lyophilized to give 2-(6-amino-5-(8-(2-bromopyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol. 1 H NMR(400MHz,d6-DMSO)δ8.02(d,J=6.0Hz,1H),7.93(dd,J=7.9,1.6Hz,1H),7.58(s,1H),7.23(ddd,J=8.5,7.2,1.6Hz,1H),6. 91~6.83(m,4H),6.03(s,3H),4.88~4.64(m,2H),3.50~3.32(m,2H),3.06~2.95(m,2H),2.24~2.06(m,2H),1.97~1.91(m,2H). Step 5: [ka]

[0251] 2-(6-amino-5-(8-(2-bromopyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol (15 mg, 33 μmol, 1 equiv.), N-(but-3-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (66 μmol, 2 equiv.), and DIEA (12.8 mg, 99 μmol, 3 equiv.) were dissolved in anhydrous DMF (0.7 mL). The resulting solution was degassed under a stream of argon for 5 minutes. Palladium(II) bis(triphenylphosphine) dichloride (16.4 mg, 0.0233 mmol, 0.1 equiv.) and CuI (2.5 mg, 13.2 μmol, 0.4 equiv.) were added. The reaction was stirred at 90° C. for 6 hours and then cooled to room temperature. The solution was purified by preparative HPLC (Method A) to give N-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide. Example 3 Preparation of (E)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)pyrimidin-2-yl)allyl)quinoxaline-2-carboxamide (Compound P-110) [ka] Step 1: [ka]

[0252] A mixture of 4-bromo-6-chloropyridazin-3-amine (2.07 g, 10.0 mmol, 2 equiv.), DIEA (6.45 g, 49.93 mmol, 8.70 mL, 10 equiv.), and tert-butyl 1,4-diazepane-1-carboxylate (1 g, 4.99 mmol, 980.39 μL, 1 equiv.) in DMSO (10 mL) was degassed and purged under N2 three times. The mixture was stirred under N2 atmosphere at 120 °C for 4 days. The reaction mixture was concentrated under reduced pressure. The resultant was diluted with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 1-100% ethyl acetate in petroleum ether) to give tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)-1,4-diazepane-1-carboxylate. 1 H NMR (400MHz, CDCl3) δ6.76(s,1H),5.07(s,1H),4.79(d,J=2.0Hz,1H),3.71~3.46(m,4H),3.37~3.18(m,4H),2.04~1.86(m,2H),1.47(s,9H). Step 2: [ka] A mixture of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)-1,4-diazepane-1-carboxylate (8 g, 24.40 mmol, 1 equiv.), (2-hydroxyphenyl)boronic acid (5.05 g, 36.61 mmol, 1.5 equiv.), CsCO (47.71 g, 146.43 mmol, 6 equiv.), and Pd(dppf)Cl (1.79 g, 2.44 mmol, 0.1 equiv.) in dioxane (100 mL) and water (20 mL) was degassed and purged under N three times. The mixture was stirred at 80 °C under N for 12 h. The reaction mixture was quenched by the addition of water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, 1–100% ethyl acetate in petroleum ether) to give tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepane-1-carboxylate. 1 H NMR(400MHz,CDCl3)δ14.04~13.51(m,1H),7.62~7.56(m,1H),7.39~7.28(m,2H),7.05(d,J=8.0Hz,1H),6.91(t ,J=7.6Hz,1H),5.02(s,1H),4.79(s,1H),3.74~3.52(m,4H),3.44~3.26(m,4H),2.11~1.90(m,2H),1.48(s,9H). Step 3: [ka]

[0253] A mixture of tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepane-1-carboxylate (8 g, 20.75 mmol, 1 equiv.) and TFA (15.40 g, 135.06 mmol, 10 mL, 6.51 equiv.) in DCM (80 mL) was prepared. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was triturated with MTBE (20 mL) to give 2-(6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl)phenol. 1 H NMR(400MHz,d4-MeOD)δ7.58(,J=1.6,8.0Hz,1H),7.49(s,1H),7.47~7.41(m,1H),7.08~7.01(m,2H), 4.04~3.96(m,2H),3.82~3.74(m,2H),3.58~3.50(m,2H),3.47~3.39(m,2H),2.29(quin,J=5.6Hz,2H). Step 4: [ka]

[0254] A mixture of 2-(6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl)phenol (3.57 g, 15.02 mmol, 1.5 equiv), DIEA (6.47 g, 50.08 mmol, 8.72 mL, 5 equiv), and DMAP (122.36 mg, 1.00 mmol, 0.1 equiv) in DMF (40 mL) was degassed and purged under N2 three times. The mixture was stirred under N2 atmosphere at 20 °C for 12 h. The reaction mixture was filtered. The residue was purified by preparative HPLC (column: Welch Xtimate C). 18 Purification using a 250 × 70 mm × 10 μm column, mobile phase: (water (NH4HCO3)-ACN), B%: 33% to 63%, 20 min) gave 2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol. 1H NMR(400MHz,d4-MeOD)δ7.90(s,1H),7.69(d,J=8.0Hz,1H),7.52(s,1H),7.28~7.20(m,1H),6.95~6.88(m,2H),6.78~6.64 (m,1H),4.22~4.09(m,1H),4.07~3.94(m,1H),3.86~3.70(m,2H),3.62~3.50(m,2H),3.44~3.35(m,2H),2.21~2.09(m,2H). Step 5: [ka]

[0255] A solution of 2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (50.0 mg, 113 μmol, 1 equiv.), tert-butyl (E)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate (38.4 mg, 136 μmol, 1.2 equiv.), triphenylphosphine (5.93 mg, 22.6 μmol, 0.2 equiv.), and cesium carbonate (110 mg, 339 μmol, 3 equiv.) in ACN (2 mL) and water (0.5 mL) was degassed under a stream of argon for 5 min. Palladium(II) acetate (1.27 mg, 5.65 μmol, 0.05 equiv.) was added. The reaction was stirred at 100° C. for 4 hours. The reaction was cooled to room temperature. The solution was purified by preparative HPLC (column: Phenomenex Luna C 18 Purification was performed using a 100 x 40 mm x 5 m mobile phase (0.1% formic acid in water to 0.1% formic acid in ACN); B%: 5% to 75%, 8 min). The fractions were combined and lyophilized to give tert-butyl (E)-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)pyrimidin-2-yl)allyl)carbamate. m / z (ESI + )519(M+H) + . Step 6: [ka]

[0256] To a solution of tert-butyl (E)-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)pyrimidin-2-yl)allyl)carbamate (55.8 mg, 108 μmol, 1 equiv) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20° C. for 1.5 h. The reaction mixture was concentrated in vacuo. The crude product was triturated with diethyl ether (20 mL) to give (E)-2-(6-amino-5-(4-(2-(3-aminoprop-1-en-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol, which was used directly in the next step. Step 7: [ka]

[0257] To a solution of quinoxaline-2-carboxylic acid (6.44 mg, 371 μmol, 1 equiv.) in DMF (1.0 mL) was added (E)-2-(6-amino-5-(4-(2-(3-aminoprop-1-en-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (23.9 mg, 37 μmol, 1 equiv.), HATU (14.1 mg, 37 μmol, 1 equiv.), and DIEA (19.1 mg, 25.8 μL, 148 μmol, 4 equiv.). The reaction mixture was stirred at 25°C for 16 hours. The solution was purified by preparative HPLC (column: Phenomenex Luna C). 18 Purification was performed using a 100 x 40 mm x 5 m mobile phase (0.1% formic acid in water to 0.1% formic acid in ACN; B%: 10% to 40%, 8 min). The fractions were combined and lyophilized to give (E)-N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)pyrimidin-2-yl)allyl)quinoxaline-2-carboxamide. m / z (ESI + )575(M+H) + . Example 4 Preparation of N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound P-124) [ka] Step 1: [ka]

[0258] To a mixture of 4,6-dichloro-2-(methylthio)pyrimidine (6 g, 30.76 mmol, 1 equiv.) in ethanol (60 mL) under a N atmosphere at 20 °C, sodium ethoxide (10.47 g, 30.76 mmol, 20% purity, 1 equiv.) was added in one portion. The mixture was stirred at room temperature for 16 h. Saturated NH4Cl solution (100 mL) was added. The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-chloro-6-ethoxy-2-(methylthio)pyrimidine, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ6.39(s,1H)4.43(q,J=7.2Hz,2H)2.54(s,3H)1.39(t,J=7.2Hz,3H). Step 2: [ka]

[0259] To a mixture of 4-chloro-6-ethoxy-2-(methylthio)pyrimidine (5.81 g, 28.39 mmol, 1 equiv.) in DCM (60 mL) was added mCPBA (48.98 g, 283.86 mmol, 10 equiv.) in one portion. The mixture was stirred at room temperature for 16 h. Saturated sodium thiosulfate solution (40 mL) was added. The organic phase was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-chloro-6-ethoxy-2-(methylsulfonyl)pyrimidine, which was used in the next step without further purification. m / z (ESI + )237.1(M+H) + . Step 3: [ka]

[0260] To a solution of 4-chloro-6-ethoxy-2-(methylsulfonyl)pyrimidine (1 g, 4.23 mmol, 1 equiv.) in THF (20 mL) at −78° C., LiHMDS (1 M, 5.07 mL, 99.5% purity, 1.2 equiv.) was added dropwise over 15 min. The mixture was stirred at −78° C. for 30 min. A solution of tert-butyl N-tert-butoxycarbonyl-N-prop-2-ynyl-carbamate (1.08 g, 4.23 mmol, 1 equiv.) in THF (20 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 2 h. Saturated NH4Cl solution (20 mL) was added. The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Method A) to give di-tert-butyl (3-(4-chloro-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)iminodicarbonate. 1 H NMR (400MHz, CDCl3) δ6.67(s,1H)4.63(s,2H)4.44(q,J=7.2Hz,2H)1.63(brs,3H)1.55(s,18H). Step 4: [ka]

[0261] To a solution of di-tert-butyl (3-(4-chloro-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)iminodicarbonate (150 mg, 364.18 μmol, 1 equiv.) in DMSO (5 mL) at 50° C., 2-[6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl]phenol (103.92 mg, 364.18 μmol, 1 equiv.) was added dropwise over 15 min. After the addition, the mixture was stirred at 50° C. for 30 min, and then DIEA (470.67 mg, 3.64 mmol, 634.33 μL, 10 equiv.) was added dropwise. The resulting mixture was stirred at 50° C. for 2 h. Saturated NH4Cl solution (1 mL) was added. The aqueous phase was extracted with ethyl acetate (2 × 0.5 mL). The combined organic phases were washed with brine (1 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)(tert-butoxycarbonyl)carbamate. 1 H NMR(400MHz,CDCl3)δ7.51~7.55(m,1H)7.32~7.34(m,1H)7.28~7.31(m,1H)7.04~7.07(m,1H)6.88~6.9 3(m,1H)4.33~4.39(m,2H)5.74(s,1H)4.13(q,J=7.2Hz,2H)3.96~4.09(m,2H)3.67~3.79(m,2H)3.45(br t,J=5.2Hz,2H)3.30~3.35(m,2H)2.09~2.13(m,2H)1.56(s,18H)1.41(s,3H). Step 5: [ka]

[0262] To a solution of tert-butyl (3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)(tert-butoxycarbonyl)carbamate (50 mg, 75.67 μmol, 1 equiv.) in DCM (1 mL) was added TFA (1 M, 378.35 μL, 5 equiv.). The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo to give 2-(6-amino-5-(4-(2-(3-aminoprop-1-yn-1-yl)-6-ethoxypyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol. m / z (ESI + )459.2(M-1) + . Step 6: [ka]

[0263] To a solution of pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (7.08 mg, 43.43 μmol, 1 equiv.) in DMF (1 mL) was added 2-(6-amino-5-(4-(2-(3-aminoprop-1-yn-1-yl)-6-ethoxypyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (20 mg, 43.43 μmol, 1 equiv.), HATU (16.51 mg, 43.43 μmol, 1 equiv.), and DIEA (11.23 mg, 86.86 μmol, 15.13 μL, 2 equiv.). The mixture was stirred at 0 °C for 1 h. Saturated NH4Cl solution (1 mL) was added. The aqueous phase was extracted with ethyl acetate (2 × 0.5 mL). The combined organic layers were washed with brine (1 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (Method A) to give N-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-yl)-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide. 1H NMR(400MHz,d4-MeOD)δ14.23~14.28(m,1H)9.16~9.21(m,1H)9.13~9.16(m,1H)8.66(dd,J=4.0,1.6Hz,1H)7.81~7.87(m,1H)7.49(s,1H) )7.23(s,2H)6.82~6.88(m,2H)6.17(s,1H)5.96(s,1H)4.33(d,J=6.0Hz,2H)4.22(q,J=6.8Hz,2H)3.37~3.43(m,2H)3.31(s,2H)3.23(br dd,J=5.2,4.4Hz,2H)3.16(d,J=5.2Hz,1H)2.02(br s,2H)1.24(t,J=7.2Hz,3H). Example 5 Preparation of 2-(5-(4-(2-(3-(1H-benzo[d]imidazo1-yl)prop-1-yn-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)-6-aminopyridazin-3-yl)phenol (Compound P-150) [ka] Step 1: [ka]

[0264] To a solution of 3-bromoprop-1-yne (80%, 3.78 g, 25.39 mmol, 2.74 mL, 3.0 equiv) in DMF (10 mL) was added KCO (2.34 g, 16.93 mmol, 2.0 equiv) and 1H-benzo[d]imidazole (1.00 g, 8.46 mmol, 1 equiv). The mixture was stirred at 25 °C for 12 h. Water (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (Method A) to give 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole. 1H NMR (400MHz, CDCl3) δ8.01(s,1H),7.84~7.79(m,1H),7.50~7.45(m,1H),7.37~7.28(m,2H),4.91(d,J=2.8Hz,2H),2.49(t,J=2.4Hz,1H). Step 2: [ka]

[0265] A mixture of 2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (35.31 mg, 226.08 μmol, 2.0 equiv.), 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole (50 mg, 113.04 μmol, 1 equiv.), Pd(PPh)Cl (7.93 mg, 11.30 μmol, 0.1 equiv.), CuI (6.46 mg, 33.91 μmol, 0.3 equiv.), and DIEA (51.13 mg, 395.65 μmol, 68.91 μL, 3.5 equiv.) in DMF (0.5 mL) was degassed and purged with nitrogen. The mixture was stirred under N2 atmosphere at 70° C. for 1 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (Method A) to give 2-(5-(4-(2-(3-(1H-benzo[d]imidazo1-yl)prop-1-yn-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)-6-aminopyridazin-3-yl)phenol. 1 H NMR(400MHz,d4-CD3OD)δ8.32(d,J=3.2Hz,1H),7.99(d,J=0.8Hz,1H),7.78~7.67(m, 2H),7.59(d,J=8.0Hz,1H),7.41(s,1H),7.38~7.28(m,2H),7.19(t,J=7.6Hz,1H),6. 88(d,J=8.0Hz,1H),6.85~6.80(m,1H),6.68~6.60(m,1H),5.40(s,2H),4.16~3.87(m ,2H),3.83~3.61(m,2H),3.58~3.41(m,2H),3.33(d,J=3.6Hz,2H),2.13~2.05(m,2H). Example 6 Preparation of o-{5-[(R)-4-{2-[(E)-3-(dimethylamino)-1-propenyl]-4-pyrimidinyl}-5-methyl-1,4-diazepan-1-yl]-6-amino-3-pyridazinyl}phenol (Compound P-218) [ka] Step 1: [ka]

[0266] To a solution of (R)-2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-5-methyl-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (350 mg, 766.98 μmol, 1 equiv.), N,N-dimethylprop-2-yn-1-amine (191.28 mg, 2.30 mmol, 243.98 μL, 3 equiv.), DIEA (346.94 mg, 2.68 mmol, 467.58 μL, 3.5 equiv.), and CuI (43.82 mg, 230.09 μmol, 0.3 equiv.) in DMF (3 mL) was added Pd(PPh)Cl (53.83 mg, 76.70 μmol, 0.1 equiv.) at 25 °C under N. The reaction mixture was degassed and purged under N2 three times. The reaction mixture was stirred at 70 °C under N2 atmosphere for 1 hour. The reaction mixture was partitioned between ethyl acetate (5 mL) and HO (5 mL). The organic phase was separated, washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-2-(6-amino-5-(4-(2-(3-(dimethylamino)prop-1-yn-1-yl)pyrimidin-4-yl)-5-methyl-1,4-diazepan-1-yl)pyridazin-3-yl)phenol, which was used directly in the next step. 1H NMR(400MHz,CD3OD)δ8.15~7.99(m,1H),7.83~7.68(m,1H),7.55~7.45(m,1H),7.28 ~7.15(m,1H),7.00~6.85(m,2H),6.74(d,J=6.0Hz,1H),4.77~4.54(m,1H),4.16~3. 99(m,1H),3.92~3.75(m,1H),3.69~3.54(m,2H),3.53(s,2H),3.38(s,1H),3.31(d, J=3.2Hz, 1H), 3.22~3.00(m, 1H), 2.92~2.72(m, 1H), 2.40(s, 6H), 1.32~1.20(m, 4H). Step 2: [ka]

[0267] To a solution of (R)-2-(6-amino-5-(4-(2-(3-(dimethylamino)prop-1-yn-1-yl)pyrimidin-4-yl)-5-methyl-1,4-diazepan-1-yl)pyridazin-3-yl)phenol (10 mg, 21.81 μmol, 1 equiv.) in THF (0.5 mL) at 25° C., Pd / C (5 mg, 21.81 μmol, 60 wt.%, 1 equiv.) was added under an argon atmosphere. The reaction mixture was stirred at 25° C. for 1 hour under an H atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C). 18 Purification using a column (75 mm × 30 mm × 3 μm; mobile phase: [water (+1% formic acid)-ACN]; B%: 1% to 30%, 8 min gradient) gave o-{5-[(R)-4-{2-[(E)-3-(dimethylamino)-1-propenyl]-4-pyrimidinyl}-5-methyl-1,4-diazepan-1-yl]-6-amino-3-pyridazinyl}phenol. 1H NMR(400MHz,CD3OD)δ8.50~8.45(m,1H),8.13~8.12(m,1H),7.80~7.72(m,1H),7.52~7.49(m,1H),7.30~7.26(m,1H),6.92~6.85(m,2H),6.80~6. 61(m,1H),4.13~4.12(m,1H),3.87~3.84(m,2H),3.63~3.60(m,5H),3.2 5~3.19(m,3H),3.15~3.10(m,6H),2.40~2.19(m,4H),1.36~1.28(m,3H). Example 7 Preparation of o-[6-amino-5-(3-{2-[3-(dimethylamino)-1-propynyl]-4-pyridyloxy}-1-azetidinyl)-3-pyridazinyl]phenol (Compound P-387) [ka] Step 1: [ka]

[0268] A solution of 4-bromo-6-chloropyridazin-3-amine (5 g, 23.99 mmol, 1 equiv.), azetidin-3-ol (2.63 g, 23.99 mmol, 1 equiv., HCl), and DIEA (31.00 g, 239.87 mmol, 41.78 mL, 10 equiv.) in DMF (50 mL) was degassed and purged with N, and the mixture was stirred at 120 °C for 12 h under a N atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, 0–10% methanol in ethyl acetate) to give 1-(3-amino-6-chloropyridazin-4-yl)azetidin-3-ol. 1 H NMR (400MHz, d6-DMSO) δ6.32(s,1H),5.73(s,2H),5.68(d,J=6.4Hz,1H),4.52~4.46(m,1H),4.35~4.28(m,2H),3.73(dd,J=4.8,9.2Hz,2H). Step 2: [ka]

[0269] A mixture of 1-(3-amino-6-chloropyridazin-4-yl)azetidin-3-ol (4.4 g, 21.93 mmol, 1 equiv.), [2-(methoxymethoxy)phenyl]boronic acid (4.39 g, 24.12 mmol, 1.1 equiv.), Pd(dppf)Cl (1.60 g, 2.19 mmol, 0.1 equiv.), and CsCO (42.87 g, 131.59 mmol, 6 equiv.) in dioxane (45 mL) and water (22.5 mL) was degassed and purged with N three times. The mixture was stirred at 80 °C under N atmosphere for 5 h. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was triturated with ACN (20 mL) to give 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetidin-3-ol. 1 H NMR(400MHz,d6-DMSO)δ7.59(d,J=7.6Hz,1H),7.34(t,J=7.6Hz,1H),7.17(d,J=8.0Hz,1H),7.07(t,J=7.6Hz,1H),6.65(s,1H) ,5.68(s,1H),5.61(s,2H),5.20(s,2H),4.50(d,J=6.0Hz,1H),4.28(t,J=7.2Hz,2H),3.63(t,J=6.4Hz,2H),3.38~3.36(m,3H). Step 3: [ka]

[0270] To a solution of 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetidin-3-ol (1 g, 3.31 mmol, 1 equiv.) in DMF (10 mL) was added NaH (661.47 mg, 16.54 mmol, 60% purity, 5 equiv.) in several portions at 0 °C under N. After 10 min, a solution of 2-bromo-4-fluoro-pyridine (582.10 mg, 3.31 mmol, 1 equiv.) in DMF (5 mL) was added dropwise to the solution at 0 °C. The mixture was stirred at 20 °C for 1 h. Saturated NH Cl solution (10 mL) was added, and the reaction was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over Na SO , filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with ACN (5 mL) to give 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine. 1 H NMR(400MHz,d6-DMSO)δ8.24(d,J=6.0Hz,1H),7.59(dd,J=1.6,7.6Hz,1H),7.39~7.29(m,1H),7.21~7.15(m,2H),7.08(dt,J=1.2,7.6Hz,1H),7.01(d d,J=2.4,5.6Hz,1H),6.73(s,1H),5.66(s,2H),5.23(td,J=2.8,6.4Hz,1H) ,5.19(s,2H),4.49(dd,J=6.4,9.6Hz,2H),4.08~4.01(m,2H),3.33(s,3H). Step 4: [ka]

[0271] A solution of 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine (140 mg, 305.47 μmol, 1 equiv) in HCOOH (1.4 mL) was stirred at 20 °C for 5 h. Saturated NaHCO solution (5 mL) was added and the mixture was extracted with ethyl acetate (3 × 2 mL). The combined organic phases were washed with brine (2 × 2 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine. 1 H NMR(400MHz,d6-DMSO)δ14.62(s,1H),8.25(d,J=5.6Hz,1H),7.92(dd,J=1.6,8.4Hz,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=3.6,6.4Hz,1H),4.65(dd,J=6.4,9.6Hz,2H),4.22(dd,J=3.2,9.6Hz,2H) Step 5: [ka]

[0272] A mixture of 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine (20 mg, 48.28 μmol, 1 equiv.), N,N-dimethylprop-2-yn-1-amine (12.04 mg, 144.84 μmol, 15.36 μL, 3 equiv.), CuI (2.76 mg, 14.48 μmol, 0.3 equiv.), DIEA (31.20 mg, 241.40 μmol, 42.05 μL, 5 equiv.), and Pd(PPh)Cl (6.78 mg, 9.66 μmol, 0.2 equiv.) in DMF (0.2 mL) was degassed and purged with N three times. The mixture was stirred at 40 °C under N for 2 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (Phenomenex Luna C18 Purification using a column (75 mm × 30 mm × 3 μm; mobile phase: [water (+1% formic acid)-ACN]; B%: 1% to 30%, 8 min gradient) gave o-[6-amino-5-(3-{2-[3-(dimethylamino)-1-propynyl]-4-pyridyloxy}-1-azetidinyl)-3-pyridazinyl]phenol. 1 H NMR(400MHz,d6-DMSO)δ14.97~13.52(m,1H),8.40(s,1H),8.26~8.04(m,1 H),7.92(d,J=7.6Hz,1H),7.22(t,J=7.6Hz,1H),7.07~7.00(m,2H),6.98~ 6.93(m,1H),6.88~6.82(m,2H),5.97(s,2H),5.30~5.22(m,1H),4.65(dd, J=6.4,9.6Hz,2H),4.21(dd,J=3.2,9.6Hz,2H),3.49(s,2H),2.26(s,6H).

[0273] Each of the compounds listed in Table 3 was prepared according to the procedures described above. TIFF2025525340000276.tif151170TIFF2025525340000277.tif246170TIFF2025525340000278.tif251170TIFF2025525340000279.tif251170TIFF2025525340000280.tif232170TIFF2025525340000281.tif234170TIFF2025525340000282.tif240170TIFF2025525340000283.tif230170TIFF2025525340000284.tif227170TIFF2025525340000285.tif221170TIFF2025525340000286.tif227170TIFF2025525340000287.tif219170TIFF2025525340000288.tif240170TIFF2025525340000289.tif250170TIFF2025525340000290.tif242170TIFF2025525340000291.tif221170TIFF2025525340000292.tif217170TIFF2025525340000293.tif234170TIFF2025525340000294.tif227170TIFF2025525340000295.tif250170TIFF2025525340000296.tif231170TIFF2025525340000297.tif237170TIFF2025525340000298.tif245170TIFF2025525340000299.tif251170TIFF2025525340000300.tif251170TIFF2025525340000301.tif252170TIFF2025525340000302.tif250170TIFF2025525340000303.tif250170TIFF2025525340000304.tif252170TIFF2025525340000305.tif250170TIFF2025525340000306.tif245170TIFF2025525340000307.tif245170TIFF2025525340000308.tif252170TIFF2025525340000309.tif250170TIFF2025525340000310.tif247170TIFF2025525340000311.tif240170TIFF2025525340000312.tif240170TIFF2025525340000313.tif250170TIFF2025525340000314.tif250170TIFF2025525340000315.tif251170TIFF2025525340000316.tif250170TIFF2025525340000317.tif245170TIFF2025525340000318.tif250170TIFF2025525340000319.tif240170TIFF2025525340000320.tif250170TIFF2025525340000321.tif252170TIFF2025525340000322.tif250170TIFF2025525340000323.tif251170TIFF2025525340000324.tif251170TIFF2025525340000325.tif250170TIFF2025525340000326.tif250170TIFF2025525340000327.tif252170TIFF2025525340000328.tif240170TIFF2025525340000329.tif250170TIFF2025525340000330.tif250170TIFF2025525340000331.tif250170TIFF2025525340000332.tif250170TIFF2025525340000333.tif250170TIFF2025525340000334.tif250170TIFF2025525340000335.tif251170TIFF2025525340000336.tif250170TIFF2025525340000337.tif250170TIFF2025525340000338.tif250170TIFF2025525340000339.tif242170TIFF2025525340000340.tif250170TIFF2025525340000341.tif245170TIFF2025525340000342.tif240170TIFF2025525340000343.tif245170TIFF2025525340000344.tif252170TIFF2025525340000345.tif252170TIFF2025525340000346.tif250170TIFF2025525340000347.tif250170TIFF2025525340000348.tif251170TIFF2025525340000349.tif250170TIFF2025525340000350.tif251170TIFF2025525340000351.tif250170TIFF2025525340000352.tif250170TIFF2025525340000353.tif240170TIFF2025525340000354.tif251170TIFF2025525340000355.tif252170TIFF2025525340000356.tif251170TIFF2025525340000357.tif252170TIFF2025525340000358.tif254170TIFF2025525340000359.tif251170TIFF2025525340000360.tif252170TIFF2025525340000361.tif252170TIFF2025525340000362.tif252170TIFF2025525340000363.tif250170TIFF2025525340000364.tif251170TIFF2025525340000365.tif251170TIFF2025525340000366.tif250170TIFF2025525340000367.tif252170TIFF2025525340000368.tif19170.

[0274] Biological Examples Degradation assays of SMARCA2 and SMARCA4 Degradation of proteins expressed from the SMARCA2 and SMARCA4 genes was monitored using Promega's engineered HiBiT-fused HeLa cell lines. Briefly, 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 attachment. After overnight incubation, test compounds were added in 10-point serial dilutions (typically 10 μM to 300 μM) using a TECAN D300e Digital Dispenser, and the plates were then incubated at 37°C for 24 hours. After 24 hours of treatment, protein levels were quantified by adding HiBiT lysis buffer, LgBiT protein, and HiBiT substrate according to the manufacturer's instructions. The plates were incubated for 10 minutes at room temperature on an orbital plate shaker. The resulting luminescence values were read using a ClarioStar plate reader and used to construct dose-response curves and determine the degraded DC 50 The calculation was performed using GraphPad Prism.

[0275] Table 4 presents the data from the assay. The activity of the test compounds is presented in Table 4 below. A=DC 50 <0.050 μM; B = 0.05 μM <DC 50 <0.50 μM; C = <0.5 μM <DC 50 <5.0 μM; D = DC 50 >5.0 μM. For the SMARCA2 and SMARCA4 degradation activity at 1 μM, +++ is >70%, ++ is 30-70%, and + is <30%. TIFF2025525340000369.tif212170TIFF2025525340000370.tif253170TIFF2025525340 000371.tif253170TIFF2025525340000372.tif253170TIFF2025525340000373.tif25317 0TIFF2025525340000374.tif253170TIFF2025525340000375.tif253170TIFF2025525340 000376.tif253170TIFF2025525340000377.tif253170TIFF2025525340000378.tif12170

[0276] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0277] The disclosure illustratively set forth herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," and "containing" shall be read expansively and not limiting. Furthermore, the terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the shown and described features or portions thereof, although it is recognized that various modifications are possible within the scope of the claims.

[0278] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In case of conflict, the present specification, including definitions, will control. While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to illustrate, but not limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains.

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