Compounds and pharmaceutical compositions for degrading SWI / SNF-related matrix-related actin-dependent chromatin subfamily A modulators

Abstract

Disclosed are compounds of Formula I, or pharmaceutically acceptable salts, solvates, stereoisomers, or tautomers thereof, which are useful for modulating or degrading proteins expressed from one or more SWI / SNF-related matrix-related actin-dependent chromatin subfamily A modulators (SMARCAs) (e.g., SMARCA2 and / or SMARCA4). I) # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 352,936, filed on June 16, 2022, under 35 U.S.C. §119(e), the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure provides compounds useful as modulators of targeted ubiquitination, including pharmaceutically acceptable salts thereof. The compounds disclosed herein bind to and degrade proteins expressed from one or more SWI / SNF-related matrix-associated actin-dependent chromatin subfamily A regulators ("SMARCA") . Pharmaceutical compositions comprising the compounds are also disclosed, as well as methods of using such compounds to treat various SMARCA-mediated diseases or conditions. Background Art

[0004] The ubiquitin-proteasome pathway (UPP) is a key pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes and, if defective or unbalanced, contributes to the pathogenesis of various diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0005] There are more than 600 E3 ubiquitin ligases that promote ubiquitination of different proteins in vivo and can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. See, e.g., Li et al., "Genome-wide and functional annotation of human E3ubiquitin ligases identifies MULAN, amitochondrial E3 that regulates the organelle's dynamics and signaling." PLOSOne 2008, (3) 1487; Berndsen et al., "New insights into ubiquitin E3 ligasemechanism"Nat.Struct.Mol.Biol.2014,21:301;Deshaies et al.,"RING domain E3ubiquitin ligases"Ann.Rev.Biochem.2009,78:399;Sprattetal."RBRE3 ubiquitinligases: new structures,new insights,new questions" Biochem. 2014, 458: 421; and Wang et al., "Roles of F-box proteins in cancer" Nat. Rev. Cancer. 2014, 14: 233.

[0006] The UPP plays a key role in degrading short-lived and regulatory proteins that are important in a variety of fundamental cellular processes, including regulation of the cell cycle, regulation of cell surface receptors and ion channels, and antigen presentation. The pathway is implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndrome, and Liddle syndrome), in immune surveillance / viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with abnormal UPP and adversely affect the cell cycle and division, the response of cells to stress and to extracellular regulators, the morphogenesis of neuronal networks, the regulation of cell surface receptors, ion channels, secretory pathways, DNA repair, and the biogenesis of organelles.

[0007] Aberrations in this process have recently been implicated as the cause of the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two broad categories: (a) those resulting from loss of function leading to stabilization of certain proteins, and (b) those resulting from gain of function, i.e., aberrant or accelerated degradation of protein targets.

[0008] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Compounds acting as molecular glues can induce or stabilize protein-protein interactions between target proteins and E3 ubiquitin ligase ligands, thereby leading to protein ubiquitination and subsequent proteasome-mediated degradation via recruitment to E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules provide the possibility of temporal control of protein expression. Such compounds can induce the inactivation of proteins of interest when added to cells or administered to animals or humans, and can be used as biochemical reagents and bring about a new paradigm for treating diseases by removing pathogenic or oncogenic proteins. See, for example, Crews, Chem. & Biol. 2010, 17 (6): 551; Schneekloth and Crews, Chem BioChem., 2005, 6 (1): 40.

[0009] There is a continuing need in the art for effective treatment of diseases, especially hyperplasia and cancer. However, nonspecific effects and the inability to target and regulate entire classes of proteins, such as transcription factors, remain obstacles to the development of effective anticancer agents. Therefore, small molecule therapeutics that utilize E3 ligase-mediated protein degradation to target cancer-related proteins, such as one or more SWESNF-related matrix-associated actin-dependent chromatin subfamily A regulators ("SMARCA") and / or polybrominated-1 ("PB1") proteins, are promising therapeutic agents. Therefore, there remains a need to find compounds that are degraders of proteins expressed from SMARCA genes that can be used as therapeutic agents. Summary of the invention

[0010] Disclosed are compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof, and methods for using the compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which can be used as inducers of targeted ubiquitination of proteins expressed from SMARCA genes, which are then degraded and / or inhibited by monovalent compounds as described herein. The compounds provided herein have the advantage of potentially having a wide range of pharmacological activities, consistent with degradation / inhibition of proteins expressed from SMARCA genes. In addition, the present disclosure provides methods for treating or improving a disease condition (such as cancer, e.g., lung cancer) in a subject in need thereof using an effective amount of a compound as described herein.

[0011] In some embodiments, the disclosed compounds are represented by Formula I:

[0012]

[0013] 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.

[0014] In some embodiments, the disclosed compounds are represented by Formula IA:

[0015]

[0016] 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.

[0017] In some embodiments, the disclosed compounds are represented by Formula I':

[0018]

[0019] 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.

[0020] In some embodiments, the compounds as described herein regulate proteins expressed from SMARCA genes. In some embodiments, the compounds as described herein degrade proteins expressed from SMARCA genes. In some embodiments, the regulated or degraded proteins are expressed from SMARCA gene member 2 (SMARCA2). In some embodiments, the regulated or degraded proteins are expressed by SMARCA gene member 4 (SMARCA4).

[0021] 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.

[0022] 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 with an effective amount of a compound of Formula I or I' or any subformula thereof under conditions where the protein expressed from the SMARCA gene binds to the compound and is regulated or degraded. In some embodiments, the regulated or degraded protein is a protein expressed from the SMARCA2 gene. In some embodiments, the regulated or degraded protein is a protein expressed from the SMARCA4 gene.

[0023] In some embodiments, the present disclosure provides a method for regulating or degrading a protein expressed from a SMARCA gene, 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 where the protein expressed from the SMARCA gene binds to the compound and is regulated or degraded. In some embodiments, the protein regulated or degraded in the subject is a protein expressed from the SMARCA2 gene. In some embodiments, the protein regulated or degraded in the subject is a protein expressed from the SMARCA4 gene.

[0024] 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.

[0025] In some embodiments, the present 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

[0026] The present disclosure provides compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and compositions to treat diseases, disorders, or conditions mediated at least in part by SMARCA2 or SMARCA4 transcription factors. However, before providing a detailed description of the present disclosure, the following terms will first be defined. If not defined, the terms used herein have their generally accepted scientific meanings.

[0027] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present 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.

[0028] A dash ("-") 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 a carbon atom. Dashes preceding or at the ends of chemical groups are for convenience; a chemical group may be represented with or without one or more dashes without losing its usual meaning. A wavy or dotted line drawn through a line in a structure indicates a designated point of attachment for a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0029] 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 1 to 6 carbon atoms.

[0030] When used before a numerical value name (e.g., temperature, time, amount, concentration, etc., including ranges), the term "about" indicates an approximate value, which may vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue therebetween. In one embodiment, when used in relation to a dosage amount, the term "about" means that the dosage may vary by + / - 10%.

[0031] “Comprising” or “comprises” is intended to mean that compositions and methods include the recited elements, but not excluding other elements.

[0032] "Consisting essentially of" when used to define compositions and methods shall be intended to exclude any other elements that are of substantial importance for the stated purpose. Thus, a composition consisting essentially of elements as defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed disclosure.

[0033] "Consisting of shall be meant to exclude more than trace amounts of other ingredient elements and substantial process steps. Embodiments defined by each of these transition terms are within the scope of the present disclosure.

[0034] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 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 1-4 Alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons are contemplated; 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).

[0035] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, divalent heteroaryl groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups (e.g., methylene, ethylene, and propylene), "arylene" groups or "arylenyl" groups (e.g., phenylene or naphthylene, or for heteroarylene, quinolyl). In addition, unless otherwise expressly stated, where a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0036] "Alkenyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 Examples of the alkenyl group include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0037] "Alkynyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon triple bond and having from 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 those groups having one triple bond and one double bond.

[0038] “Alkoxy” refers to the group “alkyl-O—.” Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0039] "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.

[0040] "Acyl" refers to the group -C(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0041] "Acylamide" refers to both a "C-acylamide" group (which refers to the group -C(O)NR y R z ) also refers to an "N-amido" group (which refers to the group -NR y C(O)R z ), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted, as defined herein, or R y and R z Together they form a cycloalkyl or heterocyclyl; each of which may be unsubstituted or substituted as defined herein.

[0042] "Amino" refers to the group -NR y R z , where R y and R zis independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0043] "Amidino" refers to -C(NR y )(NR z 2), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0044] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 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 anthracenyl. However, aryl does not encompass heteroaryl as defined below or overlap in any way with heteroaryl as defined below. If one or more aryl groups are fused to heteroaryl, the resulting ring system is heteroaryl, regardless of the point of attachment. If one or more aryl groups are fused to heterocyclyl, the resulting ring system is heterocyclyl, regardless of the point of attachment. If one or more aryl groups are fused to cycloalkyl, the resulting ring system is cycloalkyl, regardless of the point of attachment.

[0045] "Carbamoyl" refers to both an "O-carbamoyl" group (which refers to the group -OC(O)NR y R z ) also refers to an "N-carbamoyl" group (which refers to the group -NR y C(O)OR z ), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0046] "Carboxyl ester" or "ester" refers to -OC(O)R x Also refers to -C(O)OR x , where R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0047] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp 3 As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-14 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) or 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] heptyl, bicyclo [2.2.2] octyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1] heptyl, etc. In addition, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to an aryl ring, regardless of the connection to the rest of the molecule. In addition, when there are two substitution positions on the same carbon atom, cycloalkyl also includes "spiro cycloalkyl", such as spiral [2.5] octyl, spiral [4.5] decyl or spiral [5.5] undecyl.

[0048] "Imino" refers to the group -C(NR y )R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0049] "Imido" refers to the group -C(O)NR y C(O)R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0050] "Halogen" or "halo" refers to an atom occupying Group VIIA of the periodic table, such as fluorine, chlorine, bromine or iodine.

[0051] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogen. For example, in the case where the residue is replaced by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties connected. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted by two ("two") or three ("three") halo groups, which halo groups can be, but are not necessarily, identical halogens. The example of haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0052] "Haloalkoxy" refers to an alkoxy group as defined above wherein one or more (eg, 1 to 6 or 1 to 3) of the hydrogen atoms are replaced by a halogen.

[0053] "Hydroxyalkyl" means an alkyl group as defined above in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0054] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) (excluding any terminal carbon atoms) are each independently replaced with the same or different heteroatom groups, provided that the point of attachment to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms may 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., where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted, as defined herein. Examples of heteroalkyl groups include, for example, ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.) and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR yCH2CH2NR y CH3, etc., where R y The term "alkyl" refers to a group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be unsubstituted or substituted, as defined herein). As used herein, heteroalkyl includes 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.

[0055] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group includes 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 3-8In some cases, the heteroaryl group includes a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each of which independently has 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, and the ring heteroatoms are 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]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indole, oxazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidized pyridinyl, 1-oxidized pyrimidinyl, 1-oxidized pyrazinyl, 1-oxidized pyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolyl, quinuclidine, 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, quinolyl, isoquinolyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be attached via any one of the rings of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of the connection 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.

[0056] "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 spiro heterocyclyl groups. The heterocyclyl group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged or spiro, and can contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O -) moiety. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., the attachment may be through a carbon atom or a heteroatom). In addition, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of the attachment to the rest of the molecule. As used herein, a heterocyclyl has from 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclic) or 3 to 6 ring carbon atoms (i.e., C 3-6heterocyclyl); 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, the ring heteroatoms being independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepine, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithioxanyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolyl, isothiazolidine 1,1-dioxo- ... Examples of spiral heterocyclyl rings include, for example, bicyclic and tricyclic ring systems, such as oxabicyclo [2.2.2] octyl, 2-oxa-7-azaspiro [3.5] nonyl, 2-oxa-6-azaspiro [3.4] octyl and 6-oxa-1-azaspiro [3.3] heptyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolyl, 4,5,6,7-tetrahydrothieno [2,3-c] pyridinyl, indolinyl and isoindolinyl, wherein the heterocyclyl can be bound via any one of the fused systems. In some embodiments, heterocycloalkyl can be substituted on a heteroatom by one or more oxo groups (e.g., S=O, S(=O)2).

[0057] "Oxime" refers to the group -CR y (=NOH), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0058] "Oxo" refers to the moiety =0.

[0059] "Sulfonyl" refers to the group -S(O)2R y , where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0060] "Sulfinyl" refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0061] "Sulfonamide" refers to the group -SO2NR y R z and-NR y S02R z , where R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be unsubstituted or substituted as defined herein.

[0062] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs as well as instances where it does not occur. In addition, the term "unsubstituted or substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a non-hydrogen moiety.

[0063] As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, aryl, amido, amido, amidino, amido, amido, amido, amido, amido, amido, amido, amido, amido, amido, amido, aryl, aralkyl ... , carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thioxo, N-oxide, or -Si(R y )3, where each R yand R is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0064] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by 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 In certain embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by -C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-CH2SO2R gor -CH2SO2NR g R h Replace. In the above, R g and R h R is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl. In certain embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by bonds with amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl, or R is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl. g and R h Two of the are taken together with the atoms to which they are attached to form a heterocyclyl ring which is unsubstituted or substituted with oxo, halo or alkyl which is unsubstituted or substituted with oxo, halo, amino, hydroxy or alkoxy.

[0065] Polymers or similar indefinite structures obtained by defining substituents with unlimited additional further substituents (e.g., substituted aryl with substituted alkyl, the substituted alkyl itself is substituted by a substituted aryl group, the substituted aryl group is also substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of continuous substitutions in the compounds described herein is three. For example, the continuous substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition is not intended to include substitution patterns that are not allowed (e.g., methyl is substituted by 5 fluorine atoms or heteroaryl groups have two adjacent oxygen ring atoms). Such substitution patterns that are not allowed are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" can describe other chemical groups defined herein.

[0066] In certain embodiments, as used herein, the expression "one or more" refers to one to five. In certain embodiments, as used herein, the expression "one or more" refers to one to three.

[0067] Any compound or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. These forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have structures depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotope-labeled compounds disclosed herein, for example, compounds into which radioactive isotopes such as 3 H and 14 Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) (including drug or substrate tissue distribution assays), or in radiotherapy of patients.

[0068] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens are replaced by deuterium, such as hydrogens on carbon atoms. Such compounds exhibit increased metabolic resistance when administered to mammals, particularly humans, and are therefore useful for increasing the half-life of any compound. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0069] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, involving absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and / or improvements in therapeutic index. 18 F. 3 H or 11 C-labeled compounds can be used for PET or SPECT or other imaging studies. Isotope-labeled compounds and prodrugs thereof disclosed herein can generally be prepared by performing the procedures disclosed in the schemes or in the examples and the preparation methods described below by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents. It should be understood that in this context, deuterium is considered a substituent in the compounds described herein.

[0070] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen at its natural abundance isotopic composition. Therefore, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0071] 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.

[0072] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0073] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of a 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. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. On the contrary, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. 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. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. By way of example only, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trialenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted substituted alkenyl)), di(substituted alkenyl)amine (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amine (i.e., N(substituted alkenyl)3, mono-, di- or tri-cycloalkylamine (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri-arylamine (i.e., NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0074] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the equilibrium properties between the tautomers, it will be understood by those of ordinary skill in the art that these compounds contain both amides and imidic acid tautomers. Therefore, compounds containing amides are understood to include their imidic acid tautomers. Similarly, compounds containing imidic acid are understood to include their amide tautomers.

[0075] Compounds or pharmaceutically acceptable salts thereof include asymmetric centers and may therefore produce enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)- or as (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and / or fractional crystallization. Conventional techniques for preparing / separating 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 indicated, it is intended that the compounds include both E and Z geometric isomers.

[0076] "Stereoisomers" refer to compounds made up of the same atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers or mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0077] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0078] Relative centers of compounds as drawn herein are indicated graphically using a "thick bond" style (bold or parallel lines), and absolute stereochemistry is drawn using wedge-shaped bonds (thick or parallel lines).

[0079] "Prodrug" means any compound that releases an active parent drug according to the structure described herein in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying the functional groups present in the compounds described herein in a manner such that the modifications can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in the compounds described herein in a manner such that the modifications are cleaved into the parent compound in conventional operations or in vivo. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl or sulfhydryl groups in the compounds described herein are bonded to any group that can be cleaved in vivo to regenerate free hydroxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives) of hydroxyl functional groups in the compounds described herein, amides, guanidines, carbamates (e.g., N, N-dimethylaminocarbonyl), etc. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14, the ACSSymposium 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 hereby incorporated by reference in its entirety.

[0080] "Subject" refers to a mammal. A mammal can be a human or a non-human mammalian organism. "Patient" refers to a human subject.

[0081] "Treating" or "treatment" of a disease or condition in a subject means 1) preventing the disease or condition from occurring in a subject that is susceptible to the disease or condition or that does not yet exhibit symptoms of the disease or condition; 2) inhibiting the disease or condition or arresting its development; or 3) ameliorating the disease or condition or causing regression of the disease or condition.

[0082] An "effective amount" refers to an amount of a compound described herein sufficient to treat a disease or condition afflicting a subject or to prevent the onset of such a disease or condition in the subject or patient.

[0083] "Administering" refers to any art-recognized form of administration to a subject, including oral (including oral tube feeding), 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 patient's age, weight and general health and the severity of the condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally.

[0084] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to a specific substrate protein, thereby targeting the substrate protein for degradation. For example, E3 ubiquitin ligase proteins cause ubiquitin to attach to lysine on the target protein alone or in combination with E2 ubiquitin conjugating enzymes, and then target the specific protein substrate to be degraded by the proteasome. Therefore, E3 ubiquitin ligases are responsible for the transfer of ubiquitin to the target protein alone or in combination with E2 ubiquitin conjugating enzymes. In general, ubiquitin ligases participate in polyubiquitination, so that the second ubiquitin is attached to the first ubiquitin; the third ubiquitin is attached to the second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events limited to monoubiquitination, in which ubiquitin ligases only add a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but can instead change their cellular location or function, such as by binding to other proteins with domains capable of binding ubiquitin. More complicated is that different lysines on ubiquitin can be targeted by E3 to produce chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to achieve polyubiquitination by the proteasome.

[0085] Compound

[0086] In one embodiment, the present disclosure provides a compound of Formula I:

[0087]

[0088] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein:

[0089] X is hydroxyl, halogen, cyano, C 1-4 Alkoxy or -N(R)2;

[0090] Y is N, C or CH;

[0091] Y 1 is N, C or CH;

[0092] X 1 CH, CR 6 or N;

[0093] X 2 CH, CR 6or N; where X 1 or X 2 At least one of is N;

[0094] T is -N(R)2;

[0095] Ring A is C 4-8 Cycloalkyl, C 6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 replace;

[0096] L is a bond, -CH2- or -O-;

[0097] L 1 is -RC=CR- or -C≡C-;

[0098] L 2 Selected from:

[0099] a)

[0100] b) and

[0101] c)

[0102] Where t is 0 or 1, p is 0, 1, 2 or 3, and the dashed line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 The connection point to Z;

[0103] Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 substituted, and wherein each alkyl, alkoxy or cycloalkyl is independently unsubstituted or substituted with one to three R 3 replace;

[0104] Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted by one to three R 4 replace; or

[0105] Two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl group which is unsubstituted or substituted with one to four R 4 replace;

[0106] Each R x and R y are independently hydrogen, C 1-4 Alkyl or C substituted by 1 to 3 halogen groups 1-4 haloalkyl; or

[0107] R x and R y , together with the atoms to which they are attached, form C 3-6 Cycloalkyl, which is unsubstituted or substituted by one to four R 4 replace;

[0108] Each R 1 are independently cyano, halo, hydroxy, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted by 1 to 3 halogen 1-4 haloalkyl, unsubstituted or substituted by 1 to 3 halo 1-4 alkoxy, C having 1 to 3 heteroatoms selected from O, N, NR and / or S 5-6 heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R;

[0109] Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 alkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl;

[0110] Each R 3 are independently oxo, cyano, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C 1-6Aryl, C substituted with 1 to 3 phenyl groups 1-4 Alkyl, or C 3-6 Cycloalkyl;

[0111] Each R 4 are independently -N(R)2, cyano, halo or hydroxy;

[0112] Each R 5 D, halogenated, C 1-3 Haloalkyl or C 1-4 Alkoxy;

[0113] Each R 6 is N(R)2, SR, halo, cyano, unsubstituted or substituted by 1 to 3 halo 1-4 Alkoxy, unsubstituted C 1-4 Alkyl, C 1-2 Alkoxy substituted C 1-4 Alkyl, or C substituted by hydroxy 1-4 alkyl;

[0114] m is 0, 1 or 2; and

[0115] n is 0, 1, 2 or 3;

[0116] Provided that when the compound

[0117]

[0118] For the following parts:

[0119]

[0120] And L 2 When Z is -C(O)NH-, a bond, -CH2- or -(CH2)2-, then Z is not a heterocyclic group (wherein the heterocyclic group is unsubstituted or substituted), -C 1-6 Alkylene -NH2 or -C 1-6 Alkylene-OH,

[0121] And the compound is not:

[0122] 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]oct-3-yl)pyridazin-3-yl)phenol,

[0123] 2-(6-amino-5-(8-(2-(3-(2-hydroxyethoxyprop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridazin-3-yl)phenol,

[0124] 2-(6-amino-5-(8-(2-(3-(diethylamino)prop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridazin-3-yl)phenol,

[0125] 2-(6-amino-5-(8-(2-(3-(piperidin-3-yloxy)prop-1-yn-1-yl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridazin-3-yl)phenol,

[0126] 2-(6-amino-5-(8-(2-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridazin-3-yl)phenol,

[0127] N-[3-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-pyridinyl]prop-2-ynyl]piperidine-4-carboxamide,

[0128] 2-[6-amino-5-[8-[2-[3-(azepan-1-yl)prop-1-ynyl]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl]pyridazin-3-yl]phenol,

[0129] 2-[6-amino-5-[9-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridinyl]-3,9-diazaspiro[5.5]undec-3-yl]pyridazin-3-yl]phenol,

[0130] 2-[6-amino-5-[2-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridinyl]-2,8-diazaspiro[4.5]dec-8-yl]pyridazin-3-yl]phenol,

[0131] 2-[6-amino-5-[6-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridinyl]-2,6-diazaspiro[3.3]hept-2-yl]pyridazin-3-yl]phenol,

[0132] 2-(6-amino-5-(8-(2-(((1r,4r)-4-aminocyclohexyl)ethynyl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridazin-3-yl)phenol, or

[0133] 2-[6-amino-5-[8-[2-[(E)-3-(azepan-1-yl)prop-1-enyl]-4-pyridinyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]pyridazin-3-yl]phenol.

[0134] In one embodiment, the present disclosure provides a compound of Formula IA:

[0135]

[0136] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein:

[0137] X is hydroxyl, halogen, cyano, C 1-4 Alkoxy or -N(R)2;

[0138] Y is N, C or CH;

[0139] Y 1 is N, C or CH;

[0140] T is -N(R)2;

[0141] Ring A is C 4-8 Cycloalkyl, C 6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 replace;

[0142] L is a bond, -CH2- or -O-;

[0143] L 1 is -RC=CR- or -C≡C-;

[0144] L 2 Selected from:

[0145] a)

[0146] b) and

[0147] c)

[0148] where t is 0 or 1, p is 0, 1, 2, or 3, and where the dashed line (___) represents the transition from L 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 The connection point to Z;

[0149] Z is C1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 substituted, and wherein each alkyl, alkoxy or cycloalkyl is independently unsubstituted or substituted with one to three R 3 replace;

[0150] Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted by one to three R 4 replace; or

[0151] Two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl group which is unsubstituted or substituted with one to four R 4 replace;

[0152] Each R x and R y are independently hydrogen, C 1-4 Alkyl or C substituted by 1 to 3 halogen groups 1-4 haloalkyl; or

[0153] R x and R y , together with the atoms to which they are attached, form C 3-6 Cycloalkyl, which is unsubstituted or substituted by one to four R 4 replace;

[0154] Each R 1 are independently cyano, halo, hydroxy, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted by 1 to 3 halogen 1-4 haloalkyl, unsubstituted or substituted by 1 to 3 halo 1-4 alkoxy, C having 1 to 3 heteroatoms selected from O, N, NR and / or S 5-6 heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R;

[0155] Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 alkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl;

[0156] Each R 3 are independently oxo, cyano, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C 1-6 Aryl, C substituted with 1 to 3 phenyl groups 1-4 Alkyl, or C 3-6 Cycloalkyl;

[0157] Each R 4 are independently -N(R)2, cyano, halo or hydroxy;

[0158] Each R 5 D, halogenated, C 1-3 Haloalkyl or C 1-4 Alkoxy;

[0159] Each R 6 is N(R)2, SR, halo, cyano, unsubstituted or substituted by 1 to 3 halo 1-4 Alkoxy, unsubstituted C 1-4 Alkyl, C 1-2 Alkoxy substituted C 1-4 Alkyl, or C substituted by hydroxy 1-4 alkyl;

[0160] m is 0, 1 or 2; and

[0161] n is 0, 1, 2 or 3;

[0162] with the proviso that 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]oct-3-yl]pyridazin-3-yl]phenol.

[0163] In one embodiment, the present disclosure provides a compound of Formula I':

[0164]

[0165] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein:

[0166] X is hydroxyl, halogen, cyano, C 1-4 Alkoxy or -N(R)2;

[0167] Y is N, C or CH;

[0168] Y 1 is N, C or CH;

[0169] T is -N(R)2;

[0170] Ring A is C 4-8 Cycloalkyl, C 6-10 aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 replace;

[0171] L 1 is -RC=CR- or -C≡C-;

[0172] L 2 Selected from:

[0173] a)

[0174] b) and

[0175] c)

[0176] Where t is 0 or 1, p is 0, 1, 2 or 3, and the dashed line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 The connection point to Z;

[0177] Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 substituted, and wherein each alkyl, alkoxy or cycloalkyl is independently unsubstituted or substituted with one to three R 3 replace;

[0178] Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted by one to three R 4 replace; or

[0179] Two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl group which is unsubstituted or substituted with one to four R 4 replace;

[0180] Each R x and R y are independently hydrogen, C 1-4 Alkyl or C substituted by 1 to 3 halogen groups 1-4 haloalkyl; or

[0181] R x and R y , together with the atoms to which they are attached, form C 3-6 Cycloalkyl, which is unsubstituted or substituted by one to four R 4 replace;

[0182] Each R 1 are independently cyano, halo, hydroxy, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted by 1 to 3 halogen 1-4 haloalkyl, unsubstituted or substituted by 1 to 3 halo 1-4 alkoxy, C having 1 to 3 heteroatoms selected from O, N, NR and / or S 5-6 heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R;

[0183] Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 alkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl;

[0184] Each R 3 are independently oxo, halogen, C 1-4 Alkyl, C 1-4Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, or C 3-6 Cycloalkyl;

[0185] Each R 4 are independently -N(R)2, cyano, halo or hydroxy;

[0186] Each R 5 D, halogenated, C 1-3 Haloalkyl or C 1-4 Alkoxy;

[0187] Each R 6 is N(R)2, SR, cyano, unsubstituted or substituted by 1 to 3 halogenated C 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 Alkyl, or C substituted by hydroxy 1-4 alkyl;

[0188] m is 0, 1 or 2; and

[0189] n is 0, 1, 2 or 3;

[0190] with the proviso that 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]oct-3-yl]pyridazin-3-yl]phenol.

[0191] In one embodiment, the present disclosure provides a compound of Formula I':

[0192]

[0193] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein:

[0194] X is hydroxyl, halogen, cyano, C 1-4 Alkoxy or -N(R)2;

[0195] Y is N, C or CH;

[0196] Y 1 is N, C or CH;

[0197] T is -N(R)2;

[0198] Ring A is C 4-8 Cycloalkyl, C 6-10aryl, 4- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 replace;

[0199] L 1 is -RC=CR- or -C≡C-;

[0200] L 2 Selected from:

[0201] a)

[0202] b) and

[0203] c)

[0204] Where t is 0 or 1, p is 0, 1, 2 or 3, and the dashed line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 The connection point to Z;

[0205] Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 substituted, and wherein each alkyl, alkoxy or cycloalkyl is independently unsubstituted or substituted with one to three R 3 replace;

[0206] Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted by one to three R 4 replace; or

[0207] Two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl group which is unsubstituted or substituted with one to four R 4 replace;

[0208] Each R x and R y are independently hydrogen, C 1-4 Alkyl or C substituted by 1 to 3 halogen groups 1-4haloalkyl; or

[0209] R x and R y , together with the atoms to which they are attached, form C 3-6 Cycloalkyl, which is unsubstituted or substituted by one to four R 4 replace;

[0210] Each R 1 are independently cyano, halo, hydroxy, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted by 1 to 3 halogen 1-4 haloalkyl, unsubstituted or substituted by 1 to 3 halo 1-4 alkoxy, C having 1 to 3 heteroatoms selected from O, N, NR and / or S 5-6 heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms selected from oxygen, nitrogen and / or sulfur, -C(O)OR, -OC(O)R or -C(O)R;

[0211] Each R 2 are independently oxo, hydroxy, cyano, halo, -N(R)2, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 alkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl;

[0212] Each R 3 are independently oxo, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, or C 3-6 Cycloalkyl;

[0213] Each R 4 are independently -N(R)2, cyano, halo or hydroxy;

[0214] Each R 5 D, halogenated, C 1-3 Haloalkyl or C 1-4 Alkoxy;

[0215] Each R 6is N(R)2, SR, cyano, unsubstituted or substituted by 1 to 3 halogenated C 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 Alkyl, or C substituted by hydroxy 1-4 alkyl;

[0216] m is 0, 1 or 2; and

[0217] n is 0, 1, 2 or 3.

[0218] In some embodiments, provided is a compound of Formula I represented by Formula II:

[0219]

[0220] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0221] Among them, 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.

[0222] In some embodiments, provided is a compound of formula II represented by formula II-1:

[0223]

[0224] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0225] Among them, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0226] In some embodiments, provided is a compound of formula II represented by formula II-2:

[0227]

[0228] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0229] Among them, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0230] In some embodiments, provided is a compound of formula II represented by formula II-3:

[0231]

[0232] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0233] Among them, L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0234] In some embodiments, provided is a compound of Formula I represented by Formula IIa:

[0235]

[0236] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0237] Where 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.

[0238] In some embodiments, provided is a compound of Formula I represented by Formula IIb:

[0239]

[0240] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0241] Where 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.

[0242] In some embodiments, provided is a compound of Formula I represented by Formula IIc:

[0243]

[0244]

[0245] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0246] Among them, 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.

[0247] In some embodiments, provided is a compound of formula IIc represented by formula IIc-1:

[0248]

[0249] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0250] Among them, 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.

[0251] In some embodiments, provided is a compound of formula IIc represented by formula IIc-2:

[0252]

[0253] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0254] Among them, 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.

[0255] In some embodiments, provided is a compound of formula IIc represented by formula IIc-3:

[0256]

[0257] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0258] Among them, L, m, n, p, R x , Ry , R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0259] In some embodiments, provided is a compound of Formula I represented by Formula III-E:

[0260]

[0261] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0262] Among them, 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.

[0263] In some embodiments, provided is a compound of Formula I represented by Formula IIIb-E:

[0264]

[0265] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0266] Among them, 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.

[0267] In some embodiments, provided are compounds of formula I' represented by formula II':

[0268]

[0269] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0270] Where L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0271] In some embodiments, the compound of Formula II' is represented by Formula IIa':

[0272]

[0273]

[0274] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0275] Where 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.

[0276] In some embodiments, the compound of Formula IIa' is represented by Formula IIa'-1:

[0277]

[0278] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0279] Where m, n, R, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0280] In some embodiments, the compound of Formula IIa' is represented by Formula IIa'-2:

[0281]

[0282] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0283] Where m, n, R, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0284] In some embodiments, the compound of Formula II' is represented by Formula IIb':

[0285]

[0286] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0287] Where m, n, p, R, R 5 , R 6 , R x , Ry ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0288] In some embodiments, the compound of Formula II' is represented by Formula IIc':

[0289]

[0290] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0291] Where 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.

[0292] In some embodiments, the compound of Formula II' is represented by Formula IId':

[0293]

[0294] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0295] Where 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.

[0296] In some embodiments, provided is a compound of formula I' represented by formula III'-E:

[0297]

[0298] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0299] Where L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0300] In some embodiments, the compound of Formula III′-E is represented by Formula IIIa′-E:

[0301]

[0302] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0303] Where 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.

[0304] In some embodiments, the compound of Formula III'-E is represented by Formula IIIb'-E:

[0305]

[0306] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0307] Where 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.

[0308] In some embodiments, provided is a compound of formula I' represented by formula III'-Z:

[0309]

[0310] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0311] Where L 2 , m, n, R 5 , R 6 ,T,X,Y,Y 1 , Z and Ring A are each independently as defined herein.

[0312] In some embodiments, the compound of Formula III′-Z is represented by Formula IIIa′-Z:

[0313]

[0314]

[0315] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0316] Where 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.

[0317] In some embodiments, the compound of Formula III'-Z is represented by Formula IIIb'-Z:

[0318]

[0319] or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof,

[0320] Where 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.

[0321] In some embodiments of the compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a monocyclic nitrogen-containing 4- to 11-membered heterocycloalkyl. In some embodiments, Selected from

[0322] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0323] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a monocyclic nitrogen-containing 4- to 11-membered heterocycloalkyl. In some embodiments, Selected from

[0324] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to the pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0325] In some embodiments of the compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a fused bicyclic nitrogen-containing 4- to 11-membered heterocycloalkyl. Selected from

[0326] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0327] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a fused bicyclic nitrogen-containing 4- to 11-membered heterocycloalkyl. Selected from

[0328] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to the pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0329] In some embodiments of the compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a spirocyclic nitrogen-containing 4- to 11-membered heterocycloalkyl. In some embodiments, Selected from

[0330] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0331] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a spirocyclic nitrogen-containing 4- to 11-membered heterocycloalkyl. In some embodiments, Selected from

[0332] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to the pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0333] In some embodiments of the compound of Formula I or Formula I', or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a bridged nitrogen-containing 4- to 11-membered heterocycloalkyl. In some embodiments, Selected from

[0334] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0335] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, is a bridged nitrogen-containing 4- to 11-membered heterocycloalkyl. In some embodiments, Selected from

[0336] The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to the pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

[0337] 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 nitrogen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, Z is selected from

[0338] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, hydroxyl, cyano, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0339] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is a nitrogen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, Z is selected from

[0340] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0341] 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- to 10-membered heterocycloalkyl containing oxygen and nitrogen. In some embodiments, Z is selected from

[0342] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0343] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is a 4- to 10-membered heterocycloalkyl containing oxygen and nitrogen. In some embodiments, Z is selected from

[0344] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0345] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is a 4- to 10-membered heterocycloalkyl containing sulfur and nitrogen. In some embodiments, Z is

[0346] wherein Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0347] In some embodiments of the compound of Formula I or Formula I' or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is an oxygen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, Z is selected from

[0348] wherein Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0349] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is an oxygen-containing 4- to 10-membered heterocycloalkyl. In some embodiments, Z is

[0350] wherein Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0351] 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 nitrogen-containing 5- to 10-membered heteroaryl. In some embodiments, Z is selected from

[0352] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0353] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is a nitrogen-containing 5- to 10-membered heteroaryl. In some embodiments, Z is selected from

[0354] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0355] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is a 5- to 10-membered heteroaryl containing oxygen and nitrogen. In some embodiments, Z is selected from

[0356] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0357] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is a 5- to 10-membered heteroaryl containing sulfur and nitrogen. In some embodiments, Z is selected from

[0358] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0359] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is an oxygen-containing 5- to 10-membered heteroaryl. In some embodiments, Z is selected from

[0360] wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

[0361] In some embodiments of the compound of Formula I or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, Z is C 1-10In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, Z is -N(R)2. In some embodiments of the compound of Formula I or its pharmaceutically acceptable salt, solvate, stereoisomer or tautomer, Z is C 1-10 Alkoxy. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, Z is -OH.

[0362] In some embodiments, a compound of Formula I is provided, wherein X is hydroxy.

[0363] In some embodiments, a compound of Formula I is provided, wherein T is -NH2.

[0364] In some embodiments, a compound of formula I is provided, wherein Y is N. In some embodiments, a compound of formula I is provided, wherein Y 1 is N. In some embodiments, a compound of Formula I is provided, wherein Y and Y 1 Both are N.

[0365] In some embodiments, a compound of Formula I is provided, wherein L 2 for Where t is 0 or 1, p is 1, 2 or 3, and the dashed line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 to the point of attachment to Z. In some embodiments, a compound of Formula I is provided, wherein L 2 for The dotted line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 Connection point to Z.

[0366] Representative and non-limiting examples of compounds within the scope of the above-mentioned Formula I are listed in Table 1, each of which includes their pharmaceutically acceptable salts, solvates, hydrates or tautomers.

[0367] Table 1

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389] Also provided herein are the following compounds within the scope of Formula I, or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof.

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] Representative and non-limiting examples of compounds within the scope of the above-mentioned Formula I or Formula I' are listed in Table 1A, each of which includes their pharmaceutically acceptable salts, solvates, hydrates or tautomers.

[0399] Table 1A

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440] Representative and non-limiting examples of compounds within the scope of the above-mentioned Formula I or Formula I' are listed in Table 2, each of which includes their pharmaceutically acceptable salts, solvates, hydrates or tautomers.

[0441] Table 2

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] In some embodiments, the present disclosure provides a method for regulating or degrading a protein expressed from a 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 where the protein expressed from the SMARCA2 gene is regulated or degraded.

[0488] In some embodiments, the present disclosure provides a method for regulating or degrading a protein expressed from a 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 where the protein expressed from the SMARCA4 gene is regulated or degraded.

[0489] In some embodiments, a method for regulating or degrading a protein expressed from a SMARCA2 gene in a subject is provided, the method comprising administering to the subject an effective amount 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, A compound of formula I, IIIa′-Z or IIIb′-Z, or 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.

[0490] In some embodiments, a method for regulating or degrading a protein expressed from a SMARCA4 gene in a subject is provided, the method comprising administering to the subject an effective amount 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, A compound of formula I, IIIa′-Z or IIIb′-Z, or 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.

[0491] In some embodiments, a method for treating cancer in a subject in need thereof is provided, the method comprising selecting a subject whose cancer is at least partially mediated by SMARCA2 and administering to the subject an effective amount 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, II A pharmaceutical composition comprising a compound of formula I′-Z, IIIa′-Z or IIIb′-Z or an effective amount of 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.

[0492] In some embodiments, a method for treating cancer in a subject in need thereof is provided, the method comprising selecting a subject whose cancer is at least partially mediated by SMARCA4 and administering to the subject an effective amount 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, II A pharmaceutical composition comprising a compound of formula I′-Z, IIIa′-Z or IIIb′-Z or an effective amount of 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.

[0493] General Synthesis Methods

[0494] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that where typical process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but those skilled in the art can determine such conditions by conventional optimization procedures.

[0495] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999 and the references cited therein.

[0496] The starting material for the following reactions is a known compound, or can be prepared by known procedures or its obvious modifications. For example, many starting materials can be obtained from commercial suppliers, such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), Emka-Chemce (St. Louis, Missouri, USA). Other starting materials can be prepared by the procedures described in the standard reference text or its obvious modifications, such as 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 supplement (Elsevier Science Publishers, 2001), Organic Reactions Volumes 1-40 (John Wiley, and Sons, 2019), March's Advanced Organic Chemistry (John Wiley, and Sons, 8th edition, 2019) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0497] Synthesis of representative compounds

[0498] The general synthesis of the compounds described herein is illustrated in the following reaction schemes. Schemes 1, 2, 3, 4, 5 and 6 illustrate 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 in the case of Sonogashira coupling, boronic acid or ester in the case of Suzuki coupling, etc.).

[0499]

[0500] In some embodiments, compounds of Formula I' and its subformulae are prepared as shown in Scheme 1. In Scheme 1, the first step is a conventional SN ARReaction, wherein at least a stoichiometric amount of protected ring A compound 2 is combined with compound 1 in an inert diluent such as tetrahydrofuran, dioxane, DMSO, DMF, etc., typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, etc. The reaction is typically maintained at 25° C. to 100° C. until substantially complete. Conventional work-up of the reaction solution may be followed by separation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 3.

[0501] In the next step, a conventional Suzuki coupling reaction is performed, wherein at least a stoichiometric amount of arylboronic acid compound 4 is combined 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, and the like in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like. The reaction is typically maintained at 10° C. to 65° C. until substantially complete. Conventional workup of the reaction solution may be followed by a separation / purification process such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 5.

[0502] In the next step, the protecting group, such as tert-butyloxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group used. The t-BOC group is only illustrative, and other conventional amino protecting groups may be used, such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc.

[0503] In the next step, a conventional SN AR Reaction, wherein at least a stoichiometric amount of the deprotected product from the previous step is combined with 2,4-dibromopyrimidine compound 6, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like in an inert diluent such as tetrahydrofuran, dioxane, DMSO, DMF, and the like. The reaction is typically maintained at 25° C. to 100° C. until substantially complete. Conventional workup of the reaction solution may be followed by an isolation / purification process such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 7.

[0504] In the last step, a conventional coupling reaction is performed, including but not limited to Sonogashira coupling, Suzuki coupling, etc., wherein at least a stoichiometric amount of a suitable coupling partner compound 8 is combined with compound 7 under conventional coupling reaction conditions well known in the art, including the use of a palladium catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride, palladium diacetate, etc.), a cocatalyst (e.g., copper(I) iodide, etc.), and usually in the presence of a suitable base (e.g., diisopropylethylamine, triethylamine, pyridine, cesium carbonate, etc.). The coupling reaction is usually carried out in an inert solvent such as toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, etc. The reaction is usually carried out at about 10°C to about 110°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide a compound of formula I'.

[0505]

[0506] In some embodiments, compounds of Formula I' and its subformulae are prepared as shown in Scheme 2. In Scheme 2, the first step is a conventional Sonogashira coupling reaction, which uses at least a stoichiometric amount of a protected propargylamine compound 9 and a compound 7 combined under conventional reaction conditions well known in the art, including the use of bis(triphenylphosphine)palladium(II) dichloride and copper(I) iodide as catalysts and generally in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, cesium carbonate, and the like. The reaction is generally carried out in an inert solvent such as toluene, N,N-dimethylformamide, and the like. The reaction is generally carried out at about 25°C to about 110°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like, to provide compound 10.

[0507] In the next step, the protecting group, such as tert-butyloxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups may be employed, such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 11.

[0508] In the last step, at least a stoichiometric amount of a suitable carboxylic acid compound 12 is combined with compound 11 under conventional amide bond forming reaction conditions well known in the art, including the use of N, N-dicyclohexylcarbodiimide (DCC) as an activator for the carboxyl group. Other activators are well known in the art. The reaction is usually carried out in an inert solvent such as chloroform, dichloromethane, toluene, N, N-dimethylformamide, etc. The reaction is usually carried out at about 0°C to about 30°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is completed, the conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide a compound of formula I'.

[0509]

[0510] In some embodiments, compounds of Formula I' and its subformulae are prepared as shown in Scheme 3. In Scheme 3, the first step is a conventional Suzuki coupling reaction, wherein 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, and the like in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like. The reaction is typically maintained at 10°C to 65°C until substantially complete. Conventional workup of the reaction solution may be followed by a separation / purification process such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 14.

[0511] In the next step, the protecting group, such as tert-butyloxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups may be employed, such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 15.

[0512] In the last step, at least a stoichiometric amount of a suitable carboxylic acid compound 12 is combined with compound 15 under conventional amide bond forming reaction conditions well known in the art, including the use of N, N-dicyclohexylcarbodiimide (DCC) as an activator for the carboxyl group. Other activators are well known in the art. The reaction is usually carried out in an inert solvent such as chloroform, dichloromethane, toluene, N, N-dimethylformamide, etc. The reaction is usually carried out at about 0°C to about 30°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is completed, the conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide a compound of formula I'.

[0513]

[0514] In some embodiments, compounds of Formula I and its subformulae are prepared as shown in Scheme 4. In Scheme 4, the first step is conventional SN AR Reaction, wherein at least a stoichiometric amount of protected ring A compound 2A is combined with compound 1, typically in the presence of a suitable base such as sodium hydride, potassium carbonate, cesium carbonate, etc., in an inert diluent such as tetrahydrofuran, dioxane, DMSO, DMF, etc. The reaction is typically maintained at 25° C. to 100° C. until substantially complete. Conventional workup of the reaction solution may be followed by separation / purification processes such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 3A.

[0515] In the next step, a conventional Suzuki coupling reaction is performed, wherein at least a stoichiometric amount of arylboronic acid compound 4 is combined 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, and the like in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, and the like. The reaction is typically maintained at 10° C. to 65° C. until substantially complete. Conventional workup of the reaction solution may be followed by an isolation / purification process such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 5A.

[0516] In the next step, the protecting group, such as tert-butyloxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group used. The t-BOC group is only illustrative, and other conventional amino protecting groups may be used, such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc.

[0517] In the next step, a conventional SNAR Reaction, wherein at least a stoichiometric amount of the deprotected product from the previous step is combined with 2,4-dibromopyrimidine compound 6, typically in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, and the like in an inert diluent such as tetrahydrofuran, dioxane, DMSO, DMF, and the like. The reaction is typically maintained at 25° C. to 100° C. until substantially complete. Conventional workup of the reaction solution may be followed by an isolation / purification process such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like to provide compound 7A.

[0518] In the last step, a conventional coupling reaction is performed, including but not limited to Sonogashira coupling, Suzuki coupling, etc., wherein at least a stoichiometric amount of a suitable coupling partner compound 8 is combined with compound 7 under conventional coupling reaction conditions well known in the art, including the use of a palladium catalyst (e.g., bis(triphenylphosphine)palladium dichloride (II), palladium diacetate, etc.), a cocatalyst (e.g., copper (I) iodide, etc.) and usually in the presence of a suitable base (e.g., diisopropylethylamine, triethylamine, pyridine, cesium carbonate, etc.). The coupling reaction is usually carried out in an inert solvent such as toluene, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, etc. The reaction is usually carried out at about 10°C to about 110°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide a compound of Formula I.

[0519]

[0520] In some embodiments, compounds of Formula I and its subformulae are prepared as shown in Scheme 5. In Scheme 5, the first step is a conventional Sonogashira coupling reaction, which uses at least a stoichiometric amount of a protected propargylamine compound 9 and a compound 7A combined under conventional reaction conditions well known in the art, including the use of bis(triphenylphosphine)palladium(II) dichloride and copper(I) iodide as catalysts and generally in the presence of a suitable base such as diisopropylethylamine, triethylamine, pyridine, cesium carbonate, and the like. The reaction is generally carried out in an inert solvent such as toluene, N,N-dimethylformamide, and the like. The reaction is generally carried out at about 25°C to about 110°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), and the like, to provide compound 10A.

[0521] In the next step, the protecting group, such as tert-butyloxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups may be employed, such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 11A.

[0522] In the last step, at least a stoichiometric amount of a suitable carboxylic acid compound 12 is combined with compound 11A under conventional amide bond formation reaction conditions well known in the art, including the use of N, N-dicyclohexylcarbodiimide (DCC) as an activator for the carboxyl group. Other activators are well known in the art. The reaction is usually carried out in an inert solvent such as chloroform, dichloromethane, toluene, N, N-dimethylformamide, etc. The reaction is usually carried out at about 0°C to about 30°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is completed, the conventional post-treatment of the reaction solution can be a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide a compound of Formula I.

[0523]

[0524] In some embodiments, compounds of Formula I and its subformulae are prepared as shown in Scheme 3'. In Scheme 3', the first step is a conventional Suzuki coupling reaction, wherein at least a stoichiometric amount of protected aminovinylboronic acid compound 13 is combined with compound 7A in an inert diluent such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, etc., typically in the presence of a palladium catalyst (e.g., palladium diacetate) and a suitable base such as diisopropylethylamine, triethylamine, pyridine, potassium carbonate, etc. The reaction is typically maintained at 10° C. to 65° C. until substantially complete. Conventional post-treatment of the reaction solution may be followed by a separation / purification process such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 14A.

[0525] In the next step, the protecting group, such as tert-butyloxycarbonyl (t-BOC), is removed under conventional conditions, depending on the specific protecting group employed. The t-BOC group is illustrative only, and other conventional amino protecting groups may be employed, such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc. After the reaction is complete, conventional post-treatment of the reaction solution may be followed by a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide compound 15A.

[0526] In the last step, at least a stoichiometric amount of a suitable carboxylic acid compound 12 is combined with compound 15A under conventional amide bond formation reaction conditions well known in the art, including the use of N, N-dicyclohexylcarbodiimide (DCC) as an activator for the carboxyl group. Other activators are well known in the art. The reaction is usually carried out in an inert solvent such as chloroform, dichloromethane, toluene, N, N-dimethylformamide, etc. The reaction is usually carried out at about 0°C to about 30°C for a period of time sufficient to substantially complete the reaction, as confirmed by, for example, thin layer chromatography. After the reaction is completed, the conventional post-treatment of the reaction solution can be a separation / purification process, such as crystallization, chromatography, high performance liquid chromatography (HPLC), etc., to provide a compound of Formula I.

[0527] Other starting materials used herein are well known in the art, commercially available, or can be prepared by conventional synthetic methods.

[0528] method

[0529] In one embodiment, the compounds and compositions described herein can be used in methods for treating SMARCA2-dependent diseases or conditions or diseases or conditions mediated at least in part by SMARCA2. The method comprises administering to a subject suffering from a SMARCA2-dependent disease or condition an effective amount of a compound as 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.

[0530] In one embodiment, provided is a compound as 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, for use in treating a SMARCA2-dependent disease or disorder.

[0531] In one embodiment, the method relates to a compound as 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, for the manufacture of a medicament for reducing the level of protein expressed from the SMARCA2 gene, wherein such reduction in protein levels treats or ameliorates the disease or condition.

[0532] In one embodiment, the methods described herein comprise the use of prodrugs of the compounds described herein.

[0533] In one embodiment, the method relates to a compound as 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, for use as described herein, wherein at a concentration of 1 μM of the compound described herein, the degradation of the protein expressed from the SMARCA2 gene is in the range of about 25%-99%. The degradation of the protein expressed from the SMARCA2 gene is measured by the assay described in the biological examples. In some embodiments, the 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, the 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%, about 85% to about 99%. In some embodiments, the degradation of the protein expressed from the SMARCA2 gene is more than 60%. In some embodiments, the degradation of the protein expressed from the SMARCA2 gene is more than 70%. In some embodiments, the degradation of the protein expressed from the SMARCA2 gene is more than 80%. In some embodiments, the degradation of the protein expressed from the SMARCA2 gene is more than 90%.

[0534] The compounds and compositions described herein can be used to treat 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, oropharyngeal, penile, anal, thyroid or vaginal cancer or Epstein-Barr virus-associated nasopharyngeal carcinoma, gastric cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse large B-cell lymphoma. Cancer can be selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, skin melanoma, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumors, nasopharyngeal cancer, tongue cancer, pancreatic cancer, esophageal cancer, bile duct cancer, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdoid cancer, immune response defective 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 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).

[0535] The compounds of the present disclosure may be administered in an amount effective to treat or prevent a disorder and / or prevent its development in a subject.

[0536] Generally, methods of using the compounds of the present application comprise administering to a subject in need thereof a therapeutically effective amount of a compound as described herein.

[0537] In certain embodiments, the compounds as described herein can be used to treat proliferative disorders (e.g., cancer, benign neoplasms, inflammatory diseases, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, the level of a cell protein of interest (e.g., pathogenic proteins and oncoproteins) is regulated by contacting the cell with a compound or composition as described herein, or inhibiting its growth, or degrading the protein. In other embodiments, the compounds can be used to treat cancer.

[0538] Therefore, in another aspect of the present application, a method for treating cancer is provided, which includes administering a therapeutically effective amount of a compound or composition as described herein to a subject in need thereof. In certain embodiments, a method for treating cancer is provided, which includes administering a therapeutically effective amount of a compound or a pharmaceutical composition comprising a compound as described herein to a subject in need thereof in an amount and time required 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, the "therapeutically effective amount" of a compound or pharmaceutical composition is an amount effective in killing tumor cells or inhibiting tumor cell growth. The compounds and compositions according to the methods of the present application can be administered using any amount and any administration route effective in killing tumor cells or inhibiting tumor cell growth. Therefore, as used herein, the expression "an amount effective in killing tumor cells or inhibiting tumor cell growth" refers to an amount 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, a specific anticancer 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 skin cell growth.

[0539] In certain embodiments, the method involves administering a therapeutically effective amount of a compound or a pharmaceutically acceptable derivative thereof to a subject (including but not limited to a person or other mammal in need thereof). In certain embodiments, the compounds or compositions described herein can be used to treat 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, gastric cancer, brain cancer, liver cancer or esophageal cancer).

[0540] In certain embodiments, the compounds or compositions described herein can be used to treat 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 active against solid tumors.

[0541] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or any of these in combination with one or more additional therapeutic agents.

[0542] 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 the step of administering to the patient a compound of formula I or a composition comprising the compound.

[0543] It should be understood that the compounds and compositions according to the methods of the present application can be administered using any amount and any route of administration effective for treating cancer and / or conditions associated with excessive cell proliferation. For example, when using the compounds to treat cancer, the expression "effective amount" as used herein refers to an amount sufficient to inhibit proliferation, or refers to an amount sufficient to reduce the effects of cancer. 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 specific anticancer agent, its mode of administration, etc.

[0544] The present application provides a method for treating 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. Proliferative disorders can be cancer or a precancerous condition. The present application also provides a compound of the present application or a pharmaceutically acceptable salt, salt, solvate, stereoisomer or tautomer thereof for the preparation of a drug that can be used to treat a proliferative disorder.

[0545] The application also provides a method of preventing a subject in need of such treatment from suffering from a proliferative disorder by administering a therapeutically effective amount of a compound of the application or a pharmaceutically acceptable salt, salt, solvate, stereoisomer or tautomer thereof to a subject in need of such treatment. Proliferative disorders can be cancer or a precancerous condition. The application also provides a compound of the application or a pharmaceutically acceptable salt, salt, solvate, stereoisomer or tautomer thereof for the preparation of a drug that can be used to prevent proliferative disorders.

[0546] As used herein, the term "proliferative disorder" refers to a condition in which unregulated growth or abnormal growth of cells or both may lead to an undesirable condition or disease, which may or may not be cancerous. Exemplary proliferative disorders of the present application cover a variety of conditions in which cell division is dysregulated. Exemplary proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, precancerous patients, tumors in situ, cystic tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, blood 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 exceeding or greater than that expected or observed in adjacent or juxtaposed cells in the same tissue. Proliferative disorders include precancers 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 tumors and / or malignant tumors. "Precancerous cancer cells" or "precancerous cells" are cells that exhibit proliferative disorders, and the proliferative disorders are precancers or precancerous conditions. A "cancer cell" or "cancer cell" is a cell that exhibits a proliferative disorder, which is cancer. Any reproducible measurement means can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified by using appropriate molecular markers.

[0547] 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; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic lung inflammation; inflammatory bowel disease; Crohn's disease; psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; liver 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 pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; Reiter's syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; herniated, ruptured or prolapsed disc syndrome; osteosclerosis; 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 herpes zoster, herpes simplex type I or II, influenza virus and cytomegalovirus; and diabetes.

[0548] Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, childhood cerebellar astrocytoma, childhood brain astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urethral bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma , Brain Astrocytoma / Glioma, Ependymoma, Medulloblastoma, Supratentorial Primitive Neuroectodermal Tumor, Visual Pathway and Hypothalamic Glioma, Breast Cancer, Bronchial Adenoma / Carcinoid, Carcinoid Tumor, Gastrointestinal, Nervous System Cancer, Nervous System Lymphoma, Central Nervous System Cancer, Central Nervous System Lymphoma, Cervical Cancer, Childhood Cancer, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma Tumors, lymphomas, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, extraglandular germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric (gastric / stomach) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, ovarian germ cell tumors, gestational trophoblastic tumors, gliomas, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma Tumor, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, renal cancer, kidney cancer, kidney cancer, laryngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, primary macroglobulinemia ( macroglobulinemia), medulloblastoma, melanoma, intraocular (eye) melanoma, merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, oral cancer, tongue cancer, multiple endocrine neoplasms 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 cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, Plasma cell neoplasms / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, transitional cell cancer of the renal pelvis and ureter, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family of sarcoma tumors, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (stomach / gastric) cancer, supratentorial primitive neuroectodermal cancer, testicular cancer, laryngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0549] "Hematologic proliferative disorders" are proliferative disorders involving cells of the hematologic system. Hematologic proliferative disorders may include lymphomas, leukemias, myeloid tumors, mast cell tumors, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomas, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, idiopathic myeloid exogenesis, and essential thrombocythemia. Hematologic proliferative disorders may include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system. The compositions of the present application may be used to treat a cancer selected from the hematologic cancers of the present application or the hematologic proliferative disorders of the present application. The blood cancer of the present application may include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, and lymphoma of lymphocyte and skin origin), leukemia (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia and mast cell leukemia), myeloid tumors and mast cell tumors.

[0550] "Proliferative disorders of the lung" are proliferative disorders involving cells of the lung. Proliferative disorders of the lung may include all forms of proliferative disorders that affect lung cells. Proliferative disorders of the lung may include lung cancer, precancer or precancerous conditions of the lung, benign growths or lesions of the lung, malignant growths or lesions of the lung, and metastatic lesions in body tissues and organs other than the lung. The compositions of the present application may be used to treat lung cancer or proliferative disorders of the lung. Lung cancer may include all forms of cancer of the lung. Lung cancer may include malignant lung tumors, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer may include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lung cancer may include "scar cancer", bronchioloalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer may include lung tumors with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0551] Proliferative disorders of the lungs may include all forms of proliferative disorders that affect lung cells. Proliferative disorders of the lungs may include lung cancer, precancerous conditions of the lungs. Proliferative disorders of the lungs may include hyperplasia, metaplasia and dysplasia of the lungs. Proliferative disorders of the lungs may include asbestos-induced hyperplasia, squamous metaplasia and benign reactive mesothelial metaplasia. Proliferative disorders of the lungs may include stratified squamous epithelial replacement of columnar epithelium and mucosal dysplasia. Individuals exposed to inhaled harmful environmental agents such as cigarette smoke and asbestos may increase the risk of suffering from proliferative disorders of the lungs. Previous lung diseases that may make individuals susceptible to proliferative disorders of the lungs may include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatoid arthritis, sarcoidosis, interstitial pneumonia, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granulomas, asbestosis, fibrosing alveolitis and Hodgkin's disease.

[0552] "Proliferative disorders of the colon" are proliferative disorders involving cells of the colon. In one embodiment, the proliferative disorder of the colon is colon cancer. In one embodiment, the composition 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 cancer of the colon. 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 adenocarcinomas, squamous cell carcinomas, and adenosquamous cell carcinomas. Colon cancer can be associated with a hereditary syndrome selected from hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis. Colon cancer can be caused by a hereditary syndrome selected from hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis.

[0553] Proliferative disorders of the colon may include all forms of proliferative disorders that affect colon cells. Proliferative disorders of the colon may include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Proliferative disorders of the colon may include adenomas. Proliferative disorders of the colon may be characterized by hyperplasia, metaplasia, and dysplasia of the colon. Previous colon diseases that may predispose individuals to proliferative disorders of the colon include previous colon cancer. Current diseases that may predispose individuals to proliferative disorders of the colon may include Crohn's disease and ulcerative colitis. Proliferative disorders of the colon may be associated with mutations in genes selected from p53, ras, FAP, and DCC. Due to the presence of mutations in genes selected from p53, ras, FAP, and DCC, individuals may have an increased risk of developing proliferative disorders of the colon.

[0554] "Proliferative disorders of the pancreas" are proliferative disorders of cells related to the pancreas. Proliferative disorders of the pancreas can include all forms of proliferative disorders that affect pancreatic cells. Proliferative disorders of the pancreas can include pancreatic cancer, precancerous or precancerous conditions of the pancreas, hyperplasia of the pancreas and pancreatic dysplasia, benign growth or lesions of the pancreas, malignant growth or lesions of the pancreas, and metastatic lesions in body tissues and organs beyond the pancreas. Pancreatic cancer includes all forms of cancer of the pancreas. 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 tumors, mucinous cystadenoma, papillary cystic tumors and serous cystadenoma. Pancreatic cancer can also include pancreatic tumors with histology and ultrastructural heterogeneity (e.g., mixed cell types).

[0555] "Proliferative disorders of the prostate" are proliferative disorders of cells involving the prostate. Proliferative disorders of the prostate can include all forms of proliferative disorders that affect prostate cells. Proliferative disorders of the prostate can include prostate cancer, precancer or precancerous conditions of the prostate, benign growths or lesions of the prostate, malignant growths or lesions of the prostate, and metastatic lesions in body tissues and organs other than the prostate. Proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate.

[0556] A "proliferative disorder of the skin" is a proliferative disorder involving cells of the skin. Proliferative disorders of the skin can include all forms of proliferative disorders affecting skin cells. Proliferative disorders of the skin can include precancers or precancerous conditions of the skin, benign growths or lesions of the skin, melanomas, malignant melanomas, and other malignant growths or lesions of the skin, and metastatic lesions in body tissues and organs other than the skin. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.

[0557] A "proliferative disorder of the ovary" is a proliferative disorder involving cells of the ovary. Proliferative disorders of the ovary can include all forms of proliferative disorders affecting cells of the ovary. Proliferative disorders of the ovary can include precancer or precancerous conditions of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in body tissues and organs other than the ovary. Proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of cells of the ovary.

[0558] "Proliferative disorders of the breast" are proliferative disorders involving cells of the breast. Proliferative disorders of the breast can include all forms of proliferative disorders that affect breast cells. Proliferative disorders of the breast can include breast cancer, precancer or precancerous conditions of the breast, benign growths or lesions of the breast, malignant growths or lesions of the breast, and metastatic lesions in body tissues and organs other than the breast. Proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.

[0559] The cancer to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, wherein the tumor (T) has been designated as TX stage, T1 stage, T1mic stage, T1a stage, T1b stage, T1c stage, T2 stage, T3 stage, T4 stage, T4a stage, T4b stage, T4c stage, or T4d stage; wherein the regional lymph nodes (N) have been designated as NX stage, N0 stage, N1 stage, N2 stage, N2a stage, N2b stage, N3 stage, N3a stage, N3b stage, or N3c stage; wherein distant metastasis (M) can be designated as MX stage, M0 stage, or M1 stage. The cancer to be treated can be staged as I stage, IIA stage, IIB stage, IIIA stage, IIIB stage, IIIC stage, or IV stage according to the American Joint Committee on Cancer (AJCC) classification. A cancer to be treated can be assigned a grade of GX (e.g., grade cannot be assessed), 1, 2, 3, or 4 according to the AJCC classification. A cancer to be treated can 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.

[0560] The cancer to be treated may include a tumor with a determined diameter of less than or equal to about 2 centimeters. The cancer to be treated may include a tumor with a determined diameter of about 2 to about 5 centimeters. The cancer to be treated may include a tumor with a determined diameter of greater than or equal to about 3 centimeters. The cancer to be treated may include a tumor with a determined diameter greater than 5 centimeters. The cancer to be treated may be classified as well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated according to the microscopic appearance. The cancer to be treated may be classified according to the microscopic appearance by mitotic count (e.g., the amount of cell division) or nuclear pleomorphism (e.g., changes in cells). The cancer to be treated may be classified according to the microscopic appearance as being associated with a necrotic region (e.g., a region of dying or degenerating cells). The cancer to be treated may be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes with abnormal appearance. The cancer to be treated may be classified as aneuploid, triploid, tetraploid, or having altered ploidy. The cancer to be treated may be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of a deletion, duplication, or amplification of a portion of a chromosome.

[0561] A cancer to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. A cancer to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis phase of cell division (e.g., S phase of cell division). A cancer to be treated can be typed as having a low S phase fraction or a high S phase fraction.

[0562] As used herein, a "normal cell" is a cell that cannot be classified as part of a "proliferative disorder." A normal cell lacks unregulated or abnormal growth, or both, which may lead to the development of an unwanted condition or disease. In one embodiment, a normal cell has a functioning cell cycle checkpoint control mechanism.

[0563] Those skilled in the art can refer to general references for detailed descriptions of known techniques or equivalent techniques discussed herein. These include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd Edition), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, 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). Of course, these references may also be referenced when implementing or using an aspect of the present application.

[0564] In certain embodiments, the compounds of the present application can be used to treat proliferative disorders (e.g., cancer, benign neoplasms, inflammatory diseases, and autoimmune diseases). In certain embodiments, according to the methods of treatment of the present application, the level of a cell protein of interest (e.g., pathogenic proteins and oncoproteins) is regulated or its growth is inhibited by contacting the cell with a compound or composition as described herein. In other embodiments, the compounds can be used to treat cancer.

[0565] In certain embodiments, the method involves administering a therapeutically effective amount of the compound or a pharmaceutically acceptable derivative thereof to a subject (including but not limited to a human or animal) in need thereof. In certain embodiments, the compound can be used to treat 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, gastric cancer, brain cancer, liver cancer or esophageal cancer).

[0566] In certain embodiments, the anticancer agent can be used to treat 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 anticancer agent is active against solid tumors.

[0567] Additionally, the present application provides pharmaceutically acceptable derivatives of the compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or any of these in combination with one or more additional therapeutic agents.

[0568] For example, other therapies or anticancer agents that can be used in combination with the compounds disclosed herein include surgery, radiation therapy, endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), etc.), hyperthermia and cryotherapy, agents that reduce any adverse reactions (e.g., antiemetics), and other approved chemotherapeutic drugs, including but not limited to alkylating drugs (nitrogen mustard, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (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, leuprorelin, flutamide and megestrol acetate), etc. For a more comprehensive discussion of cancer therapy overview, see the Merck Manual 20th Edition (2020), the entire contents of which are hereby incorporated by reference. Also refer to the National Cancer Institute (NCI) website (www.nci.nih.gov) and the U.S. Food and Drug Administration (FDA) website for a list of FDA-approved oncology drugs (www.fda.gov / cder / cancer / druglistframe).

[0569] In certain embodiments, the pharmaceutical composition comprising the compounds disclosed herein further comprises one or more additional therapeutically active ingredients (e.g., chemotherapy and / or palliative). For the purposes of this application, the term "palliative" refers to a treatment that focuses on relieving the symptoms of the disease and / or the side effects of the treatment regimen but is not curative. For example, palliative treatments include analgesics, anti-nausea drugs, and antiemetic drugs. In addition, chemotherapy, radiotherapy, and surgery can all be used palliatively (i.e., to alleviate symptoms without seeking a cure; for example, to shrink tumors and reduce pressure, bleeding, pain, and other symptoms of cancer).

[0570] Administration, pharmaceutical composition

[0571] Administration of the disclosed compounds and pharmaceutical compositions can be achieved via any mode of administration of the therapeutic agent. These modes include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical modes of administration.

[0572] Depending on the intended mode of administration, the disclosed compositions can be in solid, semisolid or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses and in accordance with conventional pharmaceutical practice. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular forms, and all use forms well known to those skilled in the art of medicine.

[0573] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, for example, 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 their esters or triglycerides or a mixture thereof), omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, chlorine for tablets: c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, waxes and / or polyvinyl pyrrolidone (if necessary); d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt or an effervescent mixture; e) absorbents, colorants, flavorings and sweeteners; f) emulsifiers or dispersants, for example, Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmulMCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifiers; and / or g) agents that enhance compound absorption, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0574] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed compounds are dissolved in or mixed with a pharmaceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicrons, or serum proteins can be used to dissolve the disclosed compounds.

[0575] The disclosed compounds may also be formulated as suppositories, which may be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol as carriers.

[0576] The disclosed compounds 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, including cholesterol, stearylamine or phosphatidylcholines.

[0577] In some embodiments, the 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, which is hereby incorporated by reference in its entirety.

[0578] The disclosed compound can also be delivered as an individual carrier by using the monoclonal antibody coupled with the disclosed compound. The disclosed compound can also be coupled with a soluble polymer as a targetable drug carrier. Such polymers can include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine phenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the disclosed compound can be coupled with a class of biodegradable polymers that can be used to realize the controlled release of drugs, such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic hydrogel block copolymers. In one embodiment, the disclosed compound is not covalently bound to a polymer such as a polycarboxylic acid polymer or polyacrylate.

[0579] Parenteral injection administration is generally for subcutaneous, intramuscular or intravenous injection and infusion. Injections can be prepared in conventional forms, either as liquid solutions or suspensions or in solid forms suitable for dissolution in liquid prior to injection.

[0580] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also include an excipient, a diluent, or a surfactant.

[0581] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compound by weight or volume.

[0582] In one embodiment, the disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the disclosure. In one embodiment, the kit comprises means for separately maintaining the compositions, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as a blister pack commonly used for packaging tablets, capsules, etc.

[0583] The kits of the present disclosure can be used to administer different dosage forms (e.g., oral and parenteral), for administering the separate compositions at different dosage intervals, or for titrating the separate compositions relative to each other. To aid compliance, the kits of the present disclosure typically include instructions for administration.

[0584] The pharmaceutical dosage forms of the compounds of the present disclosure can be manufactured by any method well known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, making dragees, tableting, suspending, extruding, spray drying, grinding into fine powders, emulsifying, (nano / micron) encapsulation, embedding or lyophilizing processes. As described above, the compositions of the present disclosure may include one or more physiologically acceptable inactive ingredients that aid in processing the active molecules into preparations for pharmaceutical use.

[0585] As described above, the composition is generally composed of a compound of the present disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, facilitate administration, and do not adversely affect the therapeutic benefits of the claimed compound. Such excipients can be any solid, liquid, semisolid, or (in the case of aerosol compositions) gaseous excipients that are generally available to those skilled in the art.

[0586] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skimmed milk powder, etc. Liquid and semisolid 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 liquid carriers for injectable solutions) include water, saline, aqueous dextrose and glycols.

[0587] Compressed gases can be used to disperse the compounds of the present disclosure in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 18th edition, 1990).

[0588] If desired, the compositions of the present disclosure may be provided in a package or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a package or device may, for example, include metal or plastic foil, such as a blister pack, or glass, and a rubber stopper, such as in a vial. The package or dispenser device may be accompanied by instructions for administration. Compositions comprising the compounds of the present disclosure may also be prepared, which compositions may be formulated in a compatible pharmaceutical carrier, placed in an appropriate container, and labeled for use in treating the indicated condition.

[0589] The amount of compound in the preparation can change in the whole range adopted by those skilled in the art.Usually, in weight percentage (wt%), the preparation will contain about 0.01-99.99 wt % of the compound of the present disclosure based on the total preparation, and the surplus is one or more suitable pharmaceutical excipients.In one embodiment, the compound exists at a level of about 1-80 wt %.Representative pharmaceutical preparations are described below.

[0590] Preparation Examples

[0591] The following are representative pharmaceutical formulations containing compounds of the present disclosure.

[0592] Formulation Example 1 - Tablet Formulation

[0593] The following ingredients are intimately mixed and compressed into single scored tablets.

[0594]

[0595]

[0596] Preparation Example 2 - Capsule Preparation

[0597] The following ingredients are mixed intimately and loaded into hard shell gelatin capsules.

[0598]

[0599] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration.

[0600]

[0601] Formulation Example 4 - Injectable Formulation The following ingredients are mixed to form an injectable formulation.

[0602]

[0603] Preparation Example 5 - Suppository Preparation

[0604] By combining the compounds of the present disclosure with H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to prepare a suppository with a total weight of 2.5 g, which had the following composition:

[0605]

[0606] Drug administration

[0607] The dosage regimen for using the disclosed compounds is selected based on a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or liver function; and the specific disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition.

[0608] When used for the indicated effects, as required for the treatment of a condition, the effective dosage amount of the disclosed compounds is in the range of about 0.5 mg to about 5000 mg of the disclosed compounds. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the disclosed compounds, or within the range of one amount to another in the dosage list. In one embodiment, the composition is in the form of a tablet that can be scored.

[0609] Example

[0610] The present disclosure may be further understood with reference to the following examples, which are intended to illustrate the present disclosure only. The scope of the present disclosure is not limited by the illustrated embodiments, which are intended to illustrate only a single aspect of the present disclosure. Any method that is functionally equivalent is within the scope of the present disclosure. In addition to those described herein, various modifications of the present disclosure will become apparent to those skilled in the art based on the foregoing description and the accompanying drawings. Such modifications fall within the scope of the appended claims.

[0611] In the specification and the following examples, all temperatures are in degrees Celsius. In addition, the following abbreviations have the following meanings. If not defined, these abbreviations have their meanings generally recognized in the art.

[0612] Abbreviation meaning

[0613] δ Chemical shift (ppm)

[0614] Angstrom

[0615] ACN or MeCN Acetonitrile

[0616] Boc or t-Boc tert-butoxycarbonyl

[0617] Cbz benzyloxycarbonyl

[0618] CDCl3 deuterated chloroform

[0619] DC 50 Concentration resulting in 50% targeted protein degradation

[0620] DCC N,N-Dicyclohexylcarbodiimide

[0621] DCM Dichloromethane

[0622] DHA Docosahexaenoic acid

[0623] DIEA Diisopropylethylamine

[0624] DMAP 4-dimethylaminopyridine

[0625] DMF N,N-Dimethylformamide

[0626] DMSO Dimethyl sulfoxide

[0627] d6-DMSO Deuterated dimethyl sulfoxide

[0628] d4-MeOD deuterated methanol

[0629] EPA Eicosapentaenoic acid

[0630] eq. equivalent

[0631] ESI Electrospray ionization

[0632] EtOH

[0633] Fmoc Fluorenylmethoxycarbonyl

[0634] g

[0635] 1 H NMR Proton nuclear magnetic resonance spectroscopy

[0636] h or hr hour

[0637] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0638] HPLC High Performance Liquid Chromatography

[0639] HPMC Hydroxypropyl Methylcellulose

[0640] L Liter

[0641] LC Liquid Chromatography

[0642] LC-MS liquid chromatography-mass spectrometry

[0643] LiHMDS Lithium bis(trimethylsilyl)amide

[0644] M mole / liter

[0645] mCPBA meta-chloroperbenzoic acid

[0646] mg milligram

[0647] m / z mass-to-charge ratio

[0648] min

[0649] mmol millimole

[0650] mL milliliters

[0651] MTBE Methyl tert-butyl ether

[0652] μL microliter

[0653] μmol or μmol micromole

[0654] μM micromoles / liter

[0655] N Standard

[0656] Pd(dppf)Cl2 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0657] Pd(OAc)2 Palladium(II) acetate

[0658] Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride

[0659] PPh3 Triphenylphosphine

[0660] qs sufficient amount

[0661] TEA Triethylamine

[0662] TFA Trifluoroacetic acid

[0663] THF Tetrahydrofuran

[0664] UV

[0665] wt% weight percentage

[0666] NMR abbreviation br = broad

[0667] d = double peak

[0668] dd = doublet

[0669] m = multiplet

[0670] q = quartet

[0671] s = single peak

[0672] t = triplet

[0673] LC-MS Methods (General Methods)

[0674] Method A: Experimental use 5μm C 18 (2) LC column 250×21.2mm, AXIA TM The mass spectrometer was loaded with (00G-4252-P0-AX), a flow rate of 20 mL / min and used ESI as the ionization source. Solvent A was 4.0 mL TFA / 4 L water and solvent B was 4.0 mL TFA / 4 L acetonitrile. The gradient consisted of 10-100% solvent B over 20 minutes with a LC column temperature of 40° C. UV absorbance was collected at 220 nm and 254 nm.

[0675] Example 1

[0676] 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)

[0677]

[0678] Step 1:

[0679]

[0680] To a solution of 4-bromo-6-chloropyridazine-3-amine (1 g, 4.80 mmol, 1 eq) in EtOH (10 mL) was added DIEA (1.86 g, 14.39 mmol, 2.51 mL, 3 eq) and tert-butyl piperazine-1-carboxylate (1.34 g, 7.20 mmol, 1.5 eq). The mixture was stirred at 80 ° C for 12 hours. The reaction was concentrated under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (20 mL) and washed with water, dried over magnesium sulfate, and the solvent was evaporated in vacuo to obtain tert-butyl 4-(3-amino-6-chloropyridazine-4-yl)piperazine-1-carboxylate.

[0681] Step 2:

[0682]

[0683] A mixture of tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)piperazine-1-carboxylate (1.3 g, 4.14 mmol, 1 eq), (2-hydroxyphenyl)boronic acid (857.16 mg, 6.21 mmol, 1.5 eq), Pd(dppf)2Cl2 (303.15 mg, 414.30 μmol, 0.1 eq) and Cs2CO3 (8.10 g, 24.86 mmol, 6 eq) in dioxane (14 mL) and H2O (1.4 mL) was degassed and purged with N2. The mixture was stirred at 80°C for 12 hours under N2 atmosphere. 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 to 100% ethyl acetate / 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).

[0684] Step 3:

[0685]

[0686] To a solution of tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)piperazine-1-carboxylate (1 g, 2.69 mmol, 1 eq) in DCM (8 mL) was added TFA (4 mL). The mixture was stirred at 25 °C for 12 hours. 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 as a TFA salt. 1 H 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).

[0687] Step 4:

[0688]

[0689] To a 0°C solution of 4-bromo-2-(methylthio)pyrimidine (5 g, 24.38 mmol, 1 eq) in MeCN (20 mL), DCM (20 mL) and H2O (20 mL) was added NaIO4 (10.41 g, 48.76 mmol, 2 eq). RuCl3 (0.1 g, 0.02 eq) was added and the reaction was warmed to 25°C and stirred for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (100 mL). The organic layer was separated, washed with saturated Na2S2O3 (50 mL) and dried over sodium sulfate. The organic layer was concentrated to give a residue which was purified by column chromatography to give 4-bromo-2-(methylsulfonyl)pyrimidine.

[0690] Step 5:

[0691]

[0692] To a solution of LiHMDS (10mL, 1.2eq, 1N) in THF (30mL) at -78 ° C, propane-2-alkynes-1-yl iminodicarbonate di-tert-butyl ester (2.16g, 8.44mmol, 1eq) was added, and stirred for 1 hour. 4-bromo-2-(methylsulfonyl) pyrimidine (2g, 8.44mmol, 1eq) in DCM (10mL) was added dropwise and stirred for 2 hours at -78 ° C. The reaction mixture was quenched with saturated NH4Cl (30mL), diluted with water (50mL), and extracted with MTBE (50mL). The organic layer was separated, dried over sodium sulfate, and concentrated to obtain a residue. The residue was purified by column chromatography to obtain (3-(4-bromopyrimidine-2-yl) propane-2-alkynes-1-yl) iminodicarbonate di-tert-butyl ester. 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).

[0693] Step 6:

[0694]

[0695] A solution of 2-(6-amino-5-(piperazin-1-yl)pyridazin-3-yl)phenol (802 mg, 2.08 mmol, 1 eq), di-tert-butyl (3-(4-bromopyrimidin-2-yl)prop-2-yn-1-yl)imidodicarbonate (650 mg, 2.08 mmol, 1 eq) and DIEA (807 mg, 6.25 mmol, 3 eq) in DMF (5.0 mL) was stirred at room temperature overnight. 1 M citric acid solution was added to the reaction mixture until pH = ~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.

[0696] Step 7:

[0697]

[0698] 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.

[0699] Step 8:

[0700]

[0701] 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. 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 eq) in DMF (0.2 mL) were added. The solution was stirred at room temperature for 5 hours. The residue was purified by preparative HPLC (column: Phenomenex Luna C 18 100×40mm×5mm; mobile phase: (0.1% formic acid / water-0.1% formic acid / ACN); B%: 5%-50%, 8 minutes) to purify the solution. The fractions were combined and lyophilized to obtain 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.

[0702] Example 2

[0703] Preparation of N-(3-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (Compound P-119)

[0704]

[0705] Step 1:

[0706]

[0707] To a solution of 4-bromo-6-chloropyridazin-3-amine (1 g, 4.80 mmol, 1 eq.) in EtOH (10 mL) were added DIEA (1.86 g, 14.39 mmol, 2.51 mL, 3 eq.) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.53 g, 7.20 mmol, 1.5 eq.). 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) + .

[0708] Step 2:

[0709]

[0710] 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 eq), (2-hydroxyphenyl)boronic acid (1.46 g, 10.59 mmol, 1.5 eq), Pd(dppf)2Cl2 (516.78 mg, 706.26 μmol, 0.1 eq) and Cs2CO3 (13.81 g, 42.38 mmol, 6 eq) in dioxane (20 mL) and H2O (2 mL) was degassed and purged with N2. The mixture was stirred at 80°C under N2 atmosphere for 12 hours. 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 to 100% ethyl acetate / 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) + .

[0711] Step 3:

[0712]

[0713] 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 eq) 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 which was triturated with MTBE to give 2-(6-amino-5-(3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol as a TFA salt. 1 H NMR(400MHz,d6-DMSO)δ9.15(br s,2H)7.69(brd,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).

[0714] Step 4:

[0715]

[0716] 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 eq) in DMF (4 mL) was added DIEA (259 mg, 2.01 mmol, 3.3 eq) and 2,4-dibromopyrimidine (145 mg, 608 μmol, 1 eq). The reaction was stirred at room temperature for 16 hours. The residue was purified by preparative HPLC (column: Phenomenex Luna C 18 100mm×40mm×5μm; mobile phase: (0.1% formic acid / water-0.1% formic acid / ACN); B%: 20%-80%, 8 minutes) to purify the solution. The fractions were combined and lyophilized to obtain 2-(6-amino-5-(8-(2-bromopyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)phenol. 1H 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).

[0717] Step 5:

[0718]

[0719] 2-(6-amino-5-(8-(2-bromopyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridazin-3-yl)phenol (15 mg, 33 μmol, 1 eq), N-(but-3-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (66 μmol, 2 eq) and DIEA (12.8 mg, 99 μmol, 3 eq) were dissolved in anhydrous DMF (0.7 mL) and the resulting solution was degassed under an argon stream for 5 minutes. Bis(triphenylphosphine)palladium dichloride (16.4 mg, 0.0233 mmol, 0.1 eq.) and CuI (2.5 mg, 13.2 μmol, 0.4 eq) 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]oct-8-yl)pyrimidin-2-yl)prop-2-yn-1-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide.

[0720] Example 3

[0721] 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)

[0722]

[0723] Step 1:

[0724]

[0725] A mixture of 4-bromo-6-chloropyridazine-3-amine (2.07 g, 10.0 mmol, 2 eq), DIEA (6.45 g, 49.93 mmol, 8.70 mL, 10 eq) and tert-butyl 1,4-diazacycloheptane-1-carboxylate (1 g, 4.99 mmol, 980.39 μL, 1 eq) in DMSO (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 120 ° C for 4 days under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were combined, 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 to 100% ethyl acetate / petroleum ether) to give tert-butyl 4-(3-amino-6-chloropyridazin-4-yl)-1,4-diazepan-1-carboxylate. 1 HNMR (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).

[0726] Step 2:

[0727]

[0728] A mixture of tert-butyl 4-(3-amino-6-chloropyridazine-4-yl)-1,4-diazacycloheptane-1-carboxylate (8 g, 24.40 mmol, 1 eq), (2-hydroxyphenyl)boronic acid (5.05 g, 36.61 mmol, 1.5 eq), Cs2CO3 (47.71 g, 146.43 mmol, 6 eq) and Pd(dppf)Cl2 (1.79 g, 2.44 mmol, 0.1 eq) in dioxane (100 mL) and water (20 mL) was degassed and purged with N2 three times. The mixture was stirred at 80 ° C for 12 hours under N2 atmosphere. The reaction mixture was quenched by adding water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 1 to 100% ethyl acetate / petroleum ether) to afford tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-carboxylate. 1H 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).

[0729] Step 3:

[0730]

[0731] Prepare a mixture of tert-butyl 4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-1,4-diazepan-1-carboxylate (8 g, 20.75 mmol, 1 eq) and TFA (15.40 g, 135.06 mmol, 10 mL, 6.51 eq) in DCM (80 mL). Stir the mixture at 20 °C for 2 hours. Concentrate the reaction mixture in vacuo. Triturate the crude product with MTBE (20 mL) to give 2-(6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl)phenol. 1 H NMR (400 MHz, d4-MeOD) δ 7.58 (, J = 1.6, 8.0 Hz, 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 (quintet, J = 5.6 Hz, 2H).

[0732] Step 4:

[0733]

[0734] A mixture of 2-(6-amino-5-(1,4-diazepine-1-yl)pyridazine-3-yl)phenol (3.57 g, 15.02 mmol, 1.5 eq), DIEA (6.47 g, 50.08 mmol, 8.72 mL, 5 eq) and DMAP (122.36 mg, 1.00 mmol, 0.1 eq) in DMF (40 mL) was degassed and purged with N2 three times. The mixture was stirred at 20 ° C for 12 hours under N2 atmosphere. The reaction mixture was filtered. The column was purified by preparative HPLC (column: Welch Xtimate C 18250×70mm×10μm; mobile phase: (water (NH4HCO3)-ACN); B%: 33%-63%, 20 minutes) The residue was purified to give 2-(6-amino-5-(4-(2-bromopyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol. 1 HNMR(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).

[0735] Step 5:

[0736]

[0737] 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 eq.), (E)-tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate (38.4 mg, 136 μmol, 1.2 eq.), triphenylphosphine (5.93 mg, 22.6 μmol, 0.2 eq.) and cesium carbonate (110 mg, 339 μmol, 3 eq.) in ACN (2 mL) and water (0.5 mL) was degassed under a stream of argon for 5 minutes. Palladium(II) acetate (1.27 mg, 5.65 μmol, 0.05 eq.) was added. The reaction was stirred at 100° C. for 4 hours. The reaction was cooled to room temperature. The results were analyzed by preparative HPLC (column: Phenomenex Luna C 18 100×40mm×5mm; mobile phase: (0.1% formic acid / water-0.1% formic acid / ACN); B%: 5%-75%, 8 minutes) to purify the solution. The fractions were combined and lyophilized to obtain 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) + .

[0738] Step 6:

[0739]

[0740] To a solution of (E)-tert-butyl(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 eq) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20 °C for 1.5 hours. The reaction mixture was concentrated in vacuo. The crude product was triturated with 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.

[0741] Step 7:

[0742]

[0743] To a solution of quinoxaline-2-carboxylic acid (6.44 mg, 371 μmol, 1 eq) 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 eq), HATU (14.1 mg, 37 μmol, 1 eq) and DIEA (19.1 mg, 25.8 μL, 148 μmol, 4 eq). The reaction was stirred at 25 °C for 16 hours. The residue was purified by preparative HPLC (column: Phenomenex Luna C 18 100×40mm×5mm; mobile phase: (0.1% formic acid / water-0.1% formic acid / ACN); B%: 10%-40%, 8 minutes) to purify the solution. The fractions were combined and lyophilized to obtain (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) + .

[0744] Example 4

[0745] 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)

[0746]

[0747] Step 1:

[0748]

[0749] To a mixture of 4,6-dichloro-2-(methylthio)pyrimidine (6 g, 30.76 mmol, 1 eq) in ethanol (60 mL) was added sodium ethoxide (10.47 g, 30.76 mmol, 20% purity, 1 eq) in one portion at 20 °C under N2 atmosphere. The mixture was stirred at room temperature for 16 hours. Saturated NH4Cl solution (100 mL) was added. The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were combined, 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).

[0750] Step 2:

[0751]

[0752] To a mixture of 4-chloro-6-ethoxy-2-(methylthio)pyrimidine (5.81 g, 28.39 mmol, 1 eq) in DCM (60 mL) was added mCPBA (48.98 g, 283.86 mmol, 10 eq) in one portion. The mixture was stirred at room temperature for 16 hours. Saturated sodium thiosulfate solution (40 mL) was added. The organic layer 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) + .

[0753] Step 3:

[0754]

[0755] To a -78°C solution of 4-chloro-6-ethoxy-2-(methylsulfonyl)pyrimidine (1 g, 4.23 mmol, 1 eq) in THF (20 mL) was added LiHMDS (1 M, 5.07 mL, 99.5% purity, 1.2 eq) dropwise over 15 minutes. The mixture was stirred at -78°C for 30 minutes. N-tert-butoxycarbonyl-N-prop-2-ynyl-carbamic acid tert-butyl ester (1.08 g, 4.23 mmol, 1 eq) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -78°C for 2 hours. Saturated NH4Cl solution (20 mL) was added. The aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layers were combined, 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)imidodicarbonate. 1 H NMR (400MHz, CDCl3) δ6.67 (s, 1H) 4.63 (s, 2H) 4.44 (q, J = 7.2Hz, 2H) 1.63 (br s, 3H) 1.55 (s, 18H).

[0756] Step 4:

[0757]

[0758] To a solution of di-tert-butyl (3-(4-chloro-6-ethoxypyrimidin-2-yl)prop-2-yn-1-yl)imidodicarbonate (150 mg, 364.18 μmol, 1 eq) in DMSO (5 mL) was added 2-[6-amino-5-(1,4-diazepan-1-yl)pyridazin-3-yl]phenol (103.92 mg, 364.18 μmol, 1 eq) dropwise at 50°C for 15 minutes. After the addition, the mixture was stirred at 50°C for 30 minutes, and then DIEA (470.67 mg, 3.64 mmol, 634.33 μL, 10 eq) was added dropwise. The resulting mixture was stirred at 50°C for 2 hours. Saturated NH4Cl solution (1 mL) was added. The aqueous layer was extracted with ethyl acetate (2×0.5 mL). The organic layers were combined, 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. 1H 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).

[0759] Step 5:

[0760]

[0761] 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 eq) in DCM (1 mL) was added TFA (1 M, 378.35 μL, 5 eq). The mixture 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)-6-ethoxypyrimidin-4-yl)-1,4-diazepan-1-yl)pyridazin-3-yl)phenol. m / z (ESI + )459.2(M-1) + .

[0762] Step 6:

[0763]

[0764] To a solution of pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (7.08 mg, 43.43 μmol, 1 eq) 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 eq), HATU (16.51 mg, 43.43 μmol, 1 eq) and DIEA (11.23 mg, 86.86 μmol, 15.13 μL, 2 eq). The mixture was stirred at 0°C for 1 hour. Saturated NH4Cl solution (1 mL) was added. The aqueous layer was extracted with ethyl acetate (2×0.5 mL). The organic layers were combined, washed with brine (1 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 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. 1 H 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).

[0765] Example 5

[0766] Preparation of 2-(5-(4-(2-(3-(1H-benzo[d]imidazol-1-yl)prop-1-yn-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)-6-aminopyridazin-3-yl)phenol (Compound P-150)

[0767]

[0768] Step 1:

[0769]

[0770] To a solution of 3-bromoprop-1-yne (80%, 3.78 g, 25.39 mmol, 2.74 mL, 3.0 eq) in DMF (10 mL) was added KCO (2.34 g, 16.93 mmol, 2.0 eq) and 1H-benzo[d]imidazole (1.00 g, 8.46 mmol, 1 eq). The mixture was stirred at 25°C for 12 hours. Water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (2 x 60 mL). The organic layers were combined, 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. 1 H 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).

[0771] Step 2:

[0772]

[0773] 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 eq), 1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole (50 mg, 113.04 μmol, 1 eq), Pd(PPh3)2Cl2 (7.93 mg, 11.30 μmol, 0.1 eq), CuI (6.46 mg, 33.91 μmol, 0.3 eq) and DIEA (51.13 mg, 395.65 μmol, 68.91 μL, 3.5 eq) in DMF (0.5 mL) was degassed and purged with nitrogen. The mixture was stirred at 70°C under N2 atmosphere for 1 hour. 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]imidazol-1-yl)prop-1-yn-1-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)-6-aminopyridazin-3-yl)phenol. 1H 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).

[0774] Example 6

[0775] 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)

[0776]

[0777] Step 1:

[0778]

[0779] 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 eq), N,N-dimethylprop-2-yn-1-amine (191.28 mg, 2.30 mmol, 243.98 μL, 3 eq), DIEA (346.94 mg, 2.68 mmol, 467.58 μL, 3.5 eq), CuI (43.82 mg, 230.09 μmol, 0.3 eq) in DMF (3 mL) was added Pd(PPh3)2Cl2 (53.83 mg, 76.70 μmol, 0.1 eq) under N2 at 25°C. The reaction mixture was degassed and purged with N2 three times. The reaction mixture was stirred at 70 ° C for 1 hour under N2 atmosphere. The reaction mixture was distributed between ethyl acetate (5mL) and H2O (5mL). The organic phase was separated, washed with brine (3mL), 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)pyrimidine-4-yl)-5-methyl-1,4-diazacyclohept-1-yl)pyridazine-3-yl)phenol, which was directly used in the next step. 1 HNMR(400MHz,CD3OD)δ8.15-7.99(m,1H),7.83-7.68(m,1H),7.55-7.45(m,1H),7.2 8-7.15(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).

[0780] Step 2:

[0781]

[0782] 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 eq) in THF (0.5 mL) was added Pd / C (5 mg, 21.81 μmol, 60 wt%, 1 eq) at 25 °C under argon atmosphere. The reaction mixture was stirred at 25 °C for 1 hour under H2 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 75mm×30mm×3μm; mobile phase: [water (+1% formic acid)-ACN]; B%: 1%-30%, 8 min gradient) to obtain o-{5-[(R)-4-{2-[(E)-3-(dimethylamino)-1-propenyl]-4-pyrimidinyl}-5-methyl-1,4-diazepan-1-yl]-6-amino-3-pyridazinyl}phenol. 1 H 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).

[0783] Example 7

[0784] Preparation of o-[6-amino-5-(3-{2-[3-(dimethylamino)-1-propynyl]-4-pyridyloxy}-1-azetidinyl)-3-pyridazinyl]phenol (Compound P-387)

[0785]

[0786] Step 1:

[0787]

[0788] By 4- bromo- 6- chloropyridazine -3- amine (5g, 23.99mmol, 1eq), azetidin -3- alcohol (2.63g, 23.99mmol, 1eq, HCl) and DIEA (31.00g, 239.87mmol, 41.78mL, 10eq) solution in DMF (50mL) degassed and N2 purged, and the mixture was stirred at 120 ° C for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue. By column chromatography (SiO2, 0 to 10% methanol / ethyl acetate) the residue was purified to obtain 1- (3- amino -6- chloropyridazine -4- bases) azetidin -3- alcohol. 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).

[0789] Step 2:

[0790]

[0791] 1-(3-amino-6-chloropyridazin-4-yl)azetidin-3-ol (4.4 g, 21.93 mmol, 1 eq), [2-(methoxymethoxy)phenyl]boronic acid (4.39 g, 24.12 mmol, 1.1 eq), Pd(dppf)Cl2 (1.60 g, 2.19 mmol, 0.1 eq) and Cs2CO3 (42.87 g, 131.59 mmol, 6 eq) in dioxane (45 mL) and water (22.5 mL) were degassed and purged with N2 three times. The mixture was stirred at 80°C under N2 atmosphere for 5 hours. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with brine (2×50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with ACN (20 mL) to give 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetidin-3-ol. 1HNMR(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).

[0792] Step 3:

[0793]

[0794] To a solution of 1-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)azetidin-3-ol (1 g, 3.31 mmol, 1 eq) in DMF (10 mL) was added NaH (661.47 mg, 16.54 mmol, 60% purity, 5 eq) in portions at 0°C under N2. After 10 minutes, 2-bromo-4-fluoro-pyridine (582.10 mg, 3.31 mmol, 1 eq) in DMF (5 mL) was added dropwise at 0°C. The mixture was stirred at 20°C for 1 hour. Saturated NH4Cl solution (10 mL) was added and the reaction was extracted with ethyl acetate (3×10 mL). The organic layers were combined, washed with brine (2×10 mL), dried over Na2SO4, 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).

[0795] Step 4:

[0796]

[0797] A solution of 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazine-3-amine (140 mg, 305.47 μmol, 1 eq) in HCOOH (1.4 mL) was stirred at 20 ° C for 5 hours. Saturated NaHCO solution (5 mL) was added, and the mixture was extracted with ethyl acetate (3×2 mL). The organic layers were combined, washed with brine (2×2 mL), dried over Na2SO4, 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)pyridazine-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)

[0798] Step 5:

[0799]

[0800] A mixture of 4-(3-((2-bromopyridin-4-yl)oxy)azetidin-1-yl)-6-(2-(methoxymethoxy)phenyl)pyridazine-3-amine (20 mg, 48.28 μmol, 1 eq), N,N-dimethylprop-2-yn-1-amine (12.04 mg, 144.84 μmol, 15.36 μL, 3 eq), CuI (2.76 mg, 14.48 μmol, 0.3 eq), DIEA (31.20 mg, 241.40 μmol, 42.05 μL, 5 eq) and Pd(PPh3)2Cl2 (6.78 mg, 9.66 μmol, 0.2 eq) in DMF (0.2 mL) was degassed and purged three times with N2. The mixture was stirred at 40 ° C for 2 hours under N2 atmosphere. The reaction mixture was filtered and purified by preparative HPLC (Phenomenex LunaC 1875mm×30mm×3μm; mobile phase: [water (+1% formic acid)-ACN]; B%: 1%-30%, 8 min gradient) purified the filtrate to give o-[6-amino-5-(3-{2-[3-(dimethylamino)-1-propynyl]-4-pyridinyloxy}-1-azetidinyl)-3-pyridazinyl]phenol.

[0801] 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).

[0802] Each of the compounds listed in Table 3 was prepared according to the procedures set forth above.

[0803] Table 3

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893] Biological Examples

[0894] SMARCA2 and SMARCA4 degradation assay

[0895] The degradation of proteins expressed from SMARCA2 and SMARCA4 genes was monitored using an engineered HiBiT fusion HeLa cell line from Promega. Briefly, SMARCA2-HiBiT or SMARCA4-HiBiT HeLa cells were seeded into 384-well white opaque plates (Greiner) at 8,000 cells / well and incubated overnight at 37°C to allow cells to attach. After overnight incubation, test compounds were added using a TECAN D300e digital dispenser in a 10-point dilution series (usually 10 μM to 300 pM), and the plates were subsequently incubated at 37°C for 24 hours. 24 hours after treatment, protein levels were quantified by adding HiBiT lysis buffer, LgBiT protein, and HiBiT substrate according to the manufacturer's instructions. The plate was incubated on an orbital plate oscillator at room temperature for 10 minutes. The resulting luminescence values ​​were read out using a ClarioStar plate reader and used to construct a dose-response curve and calculate degradation DC 50 (GraphPad Prism).

[0896] Table 4 provides the data from the assay. The activities of the test compounds are provided in Table 4 below as follows: A = DC 50 <0.050μM; B=0.05μM <DC 50 <0.50μM; C=<0.5μM <DC 50 <5.0μM; D=DC 50 >5.0 μM. For SMARCA2 and SMARCA4 degradation activity at 1 μM, +++=>70%; ++=30-70%; +=<30%.

[0897] Table 4

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912] Unless defined otherwise, 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.

[0913] The disclosure illustratively described herein may be appropriately implemented in the absence of any one or more elements, one or more limitations not specifically disclosed herein. Thus, for example, the terms "comprises," "includes," "containing," and the like are to be understood broadly and without limitation. In addition, the terms and expressions employed herein have been used as terms of description rather than limitation, and when such terms and expressions are used, it is not intended to exclude any equivalents of the features shown and described or portions thereof, but it should be recognized that various modifications may be made within the scope of the claims.

[0914] 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 the event of a conflict, the present specification, including definitions, will control.

[0915] It should be understood that although the present disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate rather than 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 belongs.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein: X is hydroxyl, halogen, cyano, C 1-4 Alkoxy or -N(R)2; Y is N, C or CH; Y 1 is N, C or CH; X 1 CH, CR 6 or N; X 2 CH, CR 6 or N; where 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- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 replace; L is a bond, -CH2- or -O-; L 1 is -RC=CR- or -C≡C-; L 2 Selected from: a) b) and c) Where t is 0 or 1, p is 0, 1, 2 or 3, and the dashed line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 The connection point to Z; Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 substituted, and wherein each alkyl, alkoxy or cycloalkyl is independently unsubstituted or substituted with one to three R 3 replace; Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted by one to three R 4 replace; or Two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl group which is unsubstituted or substituted with one to four R 4 replace; Each R x and R y are independently hydrogen, C 1-4 Alkyl or C substituted by 1 to 3 halogen groups 1-4 haloalkyl; or R x and R y , together with the atoms to which they are attached, form C 3-6 Cycloalkyl, which is unsubstituted or substituted by one to four R 4 replace; Each R 1 are independently cyano, halo, hydroxy, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted by 1 to 3 halogen 1-4 haloalkyl, unsubstituted or substituted by 1 to 3 halo 1-4 alkoxy, C having 1 to 3 heteroatoms selected from O, N, NR and / or S 5-6 heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 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 by 1 to 3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 alkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl; Each R 3 are independently oxo, cyano, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C 1-6 Aryl, C substituted with 1 to 3 phenyl groups 1-4 Alkyl, or C 3-6 Cycloalkyl; Each R 4 are independently -N(R)2, cyano, halo or hydroxy; Each R 5 D, halogenated, C 1-3 Haloalkyl or C 1-4 Alkoxy; Each R 6 is N(R)2, SR, halo, cyano, unsubstituted or substituted by 1 to 3 halo 1-4 Alkoxy, unsubstituted C 1-4 Alkyl, C 1-2 Alkoxy substituted C 1-4 Alkyl, or C substituted by hydroxy 1-4 alkyl; m is 0, 1 or 2; and n is 0, 1, 2 or 3; Provided that when the compound For the following parts: And L 2 When Z is -C(O)NH-, a bond, -CH2- or -(CH2)2-, then Z is not a heterocyclic group (wherein the heterocyclic group is unsubstituted or substituted), -C 1-6 Alkylene -NH2 or -C 1-6 Alkylene-OH, And the compound is not: 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]oct-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]oct-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]oct-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]oct-3-yl)pyridazin-3-yl)phenol, 2-(6-amino-5-(8-(2-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyridin-4-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl)pyridazin-3-yl)phenol, N-[3-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-2-pyridinyl]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]oct-3-yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[9-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridinyl]-3,9-diazaspiro[5.5]undec-3-yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[2-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridinyl]-2,8-diazaspiro[4.5]dec-8-yl]pyridazin-3-yl]phenol, 2-[6-amino-5-[6-[2-[3-(azepan-1-yl)prop-1-ynyl]-4-pyridinyl]-2,6-diazaspiro[3.3]hept-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]oct-3-yl)pyridazin-3-yl)phenol, or 2-[6-amino-5-[8-[2-[(E)-3-(azepan-1-yl)prop-1-enyl]-4-pyridinyl]-3,8-diazabicyclo[3.2.1]oct-3-yl]pyridazin-3-yl]phenol.

2. A compound of formula IA: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein: X is hydroxyl, halogen, 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- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 replace; L is a bond, -CH2- or -O-; L 1 is -RC=CR- or -C≡C-; L 2 Selected from: a) b) and c) Where t is 0 or 1, p is 0, 1, 2 or 3, and the dashed line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 The connection point to Z; Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 substituted, and wherein each alkyl, alkoxy or cycloalkyl is independently unsubstituted or substituted with one to three R 3 replace; Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted by one to three R 4 replace; or Two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl group which is unsubstituted or substituted with one to four R 4 replace; Each R x and R y are independently hydrogen, C 1-4 Alkyl or C substituted by 1 to 3 halogen groups 1-4 haloalkyl; or R x and R y , together with the atoms to which they are attached, form C 3-6 Cycloalkyl, which is unsubstituted or substituted by one to four R 4 replace; Each R 1 are independently cyano, halo, hydroxy, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted by 1 to 3 halogen 1-4 haloalkyl, unsubstituted or substituted by 1 to 3 halo 1-4 alkoxy, C having 1 to 3 heteroatoms selected from O, N, NR and / or S 5-6 heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 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 by 1 to 3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 alkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl; Each R 3 are independently oxo, cyano, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, C 1-6 Aryl, C substituted with 1 to 3 phenyl groups 1-4 Alkyl, or C 3-6 Cycloalkyl; Each R 4 are independently -N(R)2, cyano, halo or hydroxy; Each R 5 D, halogenated, C 1-3 Haloalkyl or C 1-4 Alkoxy; Each R 6 is N(R)2, SR, halo, cyano, unsubstituted or substituted by 1 to 3 halo 1-4 Alkoxy, unsubstituted C 1-4 Alkyl, C 1-2 Alkoxy substituted C 1-4 Alkyl, or C substituted by hydroxy 1-4 alkyl; m is 0, 1 or 2; and n is 0, 1, 2 or 3; with the proviso that 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]oct-3-yl]pyridazin-3-yl]phenol.

3. A compound of formula I': or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein: X is hydroxyl, halogen, 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- to 11-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 3 heteroatoms selected from O, N, NR, and S, and wherein each cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently unsubstituted or substituted with one to four R 1 replace; L 1 is -RC=CR- or -C≡C-; L 2 Selected from: a) b) and c) Where t is 0 or 1, p is 0, 1, 2 or 3, and the dashed line (---) indicates the 2 To L 1 The connecting points and the wavy lines Indicates that from L 2 The connection point to Z; Z is C 1-10 Alkyl, -N(R)2, -OH, C 1-10 Alkoxy, C 3-8 cycloalkyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein each heterocycloalkyl or heteroaryl has 1 to 4 heteroatoms selected from NR, N, O, and S, and wherein each heterocycloalkyl or heteroaryl is independently unsubstituted or substituted with one to four R 2 substituted, and wherein each alkyl, alkoxy or cycloalkyl is independently unsubstituted or substituted with one to three R 3 replace; Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted by one to three R 4 replace; or Two R groups, when attached to the same nitrogen, form a 4- to 7-membered heterocycloalkyl group which is unsubstituted or substituted with one to four R 4 replace; Each R x and R y are independently hydrogen, C 1-4 Alkyl or C substituted by 1 to 3 halogen groups 1-4 haloalkyl; or R x and R y , together with the atoms to which they are attached, form C 3-6 Cycloalkyl, which is unsubstituted or substituted by one to four R 4 replace; Each R 1 are independently cyano, halo, hydroxy, nitro, oxo, -N(R)2, C 1-4 Alkyl, C substituted by 1 to 3 halogen 1-4 haloalkyl, unsubstituted or substituted by 1 to 3 halo 1-4 alkoxy, C having 1 to 3 heteroatoms selected from O, N, NR and / or S 5-6 heteroaryl, 4- to 7-membered heterocycloalkyl having 1 to 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 by 1 to 3 halo groups 1-4 Haloalkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 alkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl; Each R 3 are independently oxo, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Alkoxy, C substituted by 1 to 3 halo groups 1-4 Haloalkyl, or C 3-6 Cycloalkyl; Each R 4 are independently -N(R)2, cyano, halo or hydroxy; Each R 5 D, halogenated, C 1-3 Haloalkyl or C 1-4 Alkoxy; Each R 6 is N(R)2, SR, cyano, unsubstituted or substituted by 1 to 3 halogenated C 1-4 Alkoxy, C 1-2 Alkoxy substituted C 1-4 Alkyl, or C substituted by hydroxy 1-4 alkyl; m is 0, 1 or 2; and n is 0, 1, 2 or 3; with the proviso that 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]oct-3-yl]pyridazin-3-yl]phenol.

4. The compound according to claim 3, wherein the compound of formula I' is represented by formula II': or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

5. The compound according to claim 4, wherein the compound of formula II' is represented by formula IIa': or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

6. The compound according to claim 5, wherein the compound of formula IIa' is represented by formula IIa'-1: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

7. The compound according to claim 5, wherein the compound of formula IIa' is represented by formula IIa'-2: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

8. The compound according to claim 4, wherein the compound of formula II' is represented by formula IIb': or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

9. The compound according to claim 4, wherein the compound of formula II' is represented by formula IIc': or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

10. The compound according to claim 4, wherein the compound of formula II' is represented by formula IId': or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

11. The compound according to claim 3, wherein the compound of formula I' is represented by formula III'-E: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

12. The compound according to claim 11, wherein the compound of formula III′-E is represented by formula IIIa′-E: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

13. The compound according to claim 11, wherein the compound of formula III′-E is represented by formula IIIb′-E: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

14. The compound according to claim 3, wherein the compound of formula I' is represented by formula III'-Z: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

15. The compound according to claim 14, wherein the compound of formula III'-Z is represented by formula IIIa'-Z: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

16. The compound according to claim 14, wherein the compound of formula III'-Z is represented by formula IIIb'-Z: or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Selected from The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

18. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Selected from The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

19. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Selected from The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

20. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Selected from The dashed line (---) indicates the connection point from ring A to the pyrimidine, and the wavy line represents the point of attachment from ring A to L or pyridazine, and wherein each ring A is independently unsubstituted or substituted with one to four R 1 Substitute, where each R 1 are independently halogenated or C 1-4 alkyl.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is selected from wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

22. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is selected from wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

23. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is wherein Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

24. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is selected from wherein Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

25. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is selected from wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

26. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is selected from wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

27. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is selected from wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

28. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is selected from wherein each Z is independently unsubstituted or substituted with one to four R 2 Substitute, where each R 2 are independently oxo, halo, -C(O)OR, -NRC(O)OR, C 1-4 Alkyl, C substituted by 1 to 3 halo groups 1-4 haloalkyl, C having 1 to 3 heteroatoms selected from O, N and NR 5-6 Heteroaryl, or C 3-6 Cycloalkyl.

29. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is C 1-10 alkyl.

30. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is -N(R)2.

31. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is C 1-10 Alkoxy.

32. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein Z is -OH.

33. A compound according to any preceding claim, wherein X is hydroxy.

34. A compound according to any preceding claim, wherein T is -NH2.

35. A compound according to any preceding claim, wherein Y and Y 1 Both are N.

36. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

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

38. A method for regulating or degrading a protein expressed from a SMARCA2 gene, the method comprising contacting the protein with an effective amount of a compound according to any one of claims 1 to 3.

39. A method for regulating or degrading a protein expressed from a SMARCA4 gene, the method comprising contacting the protein with an effective amount of a compound according to any one of claims 1 to 3.

40. A method for regulating or degrading a protein expressed from a SMARCA2 gene in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 3.

41. A method for regulating or degrading a protein expressed from a SMARCA4 gene in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 3.

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

43. A method for regulating or degrading a protein expressed from a SMARCA4 gene in a subject, the method comprising administering an effective amount of the pharmaceutical composition according to claim 36 to the subject.

44. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-3.

45. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 36.

46. ​​A method for treating hyperplasia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to claim 1.

47. A method for treating hyperplasia in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 36.

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