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

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 by one or more SWI / SNF related matrix associated actin dependent chromatin regulatory factor A subfamily (SMARCA) (e.g., SMARCA2 and / or SMARCA4). I

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No. 63 / 508,804, filed June 16, 2023, which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present disclosure provides compounds, including pharmaceutically acceptable salts thereof, useful as targeted ubiquitination modulators. The compounds disclosed herein bind to and degrade proteins expressed by one or more SWI / SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin Subfamily A (“SMARCA”). Also disclosed are pharmaceutical compositions comprising the compounds, as well as methods of using such compounds to treat various SMARCA-mediated diseases or conditions. PRIOR ART

[0004] The ubiquitin-proteasome pathway (UPP) is an important pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to a variety of cellular processes and if it is defective or imbalanced, it can lead to the onset of a variety of diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0005] There are more than 600 types of E3 ubiquitin ligases that promote the ubiquitination of different proteins in the body. They can be divided into four families: HECT domain E3, U-box E3, monomeric RING E3, and multi-subunit E3. See, for example, Li et al. "Genome-wideand functional annotation of human E3 ubiquitin 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; Deshaie et al., "RING domain E3ubiquitin ligases" Ann. Rev. Biochem. 2009, 78:399; Sprattetal. "RBRE3ubiquitin ligases: new structures, new insights, new questions" Biochem. 2014, 458:421; and Wang et al., "Roles of F-box proteins in cancer" Nat. Rev. Cancer. 2014, 14:233.

[0006] UPP plays a crucial role in the degradation of short-lived and regulatory proteins important for a variety of fundamental cellular processes, including cell cycle regulation, regulation of cell surface receptors and ion channels, and antigen presentation. This pathway is involved in the pathogenesis of several forms of malignancy, several inherited diseases (including cystic fibrosis, Angelman syndrome, and Liddell syndrome), immune surveillance / viral pathogenesis, and the pathology of muscle atrophy. Many diseases are associated with abnormal UPP and negatively impact cell cycle and division, cellular responses to stress and extracellular regulators, morphogenesis of neuronal networks, regulation of cell surface receptors and ion channels, secretory pathways, DNA repair, and organelle biosynthesis.

[0007] Recent studies have shown that abnormalities in this process are associated with the pathogenesis of several genetic and acquired diseases. These diseases fall into two main categories: (a) diseases caused by loss of function leading to the stabilization of certain proteins, and (b) diseases caused by gain of function (i.e., abnormal or accelerated degradation of target proteins).

[0008] UPPs are used to induce selective protein degradation, including artificial ubiquitination of target proteins using fusion proteins and proteasome-dependent degradation using synthetic small molecule probes. Compounds acting as molecular glues can induce or stabilize protein-protein interactions between target proteins and E3 ubiquitin ligase ligands, leading to protein ubiquitination, followed by proteasome-mediated degradation via recruitment of E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of time-controlled protein expression. Such compounds can induce the inactivation of proteins of interest upon addition to cells or administration to animals or humans and can be used as biochemical agents, forming new paradigms for treating diseases by removing pathogenic or oncogenic proteins. See, for example, Crews, Chem. & Biol. 2010, 17(6): 551; Schneekloth and Crews, ChemBio Chem., 2005, 6(1): 40.

[0009] There remains a persistent need in the field for effective treatments for diseases, particularly hyperplasia and cancer. However, nonspecificity and the inability to fully target and regulate certain classes of proteins, such as transcription factors, persist as obstacles to the development of effective anticancer agents. Therefore, small molecule therapeutics that utilize E3 ligase-mediated protein degradation to target cancer-associated proteins—such as one or more SWESNF-associated matrix-associated actin-dependent chromatin regulator subfamily A (“SMARCA”) and / or polybromin-1 (“PB1”) proteins—show promise as therapeutic agents. Consequently, the search for compounds that degrade proteins expressed by the SMARCA gene and can be used as therapeutic agents remains crucial. Summary of the Invention

[0010] This disclosure discloses compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising said compounds or pharmaceutically acceptable salts thereof, and methods for using said compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof, which can be used as inducers of targeted ubiquitination of proteins expressed by the SMARCA gene, which are then degraded and / or inhibited by the monovalent compounds described herein. The compounds provided herein have the advantage of possessing broad pharmacological activity consistent with the degradation / inhibition of proteins expressed by the SMARCA gene. Additionally, this disclosure provides methods for treating or improving disease conditions (such as cancer, e.g., lung cancer) in subjects of need using effective amounts of the compounds described herein.

[0011] In some embodiments, the disclosed compound is represented by formula I:

[0012] I

[0013] Or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 1 n, p, R 1 R 2 R 3 R 4 R 5 R 6 And ring A as defined in this paper.

[0014] In some embodiments, the compounds described herein regulate proteins expressed by the SMARCA gene. In some embodiments, the compounds described herein degrade proteins expressed by the SMARCA gene. In some embodiments, the regulated or degraded protein is expressed by SMARCA gene member 2 (SMARCA2). In some embodiments, the regulated or degraded protein is expressed by SMARCA gene member 4 (SMARCA4).

[0015] In some embodiments, this disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I or any of its sub-formulas or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer.

[0016] In some embodiments, this disclosure provides a method for regulating or degrading a protein expressed by a SMARCA gene, the method comprising contacting the protein with an effective amount of a compound of formula I or any of its sub-formulas under conditions in which the protein expressed by the SMARCA gene is bound to the compound and regulated or degraded. In some embodiments, the protein to be regulated or degraded is a protein expressed by a SMARCA2 gene. In some embodiments, the protein to be regulated or degraded is a protein expressed by a SMARCA4 gene.

[0017] In some embodiments, this disclosure provides a method for regulating or degrading a protein expressed by the SMARCA gene in a subject, the method comprising administering to the subject an effective amount of a compound of formula I or any sub-formula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I or any sub-formula thereof, under conditions in which the protein expressed by the SMARCA gene is bound to and regulated or degraded by the compound. In some embodiments, the protein regulated or degraded in the subject is a protein expressed by the SMARCA2 gene. In some embodiments, the protein regulated or degraded in the subject is a protein expressed by the SMARCA4 gene.

[0018] In some embodiments, this disclosure provides a method for treating hyperplasia in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula I or any sub-formula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I or any sub-formula thereof.

[0019] In some embodiments, this disclosure provides a method for treating cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula I or any sub-formula thereof, or a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I or any sub-formula thereof. Detailed Implementation

[0020] This 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 this disclosure, the following terms will first be defined. Unless otherwise defined, the terms used herein have their generally accepted scientific meanings.

[0021] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure. As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” are intended to include the plural forms as well.

[0022] A hyphen ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached via a carbon atom. A hyphen at the beginning or end of a chemical group is for convenience; a chemical group may or may not be represented by one or more hyphens without losing its usual meaning. A wavy or dashed line drawn through a line in the structure indicates the specific attachment point of the group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0023] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0024] When used before numerical indications such as temperature, time, amount, concentration, etc., including ranges, the term "about" indicates an approximate value that can vary (+) or (-) 10%, 5%, 1%, or any subrange or subvalue between these values. In one embodiment, when used in relation to dosage, the term "about" means that the dosage can vary by + / - 10%.

[0025] "Comprising or comprise" is intended to mean that the composition and method contain the described essential elements, but does not exclude other elements.

[0026] When used to define compositions and methods, "consisting essentially of..." should mean excluding other elements that are of any significance to the combination for the stated purpose. Therefore, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the claimed basic and novel features disclosed.

[0027] "Consisting of" should imply the exclusion of other components beyond trace elements and numerous method steps. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0028] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, with 1 to 12 carbon atoms (i.e., C464). 1-12 Alkyl groups, with 1 to 8 carbon atoms (i.e., C1646). 1-8 Alkyl groups, with 1 to 6 carbon atoms (i.e., C1646). 1-6 Alkyl group or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl groups. 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 specific number of carbons is named by its chemical name or identified by its molecular formula, it can encompass all positional isomers having that number of carbons; 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); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0029] 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 (e.g., methylene, ethylene, and propylene) and "arylene" groups (e.g., phenylene or naphthylene, or quinolinyl of heteroarylene). Furthermore, unless explicitly indicated otherwise, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last mentioned group contains the atoms that link that moiety to the remainder of the molecule.

[0030] "Alkenyl" refers to a group containing at least one (e.g., 1 to 3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C20 ... 2-20 alkenyl), 2 to 12 (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 Alkyl groups (alkenyl). Examples of alkenyl groups include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0031] "Alkyne" refers to a group containing at least one (e.g., 1 to 3 or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C36, C46, ​​C56, C6 ... 2-20 2 to 12 (i.e., C10) alkynyl group 2-12 alkynyl group), 2 to 8 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C4 group) 2-4 Alkyne group. The term "alkynyl" also includes these groups having one triple bond and one double bond.

[0032] "Alkoxy" refers to an "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0033] "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.

[0034] "Acyl" refers to the group -C(O)R y , where R y It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them can be unsubstituted or substituted as defined herein. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0035] "Acylamino" refers to the "C-acylamino" group (referring to the group -C(O)NR). y R z ) and "N-amide" group (referring to the -NR group) y C(O)R z Both, of which R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may be unsubstituted or substituted, or R y and R z Together they form cycloalkyl or heterocyclic groups; each of which may be unsubstituted or substituted, as defined herein.

[0036] "Amino" refers to the -NR group. y R z , where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0037] "Amino group" refers to -C(NR) y (NR) z 2), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0038] "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, aryl groups have 6 to 20 ring carbon atoms (i.e., C64 carbon atoms). 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group) or 6 to 10 carbon ring atoms (i.e., C4 group). 6-10 Aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl regardless of the connection point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is heterocyclic regardless of the connection point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is cycloalkyl regardless of the connection point.

[0039] "Carbamoyl" refers to the "O-carbamoyl" group (referring to the group -OC(O)NR). y R z ) and "N-carbamoyl" group (referring to the -NR group) y C(O)OR z Both, of which R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0040] "Carboxylic acid ester" or "ester" refers to -OC(O)R x and -C(O)OR x Both, of which R x It is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0041] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings (including fused, bridged, and spirocyclic 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 A carbon-ring fused ring system (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 14 cyclic carbon atoms (i.e., C1456 ... 3-14 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12C ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C1646) 3-10cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 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, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any non-aryl ring that can fused with an aromatic ring, regardless of its connection to the rest of the molecule. In addition, when two substitution positions are present on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", for example, spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0042] "Imine" refers to the group -C(NR) y )R z , where R y and R z Each of them independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0043] "Imine group" refers to the group -C(O)NR y C(O)R z , where R y and R z Each of them independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0044] "Halogen" or "halogenated" refers to atoms that occupy Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0045] "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 a halogen. For example, when a residue is substituted by more than one halogen, it can be designated by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("di") or three ("tri") halogen groups (which may be, but do not necessarily have to be, the same halogen). Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

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

[0047] "Hydroxyalkyl" refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxyl group.

[0048] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms, excluding any terminal carbon atoms) are independently replaced by the same or different heteroatom groups, provided that the connection point to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR. y -, -O-, -S-, -S(O)-, -S(O)2, etc., among which R y The group can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these can be unsubstituted or substituted as defined herein. Examples of heteroalkyl groups include, for example, diethyl 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 y CH2CH2NR y CH3, etc., of which R y The radical is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these may be unsubstituted or substituted as defined herein. As used herein, a heteroalkyl group comprises 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0049] "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, heteroaryl groups comprise 1 to 20 ring carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-20 heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C 3-8 (Heteroaryl) and one to five, one to four, one to three, one to two, or one cyclic heteroatom independently selected from nitrogen, oxygen, and sulfur. In some cases, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having one to four, one to three, one to two, or one cyclic heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothiophene (benzobenzenethio), benzotriazolyl, benzo[4,6]imidazol[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzobenzenethio, furanyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isothiazolyl, imidazolyl, indazole, indazole, isothiazolyl ... Indolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, phenylthio (i.e., thiophene), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]phenylthio, inzolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked via any ring of the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its connection to the rest of the molecule (i.e., through any of the fused rings). A heteroaryl does not encompass aryl groups as defined above or overlap with them.

[0050] "Heterocyclic group"—used interchangeably with "heterocyclic alkyl group"—refers to a saturated or partially unsaturated cyclic alkyl group in which one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic, and can contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) atoms. - The term "heterocyclic group" is intended to encompass any non-aryl ring containing at least one heteroatom, regardless of its linkage (i.e., it can be bonded by carbon atoms or heteroatoms). Furthermore, the term "heterocyclic group" is intended to cover any non-aryl ring containing at least one heteroatom that can be fused with a cycloalkyl, aryl, or heteroaryl ring, regardless of its linkage with the rest of the molecule. As used herein, heterocyclic groups have 2 to 20 ring carbon atoms (i.e., C2, C3, C4, C5, C6, C7 ... 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 Heterocyclic group), 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 group) or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclic groups); having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomole independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrocyclobutyl, azirrocycloheptyl, benzodioxane-pentenyl, benzo[b][1,4]dioxane-, 1,4-benzodioxane-, benzopyranyl, benzodioxinyl, benzopyranone-, benzofuranone-, dioxopentyl, dihydropyranyl, hydropyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanone-, imidazolinyl, imidazoalkyl, dihydroindolyl, indolazinyl, isodihydroindolyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl Dolyl, octahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolylalkyl, ethylene oxide (oxiranyl), oxetanyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazineyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. When two substitution positions exist on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spirocyclic rings include, for example, bicyclic and tricyclic 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 heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, dihydroindolyl, and isodihydroindolyl, wherein the heterocyclic group can be linked via any ring of the fused system. In some embodiments, the heterocyclic alkyl group may be substituted with an oxo group (e.g., S=O, S(=O)2) on the heteroatom.

[0051] "Oxime" refers to the group -CR y (=NOH), where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0052] "Oxytochemical" refers to the partial = O.

[0053] "Sulfonyl" refers to the group -S(O)2R y , where R y It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them can be unsubstituted or substituted as defined herein. Examples of sulfonyl groups are methanesulfonyl, ethanesulfonyl, benzenesulfonyl, and toluenesulfonyl.

[0054] "Sulinate group" refers to the group -S(O)R y , where R y It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them can be unsubstituted or substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfinyl.

[0055] "Sulfanamide group" refers to the group -SO2NR. y R z and -NR y SO2R z , where R y and R z Each of them independently is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of them may be unsubstituted or substituted as defined herein.

[0056] The terms “optional” or “optionally” mean that the events described below may or may not occur, and the description includes instances where the events or situations occur and instances where they do not occur. Furthermore, the terms “unsubstituted or substituted” mean that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a specified atom or group may or may not be substituted by portions other than hydrogen.

[0057] As used herein, the term "substituted" means any of the above-mentioned groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a non-hydrogen atom by a bond, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidyl, aryl, aralkyl, azide, carbamoyl, etc. Carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidinyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, -NHNH2, =NNH2, imino, imide, hydroxyl, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thio, N-oxide or -Si(R y )3, where each R y It can be hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic.

[0058] In some embodiments, "substituted" includes any of the above-described alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by deuterium, halogen, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, 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- 2OR g -NR g S(O) 1-2 NR g R h =NSO2R g =NOR g -S(O) 1-2 NR g R h -SF5, -SCF3, or -OCF3 substitution. In some embodiments, "substituted" also means any of the above groups in which 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 g or -CH2SO2NR g R h Permutation. In the aforementioned context, R... gand R h They are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, heterocyclic alkyl, heteroaryl and / or heteroarylalkyl. In some 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 substituted by an amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkylalkyl, heteroaryl and / or heteroarylalkyl bond, or R g and R h The two atoms in the mixture, together with the atoms they are attached to, form a heterocyclic ring, which is either unsubstituted or substituted with an oxo, halogenated, or alkyl group, which is either unsubstituted or substituted with an oxo, halogenated, amino, hydroxyl, or alkoxy group.

[0059] Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of further substituents (e.g., a substituted aryl group having a substituted alkyl group, which itself is substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substituents in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include disallowed substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein.

[0060] In some embodiments, as used herein, the phrase "one or more" refers to one to five. In some embodiments, as used herein, the phrase "one or more" refers to one to three.

[0061] Any compound or structure described herein is intended to represent both unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as “isotopically enriched analogs.” Isotopically labeled compounds have the structures described herein, except that one or more atoms are replaced by atoms having a chosen 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… 2 H, 3 H, 11 C 13 C14 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 isotopically labeled compounds disclosed herein, such as those incorporating radioactive isotopes such as 3 H and 14 Those containing C. Such isotopically labeled compounds can be used 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 for use in patients undergoing radiotherapy.

[0062] The term “isotope-enriched analogue” includes “deuterium-substituted analogues” of the compounds described herein, wherein one or more hydrogen atoms (such as hydrogen atoms on carbon atoms) are replaced by deuterium. Such compounds exhibit increased metabolic resistance and, when administered to mammals, particularly humans, are thus used to increase the half-life of any compound. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0063] The deuterium-labeled or substituted therapeutic compounds of this disclosure can possess improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirement and / or an improved therapeutic index. 18 F, 3 H or 11 C-labeled compounds can be used in PET, SPECT, or other imaging studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by performing the procedures disclosed in the schemes or examples, and the preparation described below, using readily available isotopically labeled reagents instead of unlabeled reagents. It should be understood that deuterium in this context is considered a substituent in the compounds described herein.

[0064] The concentration of such heavier isotopes (specifically deuterium) can be defined by isotope enrichment factors. In the compounds disclosed herein, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen,” that position is understood to have hydrogen in its natural abundance isotopic composition. Therefore, in the compounds disclosed herein, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0065] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or similar groups.

[0066] This document provides information on the compounds described herein or their pharmaceutically acceptable salts, isotope-enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0067] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared according to the conventional procedure 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, etc. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. For example, 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), tri... Alkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), monocycloalkylamines, dicycloalkylamines, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), monoaromaticamines, diaromaticamines, or triaromaticamines (i.e., NH2(aromatic), HN(aromatic)2, N(aromatic)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.

[0068] The term "solvent" refers to a complex formed by the combination of solvent molecules and solute molecules or ions. Solvents can be organic compounds, inorganic compounds, or mixtures of both. As used herein, the term "solvent" includes "hydrate" (i.e., a complex formed by the combination of water molecules and solute molecules or ions), hemihydrate, channel hydrate, etc. Examples of solvents include, but are not limited to, acetonitrile, methanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, and water. Generally, the solvated form is equivalent to the non-solventized form and is covered within the scope of this disclosure.

[0069] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with their imine tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compound includes both its amide and imine tautomers. Therefore, amide-containing compounds should be understood to include their imine tautomers. Similarly, imine-containing compounds should be understood to include their amide tautomers.

[0070] Compounds or pharmaceutically acceptable salts thereof contain asymmetric centers and can therefore produce enantiomers, diastereomers, and other stereoisomers, which can be defined in absolute stereochemistry as (R)- or (S)- (or as (D)- or (L)- for amino acids). This disclosure is intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques such as chromatography and / or stepwise crystallization. Conventional techniques for preparing / separating individual enantiomers involve chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise stated, it is intended that these compounds include both E-geometric isomers and Z-geometric isomers.

[0071] "Stereoisomers" are compounds formed by identical atoms bonded by identical bonds but having different, non-interchangeable, three-dimensional structures. This disclosure covers various stereoisomers or mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0072] A “diastereomer” is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0073] The relative centers of the compounds described in this article are graphically represented using a “thick bond” style (bold or parallel lines), and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0074] "Prodrug" means any compound that releases an active parent drug in vivo when administered to a mammalian subject according to the structure described herein. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds in a manner that allows the modification to cleave in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in these compounds in a manner that allows the modification to cleave in vivo, either under normal operating conditions or in vivo, to form the parent compound. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl, or thiol groups in the compounds are bonded to any group that can cleave in vivo to regenerate free hydroxyl, amino, or thiol groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetates, formates, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc., of the hydroxyl functional group in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; "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 in its entirety by reference.

[0075] "Subject" refers to a mammal. A mammal can be a human or a non-human mammalian organism. "Patient" refers to a human subject.

[0076] “Treatment” refers to 1) preventing the occurrence of a disease or ailment in a subject who is susceptible to or has not yet shown symptoms of a disease or ailment; 2) suppressing or preventing the development of a disease or ailment; or 3) improving or causing the remission of a disease or ailment.

[0077] "Effective amount" means the amount of the compound described herein that is sufficient to treat or prevent the subject from developing a disease or condition.

[0078] "Administration" means any recognized form of administration to a subject, including oral (including gavage), pulmonary, transdermal, sublingual, injection (e.g., intravenous, intramuscular), and transmucosal (e.g., vaginal, nasal, etc.). The route of administration is chosen by the attending physician based on factors such as the patient's age, weight, overall health status, and severity of condition. In one embodiment, the compounds and pharmaceutical compositions described herein are administered orally.

[0079] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, thereby causing the degradation of that substrate protein. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin conjugates, attach ubiquitin to a lysine residue on a target protein, and subsequently target a specific protein substrate, causing it to be degraded by the proteasome. Thus, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin conjugates, are responsible for transferring ubiquitin to target proteins. Typically, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to the first, a third to the second, and so on. Polyubiquitination labels the protein, making it susceptible to proteasome degradation. However, some ubiquitination events are limited to monoubiquitination, where the ubiquitin ligase adds only a single ubiquitin to the substrate molecule. Monoubiquitinated proteins are not targeted by the proteasome for degradation but may instead undergo alterations in cellular localization or function (e.g., via binding to other proteins with domains capable of binding ubiquitin). Further complicating matters, different lysine residues on ubiquitin can be targeted by E3 to form chains. The most common lysine residue on the ubiquitin chain is Lys48. This is the lysine residue used to produce polyubiquitin, which is recognized by the proteasome.

[0080] compound

[0081] In one embodiment, this disclosure provides a compound of formula I:

[0082] I

[0083] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers, wherein:

[0084] Each of n and p is independently 0, 1, or 2;

[0085] R 1 Hydroxyl, halogenated, cyano, C 1-4 alkoxy or -N(R)2;

[0086] R 2 =-N(R)2;

[0087] Each R is independently hydrogen, C 1-4 Alkyl or C 3-6Cycloalkyl, wherein each alkyl or cycloalkyl group is unsubstituted or surrounded by one to three Z groups. 1 replace;

[0088] Each R 3 Independently halogenated, cyano-based, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace;

[0089] Each R 4 Independently oxo, halogenated, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0- 2R11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace;

[0090] R 5 It can be hydrogen, halogenated, cyano, -NO2, -SF5, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace;

[0091] R 6 For hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or halogenated;

[0092] (i) L 1 For key, C 1-3 Alkylene, -O- or -QL 2 -;

[0093] L 2 For key, C 1-3 Alkylene, -S(O)2- or -C(O)NH-;

[0094] Q is a phenyl group or a 5-membered heteroaryl group containing one or two nitrogen atoms;

[0095] Or (ii) when L 1 When R is the key 2 and R 4 The R in the compound cyclizes together with the atoms it is attached to to form a heterocyclic group;

[0096] Ring A is a 4- to 14-membered heterocyclic group or a 5- to 10-membered heteroaryl group;

[0097] Each Z 1 Independently halogenated, cyano-based, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11)2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1a replace;

[0098] Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1a replace;

[0099] Each Z 1a Independently hydroxyl, halogenated, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -C(O)R 13 -C(O)OR 13 -S(O) 0-2 R 13 -NR 13 S(O) 0- 2R 13 -S(O) 0-2 N(R 13 )2、-NR 13 S(O) 0-2 N(R 13 )2、-NR 13 C(O)N(R 13 )2、-C(O)N(R 13 )2、-NR 13 C(O)R 13 -OC(O)N(R) 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1b replace;

[0100] Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1b replace;

[0101] Each Z 1b Independently halogenated, cyanoated, hydroxylated, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and

[0102] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 ynyl group)-, -C(O)N(C 1-6(halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-;

[0103] Z 1b and each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally independently converted by one to five hydroxyl groups, halogenated groups, cyano groups, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions.

[0104] In some embodiments, via R 2 and R 4 The heterocyclic base ring formed by the cyclization of R with the atoms it is attached to is not a spirocyclic ring.

[0105] In some embodiments, R 1 It is a hydroxyl group.

[0106] In some embodiments, R 2 It is -N(R)2. In some embodiments, R 2 It is -NH2.

[0107] In one embodiment, a compound of formula IA is provided:

[0108] IA,

[0109] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0110] In some embodiments, L 1 For key, C 1-3 Alkylene, -O- or -QL 2 -. In some embodiments, L 1 As a key. In some embodiments, L 1 For -O-. In some embodiments, L 1 For -QL 2-. In some embodiments, L 2 Q is connected to ring A and Q is connected to the pyridazine ring of formula I. In some embodiments, Q is connected to ring A and L 2 Connected to the pyridazine ring of Formula I.

[0111] In some embodiments, Q is a phenyl group.

[0112] In some embodiments, Q is a 5-membered heteroaryl group containing one or two nitrogen atoms. In some embodiments, Q is a 5-membered heteroaryl group containing two nitrogen atoms. In some embodiments, Q is a pyrazolyl group.

[0113] In some embodiments, L 1 For -QL 2 - where Q is phenyl or pyrazolyl.

[0114] In some embodiments, L 2 For key, C 1-3 Alkylene, -S(O)2-, or -C(O)NH-. In some embodiments, L 2 It is -CH2-, -C(O)NH-, or -S(O)2-. In some embodiments, L 2 C 1-3 Alkylene. In some embodiments, L 2 For –(CH2)-. In some embodiments, L 2 For –S(O)2-. In some embodiments, L 2 It is -C(O)NH-. In some embodiments, L 2 For key.

[0115] In some embodiments, L 2 L is a bond and Q is a phenyl group. In some embodiments, L 2 The bond is Q, and Q is a pyrazol group. In some embodiments, L 2 C 1-3 Alkylene and Q is pyrazolyl. In some embodiments, L 2 It is -S(O)2- and Q is phenyl. In some embodiments, L 2 It is -C(O)NH- and Q is phenyl.

[0116] In some embodiments, -QL 2 -Selected from: , , , ,and .

[0117] In some embodiments, L 1 For key, C 1-3 Alkylene, -O- or -QL2 -;L 2 For key, C 1-3 Alkylene, -S(O)2- or -C(O)NH-; and R 2 Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl group is unsubstituted or surrounded by one to three Z groups. 1 Replace; and each R 4 Independently oxo, halogenated, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace.

[0118] In some embodiments, L 1 For key and L 2 As the key; and R 2 Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl group is unsubstituted or surrounded by one to three Z groups. 1 Replace; and each R 4Independently oxo, halogenated, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0- 2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace.

[0119] In one embodiment, a compound of formula IB is provided:

[0120] IB,

[0121] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0122] In one embodiment, a compound of formula IC is provided:

[0123] IC

[0124] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0125] In some embodiments, a compound of formula ID is provided:

[0126] ID,

[0127] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0128] In some embodiments, L 1 As the key, and R 2 and R 4 The R in the compound cyclizes together with the atoms it is attached to to form a heterocyclic group.

[0129] In some embodiments, L 1 As the key, and R 2 and R 4 In this configuration, R and the atoms they are attached to cyclize together to form a fused tricyclic heterocyclic group. In some embodiments, L 1 As the key, and R 2 and R 4 The R in the figure is cyclized together with the atoms it is attached to to form a 9- to 10-membered fused tricyclic heterocyclic group. In some embodiments, L 1 As the key, and R 2 and R 4 The R in the compound is cyclized together with the atoms it is attached to to form a fused tricyclic heterocyclic group containing two or three nitrogen atoms.

[0130] In some embodiments, L 1 As the key, and R 2 and R 4 The R in the compound is cyclized together with the atoms it is attached to to form a 10-membered fused tricyclic heterocyclic group containing 3 nitrogen atoms.

[0131] In some embodiments, L 1 As the key, and R 2 and R 4 The R in the compound is cyclized together with the atoms it is attached to to form a 9-membered fused tricyclic heterocyclic group containing 2 nitrogen atoms.

[0132] In some embodiments, L 1 As the key, and R 2 and R 4 In this configuration, R and the atoms they are attached to cyclize together to form a spirocyclic tricyclic heterocyclic group. In some embodiments, L 1 As the key, and R 2 and R 4 The R in the figure is cyclized together with the atoms it is attached to to form a 10- to 11-membered spirocyclic tricyclic heterocyclic group. In some embodiments, L 1 As the key, and R 2 and R 4 The R in the compound is cyclized together with the atoms it is attached to to form a spirocyclic tricyclic heterocyclic group containing 2 or 3 nitrogen atoms.

[0133] In some embodiments, L 1 As the key, and R 2 and R 4 The R in the compound is cyclized together with the atoms it is attached to to form a 10-membered spirocyclic tricyclic heterocyclic group containing two nitrogen atoms.

[0134] In some embodiments, L 1 As the key, and R 2 and R 4 The R in the compound is cyclized together with the atoms it is attached to to form an 11-membered spirocyclic tricyclic heterocyclic group containing 3 nitrogen atoms.

[0135] In some embodiments, a compound of formula II is provided:

[0136] II,

[0137] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0138] In some embodiments, a compound of formula III is provided:

[0139] III

[0140] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0141] In some embodiments, a compound of formula IV is provided:

[0142] IV,

[0143] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0144] In some embodiments, a compound of formula V is provided:

[0145] V,

[0146] Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

[0147] In some embodiments, ring A is optionally surrounded by one or two Rs. 4 Replaced 4- to 8-membered monocyclic heterocyclic groups.

[0148] In some embodiments, ring A is: Ring A can be optionally divided by one or two Rs. 4 Substitution; q and r are each independently 0, 1, 2, or 3; X is N or CH; ( ) indicates that it is related to L 1The connection point; and (*) indicates the connection point with the carbonyl group.

[0149] In some embodiments, ring A is selected from: , , , , and Each ring A can be optionally divided by one or two Rs. 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0150] In some embodiments, ring A is optionally surrounded by one or two Rs. 4 Replaced 7- to 11-membered spirocyclic heterocyclic groups.

[0151] In some embodiments, ring A is Ring A can be optionally divided by one or two Rs. 4 Substitution; q, r, s, and t are each independently 0, 1, 2, or 3, provided that the sum of q, r, s, and t is not greater than 8; X is N or CH; ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0152] In some embodiments, ring A is selected from: , , , , , , and Each ring A can be optionally divided by 1 or 2 R 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0153] In some embodiments, ring A is optionally surrounded by one or two Rs. 4 Replaced 7- to 11-membered bridged ring heterocyclic groups.

[0154] In some embodiments, ring A is Ring A can be optionally divided by one or two Rs. 4 Substitute; e is 1 or 2; a, b, c, and d are each independently 0, 1, or 2, provided that the sum of a, b, c, d, and e is not greater than 7; X is N or CH; ( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0155] In some embodiments, ring A is selected from: , , and Each ring A can be optionally divided by one or two Rs. 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0156] In some embodiments, ring A is optionally surrounded by one or two Rs. 4 Replaced 8 to 14 fused polycyclic heterocyclic groups.

[0157] In some embodiments, ring A is Ring A can be optionally divided by one or two Rs. 4 Substitution; u, v, w, and x are each independently 0, 1, 2, or 3, provided that the sum of u, v, w, and x is not greater than 7; X is N or CH; ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0158] In some embodiments, ring A is ; where ring A can be optionally divided by one or two R 4 Substitute; y and z are each independently 0, 1, or 2, provided that the sum of y and z is not greater than 4; X is 0, CH, or does not exist; ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0159] In some embodiments, ring A is selected from: , , , , , , , , , and Each ring A can be optionally divided by one or two Rs. 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

[0160] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0161] In some embodiments, R 4Halogenation. In some embodiments, R 4 It is fluorine. In some embodiments, R 4 C 1-6 Alkyl group. In some embodiments, R 4 methyl. In some embodiments, R 4 It is an oxygen-based process.

[0162] In some embodiments, p is 1, and R 4 C 1-6 Alkyl, oxo, or halogenated. In some embodiments, p is 1, and R 4 For halogenation. In some embodiments, p is 1, and R 4 It is fluorine. In some embodiments, p is 1, and R 4 It is oxygenated.

[0163] In some embodiments, R 5 It is a cyano group.

[0164] In some embodiments, R 5 -C(O)R 11 , where R 11 Optionally, it can be controlled by one to five Z. 1a Substituted aryl group. In some embodiments, R 5 -C(O)R 11 , where R 11 For a Z 1a Substituted phenyl groups. In some embodiments, R 5 -C(O)R 11 , where R 11 It is a phenyl group substituted with -OCH3.

[0165] In some embodiments, R 5 for .

[0166] In some embodiments, R 5 -C(O)N(R) 11 )2, where each R 11 Independently for C 1-6 Alkyl group. In some embodiments, R 5 It is -C(O)N(CH3)2.

[0167] In some embodiments, R 5 Optionally, it can be divided into one to eight Z. 1 Replacement C 1-6 Alkyl group. In some embodiments, R 5 For one to three Z 1 Replacement C 1-6 alkyl.

[0168] In some embodiments, R 5 For a Z 1 Replacement C 1-6 Alkyl, wherein Z 1 -N(R) 11 )2. In some embodiments, R 5 C replaced by -N(CH3)2 1-6 Alkyl group. In some embodiments, R 5 C replaced by -N(CH2CH3)2 1-6 Alkyl group. In some embodiments, R 5 C replaced by -NH(iPr) 1-6 alkyl.

[0169] In some embodiments, R 5 For optional use by -N(R) 11 )2 replaced by C 1-6 Alkyl, wherein each R 11 Independently hydrogen, optionally by one to five Z 1a Replacement C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 5 For optional use by -N(R) 11 )2 replaced by C 1-6 Alkyl, wherein each R 11 Independently, it can be optionally controlled by one to five Z. 1a Replacement C 1-6 Alkyl group. In some embodiments, each R 11 For hydrogen. In some embodiments, each R... 11 C 3-6 Cycloalkyl. In some embodiments, each R 11 It is cyclobutyl. In some embodiments, each R 11 Independently for C that can be optionally replaced by one to five halogens. 1-6 Alkyl group. In some embodiments, each R 11 Independently for C that can be optionally substituted with a fluorine. 1-6 alkyl.

[0170] In some embodiments, R 5 Selected from , , , ,and .

[0171] In some embodiments, R 5 For one or two Z 1 Replacement C 1-6 Alkyl, wherein Z1 Halogenation. In some embodiments, R 5 C is replaced by one or two fluorine molecules. 1-6 Alkyl group. In some embodiments, R 5 It is difluoromethyl. In some embodiments, R 5 It is trifluoromethyl.

[0172] In some embodiments, R 5 For a Z 1 Replacement C 1-6 Alkyl, wherein Z 1 Optionally, it can be controlled by one to five Z. 1a Substituted heterocyclic groups.

[0173] In some embodiments, Z 1 For optional use by one or two Z 1a Substituted heterocyclic group. In some embodiments, Z 1 Z is a heterocyclic group that may be optionally substituted with one or two methyl groups. In some embodiments, Z 1 Z is a heterocyclic group substituted with fluorine. In some embodiments, Z 1 Z is a heterocyclic group that can be optionally substituted with -OCH3. In some embodiments, Z 1 Z is a heterocyclic group substituted with a hydroxyl group. In some embodiments, Z 1 It is a heterocyclic group substituted with -CH2-OH.

[0174] In some embodiments, R 5 For a Z 1 Replacement C 1-6 Alkyl, wherein Z 1 Optionally, it can be controlled by one to five Z. 1a The substitution is a 4- to 11-membered heterocyclic group containing one or two heteroatoms selected from N and O.

[0175] In some embodiments, Z 1 Selected from one to five Z, optionally. 1a Substituted halogenated, -N(R) 11 )2 and heterocyclic groups.

[0176] In some embodiments, R 5 Selected from: , , , , , , , , , , , , , , , , , , , , and .

[0177] In some embodiments, R 5 It is hydrogen.

[0178] In some embodiments, R 6 C 1-3 Haloalkyl. In some embodiments, R 6 It is trifluoromethyl.

[0179] In some embodiments, R 6 It is hydrogen.

[0180] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0181] In some embodiments, n is 1, and R 3 For halogenation. In some embodiments, n is 1, and R 3 It is fluorine.

[0182] In one embodiment, an IE compound is provided:

[0183] IE,

[0184] Or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 1 For key or -O-.

[0185] Some embodiments provide a compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof selected from Table 1 or Table 2.

[0186] Table 1 lists representative and non-limiting examples of compounds within the range of Formula I above, each of which includes a pharmaceutically acceptable salt, solvate, hydrate, or tautomer.

[0187] Table 1

[0188]

[0189] Table 2 lists representative and non-limiting examples of compounds within the range of Formula I above, each of which includes a pharmaceutically acceptable salt, solvate, hydrate, or tautomer.

[0190] Table 2

[0191]

[0192] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof that degrades SMARCA2 by 5%, 10% or 20% or more at a concentration of 1 µM.

[0193] In some embodiments, this disclosure provides a compound or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof that degrades SMARCA4 by 5%, 10% or 20% or more at a concentration of 1 µM.

[0194] In some embodiments, this disclosure provides a method for regulating or degrading a protein expressed by the SMARCA2 gene, the method comprising contacting the protein with an effective amount of a compound as described herein. In some embodiments, this disclosure provides a method for regulating or degrading a protein expressed by the SMARCA2 gene, the method comprising contacting the protein with an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any of its subforms, under conditions in which the protein expressed by the SMARCA2 gene is regulated or degraded.

[0195] In some embodiments, this disclosure provides a method for regulating or degrading a protein expressed by the SMARCA4 gene, the method comprising contacting the protein with an effective amount of a compound as described herein. In some embodiments, this disclosure provides a method for regulating or degrading a protein expressed by the SMARCA4 gene, the method comprising contacting the protein with an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any of its subforms, under conditions in which the protein expressed by the SMARCA4 gene is regulated or degraded.

[0196] In some embodiments, a method for regulating or degrading a protein expressed by the SMARCA2 gene in a subject is provided, the method comprising administering to the subject an effective amount of a compound as described herein or a pharmaceutical composition as described herein. In some embodiments, a method for regulating or degrading a protein expressed by the SMARCA2 gene in a subject is provided, the method comprising administering to the subject an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any subform of the compound thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any subform of the compound thereof, and a pharmaceutically acceptable excipient.

[0197] In some embodiments, a method for regulating or degrading a protein expressed by the SMARCA4 gene in a subject is provided, the method comprising administering to the subject an effective amount of a compound as described herein or a pharmaceutical composition as described herein. In some embodiments, a method for regulating or degrading a protein expressed by the SMARCA4 gene in a subject is provided, the method comprising administering to the subject an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any subform of the compound thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any subform of the compound thereof, and a pharmaceutically acceptable excipient.

[0198] In some embodiments, a method for treating cancer in a subject of need is provided, the method comprising administering to the subject an effective amount of a compound as described herein or a pharmaceutical composition as described herein. In some embodiments, a method for treating cancer in a subject of need is provided, the method comprising selecting a patient with cancer at least partially mediated by SMARCA2, and administering to the subject an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any subform of the compound thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV, or V, or any subform of the compound thereof.

[0199] In some embodiments, a method for treating cancer in a subject of need is provided, the method comprising selecting a patient with cancer at least partially mediated by SMARCA4, and administering to the subject an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV or V or any subform compound thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV or V or any subform compound thereof.

[0200] In some embodiments, a method for treating hyperplasia in a subject in need is provided, the method comprising administering to the subject an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV or V or any subform compound thereof, or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of formula I, IA, IB, IC, ID, IE, II, III, IV or V or any subform compound thereof.

[0201] General Synthesis Method

[0202] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be recognized that other process conditions may be used when typical process conditions (i.e., reaction temperature, time, reactant molar ratio, solvent, pressure, etc.) are met, unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0203] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The designation of suitable protecting groups for various functional groups, and the appropriate 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.

[0204] The starting materials used in the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Sigma Aldrich (St. Louis, Missouri, USA), Bachem (Torrance, California, USA), and Emka-Chemce (St. Louis, Missouri, USA). Other starting materials may be prepared by procedures described in standard reference texts such as the following, or obvious modifications thereof: 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 Supplements (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).

[0205] Synthesis of representative compounds

[0206] The general synthesis of the compounds described herein is illustrated by the following reaction schemes. Schemes 1 to 4 demonstrate the general method for preparing compounds of formula I. In schemes 1 to 4, the substituent L... 1 L 2 Q, R 1 R 2 R 3 R 4 R 5 R6 The definitions of ring A, n, and p are the same as those in the specification. PG is a protecting group (including but not limited to Boc, etc.). LG is a suitable coupling partner (including but not limited to hydrogen when performing the Sonogashira coupling reaction, and boric acid or ester when performing the Suzuki coupling reaction, etc.).

[0207]

[0208] Option 1

[0209] In some embodiments, Formula I and its sub-formula compounds are prepared as shown in Scheme 1. In Scheme 1, the first step is a conventional SN... AR The reaction involves mixing at least stoichiometric amounts of ring A (compound 2A) with compound 1A 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 usually maintained between 25 °C and 100 °C until substantially complete. After routine treatment of the reaction solution, separation / purification processes such as crystallization, chromatography, and high-performance liquid chromatography (HPLC) can be performed to yield compound 3A.

[0210] In the next step, a conventional Suzuki coupling reaction is carried out, in which at least stoichiometric amounts of arylboronic acid (compound 4A) are mixed with compound 3A 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. After conventional treatment of the reaction solution, separation / purification processes such as crystallization, chromatography, high-performance liquid chromatography (HPLC) can be performed to provide compound 5A.

[0211] In the next step, the protecting group, such as tert-butyloxycarbonyl (Boc), is removed under standard conditions, depending on the specific protecting group used. The Boc group is merely illustrative, and other conventional amino protecting groups (such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc.) can be used. After the reaction is complete, the reaction solution can be subjected to separation / purification processes, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., after standard treatment to provide compound 6A.

[0212] In the final step, the amine is coupled with a suitable acylation reagent (compound 7A) (such as an acyl halide (e.g., acryloyl chloride) or a carboxylic acid (e.g., acrylic acid)) in an inert solvent (such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, etc.), typically in the presence of a suitable base (such as diisopropylethylamine, triethylamine, pyridine, etc.). After the reaction is complete, conventional processing can be performed for separation and purification, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., to provide the compound of formula I.

[0213]

[0214] Option 2

[0215] In some embodiments, Formula I and its sub-formulas are prepared as shown in Scheme 2. In Scheme 2, the first step is a conventional Suzuki coupling reaction, in which at least stoichiometric amounts of bis(pinacol)diboron (compound 9A) are mixed with compound 8A in a diluent (such as tetrahydrofuran, dioxane, dimethoxyethane, and / or water, etc.), typically in the presence of a palladium catalyst and a suitable base (such as potassium carbonate, cesium carbonate, etc.). The reaction solution can be subjected to separation / purification processes, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., after conventional treatment of the solution to provide compound 10A.

[0216] Then, as described in Scheme 1 above, compound 10A is deprotected using similar reagents and reaction conditions and coupled with compound 7A to provide compound 11A.

[0217]

[0218] Option 3

[0219] In some embodiments, Formula I and its sub-formulas are prepared as shown in Scheme 3. In Scheme 3, the first step is a conventional Sonogashira coupling reaction, in which at least stoichiometric amounts of a protected aminoalkyne (compound 12A) are mixed with compound 1A under conventional reaction conditions well known in the art, including the use of palladium(II)bis(triphenylphosphine) dichloride and cuprous iodide(I) as catalysts, and typically in the presence of a suitable base (such as diisopropylethylamine, triethylamine, pyridine, cesium carbonate, etc.). The reaction is typically carried out in an inert solvent (such as toluene, N,N-dimethylformamide, etc.). The reaction is typically carried out at about 25°C to about 110°C for a period of time to substantially complete the reaction, as demonstrated by, for example, thin-layer chromatography. After the reaction is complete, the reaction solution can be subjected to separation / purification processes, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., after conventional treatment, to provide compound 13A.

[0220] In the next step, a cyclization reaction is carried out, in which at least a stoichiometric amount of compound 13A is treated with a suitable base (such as potassium tert-butoxide, cesium carbonate, etc.) in an inert diluent (such as tetrahydrofuran, dioxane, toluene, dimethoxyethane, etc.). The reaction is typically maintained at 10 °C to 50 °C until substantially complete. After routine treatment of the reaction solution, separation / purification processes such as crystallization, chromatography, high-performance liquid chromatography (HPLC) can be performed to obtain compound 14A.

[0221] In the next step, the protecting group, such as tert-butyloxycarbonyl (Boc), is removed under standard conditions, depending on the specific protecting group used. The Boc group is merely illustrative, and other conventional amino protecting groups (such as benzyl, 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), p-nitrobenzyloxycarbonyl, etc.) can be used. After the reaction is complete, the reaction solution can be subjected to separation / purification processes, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., after standard treatment to provide compound 15A.

[0222] In the next step, a cyclization reaction is carried out, wherein at least stoichiometric amounts of compound 15A are mixed with an aldehyde in an inert aqueous diluent (such as a tetrahydrofuran:water mixture), typically in the presence of a suitable base (such as potassium hydroxide, sodium hydroxide, etc.). The reaction is usually maintained at 50 °C to 90 °C until substantially complete. After routine treatment of the reaction solution, separation / purification processes such as crystallization, chromatography, high-performance liquid chromatography (HPLC) can be performed to obtain compound 16A.

[0223] In the next step, a conventional Suzuki coupling reaction is carried out, in which at least stoichiometric amounts of arylboronic acid (compound 4A) are mixed with compound 16A in an inert diluent (such as tetrahydrofuran, dioxane, dimethoxyethane, and / or water), typically in the presence of a palladium catalyst and a suitable base (such as potassium carbonate, cesium carbonate, etc.). After conventional treatment of the reaction solution, separation / purification processes such as crystallization, chromatography, and high-performance liquid chromatography (HPLC) can be performed to provide compound 17A.

[0224] Then, as described in Scheme 1 above, compound 17A is coupled to compound 7A using similar reagents and reaction conditions to provide compound 18A.

[0225]

[0226] Option 4

[0227] In some embodiments, Formula I and its sub-formulas are prepared as shown in Scheme 4. In Scheme 4, the first step is a conventional Buchwald-Hartwig reaction, in which at least a stoichiometric amount of a suitable heterocyclic alkyl acid (compound 19A) is mixed with compound 1A under conventional reaction conditions well known in the art, including the use of Pd2(dba)3 as a catalyst, typically in the presence of a suitable base (such as sodium tert-butoxide). The reaction is typically carried out in an inert solvent (such as toluene, N,N-dimethylformamide, etc.). The reaction is typically carried out at about 25 °C to about 110 °C for a period of time to substantially complete the reaction, as demonstrated by, for example, thin-layer chromatography. After the reaction is complete, the reaction solution can be subjected to separation / purification processes, such as crystallization, chromatography, high-performance liquid chromatography (HPLC), etc., after conventional treatment, to provide compound 20A.

[0228] In the next step, a conventional Suzuki coupling reaction is carried out, in which at least stoichiometric amounts of arylboronic acid (compound 4A) are mixed with compound 20A in an inert diluent (such as tetrahydrofuran, dioxane, dimethoxyethane, and / or water), typically in the presence of a palladium catalyst and a suitable base (such as potassium carbonate, cesium carbonate, etc.). After conventional treatment of the reaction solution, separation / purification processes such as crystallization, chromatography, and high-performance liquid chromatography (HPLC) can be performed to provide compound 21A.

[0229] In the next step, at least a stoichiometric amount of compound 21A is treated in an inert diluent (such as THF, MeCN, toluene, etc.) with a suitable reducing agent (such as lithium aluminum hydride, borane, etc.). The reaction is typically maintained between 0 °C and 30 °C until substantially complete. Following routine treatment of the reaction solution, separation and / or purification processes such as crystallization, chromatography, high-performance liquid chromatography (HPLC) can be performed to obtain compound 22A.

[0230] Then, as described in Scheme 1 above, compound 22A is deprotected using similar reagents and reaction conditions and coupled with compound 7A to provide compound 23A.

[0231] Other starting materials used in this paper are well-known in the art, commercially available, or can be prepared by conventional synthetic methods.

[0232] method

[0233] In one embodiment, the compounds and compositions described herein can be used for a method of treating SMARCA2 or SMARCA4-dependent diseases or disorders, or diseases or disorders at least partially mediated by SMARCA2 or SMARCA4. The method comprises administering to a subject suffering from a SMARCA2 or SMARCA4-dependent disease or disorder an effective amount of the compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

[0234] In one embodiment, a compound as described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, is provided for the treatment of SMARCA2 or SMARCA4 dependent diseases or disorders.

[0235] 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 said compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, used in the manufacture of a medicament for reducing the level of a protein expressed by the SMARCA2 or SMARCA4 gene, wherein reducing such protein levels would treat or improve a disease or ailment.

[0236] In one embodiment, the method described herein includes using a prodrug of the compound described herein.

[0237] In one embodiment, the method relates to a compound as described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, or a pharmaceutical composition comprising said compound or a pharmaceutically acceptable salt, solvate, stereoisomer, and / or tautomer thereof, for use as described herein, wherein the degradation rate of the protein expressed by the SMARCA2 or SMARCA4 gene is in the range of about 25% to 99% at a concentration of 1 µM of the compound described herein. The degradation rate of the protein expressed by the SMARCA2 or SMARCA4 gene is measured by the assay described in the biological examples. In some embodiments, the degradation rate of the protein expressed by the SMARCA2 or SMARCA4 gene is about 25% to about 50%, about 45% to about 70%, about 65% to about 90%, or about 75% to about 99%. In some embodiments, the degradation rate of proteins expressed by the SMARCA2 or SMARCA4 genes is about 25% to about 35%, about 35% to about 45%, about 45% to about 55%, about 55% to about 65%, about 65% to about 75%, about 75% to about 85%, or about 85% to about 99%. In some embodiments, the degradation rate of proteins expressed by the SMARCA2 or SMARCA4 genes exceeds 60%. In some embodiments, the degradation rate of proteins expressed by the SMARCA2 or SMARCA4 genes exceeds 70%. In some embodiments, the degradation rate of proteins expressed by the SMARCA2 or SMARCA4 genes exceeds 80%. In some embodiments, the degradation rate of proteins expressed by the SMARCA2 or SMARCA4 genes exceeds 90%.

[0238] The compounds and compositions described herein may be used to treat SMARCA2 or SMARCA4 dependent diseases or disorders, such as liposarcoma, glioblastoma, bladder cancer, adrenocortical carcinoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, human papillomavirus-associated cervical cancer, oropharyngeal cancer, penile cancer, anal cancer, thyroid cancer, or vaginal cancer, or Epstein-Barr virus-associated nasopharyngeal cancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin's lymphoma, or diffuse large B-cell lymphoma. Cancers may also be selected from prostate cancer, breast cancer, lymphoma, leukemia, myeloma, bladder cancer, colon cancer, melanoma of the skin, hepatocellular carcinoma, endometrial cancer, ovarian cancer, cervical cancer, lung cancer, kidney cancer, glioblastoma multiforme, glioma, thyroid cancer, parathyroid tumor, nasopharyngeal carcinoma, tongue cancer, pancreatic cancer, esophageal cancer, bile duct cancer, gastric cancer, soft tissue sarcoma, rhabdomyosarcoma (RMS), synovial sarcoma, osteosarcoma, rhabdomyosarcoma, immunodeficient cancers, immunogenic cancers, and Ewing's sarcoma. In one embodiment, SMARCA2 or SMARCA4 dependent diseases or disorders are selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid tumors, and gastrointestinal stromal tumors (GIST). In another embodiment, the cancer is selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, carcinoid, acute myeloid leukemia, and gastrointestinal stromal tumor (GIST). In another embodiment, SMARCA2 or SMARCA4 dependent diseases or disorders are selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), and microsatellite stable colorectal cancer (mssCRC).

[0239] The compounds disclosed herein can be administered in amounts that are effective in treating or preventing a subject’s disease and / or preventing its development.

[0240] Generally, methods of using the compounds disclosed herein include administering a therapeutically effective amount of the compounds as described herein to a subject in need.

[0241] In some embodiments, the compounds described herein can be used to treat proliferative disorders (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In some embodiments, the treatment methods according to this disclosure modulate the level of target cellular proteins (e.g., pathogenic and oncogenic proteins) or inhibit their growth or degrade the proteins by contacting the cells with compounds or compositions described herein. In other embodiments, the compounds can be used to treat cancer.

[0242] Therefore, in another aspect of this disclosure, a method for treating cancer is provided, comprising administering a therapeutically effective amount of a compound or composition as described herein to a subject in need. In some embodiments, a method for treating cancer is provided, comprising administering a therapeutically effective amount of a compound or a pharmaceutical composition comprising a compound described herein to a subject in need, the amount and timing of which are intended to achieve the desired outcome. In some embodiments, the compounds of this disclosure are administered orally or intravenously. In some embodiments of this disclosure, a “therapeutically effective amount” of a compound or pharmaceutical composition refers to an amount that effectively kills or inhibits the growth of tumor cells. According to the method of this disclosure, the compound and composition can be administered using any dose and any route of administration that effectively kills or inhibits the growth of tumor cells. Therefore, as used herein, expressing an “amount that effectively kills or inhibits the growth of tumor cells” means a sufficient dose of medicine for killing or inhibiting the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the subject’s species, age and general condition, severity of disease, specific anticancer agent, mode of administration, etc. In some embodiments of this disclosure, a “therapeuticly effective amount” of a compound or pharmaceutical composition described herein refers to an amount that effectively reduces the level of a target protein. In some embodiments of this disclosure, a “therapeuticly effective amount” of a compound or pharmaceutical composition refers to an amount that effectively kills or inhibits the growth of skin cells.

[0243] In some 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 person or other mammal in need of such treatment). In some embodiments, the compounds or compositions described herein may be used to treat cancers (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colorectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer).

[0244] In some embodiments, the compounds or compositions described herein may 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 some embodiments, the compounds or compositions described herein are active against solid tumors.

[0245] Another aspect of this disclosure relates to a method for treating a patient with a disease or condition associated with a proliferative disorder or for reducing its severity, the method comprising the step of administering a compound of formula I or a composition comprising the compound to the patient.

[0246] It should be understood that compounds and compositions according to the methods of this disclosure can be administered in any amount and via any route of administration that are effective in treating cancer and / or diseases associated with excessive cell proliferation. For example, when using a compound to treat cancer, as used herein, the term "effective amount" means a sufficient dose of the drug to inhibit proliferation or a sufficient amount to reduce the effects of cancer. The exact amount required will vary from subject to subject, depending on the subject's species, age and general condition, severity of disease, specific anticancer agent, mode of administration, etc.

[0247] This disclosure provides a method for treating a proliferative disorder in a subject in need of treatment by administering a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof to the subject in need of such treatment. The proliferative disorder may be cancer or a precancerous condition. This disclosure further provides the use of the disclosed compound or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, or tautomer thereof in the preparation of a medicament for treating a proliferative disorder.

[0248] This disclosure also provides a method for protecting subjects in need from proliferative disorders by administering a therapeutically effective amount of the disclosed compound 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 precancerous conditions. This disclosure also provides the use of the disclosed compound or a pharmaceutically acceptable salt, salt, solvate, stereoisomer, or tautomer thereof in the preparation of a medicament for preventing proliferative disorders.

[0249] As used herein, the term "proliferative disorder" refers to a condition in which cell growth is disordered or abnormal, or both, and may lead to the development of an undesirable condition or disease (which may or may not be cancerous). Exemplary proliferative disorders of this disclosure cover a variety of conditions in which cell division is disordered. Exemplary proliferative disorders include, but are not limited to, tumors, benign tumors, malignant tumors, precancerous conditions, tumors in situ, cystic tumors, metastatic tumors, fluid-filled tumors, solid tumors, immunotumors, hematologic malignancies, cancer, carcinoma, leukemia, lymphoma, sarcoma, and rapidly dividing cells. As used herein, the term "rapidly dividing cell" is defined as any cell whose division rate exceeds or is higher than the rate expected or observed in adjacent or side-by-side cells within the same tissue. Proliferative disorders include early-stage cancer or precancerous conditions. Proliferative disorders include cancer. The methods provided herein are for treating or alleviating cancer symptoms. The term "cancer" includes solid tumors as well as hematologic malignancies and / or malignant tumors. "Early-stage cancer cells" or "precancerous cells" are cells exhibiting a proliferative disorder (i.e., early-stage cancer or precancerous conditions). "Cancer cells" or "cancerous cells" are cells that exhibit a proliferative disorder (i.e., cancer). Any reproducible measurement method can be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of tissue samples (e.g., biopsy samples). Cancer cells or precancerous cells can be identified by using appropriate molecular markers.

[0250] In some embodiments, this document provides methods for treating non-cancerous conditions or disorders, including administering a therapeutically effective amount of a compound or composition as described herein. Exemplary non-cancerous conditions or disorders treatable by the compounds described herein include, but are not limited to: rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative disorders; acromegaly; rheumatoid spondylitis; osteoarthritis; gout and other arthritis; sepsis; septic shock; endotoxin shock; Gram-negative bacterial 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; nerve trauma. Injuries; 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; Wright 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 disease; multiple sclerosis; lupus; fibromyalgia; HIV and other viral diseases such as herpes zoster, herpes simplex type I or II, influenza virus and cytomegalovirus; and diabetes.

[0251] In some embodiments, this document provides methods of treating cancer, including administering a therapeutically effective amount of the compounds or compositions described herein. Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancer, anorectal cancer, anal canal cancer, appendiceal cancer, pediatric cerebellar astrocytoma, pediatric astrocytic carcinoma, basal cell carcinoma, skin cancer (non-melanoma), bile cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urocystic bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumors, brainstem glioma, cerebellar astrocytoma, astrocytic tumor / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor. Tumors, visual pathway and hypothalamic gliomas, breast cancer, bronchial adenoma / carcinoid, carcinoid tumors, gastrointestinal cancers, nervous system cancers, nervous system lymphomas, central nervous system cancers, central nervous system lymphomas, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphomas, mycosis fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumors, gonadal extragerminal tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, retinal cell carcinoma Gastrointestinal tumors, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, ovarian germ cell tumors, gestational trophoblastomas, gliomas, head and neck cancers, hepatocellular carcinoma, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi's sarcoma, kidney cancer, renal cell carcinoma, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and mouth cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer AIDS-related lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, Waldenstrom's macroglobulinemia, medulloblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, mesothelioma, metastatic squamous neck cancer, oral cancer, tongue cancer, multiple endocrine tumor syndrome, fungal infections, myelodysplastic syndrome, myelodysplastic / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oral cavity cancerCancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, low-potency ovarian tumors, pancreatic cancer, islet cell pancreatic cancer, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma and supratentorial primitive neuroectodermal tumors, pituitary adenoma, plasmacytoma / multiple myeloma, pleural pulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing sarcoma family 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 tumor, squamous cell carcinoma, gastric cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma, thymoma and thymoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and bladder and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer and Wilms' tumor.

[0252] "Hematologic proliferative disorders" refer to proliferative disorders involving cells of the blood system. Hematologic proliferative disorders can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplastic syndromes, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera, chronic myeloid leukemia, myeloid metaplasia of unknown cause, and essential thrombocythemia. Hematologic proliferative disorders can include proliferation, dysplasia, and metaplasia of cells of the blood system. The compositions of this disclosure can be used to treat cancers selected from the group consisting of hematologic cancers or hematologic proliferative disorders of this disclosure. The hematologic malignancies disclosed herein may include multiple myeloma, lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphoma, and lymphomas of lymphocyte and skin origin), leukemias (including childhood leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, and mast cell leukemia), myeloid tumors, and mast cell tumors.

[0253] "Pulmonary proliferative disorders" are proliferative disorders involving lung cells. Pulmonary proliferative disorders can include all forms of proliferative disorders affecting lung cells. Pulmonary proliferative disorders can include lung cancer, primary or precancerous conditions of the lung, benign growths or lesions of the lung, malignant growths or lesions of the lung, and metastatic lesions of body tissues and organs outside the lung. The compositions disclosed herein can be used to treat lung cancer or pulmonary proliferative disorders. Lung cancer can include all forms of lung cancer. Lung cancer can include malignant lung tumors, carcinoma in situ, typical carcinoid, and atypical carcinoid. Lung cancer can include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lung cancer can include "scar carcinoma," bronchoalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can include lung tumors with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0254] Pulmonary proliferative disorders can include all forms of proliferative disorders affecting lung cells. Pulmonary proliferative disorders can include lung cancer and precancerous lesions. Pulmonary proliferative disorders include lung hyperplasia, metaplasia, and dysplasia. Pulmonary proliferative disorders include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia. Pulmonary proliferative disorders can include replacement of columnar epithelium with stratified squamous epithelium and mucosal dysplasia. Individuals exposed to inhaled harmful environmental factors such as cigarette smoke and asbestos may have an increased risk of developing pulmonary proliferative disorders. Predisposing lung diseases that may predispose an individual to develop pulmonary proliferative disorders can include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatoid arthritis, sarcoidosis, interstitial pneumonia, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granulomatous disease, asbestosis, fibrotic alveolitis, and Hodgkin's disease.

[0255] "Proliferative colorectal disease" refers to a proliferative disorder involving colon cells. In one embodiment, proliferative colorectal disease is colon cancer. In one embodiment, the compositions of this disclosure can be used to treat colon cancer or proliferative colorectal disease. Colon cancer can include all forms of colon cancer. Colon cancer can include sporadic and hereditary colon cancer. Colon cancer can include malignant colon tumors, carcinoma in situ, typical carcinoid, and atypical carcinoid. Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma. Colon cancer may be associated with hereditary syndromes selected from the group consisting of: hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis. Colorectal cancer can be caused by hereditary syndromes selected from the following groups: hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis.

[0256] Proliferative colorectal disorders (PDDs) can include all forms of proliferative disorders affecting colon cells. PDDs can include colon cancer, precancerous colonic diseases, colonic adenomatous polyps, and metachronic colonic diseases. PDDs can include adenomas. PDDs can be characterized by colonic hyperplasia, metaplasia, and dysplasia. Predisposing colonic diseases that may predispose an individual to PDDs can include a history of colon cancer. Current diseases that may predispose an individual to PDDs include Crohn's disease and ulcerative colitis. PDDs may be associated with mutations in genes selected from the p53, ras, FAP, and DCC groups. The presence of mutations in genes selected from the p53, ras, FAP, and DCC groups may increase an individual's risk of developing PDDs.

[0257] "Pancreatic proliferative disorders" are proliferative disorders involving pancreatic cells. Pancreatic proliferative disorders can include all forms of proliferative disorders affecting pancreatic cells. These include pancreatic cancer, primary or precancerous conditions of the pancreas, pancreatic hyperplasia, pancreatic dysplasia, benign growths or lesions of the pancreas, malignant growths or lesions of the pancreas, and metastatic lesions in tissues and organs outside the pancreas. Pancreatic cancer includes all forms of pancreatic cancer. These include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary tumor, mucinous cystadenoma, papillary cystic tumor, and serous cystadenoma. Pancreatic cancer can also include pancreatic tumors with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0258] "Benign prostatic hyperplasia" (BPH) refers to proliferative disorders involving prostate cells. BPH can include all forms of proliferative disorders affecting prostate cells. BPH can include prostate cancer, primary or precancerous prostate conditions, benign growths or lesions of the prostate, malignant growths or lesions of the prostate, and metastatic lesions in tissues and organs outside the prostate. BPH can also include prostate hyperplasia, metaplasia, and dysplasia.

[0259] "Dermatoproliferative disorders" are proliferative disorders involving skin cells. Dermatoproliferative disorders can include all forms of proliferative disorders affecting skin cells. These include primary or precancerous skin conditions, benign growths or lesions of the skin, melanoma, malignant melanoma, and other malignant growths or lesions of the skin, as well as metastatic lesions in tissues and organs outside the skin. Dermatoproliferative disorders include skin hyperplasia, metaplasia, and dysplasia.

[0260] "Ovarian proliferative disorders" refer to proliferative disorders involving ovarian cells. Ovarian proliferative disorders can include all forms of proliferative disorders affecting ovarian cells. These can include primary or precancerous ovarian conditions, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in other tissues and organs of the body outside the ovary. Cutaneous proliferative disorders include hyperplasia, metaplasia, and dysplasia of ovarian cells.

[0261] "Breast proliferative disorders" are proliferative disorders involving breast cells. Breast proliferative disorders include all forms of proliferative disorders affecting breast cells. These include breast cancer, primary or precancerous conditions of the breast, benign growths or lesions of the breast, malignant growths or lesions of the breast, and metastatic lesions in tissues and organs outside the breast. Breast proliferative disorders include hyperplasia, metaplasia, and dysplasia of the breast.

[0262] According to the American Joint Committee on Cancer (AJCC) TNM staging system, cancers to be treated can be staged, with tumors (T) assigned to TX, T1, T1mic, T1a, T1b, T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; regional lymph nodes (N) assigned to NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and distant metastases (M) assigned to MX, M0, or M1. Cancers to be treated can be staged according to the AJCC grading system as Stage I, IIA, IIB, IIIA, IIIB, IIIC, or IV. Cancers to be treated can also be assigned to grades GX (e.g., grade not assessable), 1, 2, 3, or 4 according to the AJCC grading system. Cancers that can be treated can be staged according to the AJCC pathological classification (pN), namely pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1 (mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0263] Cancers to be treated can include tumors that have been identified as having a diameter of about 2 cm or less. Cancers to be treated can include tumors that have been identified as having a diameter of about 2 cm to about 5 cm. Cancers to be treated can include tumors that have been identified as having a diameter of about 3 cm or more. Cancers to be treated can include tumors that have been identified as having a diameter of more than 5 cm. Cancers to be treated can be classified by their microscopic appearance as well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated. Cancers to be treated can be classified by their microscopic appearance regarding mitotic counts (e.g., cell division rate) or nuclear pleomorphism (e.g., changes in cells). Cancers to be treated can be classified by their microscopic appearance as cancers associated with necrotic areas (e.g., areas of dead or degenerated cells). Cancers to be treated can be classified as having an abnormal karyotype, an abnormal number of chromosomes, or one or more chromosomes with abnormal appearance. Cancers to be treated can be classified as aneuploid, triploid, tetraploid, or having altered ploidy. Cancers to be treated can be classified as having chromosomal translocations, or deletions or duplications of entire chromosomes, or deletions, duplications, or amplifications of a portion of a chromosome.

[0264] Cancers awaiting treatment can be assessed using DNA cell counting, flow cytometry, or imaging cell counting. Cancers awaiting treatment can be classified as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the anabolic phase of cell division (e.g., in the S phase). Cancers awaiting treatment can also be classified as having a low or high S phase fraction.

[0265] As used herein, "normal cell" refers to a cell that does not fall under the category of "proliferative disorders." A lack of normal cells can lead to the development of undesirable symptoms or diseases, dysregulation, or abnormal growth, or both. In one embodiment, normal cells possess normally functioning cell cycle checkpoint control mechanisms.

[0266] Those skilled in the art can refer to general reference texts to understand the detailed description of the known or equivalent techniques discussed herein. These references include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd Edition), Cold Spring Harbor Press, Cold Spring Harbor, NY (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Erma et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingle et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18th Edition (1990). Of course, these texts may also be referenced in the formation or use of aspects of this disclosure.

[0267] In some embodiments, the compounds of this disclosure can be used to treat proliferative disorders (e.g., cancer, benign tumors, inflammatory diseases, and autoimmune diseases). In some embodiments, the treatment methods according to this disclosure modulate the levels of target cellular proteins (e.g., pathogenic and oncogenic proteins) or inhibit their growth by contacting the cells with the compounds or compositions described herein. In other embodiments, the compounds can be used to treat cancer.

[0268] In some 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. In some embodiments, the compound may be used to treat cancers (including, but not limited to, glioblastoma, retinoblastoma, breast cancer, cervical cancer, colorectal cancer, leukemia, lymphoma, lung cancer (including, but not limited to, small cell lung cancer), melanoma and / or skin cancer, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer and gastric cancer, bladder cancer, uterine cancer, kidney cancer, testicular cancer, stomach cancer, brain cancer, liver cancer, or esophageal cancer).

[0269] In some embodiments, the methods provided herein further include administering an anticancer agent. In some 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 some embodiments, the anticancer agent is active against solid tumors.

[0270] In addition, this disclosure provides pharmaceutically acceptable derivatives of the compounds and methods for treating subjects using these compounds, pharmaceutical compositions thereof, or any of them in combination with one or more additional therapeutic agents.

[0271] In some embodiments, the additional therapeutic agent is another therapy or anticancer agent. Other therapies or anticancer agents that can be used in combination with the compounds disclosed herein include surgery, radiation therapy, endocrine therapy, biological response modulators (interferon, interleukin, and tumor necrosis factor (TNF), to name just a few), hyperthermia and cryotherapy, agents to reduce any side effects (e.g., antiemetics), and other approved chemotherapeutic agents, including but not limited to alkylating agents (nitrogen mustard, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists, etc. Antidotes and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine), spindle toxins (vincrine, 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 medroxyprogesterone acetate), to name just a few. For a more comprehensive discussion of the overview of cancer treatment, please see The Merck Manual, 20th edition, 2020, which are hereby incorporated in their entirety by reference. Please also see 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).

[0272] In some embodiments, pharmaceutical compositions comprising the compounds disclosed herein further comprise one or more additional therapeutically active ingredients (e.g., chemotherapy and / or palliative care). For the purposes of this disclosure, the term "palliative care" refers to treatment focused on alleviating disease symptoms and / or the side effects of a treatment regimen rather than providing a cure. For example, palliative care encompasses analgesics, antiemetics, and antinausea medications. Furthermore, chemotherapy, radiation therapy, and surgery can all be used for palliative care (i.e., symptom relief without a cure; for example, shrinking tumors and reducing stress, bleeding, pain, and other cancer symptoms).

[0273] Application, pharmaceutical composition

[0274] The disclosed compounds and pharmaceutical compositions can be administered via any mode of therapeutic application. These modes include systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, oral, rectal, or topical administration.

[0275] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, sustained-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit dose form, and consistent with conventional pharmaceutical practice. Similarly, they may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, all in forms familiar to those skilled in the art of pharmaceutical work.

[0276] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising the compounds of this disclosure and pharmaceutically acceptable carriers such as: a) diluents, such as purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils) or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA) or esters or triglycerides or mixtures thereof, ω-3 fatty acids or derivatives thereof, lactose, glucose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, such as silica, talc, stearic acid and its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, etc. Sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; also suitable for tablets; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, 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 polyvinylpyrrolidone (if desired); d) disintegrants, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginate, or their sodium salts or effervescent mixtures; e) absorbents, colorants, flavoring agents, and sweeteners; f) emulsifiers or dispersants, such as Tween 80. Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifiers; and / or g) agents that enhance the absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0277] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolution, dispersion, etc. For instance, the disclosed compound can be dissolved in or mixed with a pharmaceutically acceptable solvent (such as, for example, water, saline, dextran aqueous solution, glycerol, ethanol, etc.) to form an injectable isotonic solution or suspension. Proteins (such as albumin, frozen microparticles, or serum proteins) can be used to dissolve the disclosed compound.

[0278] The disclosed compounds can also be formulated into suppositories, which can be prepared from fat emulsions or suspensions; using polyalkylene glycols such as propylene glycol as carriers.

[0279] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids containing cholesterol, stearamine, or phosphatidylcholine.

[0280] In some embodiments, the lipid component membrane is hydrated with an aqueous solution of the drug to form a lipid layer encapsulating the drug, as described in U.S. Patent No. 5,262,564, which is hereby incorporated by reference in its entirety.

[0281] The disclosed compounds can also be delivered using a monoclonal antibody as a separate carrier conjugated to the disclosed compounds. The disclosed compounds can also be conjugated to a soluble polymer as a targeted drug carrier. Such polymers may comprise polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol, or polyoxyethylene polylysine substituted with palmitoyl residues. Furthermore, the disclosed compounds can be conjugated to a class of biodegradable polymers used to achieve controlled drug release, such as polylactic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. In one embodiment, the disclosed compounds are not covalently bound to a polymer, such as a polycarboxylic acid polymer or a polyacrylate.

[0282] Parenteral injectable preparations are typically used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable preparations can be prepared in conventional forms as liquid solutions or suspensions, or in solid forms suitable for dissolving in a liquid prior to injection.

[0283] Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise excipients, diluents, or surfactants.

[0284] The compositions can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical compositions of the present invention may contain about 0.1% to about 99%, about 5% to about 90% or about 1% to about 20% of the disclosed compounds by weight or volume.

[0285] In one embodiment, this disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of this disclosure. In one embodiment, the kit includes means for individually storing the compositions, such as a container, a separator bottle, or a separator foil package. Examples of such kits are blister packs, as commonly used for packaging tablets, capsules, etc.

[0286] The kits disclosed herein can be used to administer different dosage forms, such as oral and parenteral, to administer individual compositions at different dosing intervals, or to titrate individual compositions against each other. To aid compliance, the kits disclosed herein typically include instructions for use.

[0287] The pharmaceutical dosage forms of the compounds disclosed herein can be manufactured by any method well known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulation, sugar-coated pelleting, tableting, suspension, extrusion, spray drying, grinding, emulsification, (nano / micro) encapsulation, embedding, or lyophilization processes. As described above, the compositions of this disclosure may include one or more physiologically acceptable inactive ingredients that facilitate the processing of active molecules into articles for pharmaceutical use.

[0288] As described above, the composition typically consists of a compound of this disclosure combined with at least one pharmaceutically acceptable excipient. An acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic effect of the claimed compound. Such excipients can be gaseous excipients in the case of any solid, liquid, semi-solid, or aerosol composition commonly available to those skilled in the art.

[0289] 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, skim milk powder, etc. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal oils, vegetable oils, or synthetic oils, 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, glucose aqueous solutions, and ethylene glycol.

[0290] The compounds of this disclosure can be dispersed in aerosol form using compressed gas. Inert gases suitable for this purpose include nitrogen and carbon dioxide. Other suitable pharmaceutical excipients and formulations thereof are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 18th edition, 1990).

[0291] If desired, the compositions of this disclosure may be contained in a packaging or dispensing device comprising one or more unit dosage forms containing the active ingredient. Such packaging or devices may, for example, comprise metal or plastic foil, such as blister packs or glass, and rubber stoppers, such as vials. The packaging or dispensing device may be accompanied by instructions for use. Compositions comprising the compounds of this disclosure formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0292] The content of compounds in a formulation can vary within a range suitable for those skilled in the art. Typically, based on the total formulation, the formulation will contain about 0.01 wt% to 99.99 wt% of the compounds disclosed herein (by weight percentage (wt%)), with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compounds are present at a level of about 1 wt% to 80 wt%. Representative pharmaceutical formulations are described below.

[0293] Examples of formulations

[0294] The following are representative pharmaceutical formulations containing compounds disclosed herein.

[0295] Example of a formulation 1 - Tablet formulation

[0296] Mix the following ingredients thoroughly and compress them into single-score tablets.

[0297]

[0298] Example of formulation 2 - Capsule formulation

[0299] Mix the following ingredients thoroughly and fill them into hard-shell gelatin capsules.

[0300]

[0301] Example of formulation 3 - Suspension formulation

[0302] Mix the following ingredients to form a suspension for oral administration.

[0303]

[0304] Example of a compound - Injectable compound

[0305] Mix the following ingredients to form an injectable formulation.

[0306]

[0307] Example of formulation 5 - Suppository formulation

[0308] The suppository, with a total weight of 2.5 g, was prepared by mixing the disclosed compound with Wiptsol® H-15 (saturated vegetable fatty acid triglyceride; Riches-Nelson, Inc., New York) and has the following composition:

[0309]

[0310] Dosage

[0311] The dosage regimen using the disclosed compounds is selected based on a variety of factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed compound used. A physician or veterinarian with ordinary skill in the art can readily determine and prescribe an effective amount of the drug needed to prevent, counteract, or halt the progression of the condition.

[0312] When used for the indicated effect, the effective dose of the compound ranges from about 0.5 mg to about 5000 mg of the disclosed compound required to treat the symptoms. 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 compound, or within a range of amounts from one to another in the dosage list. In one embodiment, the composition is in the form of a scoreable tablet.

[0313] Example

[0314] This disclosure can be further understood by referring to the following examples, which are intended to be purely illustrative of this disclosure. The scope of this disclosure is not limited to the exemplary embodiments, which are intended only to illustrate a single aspect of this disclosure. Any functionally equivalent methods are within the scope of this disclosure. Various modifications to this disclosure, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and drawings. Such modifications fall within the scope of the appended claims.

[0315] In this specification and the examples below, all temperatures are in degrees Celsius. Furthermore, the following abbreviations have the following meanings. Unless otherwise defined, these abbreviations have their commonly accepted meanings in the art.

[0316]

[0317] Example 1

[0318] Preparation of 1-{8-[3-amino-6-(o-hydroxyphenyl)-4-pyridazinoxy]-3-azabicyclo[3.2.1]oct-3-yl}-2-propen-1-one (compound 5):

[0319]

[0320] Step 1:

[0321]

[0322] NaH (1.16 g, 28.78 mmol, 60%, 3 equivalents) was added dropwise to a solution of tert-butyl-8-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (2.18 g, 9.60 mmol, 1 equivalent) in THF (60 mL) at N2 and 0 °C. After the addition, the mixture was stirred at this temperature for 30 min, and 4-bromo-6-chloropyridazine-3-amine (2 g, 9.60 mmol, 1 equivalent) was added dropwise to a solution of THF (10 mL) at 0 °C. The resulting mixture was stirred at 70 °C for 12 h. The reaction was quenched at 0 °C by adding saturated aqueous NH4Cl solution (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give the residue. The residue was purified by column chromatography (SiO2, 20% to 50% ethyl acetate in petroleum ether) to give tert-butyl 8-((3-amino-6-chloropyridazine-4-yl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylic acid ester. 1 H NMR (400 MHz, CDCl3) δ 6.70 - 6.61 (m, 1H),5.14 (s, 2H), 4.57 - 4.43 (m, 1H), 4.00 - 3.61 (m, 2H), 3.26 - 2.85 (m, 2H),2.44 (m, 2H), 1.94 - 1.61 (m, 4H), 1.56 - 1.45 (m, 9H).

[0323] Step 2:

[0324]

[0325] A mixture of (2-hydroxyphenyl)boronic acid (699.69 mg, 5.07 mmol, 3 equivalents), tert-butyl-8-((3-amino-6-chloropyridazin-4-yl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylic acid ester (600 mg, 1.69 mmol, 1 equivalent), Pd(dppf)Cl2 (123.73 mg, 169.09 μmol, 0.1 equivalent), and Cs2CO3 (3.31 g, 10.15 mmol, 6 equivalents) was degassed in a solution of dioxane (20 mL) and H2O (10 mL) and purged three times with N2. The mixture was stirred at 80 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 20% to 50% ethyl acetate in petroleum ether) to give tert-butyl 8-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylic acid ester. 1 H NMR (400MHz, d6-DMSO) δ 14.33 (s, 1H), 8.02 - 7.93 (m, 1H), 7.71 - 7.60 (m, 1H), 7.29- 7.22 (m, 1H), 6.94 - 6.84 (m, 2H), 6.66 - 6.46 (m, 2H), 5.12 - 4.95 (m,1H), 3.93 - 3.46 (m, 2H), 3.44 - 3.35 (m, 1H), 3.28 - 3.03 (m, 1H), 2.46 -2.31 (m, 2H), 1.98 - 1.78 (m, 2H), 1.59 - 1.48 (m, 1H), 1.45 - 1.38 (m, 9H).

[0326] Step 3:

[0327]

[0328] Tert-butyl 8-((3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylic acid ester (500 mg, 1.21 mmol, 1 equivalent) was stirred for 1 h in a solution of DCM (5 mL) and TFA (7.68 g, 67.31 mmol, 5.00 mL, 55.53 equivalent) at 25 °C. The reaction mixture was concentrated to give a residue. The residue was milled with MTBE (20 mL) for 1 h at 25 °C to give the TFA salt of 2-(5-((3-azabicyclo[3.2.1]oct-8-yl)oxy)-6-aminopyridazin-3-yl)phenol. 1 H NMR (400 MHz, CDCl3) δ 9.23 - 8.81 (m, 1H), 9.33 - 8.75 (m, 1H), 8.55 - 8.18 (m, 1H), 7.50 - 7.29 (m, 2H), 7.09 - 6.92(m, 2H), 5.31 - 4.85 (m, 1H), 3.50 (t, J = 10.0 Hz, 2H), 3.37 - 3.17 (m, 2H), 2.98 (m, 1H), 2.65 - 2.53 (m, 2H), 2.18 - 1.74 (m, 4H).

[0329] Step 4:

[0330]

[0331] At 0 °C, a solution of 2-(5-((3-azabicyclo[3.2.1]oct-8-yl)oxy)-6-aminopyridazin-3-yl)phenol (20 mg, 64.03 μmol, 1 equivalent) and DIEA (8.28 mg, 64.03 μmol, 11.15 μL, 1 equivalent) in DCM (0.5 mL) was added with acrylonitrile chloride (2.90 mg, 32.01 μmol, 2.60 μL, 0.5 equivalent). The mixture was stirred at 0 °C for 30 min. The reaction mixture was concentrated to give the residue. The residue was analyzed by preparative HPLC (column: Phenomenex luna C). 18 Purification was performed using a 100 mm × 40 mm × 3 µm filter; mobile phase: [H2O (+0.04% HCl)-ACN]; gradient: 10% to 40% B, 8.0 min, to obtain 2-(5-((3-azabicyclo[3.2.1]oct-8-yl)oxy)-6-aminopyridazine-3-yl)phenol. 1H NMR (400 MHz, d6-DMSO) δ 14.33 (s, 1H), 8.00 (d, J = 8.0 Hz,1H), 7.70 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 6.95 - 6.86 (m, 2H), 6.81 (dd, J= 10.4, 16.8 Hz, 1H), 6.65 (s, 2H), 6.10 (dd, J = 2.4, 16.8 Hz, 1H), 5.67(dd, J = 2.4, 10.4 Hz, 1H), 5.03 (t, J = 4.8 Hz, 1H), 4.14 - 4.00 (m, 1H),3.66 (s, 2H), 3.19 (d, J = 13.2 Hz, 1H), 2.45 - 2.40 (m, 2H), 1.86 (s, 2H), 1.58 - 1.38 (m, 2H). m / z (ESI + ): 367.1 (M+H) + .

[0332] Example 2

[0333] Preparation of (E)-1-[(4bS,8aS)-3-(o-hydroxyphenyl)-6,7,8,8a,9,10-hexahydro-5H-1,2,4b,7,10-pentazophran-7-yl]-4-(dimethylamino)-2-buten-1-one (compound 7)

[0334]

[0335] Step 1:

[0336]

[0337] Pd₂(dba)₃ (3.3 g, 3.6 mmol, 1.0 equivalent) of 4-bromo-6-chloropyridazine-3-amine (7.5 g, 36.1 mmol, 1.0 equivalent) and 1-(tert-butyl)-3-methylpiperazine-1,3-dicarboxylic acid ester (11.5 g, 47.0 mmol, 1.3 equivalent) of 1-(tert-butyl)-3-methylpiperazine-1,3-dicarboxylic acid ester (11.5 g, 47.0 mmol, 1.3 equivalent) of 1-dioxane (150 mL), t-BuONa (6.9 g, 72.3 mmol, 2.0 equivalent), and BINAP (1.3 g, 2.1 mmol, 0.06 equivalent) of 1-dioxane were added to a solution of 4-bromo-6-chloropyridazine-3-amine (7.5 g, 36.1 mmol, 1.0 equivalent) at 25 °C, and the mixture was stirred at 100 °C for 12 hr. The reaction mixture was separated between EtOAc (30 mL) and H₂O (30 mL). The organic phase was separated, washed with 30 mL (3 × 10 mL) of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, 0% to 60% petroleum ether in ethyl acetate) to give tert-butyl 2-chloro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid ester. 1 H NMR (400 MHz, d6-DMSO) δ 11.75 (s, 1H), 7.04 (s, 1H), 4.38 - 4.24 (m, 1H), 4.10 - 4.01 (m, 1H), 3.99 - 3.84 (m, 2H), 3.08- 2.74 (m, 3H), 1.43 (s, 9H).

[0338] Step 2:

[0339]

[0340] Brettphos-Pd-G3 (480.3 mg, 529.9 µmol, 0.1 equivalent) and K2CO3 (2.2 g, 15.9 mmol, 3.0 equivalent) were added to a solution of tert-butyl-2-chloro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid ester (1.8 g, 5.3 mmol, 1.0 equivalent) and (2-hydroxyphenyl)boronic acid (1.5 g, 10.6 mmol, 2.0 equivalent) in H2O (10 mL) and dioxane (40 mL) at 25 °C, and the mixture was stirred at 80 °C for 12 hr. The reaction mixture was separated between EtOAc (20 mL) and H2O (20 mL). The organic phase was separated, washed with brine (3 × 4 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 0% to 25% petroleum ether in ethyl acetate) to give tert-butyl 2-(2-hydroxyphenyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid ester. 1 H NMR(400 MHz, d6-DMSO) δ 11.93 (s, 1H), 10.57 - 10.24 (m, 1H), 7.77 - 7.73 (m,1H), 7.53 - 7.48 (m, 1H), 7.02 (d, J = 3.8 Hz, 1H), 6.91 - 6.85 (m, 2H), 4.54 - 4.44 (m, 1H), 4.34 - 4.14 (m, 2H), 3.98 (s, 1H), 3.27 - 2.92 (m, 3H), 1.43 (s, 9H).

[0341] Step 3:

[0342]

[0343] BH3·THF (1.0 M, 6.3 mL, 5.0 equivalent) was added to a solution of tert-butyl 2-(2-hydroxyphenyl)-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid ester (500.0 mg, 1.3 mmol, 1.0 equivalent) in THF (2 mL) at 0 °C. The mixture was stirred at 50 °C for 2 hr. The reaction mixture was quenched with MeOH (4 mL) and concentrated under vacuum to give tert-butyl 2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carboxylic acid ester, which was ready for use in the next step without further purification. m / z (ESI) + 384.2 (M+H) + .

[0344] Step 4:

[0345]

[0346] TFA (0.3 mL) was added to a solution of tert-butyl-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-carboxylic acid ester (300.0 mg, 782.4 µmol, 1 equivalent) in DCM (1.0 mL). The solution was stirred at 20 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Method A) to give 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol. 1 H NMR (400 MHz, d4-MeOD) δ 7.57 - 7.53 (m,1H), 7.47 - 7.41 (m, 1H), 7.33 (s, 1H), 7.08 - 7.01 (m, 2H), 4.45 (d, J =12.4 Hz, 1H), 3.92 (dt, J = 3.6, 7.8 Hz, 1H), 3.76 (dd, J = 4.2, 12.4 Hz,1H), 3.61 (d, J = 13.0 Hz, 2H), 3.55 - 3.39 (m, 3H), 3.14 (t, J = 12.4 Hz,1H).

[0347] Step 5:

[0348]

[0349] HATU (290.47 mg, 763.92 μmol, 1.5 equivalent) was added to a solution of 2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (200 mg, 509.28 μmol, 1 equivalent, 3.TFA), (E)-4-(dimethylamino)but-2-enoic acid, hydrochloride (84.35 mg, 509.28 μmol, 1 equivalent), and DIEA (658.21 mg, 5.09 mmol, 887.08 μL, 10 equivalent) in DMF (2 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex luna C). 18 100 mm × 40 mm × 3 µm; mobile phase: [H2O (+0.04% HCl)-ACN]; gradient: 10% to 40% B, 8.0 min) purification to give (E)-1-[(4bS,8aS)-3-(o-hydroxyphenyl)-6,7,8,8a,9,10-hexahydro-5H-1,2,4b,7,10-pentazophran-7-yl]-4-(dimethylamino)-2-buten-1-one. m / z (ESI) + ):395.1 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.56 - 7.52 (m, 1H), 7.46 - 7.40 (m,1H), 7.20 (s, 1H), 7.13 - 7.07 (m, 1H), 7.06 - 7.02 (m, 2H), 6.82 - 6.72 (m,1H), 4.62 (t, J = 13.6 Hz, 1H), 4.44 - 4.30 (m, 1H), 4.23 - 4.16 (m, 1H), 4.00 (d, J = 7.2 Hz, 2H), 3.82 - 3.71 (m, 2H), 3.67 - 3.58 (m, 0.5H), 3.46 -3.32 (m, 2.5H), 3.27 (s, 1H), 2.93 (s, 6H).

[0350] Example 3

[0351] Preparation of 1-(2-{p-[3-amino-6-(o-hydroxyphenyl)-4-pyridazinyl]phenyl}-1-pyrrolidinyl)-2-propen-1-one (compound 26)

[0352]

[0353] Step 1:

[0354]

[0355] 4-Bromo-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine (50 mg, 161.21 μmol, 1 equivalent), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl]sulfonylpiperazine-1-carboxylic acid tert-butyl ester (72.22 mg, 193.46 μmol, 1.2 equivalent), Cs₂CO₃ (157.58 mg, 483.64 μmol, 3 equivalent), and Pd(dppf)Cl₂ (11.80 mg, 16.12 μmol, 0.1 equivalent) were degassed in a mixture of dioxane (1 mL) and H₂O (0.5 mL) and purged three times with N₂. The mixture was stirred at 80 °C for 2 hours under N₂ atmosphere. The reaction mixture was diluted with H₂O (1 mL) and extracted with ethyl acetate (2 × 1 mL). The combined organic layers were washed with brine (1 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated to give tert-butyl 2-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridazin-4-yl)phenyl)pyrrolidine-1-carboxylic acid ester, which could be used directly in the next step without further purification. m / z (ESI) + ): 477.1 (M+H) + .

[0356] Step 2:

[0357]

[0358] A solution of tert-butyl 2-(4-(3-amino-6-(2-(methoxymethoxy)phenyl)pyridine-4-yl)phenyl)pyrrolidine-1-carboxylic acid ester (70 mg, 146.88 μmol, 1 equivalent) in DCM (1 mL) and TFA (0.3 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give 2-(6-amino-5-(4-(pyrrolidine-2-yl)phenyl)pyridine-3-yl)phenol, which could be used directly in the next step without further purification. m / z (ESI) + ): 333.0 (M+H) + .

[0359] Step 3:

[0360]

[0361] At 0 °C, acrylonitrile chloride (5.45 mg, 60.17 μmol, 4.89 μL, 0.5 equivalent) was added dropwise to a solution of 2-(6-amino-5-(4-(pyrrolidone-2-yl)phenyl)pyridazin-3-yl)phenol (40 mg, 125.64 μmol, 1 equivalent) and TEA (60.88 mg, 601.69 μmol, 83.75 μL, 5 equivalent) in DCM (1 mL) and DMA (0.5 mL). After addition, the mixture was stirred at 20 °C for 20 min. The reaction mixture was concentrated to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex luna C). 18 Purification was performed using a mobile phase of 100 mm × 40 mm × 3 µm (H₂O (+0.04% HCl)-ACN) and a gradient of 10% to 40% B for 8.0 min to obtain 1-(2-{p-[3-amino-6-(o-hydroxyphenyl)-4-pyridazinyl]phenyl}-1-pyrrolidinyl)-2-propen-1-one. m / z (ESI) + ): 387.1 (M+H) + . 1 H NMR (400MHz, ET64540-279-P1A4, d6-DMSO) δ 13.33 (t, J = 6.4 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.67 - 7.52 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.25(t, J = 7.2 Hz, 1H), 6.96 - 6.85 (m, 2H), 6.18 - 6.07 (m, 3H), 5.84 - 5.42(m, 1H), 5.57 - 5.41 (m, 1H), 5.33 - 5.17 (m, 1H), 3.92 - 3.65 (m, 2H), 2.02- 1.79 (m, 4H)

[0362] Example 4

[0363] Preparation of 1-[(S)-3-(o-hydroxyphenyl)-5-methyl-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraazafluorene-6-yl]-4-(1-azacycloheptyl)-2-buten-1-one and 1-[(R)-3-(o-hydroxyphenyl)-5-methyl-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraazafluorene-6-yl]-4-(1-azacycloheptyl)-2-buten-1-one

[0364]

[0365] Step 1:

[0366]

[0367] To a solution of 4-bromo-6-chloropyridazine-3-amine (36 g, 172.7 mmol, 1.0 equivalent) in DMF (200 mL), tert-butyl N-but-3-ynylcarbamate (43.8 g, 259.1 mmol, 1.5 equivalent), CuI (3.3 g, 17.3 mmol, 0.1 equivalent), triethylamine (174.7 g, 1.7 mol, 120.2 mL, 10.0 equivalent), and Pd(PPh3)4 (10.0 g, 8.6 mmol, 0.05 equivalent) were added, and the resulting mixture was stirred at 25 °C for 12 hr. The reaction mixture was diluted with H2O (600 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, 10% to 50% ethyl acetate in petroleum ether) to give tert-butyl (4-(3-amino-6-chloropyridazine-4-yl)but-3-yn-1-yl)carbamate. 1 H NMR (400MHz, d6-DMSO) δ 7.49 (s, 1H), 6.85 (br s, 2H), 3.26 - 3.15 (m, 2H), 2.63 (t,J = 6.4 Hz, 2H), 1.39 (s, 9H).

[0368] Step 2:

[0369]

[0370] t-BuOK (1 M in THF, 93.0 mL, 1.2 equivalents) was added to a solution of tert-butyl(4-(3-amino-6-chloropyridazin-4-yl)but-3-yn-1-yl)carbamate (23 g, 77.5 mmol, 1.0 equivalent) in THF (150 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched at 0 °C by adding 80 mL of saturated aqueous NH4Cl solution. The mixture was diluted with H2O (300 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, 12.5% ​​to 50% ethyl acetate in petroleum ether) to give tert-butyl(2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethyl)carbamate. 1 H NMR (400 MHz, d6-DMSO) δ 12.47 (s, 1H), 7.86(s, 1H), 7.01 (t, J = 5.2 Hz, 1H), 6.32 (s, 1H), 3.39 - 3.35 (m, 2H), 2.95(t, J = 6.8 Hz, 2H), 1.36 (s, 9H).

[0371] Step 3:

[0372]

[0373] A solution of tert-butyl(2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethyl)carbamate (10 g, 33.7 mmol, 1.0 equivalent) in HCl / dioxane (150 mL) was stirred at 25 °C for 2 hr. LCMS showed that the reaction was complete. The reaction mixture was concentrated to give 2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethyl-1-amine, which was used directly in the next step without further purification. 1 H NMR (400 MHz, d6-DMSO) δ 12.68 (s, 1H), 8.16 (s, 2H), 3.29 - 3.13 (m, 4H).

[0374] Step 4:

[0375]

[0376] Acetaldehyde (5.0 g, 45.8 mmol, 6.4 mL, 40% purity, 2.0 equivalent) and NaOH (1 M, 45.8 mL, 2.0 equivalent) were added to a solution of 2-(3-chloro-7H-pyrrolo[2,3-c]pyridazin-6-yl)ethyl-1-amine (4.5 g, 22.9 mmol, 1.0 equivalent) in H2O (30 mL) at 25 °C. The mixture was stirred at 70 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove H2O. The crude product was milled with ACN to give 3-chloro-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine. 1 H NMR (400 MHz, d6-DMSO) δ 7.50 (s, 1H), 4.03 (d, J =6.8 Hz, 1H), 3.51 - 3.36 (m, 2H), 3.17 (s, 3H), 2.91 - 2.79 (m, 2H), 1.35 (d,J = 6.8 Hz, 3H).

[0377] Step 5:

[0378]

[0379] A mixture of 3-chloro-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine (1 g, 4.49 mmol, 1 equivalent), Boc₂O (2.45 g, 11.23 mmol, 2.58 mL, 2.5 equivalent), and DIEA (1.74 g, 13.47 mmol, 2.35 mL, 3 equivalent) in THF (10 mL) was degassed and purged three times with N₂. The mixture was stirred at 25 °C for 2 hours under N₂ atmosphere. The reaction mixture was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography (SiO2, 1% to 50% ethyl acetate in petroleum ether) to give di-tert-butyl-3-chloro-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester. 1 H NMR (400 MHz, CDCl3) δ 7.56 -7.43 (m, 1H), 5.30 – 4.20 (m, 2H), 3.30 – 3.02 (m, 3H), 1.70 (s, 10H), 1.51(s, 10H), 1.46 (d, J = 6.8 Hz, 4H).

[0380] Step 6:

[0381]

[0382] Di-tert-butyl-3-chloro-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester (1 g, 2.36 mmol, 1 equivalent), [2-(methoxymethoxy)phenyl]boronic acid (645.47 mg, 3.55 mmol, 1.5 equivalent), BrettPhos Pd G3 (214.35 mg, 236.46 µmol, 0.1 equivalent), and K2CO3 (653.62 mg, 4.73 mmol, 2 equivalent) were degassed in a mixture of dioxane (30 mL) and water (7 mL) and purged three times with N2. The mixture was stirred at 80 °C for 12 hours under N2 atmosphere. Three more reactions were prepared according to the above method, and all reaction mixtures were combined for further processing. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over Na₂SO₄ and concentrated under vacuum to give di-tert-butyl-3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester, which could be used directly without further purification.

[0383] Step 7:

[0384]

[0385] TFA (5 mL) was added to a solution of di-tert-butyl-3-(2-(methoxymethoxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester (1 g, 1.91 mmol, 1 equivalent) in DCM (10 mL) at 20 °C, and the mixture was stirred for 10 min. The reaction mixture was concentrated and milled with MTBE (5 mL) for 30 min to give 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-3-yl)phenol. 1H NMR (400 MHz, d6-DMSO) δ 10.44 - 10.24 (m, 1H), 9.97 - 9.78 (m, 1H), 8.71 (s, 1H), 7.75 - 7.62 (m, 1H), 7.48 - 7.36 (m, 1H), 7.19 - 7.11 (m, 1H), 7.08 - 7.01 (m, 1H), 4.84 - 4.79 (m, 1H), 3.72 - 3.20 (m, 4H), 1.76 (d, J =6.4 Hz, 3H).

[0386] Step 8:

[0387]

[0388] A mixture of 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol (2.2 g, 7.85 mmol, 1 equivalent), TEA (5.56 g, 54.94 mmol, 7.65 mL, 7 equivalent), Boc2O (5.99 g, 27.47 mmol, 6.31 mL, 3.5 equivalent), and DMAP (95.88 mg, 784.81 μmol, 0.1 equivalent) in DMF (20 mL) was degassed and purged three times with N2. The mixture was stirred at 40 °C for 12 hours under N2 atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, 5% to 25% ethyl acetate in petroleum ether) to give di-tert-butyl-3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester. m / z(ESI) + ): 581.5 (M+H) + .

[0389] Step 9:

[0390]

[0391] Di-tert-butyl-3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester (4 g, 6.89 mmol) was separated by SFC (instrument: Waters SFC350 preparative SFC system; column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 µm); mobile phase: A was CO2 and B was EtOH (0.1% NH4.OH); gradient: B% = 14.00% isocratic elution mode; flow rate: 180.00 g / min; detection wavelength: 220 nm and 254 nm; column temperature: 40 °C). (℃) to obtain di-tert-butyl 3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester (first eluting isomer, retention time = 3.52 min), 1 H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.87 -7.83 (m, 1H), 7.59 - 7.51 (m, 1H), 7.49 - 7.43 (m, 1H), 7.31 (d, J = 8.0 Hz,1H), 5.44 - 5.29 (m, 1H), 4.41 (d, J = 3.2 Hz, 1H), 3.27 - 2.92 (m, 3H), 1.72(s, 9H), 1.54 - 1.51 (m, 12H), 1.28 (s, 9H)) and di-tert-butyl-3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester (second eluting isomer, retention time = 4.38 min, 1 H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.87 -7.83 (m, 1H), 7.59 - 7.51 (m, 1H), 7.49 - 7.43 (m, 1H), 7.31 (d, J = 8.0 Hz,1H), 5.44 - 5.29 (m, 1H), 4.41 (d, J = 3.2 Hz, 1H), 3.27 - 2.92 (m, 3H), 1.72(s, 9H), 1.54 - 1.51 (m, 12H), 1.28 (s, 9H)).

[0392] Step 10:

[0393]

[0394] TFA (1.28 g, 11.19 mmol, 831.51 μL, 5 equivalents) was added dropwise to a solution of one enantiomer of di-tert-butyl-3-(2-((tert-butoxycarbonyl)oxy)phenyl)-5-methyl-7,8-dihydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazine-6,9-dicarboxylic acid ester (1.3 g, 2.24 mmol, 1 equivalent) in DCM (13 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was ground with methyl tert-butyl ether (10 mL) for 30 min to obtain 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol trifluoroacetate. 1 H NMR (400 MHz, CD3OD) δ 8.66 (s,1H), 7.68 - 7.63 (m, 1H), 7.55 - 7.45 (m, 1H), 7.15 - 7.05 (m, 2H), 4.99 (d,J = 6.8 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.72 - 3.62 (m, 1H), 3.46 - 3.39 (m, 2H), 1.90 - 1.84 (m, 3H).

[0395] Step 11:

[0396]

[0397] (E)-4-chlorobut-2-enoyl chloride (12 mg, 99.6 µmol, 1.0 equivalent) was added to a solution of 2-(5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-3-yl)phenol trifluoroacetate (44 mg, 99.6 µmol, 1.0 equivalent) in dichloromethane (1 mL) and triethylamine (0.2 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was concentrated to give (E)-4-chloro-1-(3-(2-hydroxyphenyl)-5-methyl-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-6-yl)but-2-en-1-one, which was used directly in the next reaction.

[0398] Step 12:

[0399]

[0400] A solution of (E)-4-3-(2-hydroxyphenyl)-5-methyl-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridazin-6-yl)but-2-en-1-one (37.9 mg, 99 µmol, 1.0 equivalent) and DIEA (38.4 mg, 297 µmol, 3 equivalent) in dichloromethane (1 mL) was supplemented with aziridine (29.5 mg, 297 µmol, 3 equivalent). The reaction mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The reaction mixture was extracted with NaHCO3 (3 × 1 mL) and brine (3 × 1 mL). The organic phase was dried over Na2SO4 and the solvent was removed under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (column: Phenomenex luna C) 18 Purification was performed using a mobile phase of 100 mm × 40 mm × 3 µm (H₂O (+0.04% HCl)-ACN) and a gradient of 10% to 40% B for 8.0 min to yield 1-[3-(o-hydroxyphenyl)-5-methyl-6,7,8,9-tetrahydro-5H-1,2,6,9-tetraazafluorene-6-yl]-4-(1-azacycloheptyl)-2-buten-1-one. m / z (ESI) + ): 446(M+H) + .

[0401] Example 5

[0402] Preparation of 1-{3-[(4bS,8aS)-3-(o-hydroxyphenyl)-6,7,8,8a,9,10-hexahydro-5H-1,2,4b,7,10-pentazophran-7-yl]-1-pyrrolidinyl}-2-propen-1-one (compound 64)

[0403]

[0404] Step 1:

[0405]

[0406] NaBH(OAc)3 (561.03 mg, 2.65 mmol, 5 equivalents) was added in a single step to a solution of (R)-2-(6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (150 mg, 529.42 μmol, 1 equivalent), tert-butyl-3-oxopyrrolidine-1-carboxylic acid ester (294.18 mg, 1.59 mmol, 3 equivalents), and AcOH (3.18 mg, 52.94 μmol, 3.03 μL, 0.1 equivalents) in DMF (3 mL). The mixture was stirred at N2, 20 °C for 16 hours. The reaction mixture was filtered, and the filtrate was passed through a preparative HPLC (column: Phenomenex luna C). 18 Purification was performed using a mobile phase of [H2O (+0.1% TFA)-ACN] (100 mm × 40 mm × 3 µm; gradient: 10% to 40% B, 18.0 min) to obtain tert-butyl 3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylic acid ester. 1 H NMR (400 MHz, d6- DMSO) δ8.22 (s, 1H), 7.47 (dd, J = 1.2, 7.6 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.27 (s,1H), 7.06 (d, J = 8.4 Hz, 1H), 7.03 - 6.93 (m, 1H), 4.38 (d, J = 12.4 Hz,1H), 3.87 - 3.75 (m, 1H), 3.73 - 3.61 (m, 2H), 3.61 - 3.53 (m, 1H), 3.46 (t,J = 8.4 Hz, 3H), 3.34 - 3.19 (m, 4H), 2.89 (s, 1H), 2.67 (s, 1H), 2.26 - 2.14 (m, 1H), 1.99 (s, 1H), 1.41 (s, 9H).

[0407] Step 2:

[0408]

[0409] TFA (460.50 mg, 4.04 mmol, 0.3 mL, 60.92 equivalents) was added in a single dose to a solution of tert-butyl-3-((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)pyrrolidine-1-carboxylic acid ester (30 mg, 66.29 μmol, 1 equivalent) in DCM (1 mL) at N2 and 20 °C. The mixture was stirred at N2 and 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was ground with MTBE (5 mL) for 1 h to obtain 2-((6aS)-8-(pyrrolidine-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol. m / z (ESI) + ): 353.2 (M+H) + .

[0410] Step 3:

[0411]

[0412] At 20 °C and N2, acrylonitrile chloride (5.11 mg, 56.42 μmol, 4.58 μL, 0.8 equivalents) was added fractionally to a mixture of 2-((6aS)-8-(pyrrolidine-3-yl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (30 mg, 70.53 μmol, 1 equivalent, 2 TFA) and DIEA (91.15 mg, 705.29 μmol, 122.85 μL, 10 equivalents) in DCM (1 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex Luna C10). 18 100 mm × 40 mm × 3 µm; mobile phase: [H2O (+0.04% HCl)-ACN]; gradient: 10% to 40% B, 8.0 min) purification to give 1-{3-[(4bS,8aS)-3-(o-hydroxyphenyl)-6,7,8,8a,9,10-hexahydro-5H-1,2,4b,7,10-pentazophran-7-yl]-1-pyrrolidinyl}-2-propen-1-one. m / z (ESI) + ):407.2 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 7.56 (d, J = 7.6 Hz, 1H), 7.48 - 7.42(m, 1H), 7.36 (s, 1H), 7.13 - 6.97 (m, 2H), 6.71 - 6.52 (m, 1H), 6.41 - 6.17(m, 1H), 5.80 (dd, J = 1.6, 10.4 Hz, 1H), 4.51 (d, J = 14.4 Hz, 1H), 4.27(dd, J = 7.6, 10.4 Hz, 0.5H), 4.12 (dd, J = 7.6, 12.4 Hz, 2H), 4.07 - 3.97(m, 1.5H), 3.90 (d, J = 12.0 Hz, 1H), 3.84 - 3.74 (m, 3H), 3.74 - 3.65 (m,2H), 3.52 - 3.40 (m, 2H), 3.23 (t, J = 11.6 Hz, 1H), 2.61 (dd, J = 4.4, 5.6Hz, 1H), 2.48 - 2.25 (m, 1H).

[0413] Example 6

[0414] Preparation of 1-{6-(o-hydroxyphenyl)-1',3,4,5-tetraazaspiro[indan-1,3'-piperidin]-1'-yl}-2-propen-1-one (compound 45)

[0415]

[0416] Step 1:

[0417]

[0418] A mixture of 3,6-dichloro-N-(3,4-dimethylbenzyl)pyridazin-4-amine (2.5 g, 7.96 mmol, 1 equivalent), benzyl 3-(chlorocarbonyl)piperidine-1-carboxylate (5.83 g, 20.69 mmol, 2.6 equivalent), and TEA (4.03 g, 39.79 mmol, 5.54 mL, 5 equivalent) in DCM (15 mL) was stirred at 40 °C for 72 hours under N2 atmosphere. The reaction mixture was concentrated to obtain a residue. The residue was dissolved in DMF (15 mL), and Cs2CO3 (2.59 g, 7.96 mmol, 1 equivalent) was added to the mixture. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, 30% to 50% ethyl acetate in petroleum ether) to give benzyl 3'-chloro-7'-(3,4-dimethylbenzyl)-6'-oxo-6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-1-carboxylic acid ester. 1 H NMR (400 MHz, d6-DMSO) δ 7.73 (s, 1H), 7.41 - 7.23 (m, 4H), 7.22 - 7.09(m, 1H), 6.93 (s, 1H), 6.55 (s, 1H), 6.47 - 6.26 (m, 1H), 5.12 - 5.01 (m,2H), 4.86 - 4.76 (m, 2H), 3.84 (d, J = 13.6 Hz, 2H), 3.75 (s, 3H), 3.71 (s,3H), 3.65 - 3.51 (m, 1H), 3.46 (ddd, J = 3.2, 9.2, 12.8 Hz, 1H), 1.99 - 1.86 (m, 3H), 1.85 - 1.71 (m, 1H).

[0419] Step 2:

[0420]

[0421] Benzyl 3'-chloro-7'-(3,4-dimethylbenzyl)-6'-oxo-6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-1-carboxylic acid ester (2.2 g, 4.21 mmol, 1 equivalent), (2-hydroxyphenyl)boronic acid (1.16 g, 8.41 mmol, 2 equivalents), Cs₂CO₃ (5.48 g, 16.83 mmol, 4 equivalents), and Pd(dppf)Cl₂ (307.80 mg, 420.67 μmol, 0.1 equivalents) were degassed in a mixture of dioxane (40 mL) and water (20 mL), and then heated at N₂, 90 °C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 20% to 50% ethyl acetate in petroleum ether) to give benzyl 7'-(3,4-dimethylbenzyl)-3'-(2-hydroxyphenyl)-6'-oxo-6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-1-carboxylic acid ester. 1 H NMR (400 MHz, d6-DMSO) δ 12.60 (br s, 1H), 8.31 (s, 1H), 7.87 (d, J =7.4 Hz, 1H), 7.43 - 7.27 (m, 3H), 7.22 - 7.05 (m, 3H), 7.02 - 6.90 (m, 3H),6.57 (s, 1H), 6.47 - 6.29 (m, 1H), 5.17 - 4.94 (m, 2H), 4.92 - 4.81 (m, 2H),3.87 (d, J = 13.4 Hz, 1H), 3.80 (s, 1H), 3.78 (s, 3H), 3.72 (s, 2H), 3.71 (s,3H), 2.10 - 2.02 (m, 2H), 2.01 - 1.94 (m, 1H), 1.92 - 1.79 (m, 1H).

[0422] Step 3:

[0423]

[0424] NaBH4 (977.30 mg, 25.83 mmol, 10 equivalents) was added fractionally to a mixture of TiCl4 (2.45 g, 12.92 mmol, 5 equivalents) and DME (45 mL) at 0 °C, and the mixture was then stirred at 0 °C for 1 h. Benzyl 7'-(3,4-dimethylbenzyl)-3'-(2-hydroxyphenyl)-6'-oxo-6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-1-carboxylic acid ester (1.5 g, 2.58 mmol, 1 equivalent) was added fractionally to the mixture at 0 °C, and the mixture was stirred at 0 °C to 5 °C for 2 h. The reaction mixture was quenched at 0 °C with H2O (15 mL) and NH3·H2O (3 mL). The reaction mixture was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give benzyl 7'-(3,4-dimethylbenzyl)-3'-(2-hydroxyphenyl)-6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-1-carboxylic acid ester, which could be used in the next step without further purification. 1 H NMR (400 MHz, d6-DMSO) δ 8.11 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.34 - 7.22 (m, 7H), 6.96 - 6.88 (m, 2H), 6.58 (d, J = 2.0 Hz, 1H), 6.53 -6.41 (m, 1H), 5.14 - 5.03 (m, 2H), 4.67 - 4.46 (m, 2H), 3.74 (d, J = 9.6 Hz,8H), 3.43 (s, 2H), 3.24 (s, 2H), 2.05 (dd, J = 9.2, 11.6 Hz, 1H), 1.88 - 1.78(m, 1H), 1.77 - 1.69 (m, 1H), 1.50 - 1.39 (m, 1H).

[0425] Step 4:

[0426]

[0427] TfOH (1.06 g, 7.06 mmol, 624.65 μL, 10 equivalents) was added fractionally to a solution of benzyl 7'-(3,4-dimethylbenzyl)-3'-(2-hydroxyphenyl)-6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-1-carboxylic acid ester (400 mg, 705.91 μmol, 1 equivalent) in DCM (5 mL) at 5 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex Luna C10). 18 Purification was performed using a 100 mm × 40 mm × 3 µm filter; mobile phase: [H2O (+0.04% HCl)-ACN]; gradient: 10% to 40% B, 8.0 min, to obtain 2-(6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-3'-yl)phenol. 1 H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.68 (dd, J = 1.6, 8.0 Hz, 1H), 7.44- 7.33 (m, 1H), 7.04 - 6.97 (m, 2H), 4.00 - 3.80 (m, 2H), 3.60 (d, J = 13.2Hz, 1H), 3.49 - 3.38 (m, 2H), 3.16 (dt, J = 3.2, 12.4 Hz, 1H), 2.20 - 2.11(m, 1H), 2.10 - 2.00 (m, 2H), 1.99 - 1.86 (m, 1H).

[0428] Step 5:

[0429]

[0430] At 0 °C, acrylonitrile chloride (1.77 mg, 19.59 μmol, 1.59 μL, 1 equivalent) was added to a mixture of 2-(6',7'-dihydrospiro[piperidine-3,5'-pyrrolo[2,3-c]pyridazine]-3'-yl)phenol (10 mg, 19.59 μmol, 1 equivalent) and DIEA (12.66 mg, 97.97 μmol, 17.06 μL, 5 equivalent) in DCM (1 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to preparative HPLC (column: Phenomenex Luna C10). 18Purification was performed using a 100 mm × 40 mm × 3 µm filter; mobile phase: [H₂O (+0.04% HCl)-ACN]; gradient: 10% to 40% B, 8.0 min) to obtain 1-{6-(o-hydroxyphenyl)-1',3,4,5-tetraazaspiro[indan-1,3'-piperidin]-1'-yl}-2-propen-1-one. m / z (ESI) + ): 337.1 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.97 (d, J = 14.4 Hz, 1H), 7.84 - 7.74 (m, 1H), 7.30 - 7.23 (m, 1H), 6.97 - 6.91 (m, 2H), 6.91 - 6.66 (m, 1H), 6.23 (d, J = 16.8 Hz, 1H), 5.88 -5.67 (m, 1H), 4.42 (d, J = 12.4 Hz, 0.5H), 4.29 - 4.21 (m, 0.5H), 4.14 - 4.06(m, 0.5H), 3.94 (d, J = 13.2 Hz, 0.5H), 3.62 - 3.44 (m, 3H), 3.38 - 3.34 (m,0.5H), 3.17 (d, J = 12.8 Hz, 0.5H), 2.24 - 2.13 (m, 1H), 2.00 (d, J = 13.6Hz, 1H), 1.95 - 1.85 (m, 1H), 1.74 - 1.57 (m, 1H).

[0431] Example 7

[0432] Preparation of 1-{7-(o-hydroxyphenyl)-3,4-dihydro-1H-1,1',4,5,6-pentazaspiro[naphthalene-2,3'-piperidin]-1'-yl}-2-propen-1-one (compound 91)

[0433]

[0434] 1-{7-(o-hydroxyphenyl)-3,4-dihydro-1H-1,1',4,5,6-pentazaspiro[naphthal-2,3'-piperidine]-1'-yl}-2-propen-1-one can be prepared by the following method.

[0435] Step 1:

[0436]

[0437] 4-Amino-1-phenylmethoxycarbonylpiperidine-3-carboxylic acid, K2CO3, and 4-bromo-6-chloropyridazine-3-amine were added to a solution of cuprous dimethyl sulfide in DMA. The mixture was stirred at 120 °C until the reaction was complete to give 4-((3-amino-6-chloropyridazine-4-yl)amino)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid.

[0438] Step 2:

[0439]

[0440] DIEA and HATU were added to a solution of 4-((3-amino-6-chloropyridazin-4-yl)amino)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid in DMF at 25 °C and stirred for 2 h to obtain benzyl ester of 3'-chloro-7'-oxo-7',8'-dihydro-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazin]-1-carboxylic acid.

[0441] Step 3:

[0442]

[0443] Borane was added to a solution of 3'-chloro-7'-oxo-7',8'-dihydro-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-1-carboxylic acid benzyl ester in THF. The mixture was stirred at 65 °C for 16 h to obtain crude benzyl 3'-chloro-7',8'-dihydro-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-1-carboxylic acid ester.

[0444] Step 4:

[0445]

[0446] A solution of di-tert-butyl dicarbonate, benzyl 3'-chloro-7',8'-dihydro-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-1-carboxylic acid ester, TEA, and 4-(dimethylamino)pyridine in DCM was stirred at 25 °C for 16 h to obtain 1-benzyl 5',8'-di-tert-butyl 3'-chloro-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-1,5',8'(7'H)-tricarboxylic acid ester.

[0447] Step 5:

[0448]

[0449] A mixture of 1-benzyl 5',8'-di-tert-butyl 3'-chloro-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-1,5',8'(7'H)-tricarboxylic acid ester, potassium carbonate, l,r-bis(diphenylphosphine)ferrocene-palladium(II) dichloromethane complex, and 2-hydroxyphenylboronic acid in 1,4-dioxane and water was stirred at N2 and 110 °C for 16 h to obtain 1-benzyl 5',8'-di-tert-butyl 3'-(2-hydroxyphenyl)-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-1,5',8'(7'H)-tricarboxylic acid ester.

[0450] Step 6:

[0451]

[0452] 1-Benzyl 5',8'-di-tert-butyl 3'-(2-hydroxyphenyl)-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-1,5',8'(7'H)-tricarboxylic acid ester and Pd / C were added to MeOH and stirred for 1 h at 25 °C under H2 atmosphere. The reaction mixture was filtered and concentrated to give di-tert-butyl 3'-(2-hydroxyphenyl)-5'H-spiro[piperidine-3,6'-pyrazino[2,3-c]pyridazine]-5',8'(7'H)-dicarboxylic acid ester.

[0453] Step 7:

[0454]

[0455] At 0 °C, propionic-2-enoyl chloride was added to a solution of di-tert-butyl 3'-(2-hydroxyphenyl)-5'H-spiro[piperidin-3,6'-pyrazino[2,3-c]pyridazine]-5',8'(7'H)-dicarboxylic acid ester and DIEA in DCM. The mixture was stirred at 20 °C for 1 hour to give di-tert-butyl 1-acryloyl-3'-(2-hydroxyphenyl)-5'H-spiro[piperidin-3,6'-pyrazino[2,3-c]pyridazine]-5',8'(7'H)-dicarboxylic acid ester, which was deprotected by TFA in a solution of DCM to give 1-{7-(o-hydroxyphenyl)-3,4-dihydro-1H-1,1',4,5,6-pentazaspiro[naphth-2,3'-piperidin]-1'-yl}-2-propen-1-one.

[0456] Compound 91 was also prepared as follows.

[0457] Step 1:

[0458]

[0459] 4-Bromo-6-chloropyridazine-3-amine (2 g, 9.59 mmol, 1 equivalent), 3-amino-1-benzyloxycarbonyl-piperidine-3-carboxylic acid (2.67 g, 9.59 mmol, 1 equivalent), copper bromine, methylthiomethane (394.51 mg, 1.92 mmol, 0.2 equivalent), and K₂CO₃ (530.43 mg, 3.84 mmol, 0.4 equivalent) were heated in a solution of DMA (40 mL) at 140 °C for 16 h. LC-MS showed that the reaction was complete. The reactants were filtered, and the filtrate was purified by preparative HPLC (column: 3-Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 15% to 45% B, 8.0 min) to give intermediate 2-A (1.5 g, 3.71 mmol, yield 38.70%, purity 96%). 1 H NMR (400 MHz, DMSO-d6) δ = 11.60(s, 1H), 7.87 (s, 1H), 7.50 - 7.10 (m, 5H), 6.91 - 6.78 (m, 1H), 5.03 (s,2H), 4.12 - 3.74 (m, 2H), 3.30 (d, J = 13.2 Hz, 1H), 3.11 - 2.77 (m, 1H), 2.06 (s, 1H), 1.79 (s, 1H), 1.68 - 1.58 (m, 1H).

[0460] Step 2:

[0461]

[0462] Intermediate 2-A (250 mg, 644.63 μmol, 1 equivalent), (2-(methoxymethoxy)phenyl)boronic acid (intermediate 1, 351.93 mg, 1.93 mmol, 3 equivalents), Cs₂CO₃ (1.26 g, 3.87 mmol, 6 equivalents), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium, dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine (116.87 mg, 128.93 μmol, 0.2 equivalents) were stirred in a mixture of H₂O (2.5 mL) and dioxane (5 mL) at 60 °C for 1 h under N₂. LCMS showed that the reaction was complete. Four more reactions were set up according to the above method, and all reaction mixtures were combined for further processing and purification. The reaction mixture was diluted with 10 mL of H₂O at 20 °C and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with 10 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give intermediate 3-A (390 mg, 724.99 μmol, yield 37.49%, purity 91%). 1 H NMR (400 MHz, DMSO-d6) δ = 11.45(s, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.53 - 7.46 (m, 0.5H), 7.43 - 7.35 (m,2.5H), 7.28 (s, 1.5H), 7.24 (d, J = 8.4 Hz, 1.5H), 7.18 (s, 2H), 7.14 - 7.07(m, 1H), 5.19 (s, 2H), 5.06 - 4.89 (m, 2H), 3.99 - 3.73 (m, 2H), 3.36 - 3.32(m, 2H), 3.32 - 3.29 (m, 3H), 2.06 (d, J = 8.4 Hz, 1H), 1.90 - 1.71 (m, 2H), 1.70 - 1.57 (m, 1H).

[0463] Step 3:

[0464]

[0465] BH3·THF (1 M, 735.41 μL, 6 equivalents) was added dropwise to a mixture of intermediate 3-A (60 mg, 122.57 μmol, 1 equivalent) and THF (4 mL) for 5 min under N2 and 20 °C. After addition, the reaction mixture was stirred at 20 °C for 30 min. The resulting mixture was then heated to 50 °C and stirred at 50 °C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was cooled to 20 °C and quenched with methanol (4 mL) at 20 °C. The mixture was then stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give intermediate 4-A (60 mg, crude), which could be used for the next step without purification. LCMS (ESI) + ): m / z 432.1 (M+H) + .

[0466] Step 4:

[0467]

[0468] Trifluoromethanesulfonic acid (56.81 mg, 378.52 μmol, 33.49 μL, 3 equivalents) was added to a solution of intermediate 4-A (60 mg, 126.17 μmol, 1 equivalent) in dichloromethane (1 mL) at 0 °C. After addition, the mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was diluted with H₂O (1 mL) and extracted with dichloromethane (1 mL). The aqueous phase was concentrated under reduced pressure to give intermediate 5-A (60 mg, crude), which was used directly for the next step without purification. LCMS (ESI) + ): m / z 298.3 (M+H) + .

[0469] Step 5:

[0470]

[0471] At 0 °C, intermediate 5-A (40 mg, 134.52 μmol, 1 equivalent) and DIEA (173.85 mg, 1.35 mmol, 234.30 μL, 10 equivalent) in DMA (1 mL) solution were added dropwise to a solution of acrylonitrile chloride (12.18 mg, 134.52 μmol, 10.93 μL, 1 equivalent) in DCM (0.2 mL). After addition, the mixture was stirred at 0 °C for 0.5 h. LCMS showed that the reaction was complete. The reactants were filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex GeminiNX-C18 (75*30mm*3um); mobile phase: [H2O(0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient: 5% to 35% B, 8.0 min) to give compound 91. 1 H NMR (400 MHz, METHANOL-d4) δ = 7.60 (d, J = 7.2Hz, 1H), 7.23 - 7.20 (m, 1H), 7.07 (s, 1H), 6.95 - 6.75 (m, 2H), 6.65 - 6.59(m 1H), 6.24 - 6.12 (m, 1H), 5.80 - 5.60 (m, 1H), 3.77 - 3.56 (m, 4H), 3.49 -3.40 (m, 2H), 1.92 - 1.62 (m, 4H).

[0472] Example 8

[0473] Preparation of 1-(3'-(2-hydroxyphenyl)-7',8'-dihydro-5'H-spiro[piperidin-4,6'-pyrazino[2,3-c]pyridazine]-1-yl)prop-2-en-1-one (compound 35)

[0474] Step 1:

[0475]

[0476] 4-Bromo-6-chloropyridazine-3-amine (1.1 g, 5.28 mmol, 1 equivalent), 4-amino-1-benzyloxycarbonyl-piperidine-4-carboxylic acid (1.47 g, 5.28 mmol, 1 equivalent), copper bromine, methylthiomethane (216.98 mg, 1.06 mmol, 0.2 equivalent), and K₂CO₃ (291.74 mg, 2.11 mmol, 0.4 equivalent) were heated in a solution of DMA (22 mL) at 140 °C for 16 h. LC-MS showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Welch Xtimate C18180*70mm#10um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 30% to 60% B, 20.0 min) to give intermediate 2-B (0.8 g, 1.90 mmol, yield 35.96%, purity 92%). 1 H NMR (400 MHz, DMSO-d6) δ =11.55 (s, 1H), 7.84 (s, 1H), 7.52 - 7.24 (m, 5H), 6.77 (s, 1H), 5.26 - 4.98(m, 2H), 3.88 - 3.62 (m, 2H), 3.36 (d, J = 14.4 Hz, 2H), 1.97 (t, J = 9.6 Hz, 2H), 1.64 (d, J = 13.2 Hz, 2H).

[0477] Step 2:

[0478]

[0479] Intermediate 2-B (250 mg, 644.63 μmol, 1 equivalent), intermediate 1 (351.93 mg, 1.93 mmol, 3 equivalents), Cs₂CO₃ (1.26 g, 3.87 mmol, 6 equivalents), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine (116.87 mg, 128.93 μmol, 0.2 equivalents) were stirred in a solution of H₂O (2.5 mL) and dioxane (5 mL) at N₂ and 60 °C for 1 h. LCMS showed that the reaction was complete. Four more reactions were set up according to the above method, and all reaction mixtures were combined for processing and purification. The reaction mixtures were diluted with H₂O (10 mL) at 20 °C and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give intermediate 3-B (280 mg, 513.64 μmol, yield 39.84%, purity 89.8%). 1 H NMR (400 MHz, DMSO-d6) δ = 11.42 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.42 – 7.39 (m, 1H), 7.38 (s, 1H), 7.37 – 7.35 (m, 3H), 7.34 –7.30 (m, 1H), 7.27 – 7.19 (m, 2H), 7.11 (t, J = 7.2 Hz, 1H), 5.21 (s, 2H), 5.10 (s, 2H), 3.82 – 3.70 (m, 2H), 3.52 – 3.39 (m, 2H), 3.34 (s, 3H), 2.01 (d, J = 4.4 Hz, 1H), 1.95 (d, J = 4.4 Hz, 1H), 1.62 (d, J = 13.6 Hz, 2H).

[0480] Step 3:

[0481]

[0482] BH3·THF (1 M, 245.14 μL, 6 equivalents) was added dropwise to a solution of intermediate 3-B (20 mg, 40.86 μmol, 1 equivalent) in THF (1.5 mL) for 5 min under N2 and 20 °C. After addition, the reaction mixture was stirred at 20 °C for 30 min. The resulting mixture was then heated to 50 °C and stirred at 50 °C for 1 h. LCMS showed that the reaction was complete. The reaction mixture was cooled to 20 °C and quenched with MeOH (2 mL) at 20 °C. The mixture was then stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give intermediate 4-B (20 mg, crude), which could be used for the next step without purification. LCMS (ESI) + ): m / z 432.3 (M+H) + .

[0483] Step 4:

[0484]

[0485] Trifluoromethanesulfonic acid (18.94 mg, 126.17 μmol, 11.16 μL, 3 equivalents) was added to a solution of intermediate 4-B (20 mg, 42.06 μmol, 1 equivalent) in dichloromethane (1 mL) at 0 °C. After addition, the mixture was stirred at 0 °C for 1 h. LCMS showed the reaction was complete. The reaction mixture was diluted with dichloromethane (1 mL) and extracted with H₂O (1 mL). The aqueous phase was separated and concentrated under reduced pressure to give intermediate 5-B (20 mg, crude), which was used directly for the next step without further purification. LCMS (ESI) + ): m / z 298.3 (M+H) + .

[0486] Step 5:

[0487]

[0488] At 0 °C, intermediate 5-B (30 mg, 100.89 μmol, 1 equivalent) and DIEA (130.39 mg, 1.01 mmol, 175.73 μL, 10 equivalent) in DMA (1 mL) solution were added dropwise to a solution of acrylonitrile chloride (9.13 mg, 100.89 μmol, 8.20 μL, 1 equivalent) in DCM (0.2 mL). After addition, the mixture was stirred at 0 °C for 0.5 h. LCMS showed that the reaction was complete. The reactants were filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Luna C1875*30 mm*3 μm; mobile phase: [H2O(0.2% FA)-ACN]; gradient: 10% to 30% B, 8.0 min) to give compound 35. 1 H NMR (400 MHz, METHANOL-d4) δ = 7.54 (d, J = 7.2 Hz, 1H), 7.30 (t, J =7.2 Hz, 1H), 7.07 (s, 1H), 7.00 - 6.90 (m, 2H), 6.81 (dd, J = 10.4, 16.8 Hz,1H), 6.22 (dd, J = 1.6, 16.8 Hz, 1H), 5.77 (dd, J = 1.6, 10.8 Hz, 1H), 3.79(d, J = 5.2 Hz, 4H), 3.40 (d, J = 4.0 Hz, 2H), 1.96 - 1.68 (m, 4H).

[0489] Each compound described in Table 3 was prepared according to the above procedure.

[0490] Table 3

[0491]

[0492] Biological examples

[0493] SMARCA2 and SMARCA4 degradation assay

[0494] The degradation of proteins expressed by the SMARCA2 and SMARCA4 genes was monitored using engineered HiBiT fusion HeLa cell lines from Promega. Briefly, SMARCA2-HiBiT or SMARCA4-HiBiT HeLa cells were seeded at 8,000 cells / well in 384-well white opaque plates (Greiner) and incubated overnight at 37 °C to allow cell adhesion. After overnight incubation, the test compound was added in 10-point serial dilutions (typically from 10 µM to 300 pM) using a TECAN D300e digital dispenser, followed by incubation at 37 °C for 24 hours. 24 hours post-treatment, HiBiT lysis buffer, LgBiT protein, and HiBiT substrate were added according to the manufacturer's instructions to quantify protein levels. The plates were incubated on a track-shaker at room temperature for 10 minutes. The resulting luminescence values ​​were read using a ClarioStar microplate reader and used to construct dose-response curves and calculate degradation DCs. 50 (GraphPad Prism).

[0495] Table 4 provides the data from the measurements. Table 4 also provides the activity of the tested compounds, as follows: A = DC 50 <0.050 µM; B = 0.05 µM < DC 50 < 0.50 µM; C = < 0.5 µM < DC 50 <5.0 µM; D = DC 50 >5.0 µM. For SMARCA2 and SMARCA4 degradation activity @ 1 µM, +++ = > 70%; ++ = 30-70%; + = <30%.

[0496] Table 4

[0497]

[0498] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0499] The disclosure described herein may be practiced appropriately in the absence of any one or more elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” “containing,” etc., should be read broadly without limitation. Furthermore, the terms and expressions used herein have been used as descriptive rather than limiting terms, and are not intended to exclude any equivalent forms of the features shown and described or portions thereof in the use of such terms and expressions; however, it is recognized that various modifications are possible within the scope of the claims.

[0500] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated in their entirety by reference as if they were individually incorporated by reference. In the event of any conflict, this specification (including definitions) shall prevail.

[0501] It should be understood that although this disclosure has been described in conjunction with the foregoing embodiments, the foregoing description and examples are intended to illustrate and not limit the scope of this disclosure. Other aspects, advantages, and modifications within the scope of this disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. A compound of formula I: I Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers, wherein: Each of n and p is independently 0, 1, or 2; R 1 Hydroxyl, halogenated, cyano, C 1-4 alkoxy or -N(R)2; R 2 =-N(R)2; Each R is independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein each alkyl or cycloalkyl group is unsubstituted or surrounded by one to three Z groups. 1 replace; Each R 3 Independently halogenated, cyano-based, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0- 2N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace; Each R 4 Independently oxo, halogenated, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace; R 5 It can be hydrogen, halogenated, cyano, -NO2, -SF5, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0-2 N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to eight Z groups. 1 replace; R 6 For hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or halogenated; (i) L 1 For key, C 1-3 Alkylene, -O- or -QL 2 -; L 2 For key, C 1-3 Alkylene, -S(O)2- or -C(O)NH-; Q is a phenyl group or a 5-membered heteroaryl group containing one or two nitrogen atoms; Or (ii) when L 1 When R is the key 2 and R 4 The R in the compound cyclizes together with the atoms it is attached to to form a heterocyclic group; Ring A is a 4- to 14-membered heterocyclic group or a 5- to 10-membered heteroaryl group; Each Z 1 Independently halogenated, cyano-based, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 11 )2、-OR 11 -C(O)R 11 -C(O)OR 11 -S(O) 0-2 R 11 -NR 11 S(O) 0-2 R 11 -S(O) 0- 2N(R 11 )2、-NR 11 S(O) 0-2 N(R 11 )2、-NR 11 C(O)N(R 11 )2、-C(O)N(R 11 )2、-NR 11 C(O)R 11 -OC(O)N(R) 11 )2 or -NR 11 C(O)OR 11 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1a replace; Each R 11 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1a replace; Each Z 1a Independently hydroxyl, halogenated, cyano, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R) 13 )2、-OR 13 -C(O)R 13 -C(O)OR 13 -S(O) 0-2 R 13 -NR 13 S(O) 0-2 R 13 -S(O) 0-2 N(R 13 )2、-NR 13 S(O) 0-2 N(R 13 )2、-NR 13 C(O)N(R 13 )2、-C(O)N(R 13 )2、-NR 13 C(O)R 13 -OC(O)N(R) 13 )2 or -NR 13 C(O)OR 13 ; where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1b replace; Each R 13 Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl groups are optionally independently bound by one to five Z groups. 1b replace; Each Z 1b Independently halogenated, cyanoated, hydroxylated, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 alkenyl, -LC 2-6 alkynyl, -LC 1-6 Halogenated alkyl, -LC 3-10 Cycloalkyl, -L-heterocyclic, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 ynyl group)-, -N(C 1-6 (halogenated alkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-、-C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 ynyl group)-, -C(O)N(C 1-6 (halogenated alkyl)-, -C(O)N(C 3-10 Cycloalkyl)-, -C(O)N(heterocyclic)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)- or -S(O)2NH-; Z 1b and each C of L 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclic, aryl, and heteroaryl groups are further optionally independently converted by one to five hydroxyl groups, halogenated groups, cyano groups, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 Cycloalkyl, heterocyclic, aryl, or heteroaryl substitutions.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 1 For key.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 1 It is -O-.

4. The compound according to claim 1, wherein L 1 For -QL 2 , where Q is phenyl or pyrazolyl.

5. The compound according to claim 1 or claim 4, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 2 For key.

6. The compound according to claim 1 or claim 4, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein L 2 It can be -CH2-, -C(O)NH-, or -S(O)2-.

7. The compound according to claim 1 or claim 2, having formula ID: ID, Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

8. The compound according to claim 1 or claim 2, having formula II: II, Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

9. The compound according to claim 1 or claim 2, having formula III: III, Or its pharmaceutically acceptable salts, solvates, stereoisomers or tautomers.

10. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is optionally surrounded by one or two R... 4 Replaced 4- to 8-membered monocyclic heterocyclic groups.

11. The compound of claim 10 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is selected from: , , , , and ; Each ring A can be optionally divided by one or two Rs. 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

12. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is optionally surrounded by one or two R... 4 Replaced 7- to 11-membered spirocyclic heterocyclic groups.

13. The compound of claim 12 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is selected from: , , , , , , or ; Each ring A can be optionally divided by one or two Rs. 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

14. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is optionally surrounded by one or two R... 4 Replaced 7- to 11-membered bridged ring heterocyclic groups.

15. The compound of claim 14 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is selected from: , , and ; Each ring A can be optionally divided by one or two Rs. 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

16. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is optionally surrounded by one or two R... 4 Replaced 8 to 14 fused polycyclic heterocyclic groups.

17. The compound of claim 16 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein ring A is selected from: , , , , , , , , , and ; Each ring A can be optionally divided by one or two Rs. 4 replace;( ) indicates that it is related to L 1 The connection point; and (*) indicates the connection point with the carbonyl group.

18. The compound according to any one of claims 1 to 8 or 9 to 17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein p is 1, and R 4 C 1-6 Alkyl, oxo, or halogenated.

19. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof, wherein p is 0.

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 5 It is hydrogen.

21. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 5 For one to three Z 1 Replacement C 1-6 alkyl.

22. The compound according to claim 21, wherein Z 1 Selected from one to five Z, optionally. 1a Substituted halogenated, -N(R) 11 )2 and heterocyclic groups.

23. The compound according to claim 22, wherein Z 1 It can be optionally controlled by one or two Z. 1a Substituted heterocyclic groups.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein R 6 It is hydrogen.

25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, wherein n is 0.

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

27. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of the compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

28. A method for regulating or degrading a protein expressed by the SMARCA2 gene, the method comprising contacting the protein with an effective amount of the compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

29. A method for regulating or degrading a protein expressed by the SMARCA4 gene, the method comprising contacting the protein with an effective amount of the compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, solvate, stereoisomer or tautomer thereof.

30. A method for regulating or degrading a protein expressed by the 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 26 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

31. A method for regulating or degrading a protein expressed by the 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 26 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

32. A method for regulating or degrading a protein expressed by the SMARCA2 gene in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 27.

33. A method for regulating or degrading a protein expressed by the SMARCA4 gene in a subject, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 27.

34. A method for treating cancer in a subject in need, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof.

35. A method for treating cancer in a subject in need, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 27.

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