BRM Targeted Compounds and Related Methods of Use

Abstract

The present disclosure provides bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and related methods of use.

Description

[Technical Field]

[0001] Provided herein are bifunctional compounds comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination, particularly with respect to switch / sucrose non-fermenting (SWI / SNF)-associated, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) (i.e., BRAHMA or BRM), which are degraded and / or otherwise inhibited by the bifunctional compounds disclosed herein. [Background technology]

[0002] The human switch / sucrose non-fermentable (SWI / SNF) complexes are ATP-dependent chromatin remodelers. These large complexes play important roles in essential cellular processes such as transcription, DNA repair, and replication by regulating DNA accessibility.

[0003] Mutations in genes encoding up to 20 canonical SWI / SNF subunits are observed in approximately 20% of all human cancers, with the highest mutation frequencies observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma.

[0004] SMARCA2 (BRM) and SMARCA4 (BRG1) are catalytic ATPase domain-containing subunits that are essential for SWI / SNF function in perturbing histone-DNA contacts, thereby providing access points for transcription factors and cognate DNA elements that facilitate gene activation and repression.

[0005] SMARCA2 and SMARCA4 share a high degree of homology (up to 75%). SMARCA4 is frequently mutated (i.e., deleted or inactivated) in primary tumors, particularly in lung cancer (12%), melanoma, liver cancer, and pancreatic cancer. SMARCA2 is one of the top essential genes in SMARCA4-mutated (deleted) cancer cell lines. This is because SMARCA4-deficient cancer cells exclusively depend on SMARCA2 ATPase activity for their chromatin remodeling activity for cellular functions such as cell proliferation, survival, and growth. Therefore, targeting SMARCA2 may be a promising therapeutic approach in SMARCA4-related or -deficient cancers (genetic synthetic lethality).

[0006] Previous studies have demonstrated strong synthetic lethality using gene expression manipulations such as RNAi. Downregulation of SMARCA2 gene expression in SMARCA4-mutant cancer cells results in suppression of cancer cell proliferation. However, SMARCA2 / 4 bromodomain inhibitors (e.g., PFI-3) show no or little effect on cell proliferation inhibition [Vangamudi et al. Cancer Res 2015]. This phenotypic discrepancy between gene expression downregulation and small molecule-based approaches led us to investigate proteolytic bispecific molecules in SMARCA4-deficient cancers.

[0007] SMARCA2 has also been reported to play a role in multiple myeloma expressing the t(4;14) chromosomal translocation [Chooi et al. Cancer Res abstract 2018]. SMARCA2 interacts with NSD2 and regulates the expression of genes such as PRL3 and CCND1. Downregulation of SMARCA2 gene expression by shRNA reduces the S phase of the cell cycle and suppresses cell proliferation in t(4;14) MM cells.

[0008] There is a need for therapeutic compounds that inhibit SMARCA2 and / or SMARCA4. Summary of the Invention

[0009] The present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein The PTM has the formula IA: [ka] is part of the formula R 1 is a covalent bond or chemical moiety linking the PTM and ULM, * is the point of attachment to ULM n=0 to 3, each W is independently an optionally substituted —CH—, —C(O)—, —S(O)—, or —S(O)—; when n=2 or 3, only one W is —C(O)—, —S(O)—, or —S(O)—, and the other W is —CH— or substituted —CH—; R c1 and R d1 are independently H, D, halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, or C 1-4 is alkoxyl, R e3 is H, -C(O)R f , or -P(O)(OR g )2 and R f and R g are independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl, or C 3-8 is a substituted heterocycloalkyl; Z and Y are each independently N, CR h where R h =H, D, Halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, C1-3 haloalkyl, or absent, or R 1 is attached to Z, then Z is C and Y is N, or CR h where R h is H, or R 1 is attached to Y, Y is C and Z is N or CR h where R h is H, B is an optionally substituted 5- to 7-membered cycloalkyl ring, an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocycle, and ring B is fused to ring G via Y and Z; ULM, [ka] and [ka] is the point of attachment to the PTM, X1 is a bond, -C(O)-, -C(S)-, -CH2-, -CHCF3-, SO2-, -S(O), P(O)R b -or-P(O)OR b - and R b is H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each X2 is independently N or CR b where one X2 is a C atom with a point of attachment to the PTM.

[0010] Stereoisomers of the compounds of Formula I, as well as pharmaceutical salts and stereoisomers thereof, are also contemplated, described and encompassed herein. Methods of using the compounds of Formula I, and pharmaceutical compositions containing the compounds of Formula I, are described. DETAILED DESCRIPTION OF THE INVENTION

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0012] Where a range of values ​​is provided, it is understood that each intervening value, to one-tenth of the unit of the lower limit, between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is included in the disclosure unless the context clearly dictates otherwise (such as in the case of a group containing the number of carbon atoms where each number of carbon atoms falling within the range is provided). The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where a stated range includes one or both of the upper or lower limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0013] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term will be given its art-recognized meaning by one of ordinary skill in the art applying the term in context to its use in describing this disclosure.

[0014] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0015] The terms "co-administration" and "co-administering" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and time-staggered administration (administration of one or more therapeutic agents at a different time than the administration of the additional therapeutic agent), so long as the therapeutic agents are present in the patient at some level, preferably in effective amounts, at the same time. In certain preferred embodiments, one or more of the compounds of the invention described herein are co-administered in combination with at least one additional bioactive agent, including, in particular, an anti-cancer agent. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0016] As used herein, the term "compound," unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes in context tautomers, positional isomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), thereof, as well as pharmaceutically acceptable salts and derivatives, including prodrugs and / or deuterated forms thereof, where applicable. Contemplated deuterated small molecules are those in which one or more of the hydrogen atoms contained in a drug molecule have been replaced by deuterium.

[0017] Within its use in context, the term compound generally refers to a single compound, but may also include stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures), as well as other compounds such as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. The term also refers to prodrug forms of compounds that have been modified to facilitate administration and delivery of the compound to the active site. In describing the compounds of the present invention, it should be noted that, among other things, numerous substituents and variables associated therewith are described. It will be understood by those skilled in the art that the molecules described herein are stable compounds as generally described below.

[0018] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins and target them for degradation. For example, E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-conjugating enzymes, cause the attachment of ubiquitin to lysines on target proteins, subsequently targeting specific protein substrates for degradation by the proteasome. Thus, E3 ubiquitin ligases alone or in complex with E2 ubiquitin-conjugating enzymes are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, in which a second ubiquitin is attached to the first, a third ubiquitin is attached to the second, and so on. Polyubiquitination targets proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is attached to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation, but instead may have their cellular location or function altered, for example, by binding to other proteins that have domains capable of binding to ubiquitin. Further complicating the issue, different lysines on ubiquitin can be targeted by E3s to create chains. The most common lysine is LYS48 on the ubiquitin chain, which is the lysine used to create polyubiquitin that is recognized by the proteasome.

[0019] As used herein, "cereblon (CRBN) E3 ubiquitin ligase" refers to the substrate-recognition subunit of the Cullin-RING E3 ubiquitin ligase complex. CRBN is one of the most common E3 ligases recruited by bifunctional proteolytic targeting chimeras (PROTACs) to induce ubiquitination of target proteins and subsequent proteasomal degradation (Maniaci C. et al., Bioorg Med Chem. 2019, 27(12):2466-2479).

[0020] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having up to 12 carbon atoms. In some embodiments, the number of carbon atoms is specified (i.e., C 1- (C8 means 1 to 8 carbons.) Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted as provided herein. In some embodiments, an alkyl group is C 1- C alkyl, and in some embodiments, it is C 1- It is a C4 alkyl.

[0021] When ranges of carbon atoms are used herein, such as C1-C6, all ranges as well as individual numbers of carbon atoms are included. For example, "C1-C3" includes C 1- C3, C 1- C2, C 2- These include C3, C1, C2, and C3.

[0022] When used in conjunction with a substituent defined herein, the term "optionally substituted" means that one or more hydrogens of the substituent may, but need not, be replaced with one or more suitable functional groups or other substituents provided herein.For example, a substituent may be optionally substituted with one or more of the following: -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl), 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl). alkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si( OH)3, -Si(C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl), -N(C-C alkyl)CONH(C-C alkyl), -N(C-C alkyl)CON(C-C alkyl), -NHCONH(C-C alkyl), -NHCON(C-C alkyl), -NHCONH, -N(C-C alkyl)SONH(C-C alkyl), -N(C-C alkyl)SON(C-C alkyl), -NHSONH(C-C alkyl), -NHSON(C-C alkyl), or -NHSONH. In some embodiments, each of the above optional substituents may itself be optionally substituted with one or two groups.

[0023] The term "optionally substituted -CH-" refers to "-CH-" or substituted -CH-. The substituted -CH- may also be referred to as -CH(substituent)- or -C(substituent)(substituent)-, where each substituent is independently selected from the optional substituents described herein.

[0024] The term "cycloalkyl," as used herein, refers to a 3- to 12-membered cyclic alkyl, including bridged and spiro rings (e.g., adamantine). Cycloalkyl groups can be fully saturated or partially unsaturated. The term "cycloalkyl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), in which a single cycloalkyl ring (as defined above) can be fused to one or more groups selected from heterocycle, carbocycle, aryl, or heteroaryl to form a polycondensed ring system. Such polycondensed ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocycle or heterocycle portion of the polycondensed ring. The rings of a polycondensed ring system can be connected to each other via fused, spiro, and bridged bonds, where permitted by valence requirements. It is understood that the individual rings of a polycondensed ring system can be connected to each other in any order. It is also understood that the point of attachment of multiple fused ring systems (as defined above for cycloalkyl) can be at any position on the cycloalkyl ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, the cycloalkyl group is a 3- to 7-membered cycloalkyl.

[0025] As used herein, the term "alkenyl" refers to a C alkyl group containing at least one carbon-carbon double bond. 2- C 12In some embodiments, an alkenyl group is optionally substituted. In some embodiments, an alkenyl group is C 2- It is a C6 alkenyl.

[0026] As used herein, the term "acynyl" refers to a C alkyl group containing at least one carbon-carbon triple bond. 2- C 12 In some embodiments, an alkenyl group is optionally substituted. In some embodiments, an alkynyl group is C 2- It is a C6 alkynyl.

[0027] The terms "alkoxy," "alkylamino," and "alkylthio" are used in their conventional sense to refer to an alkyl group attached to the remainder of the molecule via an oxygen atom ("oxy"), an amino group ("amino"), or a thio group. The term "alkylamino" includes mono- and di-alkylamino groups, where the alkyl portions may be the same or different.

[0028] The terms "halo" or "halogen," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0029] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. As used herein, reference to a straight chain when used in the context of a bridging group refers to a direct chain of atoms connecting the two terminal positions of the bridging group.

[0030] As used herein, the term "aryl" refers to a monocyclic all-carbon aromatic ring or a polycondensed all-carbon ring system in which at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 12 carbon atoms. Aryl includes the phenyl radical. Aryl also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9 to 12 carbon atoms in which at least one ring is aromatic and the other rings may or may not be aromatic. Such polycondensed ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the polycondensed ring system. The rings of a polycondensed ring system can be connected to each other via fused, spiro, and bridged bonds, where permitted by valence requirements. It should be understood that the point of attachment of a polycondensed ring system, as defined above, can be at any position on the aromatic ring. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphth-yl, and the like.

[0031] The term "heteroaryl," as used herein, refers to a single aromatic ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur. "Heteroaryl" also includes multiple condensed ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form if the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. "Heteroaryl" also includes polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group, as defined above, is fused to one or more rings selected from heteroaryl (e.g., to form naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (e.g., to form 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (e.g., to form 5,6,7,8-tetrahydroquinolyl), and aryl (e.g., to form indazolyl) to form a polycondensed ring system. Thus, a heteroaryl (single aromatic ring or polycondensed ring system) has about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. A heteroaryl (single aromatic ring or polycondensed ring system) can also have about 5 to 12 members or about 5 to 10 members in the heteroaryl ring. Polycondensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. The rings of a polycondensed ring system may be connected to each other via fused, spiro, and bridged bonds, where permitted by valence requirements. It is understood that the individual rings of a polycondensed ring system may be connected to each other in any order. It is also understood that the point of attachment (as defined above for heteroaryl) of a polycondensed ring system may be at any position on the heteroaryl ring.It is also understood that the point of attachment of a heteroaryl or heteroaryl poly-fused ring system can be any suitable atom of the heteroaryl ring, including carbon atoms and heteroatoms (eg, nitrogen). Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole. In one embodiment, the term "heteroaryl" refers to a single aromatic ring containing at least one heteroatom. For example, this term includes 5- and 6-membered monocyclic aromatic rings containing one or more heteroatoms. Non-limiting examples of heteroaryls include, but are not limited to, pyridyl, furyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0032] The term "heterocyclyl" or "heterocycle," as used herein, refers to a single saturated or partially unsaturated ring having at least one atom other than carbon in the ring, the atom being selected from the group consisting of oxygen, nitrogen, and sulfur; the term also includes multiple condensed ring systems having at least one such saturated or partially unsaturated ring, which are further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also includes polycondensed ring systems (e.g., ring systems containing two, three, or four rings), where a single heterocycle (as defined above) can be fused with one or more groups selected from heterocycle (e.g., to form 1,8-decahydronaphthyridinyl), carbocycle (e.g., to form decahydroquinolyl), and aryl to form a polycondensed ring system. Thus, a heterocycle (single saturated or single partially unsaturated ring or polycondensed ring system) has about 2 to 20 carbon atoms and 1 to 6 heteroatoms in the heterocycle. Such polycondensed ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the polycondensed ring. The rings of a polycondensed ring system can be connected to each other via fused, spiro, and bridged bonds, where permitted by valence requirements. It is understood that the individual rings of a polycondensed ring system can be connected to each other in any order. Thus, a heterocyclic ring (a single saturated or single partially unsaturated ring, or a polycondensed ring system) has about 3 to 20 atoms, including about 1 to 6 heteroatoms in the heterocyclic ring system. It is also understood that the point of attachment of a polycondensed ring system (as defined above for heterocyclyl) can be at any position on the heterocyclyl ring. It is also understood that the point of attachment of a heterocyclic ring or heterocyclic polycondensed ring system can be at any suitable atom of the heterocyclic ring, including carbon atoms and heteroatoms (e.g., nitrogen).In one embodiment, the term heterocycle refers to C. 2-20 In one embodiment, the term heterocycle includes C 2-7 In one embodiment, the term heterocycle includes C 2-5 In one embodiment, the term heterocycle includes C 2-4Exemplary heterocycles include aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, and imidazolidin-2-one. These include, but are not limited to, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]-heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and pyrrolidin-2-one. In one embodiment, the term "heterocycle" refers to a monocyclic saturated or partially unsaturated 3- to 8-membered ring containing at least one heteroatom. For example, this term includes monocyclic saturated or partially unsaturated 4-, 5-, 6-, or 7-membered rings containing at least one heteroatom. Non-limiting examples of heterocycles include aziridine, azetidine, pyrrolidine, piperidine, piperazine, oxirane, morpholine, and thiomorpholine. As used herein, the term "9- or 10-membered heterobicycle" refers to a partially unsaturated or aromatic fused bicyclic ring system containing at least one heteroatom. For example, the term 9- or 10-membered heterobicycle includes bicyclic ring systems containing a benzo ring fused to a 5- or 6-membered saturated, partially unsaturated, or aromatic ring containing one or more heteroatoms.

[0033] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si). Nitrogen and sulfur may be in oxidized form, where feasible.

[0034] As used herein, the term "chiral" refers to molecules that have the property of not being superimposable on their mirror image partners, and the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0035] As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers, diastereomers, tautomers.

[0036] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or livestock, to which treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided. For treatment of an infection, condition, or disease state specific to a particular animal, such as a human patient, the term patient refers to that particular animal, including domestic animals such as dogs or cats, or livestock such as horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise stated or implied from the context of the use of the term.

[0037] The term "effective," when used within the context of its intended use, is used to describe the amount of a compound, composition, or ingredient that produces an intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0038] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of the federal or state government or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, e.g., humans.

[0039] "Pharmaceutically acceptable salts" refers to salts of compounds of the present disclosure that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may include inorganic or organic acid addition salts and base addition salts. Specific examples of such salts include the following: (1) salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc.

[0040] A "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically acceptable, and otherwise biologically suitable for administration to a subject, such as an inert substance that is added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a drug and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0041] "Solvate" refers to a physical association of a compound of Formula I with one or more solvent molecules.

[0042] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to ameliorating the disease or disorder (e.g., preventing or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0043] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein the PTM (protein targeting moiety) is of formula IA: [ka] is part of the formula R 1 is a covalent bond or chemical moiety linking the PTM and ULM, * is the point of attachment to ULM n=0 to 3, each W is independently an optionally substituted —CH—, —C(O)—, —S(O)—, or —S(O)—; when n=2 or 3, only one W is —C(O)—, —S(O)—, or —S(O)—, and the other W is —CH— or substituted —CH—; R c1 and R d1 are independently H, D, halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, or C 1-4 is alkoxyl, R e3 is H, -C(O)R f , or -P(O)(OR g )2 and R f and R g are independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl, or C 3-8 is a substituted heterocycloalkyl; Z and Y are each independently N or CR h where R h =H, D, Halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 haloalkyl, or absent, or R 1 is attached to Z, then Z is C and Y is N, or CR h where R h is H, or R 1 is attached to Y, Y is C and Z is N or CR h where R h is H, B is an optionally substituted 5- to 7-membered cycloalkyl ring, an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocycle, and ring B is fused to ring G via Y and Z; ULM, [ka] and [ka] is the point of attachment to the PTM, X1 is a bond, -C(O)-, -C(S)-, -CH2-, -CHCF3-, SO2-, -S(O), P(O)R b -or-P(O)OR b - and R b is H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each X2 is independently N or CR b where one X2 is a C atom with a point of attachment to the PTM.

[0044] In some embodiments, the compound of formula I comprises a PTM. According to the present disclosure, the PTM in the compound of formula I is represented by formula IA [ka] is part of.

[0045] According to the present disclosure, B is a ring fused to ring "C" via Y and Z.

[0046] In some embodiments, B in formula IA is an optionally substituted 5- to 7-membered cycloalkyl ring, an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocycle.

[0047] In some embodiments, B in formula IA is an optionally substituted 5-7 membered cycloalkyl ring.

[0048] In some embodiments, B in formula IA is an unsubstituted 5-7 membered cycloalkyl ring. In some embodiments, B is of formula IA and is a substituted 5-7 membered cycloalkyl ring wherein the substituent is hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0049] In some embodiments, B in formula IA is an unsubstituted 5-7 membered heteroaryl ring.

[0050] In some embodiments, B in formula IA is an unsubstituted 5-7 membered aryl ring. In some embodiments, B in formula IA is a substituted 5-7 membered aryl ring, wherein the substituent is hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0051] In some embodiments, B in formula IA is an unsubstituted 5-7 membered heteroaryl ring. In some embodiments, B in formula IA is a substituted 5-7 membered heteroaryl ring, wherein the substituent is hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0052] In other embodiments, B in formula IA is an unsubstituted 5-7 membered heterocycle.

[0053] In some embodiments, B in formula IA is an unsubstituted 5-7 membered heterocycle. In some embodiments, B in formula IA is a substituted 5-7 membered heterocyclic ring, wherein the substituents are hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0054] In some embodiments, n in formula IA is 0, 1, 2, or 3. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3.

[0055] In some embodiments, each W in formula IA is independently an optionally substituted -CH2-, -C(O)-, -S(O)-, or -S(O)2-; when n=2 or 3, only one W may be -C(O)-, -S(O)-, or -S(O)2-, and the other W is -CH2- or substituted -CH2-. When W is substituted -CH2-, preferred substituents include D, C, 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-4 Examples include alkoxyl.

[0056] In some embodiments, W in formula IA is optionally substituted -CH2-. In other embodiments, W in formula IA is -CH2-. When W is substituted -CH2-, preferred substituents include D, C, 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-4 Examples include alkoxyl.

[0057] In some embodiments, W in formula IA is —C(O)—.

[0058] In some embodiments, W in formula IA is —S(O)—.

[0059] In some embodiments, W in formula IA is -S(O)2-.

[0060] In embodiments of the present disclosure where n is 2 or 3, only one W may be -C(O)-, -S(O)-, or -S(O)2-, and the other W is -CH2- or substituted -CH2-. When W is substituted -CH2-, preferred substituents include D, C, 1-3 Alkyl, C 1-3Haloalkyl, and C 1-4 Examples include alkoxyl.

[0061] In some embodiments, R in formula IA c1 and R d1 are independently H, D, halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, or C 1-4 It is alkoxyl.

[0062] In some embodiments, R c1 is H.

[0063] In some embodiments, R c1 is D.

[0064] In some embodiments, R c1 is halo, for example, —F, —CL, —Br, or —I.

[0065] In some embodiments, R c1 is C 1-6 Alkyl, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -CH3, -CH2CH3, and the like.

[0066] In some embodiments, R c1 is C 1-6 Cycloalkyl, for example, -C1 cycloalkyl, -C2 cycloalkyl, -C3 cycloalkyl, and the like.

[0067] In some embodiments, R c1 is C 1-3 Haloalkyl, for example, —C1 haloalkyl, —C2 haloalkyl, —C3 haloalkyl, —CF3, —CH2CF3, and the like.

[0068] In some embodiments, R c1 is C 1-4Alkoxyl, for example, -C1 alkoxyl, -C2 alkoxyl, -C3 alkoxyl, -C4 alkoxyl, -OCH3, -OCH2CH3 and the like.

[0069] In some embodiments, R d1 is H.

[0070] In some embodiments, R d1 is D.

[0071] In some embodiments, R d1 is halo, for example, —F, —Cl, —Br, or —I.

[0072] In some embodiments, R d1 is C 1-6 Alkyl, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -CH3, -CH2CH3, and the like.

[0073] In some embodiments, R d1 is C 1-6 Cycloalkyl, for example, -C1 cycloalkyl, -C2 cycloalkyl, -C3 cycloalkyl, and the like.

[0074] In some embodiments, R d1 is C 1-3 Haloalkyl, for example, —C1 haloalkyl, —C2 haloalkyl, —C3 haloalkyl, —CF3, —CH2CF3, and the like.

[0075] In some embodiments, R d1 is C 1-4 Alkoxyl, for example, -C1 alkoxyl, -C2 alkoxyl, -C3 alkoxyl, -C4 alkoxyl, -OCH3, -OCH2CH3 and the like.

[0076] In some embodiments, R of formula IA e3 is H, -C(O)R f , or -P(O)(OR g )2 and Rf and R g are independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl, or C 3-8 It is a substituted heterocycloalkyl.

[0077] In some embodiments, R e3 is H.

[0078] In other embodiments, R e3 is -C(O)R f where R f is H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8 Substituted cycloalkyl, C 3-8 Heterocycloalkyl, or C 3-8 It is a substituted heterocycloalkyl.

[0079] In other embodiments, R e3 is -C(O)R f where R f is H. In other embodiments, R e3 is -C(O)R f where R f is C 1-4 Alkyl, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3, and the like.

[0080] In other embodiments, R e3 is -C(O)R f where R f is C 1-4 Substituted alkyl, for example, -C1 substituted alkyl, -C2 substituted alkyl, -C3 substituted alkyl, and -C4 substituted alkyl.

[0081] In other embodiments, R e3is -C(O)R f where R f is C 3-8 Cycloalkyl, for example, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, and C8 cycloalkyl.

[0082] In other embodiments, R e3 is -C(O)R f where R f is C 3-8 Substituted cycloalkyls include, for example, C3 substituted cycloalkyl, C4 substituted cycloalkyl, C5 substituted cycloalkyl, C6 substituted cycloalkyl, C7 substituted cycloalkyl, and C8 substituted cycloalkyl.

[0083] In other embodiments, R e3 is -C(O)R f where R f is C 3-8 Heterocycloalkyl, for example, C3 heterocycloalkyl, C4 heterocycloalkyl, C5 heterocycloalkyl, C6 heterocycloalkyl, C7 heterocycloalkyl, and C8 heterocycloalkyl.

[0084] In other embodiments, R e3 is -C(O)R f where R f is C 3-8 Substituted heterocycloalkyls include, for example, C3 substituted heterocycloalkyl, C4 substituted heterocycloalkyl, C5 substituted heterocycloalkyl, C6 substituted heterocycloalkyl, C7 substituted heterocycloalkyl, and C8 substituted heterocycloalkyl.

[0085] In other embodiments, R e3 is -P(O)(OR g )2, wherein each R g are independently H, C 1-4 Alkyl, C 1-4 Substituted alkyl, C 3-8 Cycloalkyl, C 3-8Substituted cycloalkyl, C 3-8 Heterocycloalkyl, or C 3-8 It is a substituted heterocycloalkyl.

[0086] In other embodiments, R e3 is -P(O)(OR g )2, wherein each R g is H.

[0087] In other embodiments, R e3 is -P(O)(OR g )2, wherein each R g is C 1-4 Alkyl, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3, and the like.

[0088] In other embodiments, R e3 is -P(O)(OR g )2, wherein one R g is H, and the other R g is C 1-4 Alkyl, for example, -C1 alkyl, -C2 alkyl, -C3 alkyl, -C4 alkyl, -CH3, -CH2CH3, and the like.

[0089] In other embodiments, R e3 is -P(O)(OR g )2, wherein at least one R g is C 1-4 Substituted alkyls include, for example, -C1 substituted alkyl, -C2 substituted alkyl, -C3 substituted alkyl, and -C4 substituted alkyl.

[0090] In other embodiments, R e3 is -P(O)(OR g )2, wherein at least one R g is C 3-8 Cycloalkyl, for example, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, and C8 cycloalkyl.

[0091] In other embodiments, R e3 is -P(O)(OR g )2, wherein at least one R g is C 3-8 Substituted cycloalkyls include, for example, C3 substituted cycloalkyl, C4 substituted cycloalkyl, C5 substituted cycloalkyl, C6 substituted cycloalkyl, C7 substituted cycloalkyl, and C8 substituted cycloalkyl.

[0092] In other embodiments, R e3 is -P(O)(OR g )2, wherein at least one R g is C 3-8 Heterocycloalkyl, for example, C3 heterocycloalkyl, C4 heterocycloalkyl, C5 heterocycloalkyl, C6 heterocycloalkyl, C7 heterocycloalkyl, and C8 heterocycloalkyl.

[0093] In other embodiments, R e3 is -P(O)(OR g )2, wherein at least one R g is C 3-8 Substituted heterocycloalkyls include, for example, C3 substituted heterocycloalkyl, C4 substituted heterocycloalkyl, C5 substituted heterocycloalkyl, C6 substituted heterocycloalkyl, C7 substituted heterocycloalkyl, and C8 substituted heterocycloalkyl.

[0094] In some embodiments, Z and Y in formula IA are each independently N or CR h (In the formula, R h =H, D, Halo, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 haloalkyl, or may be absent when n=1-3, resulting in a double bond between Z and Y), or R 1 is attached to Z, Z is C and Y is N or CR h (In the formula, R h is H) or R1 is attached to Y, Y is C and Z is N or CR h (In the formula, R h is H). Examples of these embodiments include: [ka]

[0095] In some embodiments, Z is N.

[0096] In other embodiments, Z is CR h and R h =H.

[0097] In other embodiments, Z is CR h and R h =D.

[0098] In other embodiments, Z is CR h and R h =Halo.

[0099] In other embodiments, Z is CR h and R h =C 1-6 It is alkyl.

[0100] In other embodiments, Z is CR h and R h =C 1-6 It is cycloalkyl.

[0101] In other embodiments, Z is CR h and R h =C 1-3 It is haloalkyl.

[0102] In other embodiments, Z is CR h and R h = absent and Z is attached to Y by a double bond.

[0103] In some embodiments, Z is C and R 1 is bonded to.

[0104] In some embodiments, Y is N.

[0105] In another embodiment, Y is CR h and R h =H.

[0106] In another embodiment, Y is CR h and R h =D.

[0107] In another embodiment, Y is CR h and R h =Halo.

[0108] In another embodiment, Y is CR h and R h =C 1-6 It is alkyl.

[0109] In another embodiment, Y is CR h and R h =C 1-6 It is cycloalkyl.

[0110] In another embodiment, Y is CR h and R h =C 1-3 It is haloalkyl.

[0111] In another embodiment, Y is CR h and R h = absent and Y is attached to Z by a double bond.

[0112] In some embodiments, Y is C and R 1 is bonded to.

[0113] In some embodiments, the PTM is a moiety of formula IA, where * is the point of attachment to the ULM.

[0114] In some embodiments, R in formula IA 1 is a covalent bond or chemical moiety that links a PTM and a ULM.

[0115] In some embodiments, R in formula IA 1 is a covalent bond.

[0116] In other embodiments, R in formula IA 1 is the chemical moiety that links the PTM and ULM.

[0117] Chemical moieties used to link PTM and ULM moieties are known in the art. These moieties are sometimes referred to in the art as "linkers." In some embodiments, R in Formula IA 1 are chemical moieties used to link PTMs and ULMs that are known in the art.

[0118] In some embodiments, R of formula IA 1 is a chemical moiety used to conjugate a PTM and a ULM, as described in U.S. Patent Application Publication No. 2019 / 0300521, which is incorporated herein by reference in its entirety.

[0119] In other embodiments, R of formula IA 1 is a chemical moiety used to conjugate a PTM and a ULM, as described in U.S. Patent Application Publication No. 2019 / 0255066, which is incorporated by reference herein in its entirety.

[0120] In other embodiments, R in formula IA 1 is a chemical moiety used to link a PTM and a ULM, as described in WO 2019 / 084030, which is incorporated by reference in its entirety.

[0121] In other embodiments, R in formula IA 1is a chemical moiety used to link a PTM and a ULM, as described in WO 2019 / 084026, which is incorporated by reference in its entirety.

[0122] In some embodiments, R in formula IA 1 is the expression: -(A) q - is a chemical structural unit represented by During the ceremony, q is an integer from 1 to 14, Each A is independently a bond, CR 1a R 1b , O, S, SO, SO2, NR 1c , SO2NR 1c ,SONR 1c , SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR 1c , N.R. 1c CONR 1d , N.R. 1c C(O)O, NR 1c SO2NR 1d , CO, CR 1a =CR 1b , C≡C, SiR 1a R 1b , P(O)R 1a , P(O)OR 1a , (CR 1a R 1b ) 1-4 , -(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 , -(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 , -(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , N.R. 1c C(=NCN)NR1d NR 1c C(=NCN), NR 1c C(=CNO2)NR 1d , 0 to 6 R 1a and / or R 1b 3-11 membered cycloalkyl optionally substituted with a group, 0-6 R 1a and / or R 1b optionally substituted 3- to 11-membered heterocyclyl group, 0-6 R 1a and / or R 1b group, optionally substituted aryl, 0 to 6 R 1a and / or R 1b and optionally substituted heteroaryl, R 1a , R 1b , R 1c , R 1d and R 1eare each independently -H, D, -halo, -C1-C8 alkyl, -C1-C6 haloalkyl, -O-C1-C8 alkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl)2, N-(3- to 11-membered cycloalkyl), )(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C1-C8 alkyl)3 , -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl or, where the context permits, R 1a or R 1b may be linked to other groups or to each other and may be linked to 0 to 4 R 1e The groups form optionally substituted cycloalkyl and / or heterocyclyl moieties.

[0123] In these embodiments, q represents the number of A groups connected. For example, when q=1, -(A) q - is -A1-, and when q=2, -(A) q - is -A1-A2- and when q=3, -(A) q - is -A1-A2-A3-, and when q=4, -(A) q - is -A1-A2-A3-A4-, and when q=5, -(A) q - is -A1-A2-A3-A4-A5-, and when q=6, -(A) q - is -A1-A2-A3-A4-A5-A6-, and when q=7, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-, and when q=8, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-, and when q=9, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-A9-, and when q=10, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 - and when q=11, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 - and when q=12, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 - and when q=13, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 - and when q=14, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 -A14 -It is.

[0124] In some embodiments, q=5 and R 1 is a chemical moiety represented by the formula: -A1-A2-A3-A4-A5-, where A1, A3 and A5 are each independently a bond, -(CR 1a R 1b ) 0-4 O(CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 S(CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 NR 1c (CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 SO(CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 SO2(CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 SO2NR 1c (CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 SONR 1c (CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 SO(=NR 1c )(CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 SO(=NR1c )NR 1d (CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 CONR 1c (CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 C(O)O(CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 NR 1c CONR 1d (CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 NR 1c C(O)O(CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 NR 1c SO2NR 1d (CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 C(O)(CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 CR 1a =CR 1b (CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 C≡C(CR 1a R 1b ) 0-4 、-(CR 1a R 1b ) 0-4 SiR 1a R1b (CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 P(O)R 1a (CR 1a R 1b ) 0-4 , -(CR 1a R 1b ) 0-4 P(O)OR 1a (CR 1a R 1b ) 0-4 , (CR 1a R 1b ) 1-4 , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl; each of A2 and A4 is independently a bond, (CR 1a R 1b ) 1-4 , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl; R 1a and R 1bare each independently -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl)2, N-(3- to 11-membered cycloalkyl), chloroalkyl)(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si( C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl )CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SONH(C1-C8 alkyl), -N(C1-C8 alkyl)SON(C1-C8 alkyl)2, -NHSONH(C1-C8 alkyl), -NHSON(C1-C8 alkyl)2, or -NHSONH2; 1c and R 1d are each independently H, D, or optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0125] In some embodiments, q=4 and R 1 is a chemical moiety represented by the formula: -A1-A2-A3-A4-, wherein A 1-4 each independently represents O, S, SO, SO2, NR 1c ,SO2NR 1c ,SONR 1c ,SO(=NR 1c ),SO(=NR 1c )NR 1d ,CONR 1c ,NR 1c CONR 1d ,NR 1c C(O)O,NR 1c SO2NR 1d ,CO,CR 1a =CR 1b ,C≡C,SiR 1a R 1b ,P(O)R 1a ,P(O)OR 1a ,(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 , -(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl; R 1a and R 1bare each independently -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl)2, N-(3- to 11-membered cycloalkyl), chloroalkyl)(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si( C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl )CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SONH(C1-C8 alkyl), -N(C1-C8 alkyl)SON(C1-C8 alkyl)2, -NHSONH(C1-C8 alkyl), -NHSON(C1-C8 alkyl)2, or -NHSONH2; 1c and R 1d are each independently H, D, or optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0126] In other embodiments, q=3 and R 1 is a chemical moiety represented by the formula: -A1-A2-A3-, wherein A 1-3 Each of these is independently O, ,S,SO,SO2,NR 1c ,SO2NR 1c ,SONR 1c ,SO(=NR 1c ),SO(=NR 1c )NR 1d ,CONR 1c ,NR 1c CONR 1d ,NR 1c C(O)O,NR 1c SO2NR 1d ,CO,CR 1a =CR 1b ,C≡C,SiR 1a R 1b ,P(O)R 1a ,P(O)OR 1a ,(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl; R 1a and R 1bare each independently -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl)2, N-(3- to 11-membered cycloalkyl), chloroalkyl)(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si( C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl )CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SONH(C1-C8 alkyl), -N(C1-C8 alkyl)SON(C1-C8 alkyl)2, -NHSONH(C1-C8 alkyl), -NHSON(C1-C8 alkyl)2, or -NHSONH2; 1c and R 1d are each independently H, D, or optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0127] In other embodiments, q=2 and R 1 is a chemical moiety represented by the formula: -A1-A2-, wherein A 1-2 each independently represents O, S, SO, SO2, NR 1c ,SO2NR 1c ,SONR 1c ,SO(=NR 1c ),SO(=NR 1c )NR 1d ,CONR 1c ,NR 1c CONR 1d ,NR 1c C(O)O,NR 1c SO2NR 1d ,CO,CR 1a =CR 1b ,C≡C,SiR 1a R 1b ,P(O)R 1a ,P(O)OR 1a ,(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl; R 1a and R 1bare each independently -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl)2, N-(3- to 11-membered cycloalkyl), chloroalkyl)(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si( C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl )CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SONH(C1-C8 alkyl), -N(C1-C8 alkyl)SON(C1-C8 alkyl)2, -NHSONH(C1-C8 alkyl), -NHSON(C1-C8 alkyl)2, or -NHSONH2; 1c and R 1d are each independently H, D, or optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0128] In some embodiments, q=1 and R 1 is a chemical moiety represented by the formula: -A1, where A1 is O, S, SO, SO2, NR 1c ,SO2NR 1c ,SONR 1c ,SO(=NR 1c ),SO(=NR 1c )NR 1d ,CONR 1c ,NR 1c CONR 1d ,NR 1c C(O)O,NR 1c SO2NR 1d ,CO,CR 1a =CR 1b ,C≡C,SiR 1a R 1b ,P(O)R 1a ,P(O)OR 1a ,(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 ,-(CR 1a R 1b ) 1-4 NR(CR 1a R 1b ) 1-4 , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl, wherein R 1a and R 1bare each independently -H, D, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, -O-(3- to 11-membered cycloalkyl), -S-(3- to 11-membered cycloalkyl), NH-(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl)2, N-(3- to 11-membered cycloalkyl), -C(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, SO(NH)C1-C8 alkyl, P(O)(OC1-C8 alkyl)(C1-C8 alkyl), -P(O)(OC1-C8 alkyl)2, -C≡C-C1-C8 alkyl, -C≡CH, -CH=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=CH(C1-C8 alkyl), -C(C1-C8 alkyl)=C(C1-C8 alkyl)2, -Si(OH)3, -Si(C 1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SON2NHC1-C8 alkyl, -SON2N(C1-C8 alkyl)2, -SO(NH)NHC1-C8 alkyl, -SO(NH)N(C1-C8 alkyl)2, -SONHC1-C8 alkyl, -SON(C1-C8 alkyl)2, -CONHC1-C8 alkyl, -CON(C1-C8 alkyl)2, -N(C1-C8 alkyl )CONH(C1-C8 alkyl), -N(C1-C8 alkyl)CON(C1-C8 alkyl)2, -NHCONH(C1-C8 alkyl), -NHCON(C1-C8 alkyl)2, -NHCONH2, -N(C1-C8 alkyl)SONH(C1-C8 alkyl), -N(C1-C8 alkyl)SON(C1-C8 alkyl)2, -NHSONH(C1-C8 alkyl), -NHSON(C1-C8 alkyl)2, or -NHSONH2; 1c or R 1d are each independently H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8It is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0129] In some embodiments, R 1 is a covalent bond, 0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group, 0-6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted by a -(CR 1a R 1b ) 1-5 , -(CR 1a =CR 1b )-, -(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -, -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5-(C≡C)-(CR 1a R 1b ) 1-5 -, -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S, or NR 1c and -(C≡C)-(CR 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3 to 11-membered cycloalkyl optionally substituted with a -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with 0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -, - (0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -, -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3 to 11-membered cycloalkyl)-A-, -(CR 1a R 1b ) 1-5-(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-A-, -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-, where each A is independently O, S, or NR 1c and -(CR 1a R 1b )1-5 -A-(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-, where each A is independently O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(CO), where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(CR 1a =CR 1b )-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(CO)-(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(CO)-(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a and / or R 1b and (3- to 11-membered cycloalkyl optionally substituted with a cycloalkyl group)-A-(CO)-, wherein each A is independently O, S, or NR 1c and -(0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-CO-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0~ 6 R's 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c and -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c and -(0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 - or - (0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -It is.

[0130] In some embodiments, R 1 -CR 1a =CR 1b -, for example, -CH=CH-.

[0131] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 For example, -(CH2) 1-5 -, -CH2-, -CH2CH2CH2-, etc.

[0132] In some embodiments, R 1 Ha-(CR 1a R 1b ) 1-5-A, where A is O, S, or NR 1c For example, -(CH2) 1-5 -O-, -(CH2) 1-5 -S-, -(CH2) 1-5 -NH- or -(CH2) 0-2 -(C(CH3)2)-(CH2) 0-2 -O-.

[0133] In other embodiments, R 1 is -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 where A is O, S, or NR 1c For example, -(CH2) 1-5 -O-(CH2) 1-5 -, -(CH2) 1-5 -S-(CH2) 1-5 -, -(CH2) 1-5 -NH-(CH2) 1-5 -etc.

[0134] In some embodiments, R 1 is -(C≡C)-(CR 1a R 1b ) 1-5 For example, -(C≡C)-(CH2)2-.

[0135] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b and optionally substituted 3- to 11-membered cycloalkyl)-, for example, -CH2-cyclobutyl-.

[0136] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b3- to 11-membered cycloalkyl)-(CR 1a R 1b ) 1-5 For example, -CH2-cyclobutyl-CH2-.

[0137] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 For example, -CH2-azetidinyl-CH2-.

[0138] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b group, for example, -CH2-azetidinyl-, etc.

[0139] In some embodiments, R 1 is -(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl)-(CR 1a R 1b ) 1-5 -, for example, -azetidinyl-CH2-, -pyrrolidinyl-CH2-, -piperidyl-CH2-, etc.

[0140] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered cycloalkyl)-(CR 1a R1b ) 1-5 -A, where A is O, S, or NR 1c For example, -CH2-cyclopropyl-CH2-O-.

[0141] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A, where A is O, S, or NR 1c For example, -CH2-piperidinyl-CH2CH2-O-.

[0142] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c For example, -CH2-azetidinyl-O-.

[0143] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c For example, -CH2-O-azetidinyl-, -CH2-NH-azetidinyl-, etc.

[0144] In other embodiments, R 1 is -(CR 1a R 1b ) 1-5-A-(0 to 6 R 1a and / or R 1b A is O, S, or NR 1c For example, -CH2-O-cyclobutylene-, -CH2-NH-cyclobutylene-, etc.

[0145] In some embodiments, R 1 is -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A, where A is O, S, or NR 1c For example, -CH2-O-CH2CH2-O-.

[0146] In some embodiments, Y in the compound of formula IA is CR h where R h is H and the compound of formula IA has the formula IA-1: [ka] and In the formula, R c1 , R d1 , R e3 , W, Z, B, n, and R 1 is as described above for formula IA.

[0147] In some embodiments, n in formula IA-1 is 1.

[0148] In some embodiments of compounds of formula IA-1, at least one W is an optionally substituted —CH 2 —.

[0149] In some embodiments of the compound of formula IA-1, at least one W is -CH2- or substituted -CH2-, wherein the substituent is alkyl, alkoxy, or alkylamino.

[0150] In some embodiments of the compound of formula IA-1, at least one W is -CH2-.

[0151] In some embodiments of the compound of formula IA-1, one W is —C(O)—.

[0152] In some embodiments of the compound of formula IA-1, one W is —S(O)—.

[0153] In some embodiments of the compound of formula IA-1, one W is -S(O)2-.

[0154] In some embodiments, B in formula IA-1 is an optionally substituted 5-7 membered cycloalkyl ring.

[0155] In some embodiments, B in formula IA-1 is an optionally substituted 5- to 7-membered cycloalkyl ring, the optional substituents being hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0156] In another embodiment, in formula IA-1, B is an optionally substituted 5-7 membered heterocycle.

[0157] In some embodiments, B in formula IA-1 is an optionally substituted 5- to 7-membered heterocycle, the optional substituents being hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0158] In other embodiments, Y in the compound of formula IA is N and Z is CR h where R h is H and the compound of formula IA has formula IA-2: [ka] and In the formula, R c1 , R d1 , R e3, W, B, n, and R 1 is as described above for formula IA.

[0159] In some embodiments, n in formula IA-2 is 1.

[0160] In some embodiments of the compound of formula IA-2, at least one W is -CH2- or substituted -CH2-.

[0161] In some embodiments of compounds of formula IA-2, at least one W is -CH2- or substituted -CH2-, wherein the substituent is alkyl, alkoxy, or alkylamino.

[0162] In some embodiments of the compound of formula IA-2, at least one W is -CH2-.

[0163] In some embodiments of the compound of formula IA-2, one W is —C(O)—.

[0164] In some embodiments of the compound of formula IA-2, one W is —S(O)—.

[0165] In some embodiments of the compound of formula IA-2, one W is -S(O)2-.

[0166] In some embodiments, B in formula IA-2 is an optionally substituted 5-7 membered heterocycle.

[0167] In some embodiments, B in formula IA-2 is an optionally substituted 5- to 7-membered heterocycle, the optional substituents being hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0168] In other embodiments, in formula IA-2, B is an optionally substituted 5-7 membered heterocycle.

[0169] In some embodiments, B in formula IA-2 is an optionally substituted 5-7 membered heterocycle, wherein the optional substituents are hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino, or cyano.

[0170] In some embodiments, the compound of formula IA has formula IA-3: [ka] is a compound of In the formula, m=1 to 3; X is optionally substituted -CH2- or NH, or R 1 is attached to X, X is —CH— or N; Q is optionally substituted -CH-, optionally substituted -(CH)-, -C(O)-, optionally substituted -CHC(O)-, -S(O)-, -S(O)-, optionally substituted -CHS(O)-, or optionally substituted -CHS(O)-, wherein R c1 , R d1 , R e3 , W, Z, B, n, and R 1 is as described above for formula IA.

[0171] In some embodiments of the compound of formula IA-3, n=1. In other embodiments of the compound of formula IA-3, n=2. In other embodiments of the compound of formula IA-3, n=3.

[0172] In some embodiments of the compound of formula IA-3, X is -CH-.

[0173] In other embodiments of the compound of formula IA-3, X is NH.

[0174] R 1 In some embodiments of the compound of formula IA-3 where is attached to X, X is CH.

[0175] R 1 In other embodiments of the compound of formula IA-3 where is attached to X, X is N.

[0176] In some embodiments of the compound of formula IA-3, Q is an optionally substituted —CH 2 —.

[0177] In some embodiments of the compound of formula IA-3, Q is an optionally substituted -CH2-, where the optional substituent is alkyl, alkoxy, or alkylamino.

[0178] In some embodiments of the compound of formula IA-3, Q is an optionally substituted —(CH 2 ) 2 —.

[0179] In some embodiments of the compound of formula IA-3, Q is an optionally substituted —(CH 2 ) 2 —, where the optional substituent is alkyl, alkoxy, or alkylamino.

[0180] In some embodiments of the compound of formula IA-3, Q is —C(O)—.

[0181] In some embodiments of the compound of formula IA-3, Q is an optionally substituted —CH 2 C(O)—.

[0182] In some embodiments of the compound of formula IA-3, Q is —S(O)—.

[0183] In some embodiments of the compound of formula IA-3, Q is -S(O)2-.

[0184] In some embodiments of the compound of formula IA-3, Q is an optionally substituted —CH 2 S(O) 2 —.

[0185] In some embodiments of the compound of formula IA-3, Q is an optionally substituted —CH 2 S(O)—.

[0186] In some embodiments, the compound of formula IA has formula IA-4: [ka] is a compound of In the formula, each R k =H, D, F, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-4 Alkoxyl, substituted C 1-3 Alkyl, substituted C 1-3 Haloalkyl or substituted C 1-4 alkoxyl, s=0 to 7, m=1 to 3, and R c1 , R d1 , R e3 , W, n, and R 1 is as described above for formula IA.

[0187] In some embodiments of the compound of formula IA-4, n=1. In other embodiments of the compound of formula IA-4, n=2. In other embodiments of the compound of formula IA-4, n=3.

[0188] In some embodiments of the compound of formula IA-4, m=1. In other embodiments of the compound of formula IA-4, m=2. In other embodiments of the compound of formula IA-4, m=3.

[0189] In some embodiments of the compound of formula IA-4, s=0. In some embodiments of the compound of formula IA-4, s=1. In other embodiments of the compound of formula IA-4, s=2. In other embodiments of the compound of formula IA-4, s=3.

[0190] In some embodiments of the compound of formula IA-4, R k =H.

[0191] In some embodiments of the compound of formula IA-4, R k=D.

[0192] In some embodiments of the compound of formula IA-4, R k =F.

[0193] In some embodiments of the compound of formula IA-4, R k =C 1-6 Alkyl, for example, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, etc.

[0194] In some embodiments of the compound of formula IA-4, R k =C 1-6 It is cycloalkyl, for example, C1 cycloalkyl, C2 cycloalkyl, C3 cycloalkyl, etc.

[0195] In some embodiments of the compound of formula IA-4, R k =C 1-3 Haloalkyl, for example, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3, and the like.

[0196] In some embodiments of the compound of formula IA-4, R k =C 1-4 Alkoxyl, for example, C1 alkoxyl, C2 alkoxyl, C3 alkoxyl, -OCH3, -OCH2CH3, etc.

[0197] In some embodiments of the compound of formula IA-4, R k =substitution C 1-6 It is alkyl, for example, substituted C1 alkyl, substituted C2 alkyl, substituted C3 alkyl, and the like.

[0198] In some embodiments of the compound of formula IA-4, R k =substitution C 1-6 Cycloalkyl, for example, substituted C1 cycloalkyl, substituted C2 cycloalkyl, substituted C3 cycloalkyl, and the like.

[0199] In some embodiments of the compound of formula IA-4, R k =substitution C 1-3 Haloalkyl, for example, substituted C1 haloalkyl, substituted C2 haloalkyl, substituted C3 haloalkyl, and the like.

[0200] In some embodiments of the compound of formula IA-4, R k =substitution C 1-4 Alkoxyl, for example, substituted C1 alkoxyl, substituted C2 alkoxyl, substituted C3 alkoxyl, and the like.

[0201] In some embodiments, the compound of formula IA has formula IA-5: [ka] is a compound of In the formula, R k =H, D, F, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, or C 1-4 alkoxyl, m=1 to 3, s=0 to 3, R c1 , R d1 , R e3 , W, and R 1 is as described above for formula IA.

[0202] In some embodiments of the compound of formula IA-5, m=1. In other embodiments of the compound of formula IA-5, m=2. In other embodiments of the compound of formula IA-5, m=3.

[0203] In some embodiments of the compound of formula IA-5, s=0. In some embodiments of the compound of formula IA-5, s=1. In other embodiments of the compound of formula IA-5, s=2. In other embodiments of the compound of formula IA-5, s=3.

[0204] In some embodiments of the compound of formula IA-5, R k =H.

[0205] In some embodiments of the compound of formula IA-5, R k =D.

[0206] In some embodiments of the compound of formula IA-5, R k =F.

[0207] In some embodiments of the compound of formula IA-5, R k =C 1-6 Alkyl, for example, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, etc.

[0208] In some embodiments of the compound of formula IA-5, R k =C 1-6 It is cycloalkyl, for example, C1 cycloalkyl, C2 cycloalkyl, C3 cycloalkyl, etc.

[0209] In some embodiments of the compound of formula IA-5, R k =C 1-3 Haloalkyl, for example, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3, and the like.

[0210] In some embodiments of the compound of formula IA-5, R k =H or C 1-4 Alkoxyl, for example, C1 alkoxyl, C2 alkoxyl, C3 alkoxyl, -OCH3, -OCH2CH3, etc.

[0211] In some embodiments, the compound of formula IA is formula IA-6, formula IA-6a, or formula IA-6b: [ka] is a compound of In the formula, R k =H, D, F, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, or C1-4 is alkoxyl, s=0 to 3, and R c1 , R d1 , R e3 , and R 1 is as described above for formula IA.

[0212] In some embodiments, the compound is a compound of formula IA-6. In some embodiments, the compound is a compound of formula IA-6a. In some embodiments, the compound is a compound of formula IA-6b.

[0213] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, s = 0. In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, s = 1. In other embodiments of the compound of formula IA-6, IA-6a, or IA-6b, s = 2. In other embodiments of the compound of formula IA-6, IA-6a, or IA-6b, s = 3.

[0214] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, R k =H.

[0215] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, R k =D.

[0216] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, R k =F.

[0217] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, R k =C 1-6 Alkyl, for example, C1 alkyl, C2 alkyl, C3 alkyl, -CH3, -CH2CH3, etc.

[0218] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, R k =C1-6 It is cycloalkyl, for example, C1 cycloalkyl, C2 cycloalkyl, C3 cycloalkyl, etc.

[0219] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, R k =C 1-3 Haloalkyl, for example, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, -CF3, -CH2CF3, and the like.

[0220] In some embodiments of the compound of formula IA-6, IA-6a, or IA-6b, R k =H or C 1-4 Alkoxyl, for example, C1 alkoxyl, C2 alkoxyl, C3 alkoxyl, -OCH3, -OCH2CH3, etc.

[0221] In some embodiments, ULM is [ka] and [ka] is the point of attachment to the PTM, X1 is a bond, -C(O)-, -C(S)-, -CH2-, -CHCF3-, SO2-, -S(O), P(O)R b -or-P(O)OR b - and R b is H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each X2 is independently N or CR b where one X2 is a C atom with a point of attachment to the PTM.

[0222] In some embodiments, ULM is [ka] is.

[0223] In some embodiments, ULM is [ka] is.

[0224] In some embodiments, ULM is [ka] is.

[0225] In some embodiments, ULM is [ka] is.

[0226] In some embodiments, ULM is [ka] is.

[0227] In some embodiments, ULM is [ka] is.

[0228] In some embodiments, ULM is [ka] is.

[0229] In some embodiments, ULM is [ka] is.

[0230] In some embodiments, ULM is [ka] is.

[0231] In some embodiments, ULM is [ka] is.

[0232] In some embodiments, X1 in ULM is a bond, —C(O)—, —C(S)—, —CH2—, —CHCF3—, SO2—, —S(O), P(O)R b Or-P(O)OR b -It is.

[0233] In some embodiments, X1 in ULM is a bond.

[0234] In some embodiments, X1 in ULM is —C(O)—.

[0235] In some embodiments, X1 in ULM is -C(S)-.

[0236] In some embodiments, X1 in ULM is -CH2-.

[0237] In some embodiments, X1 in ULM is —CHCF3—.

[0238] In some embodiments, X1 in ULM is -SO2-.

[0239] In some embodiments, X1 in ULM is —S(O).

[0240] In some embodiments, X1 in ULM is -P(O)R b is.

[0241] In some embodiments, X in ULM is —P(O)OR b -It is.

[0242] In some embodiments, R in ULM b is H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl.

[0243] In some embodiments, R in ULM b is H.

[0244] In some embodiments, R in ULM b is D.

[0245] In some embodiments, R in ULM b is -C1-C6 alkyl.

[0246] In some embodiments, R in ULM b is -C2-C6 alkenyl.

[0247] In some embodiments, R in ULM b is -C2-C6 alkynyl.

[0248] In some embodiments, R in ULM b is aryl.

[0249] In some embodiments, R in ULM b is cycloalkyl.

[0250] In some embodiments, R in ULM b is cycloalkenyl.

[0251] In some embodiments, R in ULM b is heteroaryl.

[0252] In some embodiments, R in ULM b is heterocycloalkyl.

[0253] In some embodiments, R in ULM b is heterocycloalkenyl.

[0254] In some embodiments, each X2 in ULM is independently N or CR b where one X2 is a C atom with a point of attachment to the PTM.

[0255] In some embodiments, each X2 in ULM is a CR b where one X2 is a C atom with a point of attachment to the PTM.

[0256] In some embodiments, at least one X2 in ULM is CR b where one X2 is a C atom with a point of attachment to the PTM.

[0257] In some embodiments, at least two X2 in ULM are CR b where one X2 is a C atom with a point of attachment to the PTM.

[0258] In some embodiments, at least three X2 in ULM are CR b where one X2 is a C atom with a point of attachment to the PTM.

[0259] In some embodiments, at least four X2 in ULM are CR b where one X2 is a C atom with a point of attachment to the PTM.

[0260] In some embodiments, at least five X2 in ULM are CR b where one X2 is a C atom with a point of attachment to the PTM.

[0261] In some embodiments, each X2 in a ULM is N, provided that one X2 is a C atom bearing the point of attachment to the PTM.

[0262] In some embodiments, at least one X2 in a ULM is N, provided that one X2 is a C atom bearing the point of attachment to the PTM.

[0263] In some embodiments, at least two X2 in a ULM are N, provided that one X2 is a C atom bearing the point of attachment to the PTM.

[0264] In some embodiments, at least three X2 in a ULM are N, provided that one X2 is a C atom bearing the point of attachment to the PTM.

[0265] In some embodiments, at least four X2 in the ULM are N, provided that one X2 is a C atom bearing the point of attachment to the PTM.

[0266] In some embodiments, at least five X2 in a ULM are N, provided that one X2 is a C atom with a point of attachment to a PTM.

[0267] In some embodiments, the compound of formula I has formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, or formula IA-16: [ka] TIFF2025538228000030.tif213139 The file has the file name TIFF2025538228000031.tif53120.

[0268] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, n=0.

[0269] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, n=1.

[0270] In other embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, n=2.

[0271] In other embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, n=3.

[0272] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, m=1.

[0273] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, m=2.

[0274] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, R d1 is H or F.

[0275] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, R c1 is H.

[0276] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, R e3 is H.

[0277] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, W is CH2.

[0278] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, Q is CH 2 .

[0279] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, X is CH and R 1 is connected to X.

[0280] In other embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, X is N and R 1 is connected to X.

[0281] In some embodiments of the compounds of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, and formula IA-16, each X2 is CH and X1 is CH2.

[0282] In some embodiments, the compound of Formula I has formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, or formula IA-16a: [ka] TIFF2025538228000033.tif250148, During the ceremony, Each R k are independently H, D, F, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-4 Alkoxyl, substituted C 1-3 Alkyl, substituted C 1-3 Haloalkyl or substituted C 1-4 is alkoxyl, s is 0, 1, 2, 3 or 4.

[0283] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, s=0.

[0284] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, s=1.

[0285] In other embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, s=2.

[0286] In other embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, s=3.

[0287] In other embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, s=4.

[0288] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, at least one R k is H. In some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, at least two R k is H. In some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, each R k But it's H.

[0289] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, at least one R k C 1-6 In some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, at least two R k C 1-6In some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, each R k C 1-6 It is alkyl.

[0290] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, at least one R k C 1-6 In some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, at least two R k C 1-6 In some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, each R k C 1-6 It is cycloalkyl.

[0291] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, at least one R k In some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, at least two R kIn some embodiments of the compounds of Formula IA-7a, Formula IA-8a, Formula IA-9a, Formula IA-10a, Formula IA-11a, Formula IA-12a, Formula IA-13a, Formula IA-14a, Formula IA-15a, and Formula IA-16a, each R k is methyl.

[0292] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, R d1 is H or F.

[0293] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, R c1 is H.

[0294] In some embodiments of the compounds of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, and formula IA-16a, each X2 is CH and X1 is CH2.

[0295] In some embodiments, the compound of Formula I has formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, or formula IA-16b: [ka] TIFF2025538228000035.tif239160, During the ceremony, Each R k are independently H, D, F, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-4Alkoxyl, substituted C 1-3 Alkyl, substituted C 1-3 Haloalkyl or substituted C 1-4 is alkoxyl, s is 0, 1, 2, 3 or 4; A1 is a bond, O, S, S(O), S(O)2, NR 1 , -(CR 1 R 2 ) n , -O(CR 1 R 2 ) n , -S(CR 1 R 2 ) n , -C=O, -C(=O)O, -C(=O)NR 3 , -SO2, -SO, heteroaryl, cycloalkyl, or heterocycloalkyl; A2 is a bond, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; A3 is a bond, -(CR 1 R 2 ) n , -(O-(CR 1 R 2 ) n , -S(CR 1 R 2 ) n , —C═O, —SO, SO, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; A4 is a bond, alkyl, cycloalkyl, heteroaryl, or heterocycloalkyl; Each of A1, A2, A3 and A4 is D, halo, alkyl, haloalkyl, -CN, -OR 3 , N.R. c R d , NO2, -SR 3 , -C=OR b , -C(=O)OR b , -C(=O)NR 3 R 3 , -SO2R b , -SOR b , -S(=O)(=NR b ) optionally substituted with N, cycloalkyl or heterocycloalkyl; Two substituents on each of A1, A2, A3, A4 are optionally joined to form a further 3- to 8-membered ring.

[0296] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, s=0.

[0297] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, s=1.

[0298] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, s=2.

[0299] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, s=3.

[0300] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, s=4.

[0301] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, at least one R kis H. In some embodiments of the compounds of Formula IA-7b, Formula IA-8b, Formula IA-9b, Formula IA-10b, Formula IA-11b, Formula IA-12b, Formula IA-13b, Formula IA-14b, Formula IA-15b, and Formula IA-16b, at least two R k is H. In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, each R k But it's H.

[0302] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, at least one R k C 1-6 In some embodiments of the compounds of Formula IA-7b, Formula IA-8b, Formula IA-9b, Formula IA-10b, Formula IA-11b, Formula IA-12b, Formula IA-13b, Formula IA-14b, Formula IA-15b, and Formula IA-16b, at least two R k C 1-6 In some embodiments of the compounds of Formula IA-7b, Formula IA-8b, Formula IA-9b, Formula IA-10b, Formula IA-11b, Formula IA-12b, Formula IA-13b, Formula IA-14b, Formula IA-15b, and Formula IA-16b, each R k C 1-6 It is alkyl.

[0303] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, at least one R k C 1-6 In some embodiments of the compounds of Formula IA-7b, Formula IA-8b, Formula IA-9b, Formula IA-10b, Formula IA-11b, Formula IA-12b, Formula IA-13b, Formula IA-14b, Formula IA-15b, and Formula IA-16b, at least two Rk C 1-6 In some embodiments of the compounds of Formula IA-7b, Formula IA-8b, Formula IA-9b, Formula IA-10b, Formula IA-11b, Formula IA-12b, Formula IA-13b, Formula IA-14b, Formula IA-15b, and Formula IA-16b, each R k C 1-6 It is cycloalkyl.

[0304] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, at least one R k In some embodiments of the compounds of Formula IA-7b, Formula IA-8b, Formula IA-9b, Formula IA-10b, Formula IA-11b, Formula IA-12b, Formula IA-13b, Formula IA-14b, Formula IA-15b, and Formula IA-16b, at least two R k In some embodiments of the compounds of Formula IA-7b, Formula IA-8b, Formula IA-9b, Formula IA-10b, Formula IA-11b, Formula IA-12b, Formula IA-13b, Formula IA-14b, Formula IA-15b, and Formula IA-16b, each R k is methyl.

[0305] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, R d1 is H or F.

[0306] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, R c1 is H.

[0307] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, each X2 is CH and X1 is CH2.

[0308] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is a bond.

[0309] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is O.

[0310] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is S.

[0311] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is S(O).

[0312] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is S(O)2.

[0313] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is NR 1is.

[0314] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -(CR 1 R 2 ) n is.

[0315] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -O(CR 1 R 2 ) n is.

[0316] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -S(CR 1 R 2 ) n is.

[0317] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -C=O.

[0318] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -C(=O)O.

[0319] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -C(=O)NR 3 is.

[0320] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -SO2.

[0321] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is -SO.

[0322] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is heteroaryl.

[0323] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is cycloalkyl.

[0324] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A1 is heterocycloalkyl.

[0325] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A2 is a bond.

[0326] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A2 is cycloalkyl.

[0327] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A2 is alkyl.

[0328] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A2 is cycloalkyl.

[0329] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A2 is aryl.

[0330] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A2 is heteroaryl.

[0331] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A2 is heterocycloalkyl.

[0332] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is a bond.

[0333] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is -(CR 1 R 2 ) n is.

[0334] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is -(O-(CR 1 R 2 ) n is.

[0335] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is -(S-(CR 1 R 2 ) n is.

[0336] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is -C=O.

[0337] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is -SO2.

[0338] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is -SO.

[0339] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is aryl.

[0340] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is heteroaryl.

[0341] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is cycloalkyl.

[0342] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A3 is heterocycloalkyl.

[0343] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A4 is a bond.

[0344] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A4 is alkyl.

[0345] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A4 is cycloalkyl.

[0346] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A4 is heteroaryl.

[0347] In other embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A4 is heterocycloalkyl.

[0348] In some embodiments of the compounds of formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, and formula IA-16b, A is -CR1R2, -C(=O)O, or -C(=O)NR 3 and A2 is D, halo, alkyl, haloalkyl, -CN, or OR 3 A3 is a heterocycloalkyl, heteroaryl, or cycloalkyl optionally substituted with -(CR 1 R 2 ) n and A4 is D, halo, alkyl, haloalkyl, -CN, or OR 3 Heterocycloalkyl, or heteroaryl, optionally substituted with

[0349] In some embodiments, the compound of Formula I has formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, or formula IA-16c: [ka] TIFF2025538228000037.tif246161, In the formula, each R k are independently H or C 1-6 is alkyl, s is 0, 1, 2, 3 or 4; R d1 is H or F, A1 is O, S, -CR 1 R 2 or -C=O, A2 is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl; A3 -CR 1 R 2 or -C=O, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0350] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, s=0.

[0351] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, s=1.

[0352] In other embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, s=2.

[0353] In other embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, s=3.

[0354] In other embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, s=4.

[0355] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, at least one R k is H. In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, at least two R k is H. In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, each R k But it's H.

[0356] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, at least one R k C 1-6 In some embodiments of the compounds of Formula IA-7c, Formula IA-8c, Formula IA-9c, Formula IA-10c, Formula IA-11c, Formula IA-12c, Formula IA-13c, Formula IA-14c, Formula IA-15c, and Formula IA-16c, at least two R k C 1-6In some embodiments of the compounds of Formula IA-7c, Formula IA-8c, Formula IA-9c, Formula IA-10c, Formula IA-11c, Formula IA-12c, Formula IA-13c, Formula IA-14c, Formula IA-15c, and Formula IA-16c, each R k C 1-6 It is alkyl.

[0357] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, at least one R k C 1-6 In some embodiments of the compounds of Formula IA-7c, Formula IA-8c, Formula IA-9c, Formula IA-10c, Formula IA-11c, Formula IA-12c, Formula IA-13c, Formula IA-14c, Formula IA-15c, and Formula IA-16c, at least two R k C 1-6 In some embodiments of the compounds of Formula IA-7c, Formula IA-8c, Formula IA-9c, Formula IA-10c, Formula IA-11c, Formula IA-12c, Formula IA-13c, Formula IA-14c, Formula IA-15c, and Formula IA-16c, each R k C 1-6 It is cycloalkyl.

[0358] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, at least one R k In some embodiments of the compounds of Formula IA-7c, Formula IA-8c, Formula IA-9c, Formula IA-10c, Formula IA-11c, Formula IA-12c, Formula IA-13c, Formula IA-14c, Formula IA-15c, and Formula IA-16c, at least two R kIn some embodiments of the compounds of Formula IA-7c, Formula IA-8c, Formula IA-9c, Formula IA-10c, Formula IA-11c, Formula IA-12c, Formula IA-13c, Formula IA-14c, Formula IA-15c, and Formula IA-16c, each R k is methyl.

[0359] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, R d1 is H or F.

[0360] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, A1 is O, S, -CR 1 R 2 or —C═O. In some embodiments of the compound of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, A is O. In some embodiments of the compound of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, A is S.

[0361] In some embodiments of compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, A2 is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl.

[0362] In some embodiments of the compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, A3 is -CR 1 R 2 Or -C=O. In some embodiments of compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, A3 is -CH2.

[0363] In some embodiments of compounds of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, and formula IA-16c, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0364] In some embodiments, the compound of Formula I is of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2: [ka] TIFF2025538228000039.tif229163 TIFF2025538228000040.tif233160 TIFF2025538228000041.tif202159, In the formula, each R k are independently H or C 1-6 is alkyl, s is 0, 1, 2, 3 or 4; R d1 is H or F, A1 is O, S, -CR1R2 or -C=O; A2 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl; A3 -CR 1 R 2 or -C=O, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0365] In some embodiments of a compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, s=0.

[0366] In some embodiments of a compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, s=1.

[0367] In other embodiments of a compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, s=2.

[0368] In other embodiments of a compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, s=3.

[0369] In other embodiments of a compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, s=4.

[0370] In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least one R k is H. In some embodiments of the compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least two R kis H. In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, each R k But it's H.

[0371] In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least one R k C 1-6 In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least two R k C 1-6 In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, each R k C 1-6 It is alkyl.

[0372] In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least one R k C 1-6 In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least two R k C 1-6 In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, each R k C 1-6 It is cycloalkyl.

[0373] In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least one Rk In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, at least two R k In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, each R k is methyl.

[0374] In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, R d1 is H or F.

[0375] In some embodiments of the compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, A1 is O, S, -CR 1 R 2or -C=O. In some embodiments of the compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, A1 is O. In some embodiments of the compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, A1 is S.

[0376] In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, A2 is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl.

[0377] In some embodiments of the compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, A3 is -CR 1 R 2Or -C=O. In some embodiments of a compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2, A3 is -CH2.

[0378] In some embodiments of a compound of Formula IA-7d1, Formula IA-7d2, Formula IA-8d1, Formula IA-8d2, Formula IA-9d1, Formula IA-9d2, Formula IA-10d1, Formula IA-10d2, Formula IA-11d1, Formula IA-11d2, Formula IA-12d1, Formula IA-12d2, Formula IA-13d1, Formula IA-13d2, Formula IA-14d1, Formula IA-14d2, or Formula IA-15d1, Formula IA-15d2, Formula IA-16d1, or Formula IA-16d2, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0379] In some embodiments, the compound of formula I has formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, or formula IA-16e: [ka] TIFF2025538228000043.tif207146 TIFF2025538228000044.tif52124, During the ceremony, Each R k are independently H, D, F, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-4 Alkoxyl, substituted C 1-3 Alkyl, substituted C 1-3 Haloalkyl or substituted C 1-4is alkoxyl, s is 0, 1, 2, 3 or 4.

[0380] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, s=0.

[0381] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, s=1.

[0382] In other embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, s=2.

[0383] In other embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, s=3.

[0384] In other embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, s=4.

[0385] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least one R kis H. In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least two R k is H. In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, each R k But it's H.

[0386] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least one R k is C 1-6 In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least two R k is C 1-6 In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, each R k is C 1-6 It is alkyl.

[0387] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least one R k is C 1-6In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least two R k is C 1-6 In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, each R k is C 1-6 It is cycloalkyl.

[0388] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least one R k In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, at least two R k In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, each R k is methyl.

[0389] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, R d1 is H or F.

[0390] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, R c1 is H.

[0391] In some embodiments of the compounds of formula IA-7e, formula IA-8e, formula IA-9e, formula IA-10e, formula IA-11e, formula IA-12e, formula IA-13e, formula IA-14e, formula IA-15e, and formula IA-16e, each X2 is CH and X1 is CH2.

[0392] In some embodiments, the compound of Formula I is of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, or formula IA-16f: [ka] TIFF2025538228000046.tif204165 TIFF2025538228000047.tif56150, During the ceremony, Each R k are independently H, D, F, C 1-6 Alkyl, C 1-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-4 Alkoxyl, substituted C 1-3 Alkyl, substituted C 1-3 Haloalkyl or substituted C 1-4 is alkoxyl, s is 0, 1, 2, 3 or 4; A1 is a bond, O, S, S(O), S(O)2, NR 1 , -(CR 1 R 2 ) n , -O(CR 1 R 2 ) n , -S(CR 1 R 2 )n , -C=O, -C(=O)O, -C(=O)NR 3 , -SO2, -SO, heteroaryl, cycloalkyl, or heterocycloalkyl; A2 is a bond, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; A3 is a bond, -(CR 1 R 2 ) n , -(O-(CR 1 R 2 ) n , -S(CR 1 R 2 ) n , —C═O, —SO, SO, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; A4 is a bond, alkyl, cycloalkyl, heteroaryl, or heterocycloalkyl; Each of A1, A2, A3 and A4 is D, halo, alkyl, haloalkyl, -CN, -OR 3 , N.R. c R d , NO2, -SR 3 , -C=OR b , -C(=O)OR b , -C(=O)NR 3 R 3 , -SO2R b , -SOR b , -S(=O)(=NR b ) optionally substituted with N, cycloalkyl or heterocycloalkyl; Two substituents on each of A1, A2, A3, A4 are optionally joined to form a further 3- to 8-membered ring.

[0393] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is a bond.

[0394] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is O.

[0395] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is S.

[0396] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is S(O).

[0397] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is S(O)2.

[0398] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is NR 1 is.

[0399] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -(CR 1 R 2 ) n is.

[0400] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -O(CR 1 R 2 ) n is.

[0401] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -S(CR 1 R 2 ) n is.

[0402] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -C=O.

[0403] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -C(=O)O.

[0404] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -C(=O)NR 3 is.

[0405] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -SO2.

[0406] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is -SO.

[0407] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is heteroaryl.

[0408] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is cycloalkyl.

[0409] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A1 is heterocycloalkyl.

[0410] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A2 is a bond.

[0411] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A2 is cycloalkyl.

[0412] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A2 is alkyl.

[0413] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A2 is cycloalkyl.

[0414] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A2 is aryl.

[0415] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A2 is heteroaryl.

[0416] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A2 is heterocycloalkyl.

[0417] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is a bond.

[0418] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is -(CR 1 R 2 ) n is.

[0419] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is -(O-(CR 1 R 2 ) n is.

[0420] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is -(S-(CR 1 R 2 ) n is.

[0421] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is -C=O.

[0422] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is -SO2.

[0423] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is -SO.

[0424] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is aryl.

[0425] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is heteroaryl.

[0426] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is cycloalkyl.

[0427] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A3 is heterocycloalkyl.

[0428] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A4 is a bond.

[0429] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A4 is alkyl.

[0430] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A4 is cycloalkyl.

[0431] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A4 is heteroaryl.

[0432] In other embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A4 is heterocycloalkyl.

[0433] In some embodiments of the compounds of formula IA-7f, formula IA-8f, formula IA-9f, formula IA-10f, formula IA-11f, formula IA-12f, formula IA-13f, formula IA-14f, formula IA-15f, and formula IA-16f, A is -CR1R2, -C(=O)O, or -C(=O)NR 3 and A2 is D, halo, alkyl, haloalkyl, -CN, or OR 3 A3 is a heterocycloalkyl, heteroaryl, or cycloalkyl optionally substituted with -(CR 1 R 2 ) n and A4 is D, halo, alkyl, haloalkyl, -CN, or OR 3 Heterocycloalkyl, or heteroaryl, optionally substituted with

[0434] In some embodiments, the compound of Formula I is of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, or formula IA-16g: [ka] TIFF2025538228000049.tif210160 TIFF2025538228000050.tif56143, In the formula, each R k are independently H or C 1-6 is alkyl, s is 0, 1, 2, 3 or 4; R d1 is H or F, A1 is O, S, -CR1 R 2 or -C=O, A2 is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl; A3 -CR 1 R 2 or -C=O, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0435] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, s=0.

[0436] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, s=1.

[0437] In other embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, s=2.

[0438] In other embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, s=3.

[0439] In other embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, s=4.

[0440] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, at least one R k is H. In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, at least two R k is H. In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, each R k But it's H.

[0441] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, at least one R k C 1-6 In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, at least two R k C 1-6 In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, each R k C 1-6 It is alkyl.

[0442] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, at least one R kIn some embodiments of the compounds of Formula IA-7g, Formula IA-8g, Formula IA-9g, Formula IA-10g, Formula IA-11g, Formula IA-12g, Formula IA-13g, Formula IA-14g, Formula IA-15g, and Formula IA-16g, at least two R k In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, each R k is methyl.

[0443] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, R d1 is H or F.

[0444] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, A1 is O, S, -CR 1 R 2 or —C═O. In some embodiments of the compound of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, A is O. In some embodiments of the compound of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, A is S.

[0445] In some embodiments of compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, A2 is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl.

[0446] In some embodiments of the compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, A3 is -CR 1 R 2 Or -C=O. In some embodiments of compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, A3 is -CH2.

[0447] In some embodiments of compounds of formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, and formula IA-16g, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0448] In some embodiments, the compound of Formula I has formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, or formula IA-16h: [ka] TIFF2025538228000052.tif210160 TIFF2025538228000053.tif56143, In the formula, each R k are independently H or C 1-6 is alkyl, s is 0, 1, 2, 3 or 4; R d1 is H or F, A1 is O, S, -CR1R2 or -C=O; A2 is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl; A3 -CR 1 R 2 or -C=O, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0449] In some embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, s=0.

[0450] In some embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, s=1.

[0451] In other embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, s=2.

[0452] In other embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, s=3.

[0453] In other embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, s=4.

[0454] In some embodiments of the compounds of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, at least one R kis H. In some embodiments of the compounds of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, at least two R k is H. In some embodiments of the compounds of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, each R k But it's H.

[0455] In some embodiments of the compounds of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, at least one R k is C 1-6 In some embodiments of the compounds of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, at least two R k is C 1-6 In some embodiments of the compounds of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, each R k is C 1-6 It is alkyl.

[0456] In some embodiments of the compounds of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, at least one R k In some embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, at least two R kIn some embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, each R k is methyl.

[0457] In some embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, R d1 is H or F.

[0458] In some embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, A1 is O, S, -CR 1 R 2 or —C═O. In some embodiments of the compound of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, A is O. In some embodiments of the compound of Formula IA-7h, Formula IA-8h, Formula IA-9h, Formula IA-10h, Formula IA-11h, Formula IA-12h, Formula IA-13h, Formula IA-14h, Formula IA-15h, and Formula IA-16h, A is S.

[0459] In some embodiments of compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, A2 is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl.

[0460] In some embodiments of the compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, A3 is -CR 1 R 2 Or -C=O. In some embodiments of compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, A3 is -CH2.

[0461] In some embodiments of compounds of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, and formula IA-16h, A4 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

[0462] In some embodiments of a compound of any of the above formulas, A2 and A4 are each independently piperidine, piperazine, azetidine, or pyrrolidine.

[0463] In some embodiments of the compound of any of the above formulas, A2 is piperidine.

[0464] In some embodiments of the compound of any of the above formulas, A2 is piperazine.

[0465] In some embodiments of the compound of any of the above formulas, A2 is azetidine.

[0466] In some embodiments of the compound of any of the above formulas, A2 is pyrrolidine.

[0467] In some embodiments of the compound of any of the above formulas, A4 is piperidine.

[0468] In some embodiments of the compound of any of the above formulas, A4 is piperazine.

[0469] In some embodiments of the compound of any of the above formulas, A4 is azetidine.

[0470] In some embodiments of the compound of any of the above formulas, A4 is pyrrolidine.

[0471] In some embodiments, the compound of formula I is N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)benzamide, 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5R)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2H-indazol-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione, N-(2,6-dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethylpiperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide, N-(2,6-dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethylpiperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide, and pharmaceutically acceptable salts thereof.

[0472] In some embodiments, the compound of formula I is 1-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)benzamide, N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide, 3-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione, 3-(4-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione, 3-(4-(1-((6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione, and pharmaceutically acceptable salts thereof.

[0473] It will be apparent that compounds of the present invention, including all subgenera described herein, may have multiple stereocenters. As a result, multiple stereoisomers (enantiomers and diastereomers) of the compounds (and subgenera described herein) exist. The present disclosure contemplates and includes each stereoisomer of any compound encompassed by the present disclosure, as well as mixtures of such stereoisomers.

[0474] Pharmaceutically acceptable salts and solvates of the compounds of the present disclosure (including all subgenera described herein) are also within the scope of the present disclosure.

[0475] Isotopic variations of the compounds of the present disclosure, including all subgenera described herein, are also contemplated by the present disclosure.

[0476] Pharmaceutical compositions and methods of administration The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof, as the active ingredient. If desired, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof, as well as one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0477] The pharmaceutical composition can be administered alone or in combination with one or more other drugs, which are also typically administered in the form of a pharmaceutical composition. If desired, one or more compounds of the present invention and the other drugs can be mixed in a preparation, or both components can be formulated in separate preparations and used separately or in combination at the same time.

[0478] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0. 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v, or v / v.

[0479] In some embodiments, the concentration of one or more compounds of the present invention is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0. 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number within a range defined by and inclusive of any two of the above numbers) w / w, w / v, or v / v.

[0480] In some embodiments, the concentration of one or more compounds of the present invention is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.0 The range is 8% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0481] In some embodiments, the concentration of one or more compounds of the present invention is within the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0482] In some embodiments, the amount of one or more compounds of the present invention is 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09 ... g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number within a range defined by and including any two of the foregoing numbers).

[0483] In some embodiments, the amount of one or more compounds of the present invention is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0. 0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008 g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0. 045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0 .1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0. Greater than 75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g (or a number within a range defined by and including any two of the above numbers).

[0484] In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0485] The compounds according to the present invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, and the preference and experience of the attending physician.

[0486] Pharmaceutical compositions of the present invention typically comprise an active ingredient of the present invention (e.g., a compound of the present disclosure) or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0487] Non-limiting exemplary pharmaceutical compositions and methods for preparing them are described below.

[0488] Pharmaceutical composition for oral administration In some embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0489] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration containing (i) an effective amount of a compound of the present invention, optionally (ii) an effective amount of a second pharmaceutical agent, and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains (iv) an effective amount of a third pharmaceutical agent.

[0490] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral ingestion. Pharmaceutical compositions of the present invention suitable for oral administration can be provided as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with a carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surface active agents or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0491] Because water can accelerate the degradation of some compounds, the present invention also encompasses anhydrous pharmaceutical compositions and dosage forms containing active ingredients. For example, water can be added (e.g., 5%) in pharmaceutical applications as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of a formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, allowing them to be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers, blister packs, and strip packs.

[0492] The active ingredient can be combined in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers can take a variety of forms, depending on the preparation form desired for administration. In preparing compositions for oral dosage forms, any of the usual pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used as carriers for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used for oral solid preparations, in some embodiments, without the use of lactose. For example, suitable carriers include powders, capsules, and tablets with solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0493] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as gum acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0494] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0495] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Using too much disintegrant can produce tablets that may disintegrate in the bottle. Using too little can be insufficient for disintegration to occur, thereby altering the rate and extent of release of the active ingredient from the dosage form. Therefore, a dosage form of the compound disclosed herein can be formed using a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0496] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, coagulated aerosol of synthetic silica, or mixtures thereof. Lubricants can optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0497] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with a diluent such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, emulsifying and / or suspending agents.

[0498] Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0499] Surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be used, a mixture of lipophilic surfactants can be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0500] Suitable hydrophilic surfactants will generally have an HLB value of at least 10, while suitable lipophilic surfactants will generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and have higher solubility in aqueous solutions.

[0501] Hydrophilic surfactants are generally considered to be compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (e.g., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of a surfactant is only a rough guideline that is commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0502] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidate salts, fatty acid derivatives of amino acids, oligopeptides, and polypeptides, glyceride derivatives of amino acids, oligopeptides, and polypeptides, lecithin and hydrogenated lecithin, lysolecithin and hydrogenated lysolecithin, phospholipids and derivatives thereof, lysophospholipids and derivatives thereof, carnitine fatty acid ester salts, alkyl sulfate salts, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0503] Among the aforementioned groups, ionic surfactants include, by way of example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives, carnitine fatty acid ester salts, salts of alkyl sulfates, fatty acid salts, docusate sodium, acyl lactylates, mono- and diacetylated tartaric acid esters of mono- and diglycerides, succinylated mono- and diglycerides, citrate esters of mono- and diglycerides, and mixtures thereof.

[0504] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactate, stearoyl lactate, succinyl The ionic forms may be acetylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0505] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides, alkyl maltosides, alkyl thioglucosides, lauryl macrogol glycerides, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols, polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic interesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, polyoxyethylene sterols, derivatives and analogs thereof, polyoxyethylated vitamins and derivatives thereof, polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof, polyethylene glycol sorbitan fatty acid esters, and hydrophilic interesterification products of polyols and at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar.

[0506] Other hydrophilic nonionic surfactants include PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PE G-20 Dilaurate, PEG-25 Glyceryl Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Laurate, PEG-30 Glyceryl Laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 Hydrogenated Castor Oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG- 40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate / Caprylate Glyceride, PEG-8 Caprate / Caprylate Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soysterol, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, These include, but are not limited to, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl L-oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol, PEG15-100 octylphenol, and poloxamer.

[0507] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, mono- and diglyceride lactic acid derivatives, the hydrophobic transesterification products of polyols and at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, fat-soluble vitamins / vitamin derivatives, and mixtures thereof.In this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or the hydrophobic transesterification products of polyols and at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0508] In one embodiment, the composition may contain a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and minimize precipitation of the compound of the present invention. This may be particularly important for compositions for parenteral use, such as injectable compositions. Solubilizing agents may also be added to increase the solubility of hydrophilic drugs and / or other components (e.g., surfactants) or to maintain the composition as a stable or homogeneous solution or dispersion.

[0509] Examples of suitable solubilizers include alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG, amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N- These include, but are not limited to, alkyl pyrrolidone, N-hydroxyalkyl pyrrolidone, N-alkyl piperidone, N-alkyl caprolactam, dimethyl acetamide, and polyvinyl pyrrolidone; citrates such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0510] A mixture of solubilizers may be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0511] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biologically acceptable amount, which can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize the drug concentration, it may be advantageous to include an amount of solubilizer that far exceeds the bioacceptable amount, with the excess solubilizer being removed using conventional techniques such as distillation or evaporation before providing the composition to a subject. Thus, when present, the solubilizer can be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, such as 5%, 2%, 1%, or even less, can also be used. Typically, the solubilizer may be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0512] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0513] Additionally, acids or bases may be incorporated into the compositions to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), and the like. Also suitable are bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate, can also be used. When the base is a salt, the cation can be any convenient pharmaceutically acceptable cation, such as ammonium, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0514] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0515] Injectable pharmaceutical composition In some embodiments, the present invention provides an injectable pharmaceutical composition comprising a compound of the present invention and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the drugs in the composition are as described herein.

[0516] Forms into which the novel compositions of the present invention can be incorporated for administration by injection include aqueous or oily suspensions or emulsions including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0517] Aqueous solutions in physiological saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0518] Sterile injectable solution is prepared by incorporating the compound of the present invention in the required amount into a suitable solvent with various other ingredients as listed above, as needed, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and the other necessary ingredients listed above.For the preparation of sterile injectable solution, the preferred method of preparing sterile powder is vacuum drying and freeze-drying, which produces powder of active ingredient with any other desired ingredients from the solution that has been previously sterile-filtered.

[0519] Pharmaceutical Compositions for Topical (e.g., Transdermal) Delivery In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0520] The composition of the present invention can be formulated into solid, semi-solid or liquid form preparations suitable for topical or local administration, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline, dimethyl sulfoxide (DMSO)-based solution, etc. Generally, carriers with higher density can provide areas with prolonged exposure to active ingredients.In contrast, solution formulations can provide more rapid exposure of active ingredients to selected areas.

[0521] The pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients, which are compounds that allow for increased penetration of or assist in the delivery of therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those skilled in the art of topical formulation.

[0522] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0523] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without other agents.

[0524] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0525] Inhaled pharmaceutical composition Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0526] Other pharmaceutical compositions Pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. For example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw See Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999). all of which are incorporated herein by reference in their entirety.

[0527] The compounds or pharmaceutical compositions of the present invention can be administered by any method that allows delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical (e.g., transdermal application), rectal administration, administration via local delivery by catheter or stent, or administration via inhalation. The compounds can also be administered intraadiposely or intrathecally.

[0528] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0529] The amount of compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound, and the discretion of the prescribing physician. However, effective dosages range from about 0.001 to about 100 mg / kg body weight / day, preferably from about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, dosage levels below the lower end of the aforementioned range may be more than sufficient, while in other cases, even higher doses may be used without causing adverse side effects, e.g., by dividing such higher doses into several smaller doses for administration throughout the day.

[0530] In some embodiments, the compounds of the invention are administered in a single dose.

[0531] Typically, such administration is by injection, e.g., intravenous injection, to rapidly introduce the drug. However, other routes may be used as appropriate. A single dose of the compound of the present invention may also be used to treat acute conditions.

[0532] In some embodiments, the compound of the present invention is administered in multiple doses. Dosing can be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing can be about once per month, once every two weeks, once per week, or once every other day. In another embodiment, the compound of the present invention and another agent are administered together about once per day to about six times per day. In another embodiment, administration of the compound of the present invention and another agent continues for less than about seven days. In yet another embodiment, administration continues for more than about six days, ten days, fourteen days, twenty-eight days, two months, six months, or a year. In some cases, continuous administration is achieved and maintained as long as necessary.

[0533] Administration of the compounds of the invention may continue for as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered chronically, for example, to treat chronic effects.

[0534] An effective amount of a compound of this invention can be administered by any of the accepted modes of administration for drugs with similar utilities, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant, in either a single dose or multiple doses.

[0535] The compositions of the present invention can also be delivered via impregnated or coated devices, such as stents, or cylindrical polymers inserted into the artery. Such administration methods can help prevent or improve restenosis after procedures such as balloon angioplasty. Without being bound by theory, the compounds of the present invention can slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall, which contribute to restenosis. The compounds of the present invention can be administered by local delivery, for example, from the struts of a stent, from a stent graft, from a graft, or from the cover or sheath of a stent. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and may serve to bind the compound to the stent. Suitable polymer matrices for such uses include, for example, lactone-based polyesters or copolyesters (e.g., polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA), polysiloxanes, poly(ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethylmethylmethacrylate, polyvinylpyrrolidinone), fluorinated polymers such as polytetrafluoroethylene, and cellulose esters. Suitable matrices can be non-degradable or can degrade over time, allowing the compound to be transported. The compounds of the present invention can be applied to the surface of a stent by various methods, such as dipping / spin coating, spray coating, dip coating, and / or brush coating. The compounds may be applied in a solvent, and the solvent may be evaporated to form a layer of the compound on the stent. Alternatively, the compounds may be disposed within the body of the stent or graft, for example, within microchannels or micropores. Upon implantation, the compounds diffuse from the stent body and contact the arterial wall. Such stents can be prepared by dipping a stent fabricated to contain such micropores or microchannels into a solution of the compounds of the present invention in a suitable solvent, followed by evaporation of the solvent.Excess drug on the surface of the stent can be removed via a further brief solvent wash. In yet another embodiment, the compounds of the present invention can be covalently attached to a stent or graft. A covalent linker that decomposes in vivo, resulting in the release of the compounds of the present invention, can be used. For this purpose, any biolabile bond, such as an ester, amide, or anhydride bond, can be used. The compounds of the present invention can also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds by pericarded or adventitial application of the formulations of the present invention can also be used to reduce restenosis.

[0536] Various stent devices that may be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: U.S. Patent No. 5,451,233, U.S. Patent No. 5,040,548, U.S. Patent No. 5,061,273, U.S. Patent No. 5,496,346, U.S. Patent No. 5,292,331, U.S. Patent No. 5,674,278, U.S. Patent No. 3,657,744, U.S. Patent No. 4,739,762, U.S. Patent No. 5,195,984, U.S. Patent No. 5,292,331, U.S. Patent No. 5,674,278, U.S. Patent No. 5,879,382, and U.S. Patent No. 6,344,053.

[0537] The compound of the present invention can be administered according to dosage.It is known in the art that due to the inter-subject variability in compound pharmacokinetics, individualized dosing regimen is necessary for optimal treatment.The dosing of the compound of the present invention can be found by routine experiment in light of the present disclosure.

[0538] When a compound of the invention is administered in a composition containing one or more drugs, and the drugs have a shorter half-life than the compound of the invention, the unit dosage forms of the drugs and the compound of the invention may be adjusted accordingly.

[0539] The pharmaceutical composition may be in a form suitable for oral administration as, for example, a tablet, capsule, pill, powder, sustained-release formulation, solution, or suspension; parenteral injection as a sterile solution, suspension, or emulsion; topical administration as an ointment or cream; or rectal administration as a suppository. The pharmaceutical composition may be in a unit dosage form suitable for single administration of a precise dose. The pharmaceutical composition comprises a conventional pharmaceutical carrier or excipient and a compound according to the present invention as an active ingredient. In addition, it may contain other medicinal or pharmaceutical agents, carriers, adjuvants, etc. Exemplary parenteral dosage forms include solutions or suspensions of the active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0540] How to use The method typically involves administering a therapeutically effective amount of a compound of the present invention to a subject. The therapeutically effective amount of the combination of compounds of the present invention may vary depending on the intended application (in vitro or in vivo), or the subject and disease state to be treated (e.g., the subject's weight and age, the severity of the disease state, the mode of administration, etc.), and can be easily determined by one skilled in the art. The term also applies to a dose that induces a specific response in target cells, such as a decrease in proliferation or a downregulation of the activity of a target protein. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0541] In certain embodiments, the present invention provides pharmaceutical compositions comprising a bispecific compound or a pharmaceutically acceptable salt thereof.

[0542] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use in degrading target proteins in cells.

[0543] In certain embodiments, a method for degrading a target protein, comprising administering to a cell a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt thereof, wherein the compound is effective to degrade the target protein.

[0544] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use in the treatment or prevention of diseases or disorders in which SMARCA2 and / or SMARCA4 play a role.

[0545] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use in the treatment or prevention of diseases or disorders in which SWI / SNF mutations play a role.

[0546] In certain embodiments, the target protein is SMARCA2, SMARCA4, and / or PB1.

[0547] In certain embodiments, the target protein complex is SWI / SNF in a cell.

[0548] In certain embodiments, the SMARCA2 or SMARCA4 dependent disease or disorder comprises cancer.

[0549] In certain embodiments, the SWI / SNF complex dependent disease or disorder comprises cancer.

[0550] Exemplary cancers that may be treated with the compounds of the invention, either alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, Sarcomas, including myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.

[0551] In certain embodiments, cancers that may be treated using compounds according to the present disclosure include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, B-cell precursor ALL, B-cell precursor lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0552] In certain further embodiments, the cancer is a SMARCA2 and / or SMARAC4 dependent cancer.

[0553] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use when the SMARCA2 and / or SMARCA4 dependent disease or disorder is cancer.

[0554] The compounds of the present disclosure, as well as pharmaceutical compositions comprising them, can be administered alone or in combination with medical therapies, including, for example, surgery and radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, and systemic radioisotopes), to treat any of the diseases described.

[0555] In other aspects, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered alone or in combination with one or more other agents to treat any of the diseases described.

[0556] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an agonist of a nuclear receptor agent.

[0557] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions containing them, can be administered in combination with an antagonist of a nuclear receptor agent.

[0558] In other methods, the compounds of the present disclosure, as well as pharmaceutical compositions comprising them, can be administered in combination with an anti-proliferative agent.

[0559] Combination therapy To treat cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. The compounds of the present invention can also be used in combination with drug therapies such as surgery or radiation therapy (e.g., gamma irradiation, neutron radiation therapy, electron beam radiation therapy, proton radiation therapy, brachytherapy, and whole-body radioisotopes). Examples of suitable chemotherapeutic agents include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, bortezomib, intravenous busulfan, oral busulfan, castellon, capecitabine, carboplatin, carmustine, and cetaxel. Cimab, chlorambucil, cisplatin, cladribine, cloharabine, cyclophosphamide, cicarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, exemestane , fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, hisrelin acetate, ibritumomab tiuxetan acetate, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate Lolide, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspagase, pegfilgrastim, pemetrexed disodium, pentostatin,Examples of the anticoagulant include pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

[0560] In some embodiments, the compounds of the present invention can be used in combination with therapeutic agents targeting epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferase inhibitors, histone arginine methyltransferase inhibitors, histone demethylase inhibitors, histone deacetylase inhibitors, histone acetylase inhibitors, and DNA methyltransferase inhibitors. Histone deacetylase inhibitors include, for example, vorinostat. Histone arginine methyltransferase inhibitors include inhibitors of protein arginine methyltransferases (PRMTs), such as PRMT5, PRMT1, and PRMT4. DNA methyltransferase inhibitors include inhibitors of DNMT1 and DNMT3.

[0561] For the treatment of cancer and other proliferative diseases, the compounds of the invention may be used in combination with targeted therapies including JAK kinase inhibitors (e.g., ruxolitinib), PI3 kinase inhibitors, including PI3K-delta selective and broad-spectrum PI3K inhibitors, cyclin-dependent kinase inhibitors, including MEK inhibitors, CDK4 / 6 inhibitors and CDK9 inhibitors, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (e.g., bortezomib, carfilzomib), HDAC inhibitors (e.g., panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo- and extra-terminal family member (BET) inhibitors, BTK inhibitors (e.g., ibrutinib, acalabrutinib), BCL2 inhibitors (e.g., venetoclax), dual BCL2 family inhibitors (e.g., BCL2 / BCLxL), PARP inhibitors, FLT3 inhibitors, or LSD1 inhibitors.

[0562] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), or PDR001. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, durvalumab, or BMS-935559. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0563] In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0564] The compounds of the present invention include, but are not limited to, those shown in the examples. The compounds of the present invention can be prepared using a number of preparative reactions known in the literature. The following schemes provide general guidance related to the preparation of the compounds of the present invention. Those skilled in the art will understand that, using general knowledge of organic chemistry, the preparations shown in the schemes can be modified or optimized to prepare various compounds of the present invention. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0565] The following examples are provided to illustrate some of the concepts described within this disclosure and are considered to provide embodiments, but should not be considered to limit the more general embodiments described herein. [Example]

[0566] General synthetic procedure The compounds described herein can be prepared according to the following synthetic schemes and general synthetic procedures.

[0567] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme 1. 1Compound 1-1, where R is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs), can be reacted with amine 1-2 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as XPhos Pd G3 and a base such as Cs2CO3 or K3PO4) or under standard Ullmann coupling conditions (e.g., in the presence of a copper catalyst such as CuI and a base such as K2CO3) to give compound 1-3, which can be hydrolyzed to acid 1-4 (e.g., R 2 When R is methyl or ethyl, in the presence of LiOH, 2 (In the presence of H2SO4 when is tert-butyl). Acid 1-4 can be reacted with amine 1-5 under amide coupling conditions in the presence of a coupling reagent (such as N,N'-dicyclohexyl-carbodiimide or HATU) to give compound 1-6. [ka]

[0568] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme 2. Compound 2-1 can be reacted with X in the presence of a base such as sodium hydride, NaHMDS, KHMDS, or lithium diisopropylamide. 2 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) to give compound 2-3. Compound 2-3 can be reacted with amine 1-2 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as XPhos Pd G3 and a base such as CsCO3 or KPO4) or standard Ullmann coupling conditions (e.g., in the presence of a copper catalyst such as CuI and a base such as KCO3) to give compound 2-4. [ka]

[0569] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme 3. Compound 3-1 can be reacted with X 2 is a halogen (e.g., Cl, Br, or I) or pseudohalogen (e.g., OTf or OMs) to give compound 3-2. Compound 3-2 can be reacted with amine 1-2 under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as XPhos Pd G3 and a base such as CsCO or KPO) or standard Ullmann coupling conditions (e.g., in the presence of a copper catalyst such as CuI and a base such as KCO) to give compound 3-3. [ka]

[0570] Example 1. N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)benzamide [ka] Step 1. Methyl 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoate [ka]

[0571] A mixture of methyl 4-bromo-2-fluorobenzoate (103.6 mg, 0.44 mmol), 4-piperidinemethanol (61.4 mg, 0.53 mmol), copper(I) iodide (16.9 mg, 0.09 mmol), L-proline (20.5 mg, 0.18 mmol), and potassium carbonate (184.2 mg, 1.33 mmol) in DMSO (4.0 mL) was heated at 80 °C overnight under N2. The reaction was cooled, and HCl (1 M, 4 mmol, 4 mL) was added. The reaction was stirred for 10 minutes and filtered. The filtrate was purified by preparative HPLC on a C18 column (28-48% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (36.2 mg, 0.14 mmol, 30.5% yield). 14 H 19 FNO3[M+H] + LCMS calculated for: m / z=268.13; found: 268.0.

[0572] Step 2. 2-Fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid [ka]

[0573] A mixture of methyl 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoate (34.0 mg, 0.13 mmol) and lithium hydroxide hydrate (1:1) (126 mg, 3.0 mmol) in THF / MeOH / HO (1:1:1, 3.0 mL) was heated at 50° C. for 1 h. The reaction was cooled and HCl (1 M, 3.0 mmol, 3.0 mL) was added. The reaction was stirred for 10 min and filtered. The filtrate was purified by preparative HPLC on a C18 column (16-36% MeCN in 0.1% TFA (aq), pH=2) to give the title compound (32.1 mg, 0.13 mmol, 99.3% yield). 13 H 17 FNO3[M+H] + LCMS calculated for: m / z=254.12; found: 254.0.

[0574] Step 3. N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide [ka]

[0575] To a mixture of 2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzoic acid (32.1 mg, 0.13 mmol), 3-aminopiperidine-2,6-dione (HCl salt 1:1) (41.6 mg, 0.253 mmol), and 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (72.1 mg, 0.19 mmol) in DMF (2.0 mL) was added triethylamine (0.18 mL, 1.26 mmol). The reaction was stirred at room temperature for 0.5 hours, after which trifluoroacetic acid (0.29 mL, 3.79 mmol) was added. The crude material was purified by preparative HPLC on a C18 column (10-30% MeCN in 0.1% TFA (aq), pH=2) to give the title compound (33.0 mg, 0.09 mmol, 71.9% yield). 18 H 23 FN3O4[M+H] + LCMS calculated for: m / z=364.17; found: 364.2.

[0576] Step 4. N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)benzamide

[0577] To a mixture of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(hydroxymethyl)piperidin-1-yl)benzamide (16.0 mg, 0.04 mmol) and triethylamine (0.055 mL, 0.40 mmol) in DMSO (1 mL) was added sulfur trioxide pyridine (21.0 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 1 hour. Next, a solution of [(2R,6S)-2,6-dimethylpiperazin-1-yl]-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-12-yl]methanone (1:1 TFA salt, 23.7 mg, 0.044 mmol, prepared as described in WO2022099117) in MeCN (1 mL) was added to the reaction, followed by acetic acid (38 μL, 0.66 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (37.3 mg, 0.18 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 1 hour, after which HCl (1 M, 0.5 mL) was added. The crude reaction mixture was purified by preparative HPLC on a C18 column (10-30% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (16.6 mg, 17 μmol, 37.8% yield) as the TFA salt. 40 H 50 FN 10 O5 [M+H] + LCMS calculated for: m / z=769.39; found: 769.4.

[0578] Example 2. 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione [ka] Step 1. 3-(6-iodo-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione [ka]

[0579] To a mixture of 6-iodoquinazolin-4-ol (163.0 mg, 0.60 mmol) and 3-bromopiperidine-2,6-dione (230 mg, 1.20 mmol) in DMF (6.0 mL) was added sodium hydride (60% suspension in mineral oil, 96.0 mg, 2.40 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by the slow addition of HCl (1 M, 1.5 mL). The reaction was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was diluted with DMSO and purified by preparative HPLC on a C18 column (25-45% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (72.0 mg, 0.19 mmol, 31.3% yield). C 13 H 11 IN3O3[M+H] + LCMS calculated for: m / z=383.98; found: 384.0.

[0580] Step 2. 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione [ka]

[0581] A mixture of 3-(6-iodo-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (23.0 mg, 0.06 mmol), 4-piperidinemethanol (20.7 mg, 0.18 mmol), copper(I) iodide (11.4 mg, 0.06 mmol), L-proline (13.8 mg, 0.12 mmol), and potassium carbonate (24.9 mg, 0.18 mmol) in DMSO (2.0 mL) was heated at 80° C. overnight under N. The reaction was cooled and HCl (1 M, 2 mmol, 2 mL) was added. The reaction was stirred for 10 minutes and filtered. The filtrate was purified by preparative HPLC on a C18 column (10-30% MeCN in 0.1% TFA (aq), pH=2) to give the title compound (7.0 mg, 0.02 mmol, 32% yield). 19 H 23 N4O4[M+H] + LCMS calculated for: m / z=371.17; found: 371.1.

[0582] Step 3. 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione

[0583] To a mixture of 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (5.0 mg, 0.014 mmol) and triethylamine (0.0169 mL, 0.12 mmol) in DMSO (0.5 mL) was added sulfur trioxide pyridine (6.5 mg, 0.041 mmol). The reaction mixture was stirred at room temperature for 1 hour. Next, a solution of [(2R,6S)-2,6-dimethylpiperazin-1-yl]-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-12-yl]methanone (1:1 TFA salt, 7.3 mg, 0.014 mmol, prepared as described in WO2022099117) in MeCN (0.5 mL) was added to the reaction, followed by acetic acid (12 μL, 0.20 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (11.4 mg, 0.05 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 1 h, followed by the addition of HCl (1 M, 0.3 mL). The crude reaction mixture was purified by preparative HPLC on a C18 column (8-29% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (1.3 mg, 1.3 μmol, 9.6% yield) as the TFA salt. 41 H 50 N 11 O5 [M+H] + LCMS calculated for: m / z=776.40; found: 776.4.

[0584] Example 3. 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione [ka] Step 1. 3-(6-bromo-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione [ka]

[0585] To a mixture of 6-bromophthalazinone (137 mg, 0.61 mmol) and 3-bromopiperidine-2,6-dione (175 mg, 0.91 mmol) in DMF (6.0 mL) was added sodium hydride (60% suspension in mineral oil, 60.9 mg, 1.52 mmol). The reaction was stirred overnight at room temperature. The reaction was quenched by the slow addition of HCl (1 M, 2.0 mL). The reaction was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was diluted with DMSO and purified by preparative HPLC on a C18 column (25-45% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (66.0 mg, 0.20 mmol, 32.2% yield). 13 H 11 BrN3O3[M+H] + LCMS calculated: m / z = 336.00 / 338.00; found 335.9 / 337.9.

[0586] Step 2. 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxophthalazine-2-(1H)-yl)piperidine-2,6-dione [ka]

[0587] A mixture of 3-(6-iodo-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (15.0 mg, 0.04 mmol), 4-piperidinemethanol (15.4 mg, 0.13 mmol), copper(I) iodide (4.3 mg, 0.02 mmol), L-proline (5.1 mg, 0.45 mmol), and potassium carbonate (18.5 mg, 0.13 mmol) in DMSO (2.0 mL) was heated at 80 °C overnight under N2. The reaction was cooled, and HCl (1 M, 1 mL) was added. The reaction was stirred for 10 minutes and filtered. The filtrate was purified by preparative HPLC on a C18 column (14-34% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (5.0 mg, 14 μmol, 30% yield). 19 H 23 N4O4[M+H] + LCMS calculated for: m / z=371.17; found: 371.1.

[0588] Step 3. 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione

[0589] To a mixture of 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione (5.0 mg, 0.014 mmol) and triethylamine (0.0169 mL, 0.12 mmol) in DMSO (0.5 mL) was added sulfur trioxide pyridine (6.5 mg, 0.041 mmol). The reaction mixture was stirred at room temperature for 1 hour. Next, a solution of [(2R,6S)-2,6-dimethylpiperazin-1-yl]-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-12-yl]methanone (1:1 TFA salt, 7.3 mg, 0.014 mmol, prepared as described in WO2022099117) in MeCN (0.5 mL) was added to the reaction, followed by acetic acid (12 μL, 0.20 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (11.4 mg, 54 μmol) was then added, and the resulting reaction mixture was stirred at room temperature for 1 h, followed by the addition of HCl (1 M, 0.3 mL). The crude reaction mixture was purified by preparative HPLC on a C18 column (12-32% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (1.2 mg, 0.0012 mmol, 8.8% yield) as the TFA salt. 41 H 50 N 11 O5 [M+H] + LCMS calculated for: m / z=776.40; found: 776.4.

[0590] Example 4. 3-(6-(4-(((3S,5R)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2H-indazol-2-yl)piperidine-2,6-dione [ka] Step 1. 3-(6-iodo-2H-indazol-2-yl)piperidine-2,6-dione [ka]

[0591] To a mixture of 6-iodo-1H-indazole (174 mg, 0.71 mmol) and 3-bromopiperidine-2,6-dione (274 mg, 1.43 mmol) in DMF (6.0 mL) was added sodium hydride (60% suspension in mineral oil, 114 mg, 2.85 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by the slow addition of HCl (1 M, 3.0 mL). The reaction was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was diluted with DMSO and purified by preparative HPLC on a C18 column (31-51% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (39.0 mg, 0.11 mmol, 15.4% yield, Peak A, t ピーク = 4.33 min) and positional isomer (peak B, t ピーク = 4.61 min). 1 H NMR(600MHz,DMSO-d6)δ 11.19(s,1H),8.50(d,J=1.0Hz,1H),8.08(d,J=1.4Hz,1H),7.59(d,J=8.7Hz,1H),7.31(dd,J=8.7, 1.4Hz, 1H), 5.73 (dd, J=11.8, 5.2Hz, 1H), 2.89~2.80 (m, 1H), 2.79~2.67 (m, 2H), 2.39~2.30 (m, 1H). LCMS calculated value C 12 H 11 IN3O2[M+H] + : m / z=355.99; measured value 356.0.

[0592] Step 2. 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-2H-indazol-2-yl)piperidine-2,6-dione [ka]

[0593] A mixture of 3-(6-iodo-2H-indazol-2-yl)piperidine-2,6-dione (35.0 mg, 0.10 mmol), 4-piperidinemethanol (34.1 mg, 0.30 mmol), copper(I) iodide (18.8 mg, 0.10 mmol), L-proline (22.7 mg, 0.20 mmol), and potassium carbonate (40.9 mg, 0.30 mmol) in DMSO (2.0 mL) was heated at 80 °C overnight under N2. The reaction was cooled, and HCl (1 M, 1.0 mL) was added. The reaction was stirred for 10 minutes and filtered. The filtrate was purified by preparative HPLC on a C18 column (5-25% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (28.0 mg, 0.08 mmol, 83% yield). 18 H 23 N4O3[M+H] + LCMS calculated for: m / z=343.18; found: 343.2.

[0594] Step 3. 3-(6-(4-(((3S,5R)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2H-indazol-2-yl)piperidine-2,6-dione

[0595] To a mixture of 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-2H-indazol-2-yl)piperidine-2,6-dione (14.0 mg, 0.04 mmol) and triethylamine (51 μL, 0.73 mmol) in DMSO (0.5 mL) was added sulfur trioxide pyridine (19.5 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 1 hour. Next, a solution of [(2R,6S)-2,6-dimethylpiperazin-1-yl]-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-12-yl]methanone (1:1 TFA salt, 26.6 mg, 0.04 mmol, prepared as described in WO2022099117) in MeCN (0.5 mL) was added to the reaction, followed by acetic acid (35 μL, 0.61 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (34.7 mg, 0.16 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 1 hour, after which HCl (1 M, 0.5 mL) was added. The crude reaction mixture was purified by preparative HPLC on a C18 column (6-27% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (4.3 mg, 4.4 μmol, 11% yield) as the TFA salt. 40 H 50 N 11 O4 [M+H] + LCMS calculated for: m / z=748.40; found: 748.4.

[0596] Example 5. 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione [ka] Step 1. 3-(6-iodo-1H-indazol-1-yl)piperidine-2,6-dione [ka]

[0597] To a mixture of 6-iodo-1H-indazole (174 mg, 0.713 mmol) and 3-bromopiperidine-2,6-dione (274 mg, 1.43 mmol) in DMF (6.0 mL) was added sodium hydride (60% suspension in mineral oil, 114 mg, 2.85 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by the slow addition of HCl (1 M, 3.0 mL). The reaction was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was diluted with DMSO and purified by preparative HPLC on a C18 column (31-51% MeCN in 0.1% TFA (aq), pH=2) to give the title compound (31.0 mg, 0.0873 mmol, 12.2% yield, Peak B, t ピーク = 4.61 min) and positional isomer (peak A, t ピーク = 4.33 min) was obtained. 12 H 11 IN3O2[M+H] + LCMS calculated for: m / z=355.99; found: 356.0.

[0598] Step 2. 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione [ka]

[0599] A mixture of 3-(6-iodo-1H-indazol-1-yl)piperidine-2,6-dione (23.0 mg, 0.06 mmol), 4-piperidinemethanol (44.8 mg, 0.39 mmol), copper(I) iodide (12.3 mg, 0.06 mmol), L-proline (14.9 mg, 0.13 mmol), and potassium carbonate (26.9 mg, 0.19 mmol) in DMSO (2.0 mL) was heated at 80 °C overnight under N2. The reaction was cooled, and HCl (1 M, 1.0 mL) was added. The reaction was stirred for 10 minutes and filtered. The filtrate was purified by preparative HPLC on a C18 column (5-25% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (17.0 mg, 0.05 mmol, 76.7% yield). 18 H 23 N4O3[M+H] + LCMS calculated for: m / z=343.18; found: 343.2.

[0600] Step 3. 3-(6-(4-(((3S,5R)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2H-indazol-2-yl)piperidine-2,6-dione

[0601] To a mixture of 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (9.0 mg, 0.03 mmol) and triethylamine (33 μL, 0.24 mmol) in DMSO (0.5 mL) was added sulfur trioxide pyridine (12.6 mg, 0.08 mmol). The reaction mixture was stirred at room temperature for 1 hour. Next, a solution of [(2R,6S)-2,6-dimethylpiperazin-1-yl]-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-12-yl]methanone (1:1 TFA salt, 17.1 mg, 0.03 mmol, prepared as described in WO2022099117) in MeCN (0.5 mL) was added to the reaction, followed by acetic acid (23 μL, 0.39 mmol). The reaction mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (22.3 mg, 0.11 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 1 h, followed by the addition of HCl (1 M, 0.5 mL). The crude reaction mixture was purified by preparative HPLC on a C18 column (8-29% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (1.8 mg, 0.0018 mmol, 7.0% yield) as the TFA salt. 40 H 50 N 11 O4 [M+H] + LCMS calculated for: m / z=748.40; found: 748.4.

[0602] Example 6. 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione [ka] Step 1. 3-(6-iodo-1H-indazol-1-yl)piperidine-2,6-dione [ka]

[0603] To a mixture of 6-iodo-1H-indazole (174 mg, 0.71 mmol) and 3-bromopiperidine-2,6-dione (274 mg, 1.43 mmol) in DMF (6.0 mL) was added sodium hydride (60% suspension in mineral oil, 114 mg, 2.85 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched by the slow addition of HCl (1 M, 3.0 mL). The reaction was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was diluted with DMSO and purified by preparative HPLC on a C18 column (31-51% MeCN in 0.1% TFA (aq), pH=2) to give the title compound (31.0 mg, 0.0873 mmol, 12.2% yield, Peak B, t ピーク = 4.61 min) and positional isomer (peak A, t ピーク = 4.33 min) was obtained. 12 H 11 IN3O2[M+H] + LCMS calculated for: m / z=355.99; found: 356.0.

[0604] Step 2. 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione [ka]

[0605] A mixture of 3-(6-iodo-1H-indazol-1-yl)piperidine-2,6-dione (23.0 mg, 0.06 mmol), 4-piperidinemethanol (44.8 mg, 0.39 mmol), copper(I) iodide (12.3 mg, 0.06 mmol), L-proline (14.9 mg, 0.13 mmol), and potassium carbonate (26.9 mg, 0.19 mmol) in DMSO (2.0 mL) was heated at 80 °C overnight under N2. The reaction was cooled, and HCl (1 M, 1.0 mL) was added. The reaction was stirred for 10 minutes and filtered. The filtrate was purified by preparative HPLC on a C18 column (5-25% MeCN in 0.1% TFA (aq), pH = 2) to give the title compound (17.0 mg, 0.05 mmol, 76.7% yield). 18 H 23 N4O3[M+H] + LCMS calculated for: m / z=343.18; found: 343.2.

[0606] Step 3. 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0607] To a mixture of 3-(6-(4-(hydroxymethyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (11.0 mg, 0.03 mmol) and triethylamine (40 μL, 0.29 mmol) in DMSO (0.5 mL) was added sulfur trioxide pyridine (15.3 mg, 0.09 mmol). The reaction mixture was stirred at room temperature for 1 hour. Next, a solution of 2-((S)-8-(((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (1:2 TFA salt, 19.5 mg, 0.03 mmol, prepared as described in WO2022099117) in MeCN (0.5 mL) was added to the reaction, followed by acetic acid (28 μL, 0.48 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. Sodium triacetoxyborohydride (27.2 mg, 0.13 mmol) was then added, and the resulting reaction mixture was stirred at room temperature for 1 hour, after which HCl (1 M, 0.5 mL) was added. The crude reaction mixture was purified by preparative HPLC on a C18 column (10-19% MeCN in 0.1% TFA (aq), pH=2) to afford the title compound (1.7 mg, 1.8 μmol, 5.7% yield) as the TFA salt. 39 H 47 N 10 O3 [M+H] + LCMS calculated for: m / z=703.38; found: 703.3.

[0608] Example 7. N-(2,6-Dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethylpiperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide [ka] Step 1: 4-[4-(hydroxymethyl)piperidin-1-yl]pyridine-2-carboxylic acid [ka]

[0609] A mixture of 4-chloropyridine-2-carbonitrile (250 mg, 1.8 mmol), 4-piperidinemethanol (225 mg, 1.95 mmol), and potassium carbonate (270 mg, 1.95 mmol) in DMSO (2 mL) was stirred at 120° C. for 1 hour. 6N HCl (1.5 mL, 9.02 mmol) was then added to the mixture, and stirring was continued at 120° C. overnight. The mixture was cooled to room temperature, and the volatiles were removed. The residue was carried on to the next step without further purification. A quantitative yield of 4-[4-(hydroxymethyl)piperidin-1-yl]pyridine-2-carboxylic acid was assumed. C 12 H 16 N2O3[M+H] + LCMS calculated for: m / z=237.2; found: 237.1.

[0610] Step 2: N-(2,6-dioxopiperidin-3-yl)-4-[4-(hydroxymethyl)piperidin-1-yl]pyridine-2-carboxamide [ka]

[0611] To a solution of crude 4-[4-(hydroxymethyl)piperidin-1-yl]pyridine-2-carboxylic acid (426 mg, 1.8 mmol) in DMSO (2 mL) was added 3-aminopiperidine-2,6-dione, HCl (356 mg, 2.16 mmol), N,N-diisopropylethylamine (0.94 mL, 5.41 mmol), and then 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.02 g, 2.7 mmol). The mixture was stirred at room temperature. After 15 min, DCM was added, followed by additional N,N-diisopropylethylamine (1.88 mL, 10.8 mmol). After 2 h, the volatiles were removed via rotary evaporation. The residue was purified by SiO2 chromatography: 25 g, 0-20% MeOH / DCM. The combined fractions were washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (136 mg, 0.39 mmol, 22% yield). 17 H 22 N4O4(M+H) + LCMS calculated m / z=347.2, found: 347.0.

[0612] Step 3: N-(2,6-dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethyl-piperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide [ka]

[0613] To N-(2,6-dioxopiperidin-3-yl)-4-[4-(hydroxymethyl)piperidin-1-yl]pyridine-2-carboxamide (7.0 mg, 0.02 mmol) and triethylamine (0.11 mL, 0.81 mmol) in DMSO (0.1 mL) was added sulfur trioxide pyridine (64.3 mg, 0.4 mmol) in DMSO (0.4 mL). The reaction mixture was stirred at room temperature for 20 minutes, quenched with methanol, and concentrated. To the crude solution was added DMF (1 mL), followed by [(2R,6S)-2,6-dimethylpiperazin-1-yl]-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-12-yl]methanone; dihydrochloride (10 mg, 0.02 mmol, prepared as described in WO2022099117), acetic acid (0.01 mL, 0.1 mmol), and then sodium triacetoxyborohydride (17 mg, 0.08 mmol). After 35 min, the reaction mixture was diluted with MeOH, filtered through a 0.2 μm PTFE syringe filter, and analyzed by preparative LCMS (column: Waters Purification by CSH-C18, 5 μm particle size, 30 × 100 mm, MP: Aq (0.1% TFA) / 60 ml / min in a column, gradient: 5 to 25% B in 5 min) gave N-(2,6-dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethylpiperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide trifluoroacetate (0.9 mg, 0.8 μmol, 4% yield) as a white solid. 39 H 49 N 11 O5 [M+H] + LCMS calculated for: m / z=752.2; found: 752.2.

[0614] Example 8. N-(2,6-Dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethylpiperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide [ka] Step 1: 3-[(6-bromo-1-methylindazol-3-yl)amino]propanoic acid [ka]

[0615] A mixture of 6-bromo-1-methylindazol-3-amine (5.0 g, 22.1 mmol), acrylic acid (1.52 mL, 22.1 mmol), and acetic acid (3.0 mL, 52.5 mmol) in water (5.0 mL) was stirred at 105° C. overnight. The solid was filtered, washed with water, and dried to give 3-[(6-bromo-1-methylindazol-3-yl)amino]propanoic acid (2.2 g, 7.4 mmol, 33% yield). 11 H 12 BrN3O25[M+H] + LCMS calculated for: m / z=298.2; found: 298.1.

[0616] Step 2: 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazinan-2,4-dione [ka]

[0617] A mixture of acetic acid (6.0 mL, 105 mmol), 3-[(6-bromo-1-methylindazol-3-yl)amino]-propanoic acid (2.2 g, 7.38 mmol), and urea (1.6 g, 26.6 mmol) was stirred at 120 °C overnight. The reaction was cooled to room temperature, and a few drops of concentrated HCl were added to bring the pH to approximately 1. The reaction was heated again for 30 minutes. The mixture was diluted with water. The solid was collected by filtration, washed with water, and air-dried to give 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazinan-2,4-dione (820 mg, 2.5 mmol, 34% yield). 12 H 11 LCMS calculated for BrN4O2 (M+H)+: m / z = 323.2; found: 323.0.

[0618] Step 3: 1-[6-[4-(hydroxymethyl)piperidin-1-yl]-1-methylindazol-3-yl]-1,3-diazinan-2,4-dione [ka]

[0619] A mixture of 1-(6-bromo-1-methylindazol-3-yl)-1,3-diazinan-2,4-dione (310 mg, 0.96 mmol), 4-piperidinemethanol (121 mg, 1.06 mmol), RuPhos Pd G2 (74 mg, 0.1 mmol), and cesium carbonate (625 mg, 1.92 mmol) in 1,4-dioxane (2 mL) was degassed, and the reaction was stirred at 100 °C overnight. The mixture was filtered and purified on a silica gel column (0-100% EA / Hex, followed by 10% MeOH / DCM) to give 1-[6-[4-(hydroxymethyl)piperidin-1-yl]-1-methylindazol-3-yl]-1,3-diazinan-2,4-dione (32 mg, 0.09 mmol, 9% yield). 18 H 23 N5O3[M+H] + LCMS calculated for: m / z=358.2; found: 358.2.

[0620] Step 4: 1-[6-[4-[[(1S,5R)-6-[[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-12-yl]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]piperidin-1-yl]-1-methylindazol-3-yl]-1,3-diazinan-2,4-dione [ka]

[0621] To a solution of 1-[6-[4-(hydroxymethyl)piperidin-1-yl]-1-methylindazol-3-yl]-1,3-diazinan-2,4-dione (18 mg, 0.05 mmol) in DMSO (1 mL) was added triethylamine (0.07 mL, 0.51 mmol), followed by the dropwise addition of a solution of sulfur trioxide pyridine (40 mg, 0.25 mmol) in DMSO (0.5 mL). The reaction was stirred at room temperature for 1 hour. To the mixture was added a solution of 2-[(10S)-12-[[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-4-yl]phenol (19 mg, 0.05 mmol, prepared as described in WO2022099117) in MeCN (0.5 mL), followed by acetic acid (0.06 mL, 1.12 mmol). Sodium triacetoxyborohydride (64 mg, 0.3 mmol) was then added in one portion, and the reaction was stirred at room temperature for 2 hours. The mixture was purified by preparative LCMS (Column: Waters CSH-C18, 5um particle size, 30 x 100 mm, MP: Aq (0.1% TFA) / can @ 60 ml / m, Gradient: 5 to 25% B in 5 min) to give 1-[6-[4-[[(1S,5R)-6-[[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-12-yl]methyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]piperidin-1-yl]-1-methylindazol-3-yl]-1,3-diazinan-2,4-dione (5 mg, 7 μmol, 14% yield). 39 H 47 N 11 LCMS calculated for O3 [M+H]+: m / z = 718.4; found: 718.2.

[0622] Example 9. 1-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, [ka] Step 1: 5-Vinylpyridin-2-ol (Intermediate-1) [ka]

[0623] 5-Bromopyridin-2-ol (3.0 g, 17.24 mmol), cesium carbonate (8.43 g, 25.86 mmol), and potassium vinyltrifluoroborate (4.16 g, 31.03 mmol) were added to a 100 mL round-bottom flask, followed by 1,4-dioxane (80 mL) and water (15 mL). The mixture was sparged with nitrogen for 5 minutes. Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (SPhos Pd G2) (1.24 g, 1.72 mmol) was added. The flask was equipped with a reflux condenser, sealed with a rubber septum, and purged with nitrogen for 5 minutes. The mixture was stirred at 95 °C overnight. After cooling to room temperature, the mixture was diluted with a 3:1 mixture of chloroform / isopropanol (50 mL), dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography eluting with a gradient of 0-8% methanol / dichloromethane to afford 5-vinylpyrimidin-2-ol (591 mg, 28% yield) as a light yellow solid. C7H8NO[M+H] + LCMS calculated for: m / z=122.1; found: 121.9.

[0624] Step 2: (6aS,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0625] (6aS,8R)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol (400.0 mg, 1.57 mmol), 5-vinylpyridin-2-ol (285 mg, 2.36 mmol), and triphenylphosphine (659 mg, 2.51 mmol) were added to a 20 mL vial, followed by dichloromethane (8 mL) and tetrahydrofuran (4 mL). The vial was sealed with a septum cap and purged with nitrogen for 3 minutes. Diisopropyl azodicarboxylate (526 μL, 2.51 mmol) was added via pipette after quickly removing and replacing the cap. The mixture was stirred at 50 °C for 1 hour. Volatiles were removed under reduced pressure. The crude material was purified by flash silica gel column chromatography eluting with a gradient of 0-5% methanol / dichloromethane to afford (6aS,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (370 mg, 66% yield) as a white solid. 18 H 21 ClNO[M+H] + LCMS calculated for: m / z=358.1, found: 358.1.

[0626] Step 3: 2-((6aS,8R)-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol [ka]

[0627] (6aS,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (170.0 mg, 0.49 mmol), 2-hydroxyphenylboronic acid (204 mg, 1.48 mmol), potassium carbonate (272 mg, 1.97 mmol), 1,4-dioxane (4 mL), and water (0.4 mL) were added to a 20 mL vial equipped with a stir bar. The mixture was sparged with nitrogen for 5 minutes. Next, chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (SPhos Pd G2) (42.5 mg, 0.06 mmol) was added. The vial was sealed with a septum cap and purged with nitrogen for 5 minutes. The mixture was stirred at 85 °C for 3 hours. After cooling to room temperature, the mixture was diluted with dichloromethane (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography eluting with a gradient of 0-5% methanol / dichloromethane to give 2-((6aS,8R)-6a=ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (167 mg, 82% yield) as a pale yellow solid. 24 H 26 NO2[M+H] + LCMS calculated for: m / z=416.2; found: 416.2.

[0628] Step 4: 6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde [ka]

[0629] 2-((6aS,8R)-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (170.0 mg, 0.41 mmol), 2,6-lutidine (95 μL, 0.82 mmol), 1,4-dioxane (3 mL), and water (1 mL) were added to a 20 mL vial equipped with a stir bar. Next, osmium tetroxide (260 μL, 50 μmol, 4 wt % in water) and sodium periodate (263 mg, 1.23 mmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde (estimated quantitative yield) as a brown solid. 23 H 24 N5O3[M+H] + LCMS calculated for: m / z=418.2; found: 418.1.

[0630] Step 5: 1-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[0631] 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (17.7 mg, 0.06 mmol), 6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde (Intermediate-4) (17 mg, 0.04 mmol), and dimethyl sulfoxide (1 mL) were added to a 20 mL vial charged with a stir bar, followed by the addition of N,N-diisopropylethylamine (21 μL, 0.12 mmol). The mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (43 mg, 0.20 mmol) was added. The mixture was stirred at 35 °C overnight. After cooling to room temperature, the mixture was filtered and purified by preparative (Waters CSH Phenyl-Hexyl, 5 μm particle size, 30 × 100 mm) HPLC (11.9 to 31.9% CHCN in HO containing 0.1% TFA in 5 min) to give 1-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Example 9) (10.5 mg, 27% yield) as a white solid (TFA salt). 37 H 42 NO4[M+H] + LCMS calculated for: m / z=676.3; found: 676.2.

[0632] Example 10. 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione [ka] This example was synthesized by a procedure similar to that described in Example 9, using 3-((4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-dione hydrochloride instead of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride in step 5 to provide 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione (6.7 mg, 18% yield). 38 H 44 NO4[M+H] + LCMS calculated for: m / z=690.3; found: 690.3.

[0633] Example 11. 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione [ka] This example was synthesized by a procedure similar to that described in Example 9, using 3-(3-fluoro-4-piperazin-1-ylanilino)piperidine-2,6-dione hydrochloride instead of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride in step 5 to give 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione (5.7 mg, 14% yield). 38 H43 FN9O4[M+H] + LCMS calculated for: m / z=708.3; found: 708.2.

[0634] Example 12. N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)benzamide [ka] Step 1: tert-Butyl 4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ka]

[0635] Potassium carbonate (1.11 g, 8.05 mmol), tert-butyl 1-piperazinecarboxylate (1.0 g, 5.37 mmol), methyl 4-fluorobenzoate (0.76 mL, 5.91 mmol), and dimethyl sulfoxide (20 mL) were added to a 40 mL vial. The vial was sealed with a cap, and the mixture was stirred at 150 °C for 4 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed sequentially with 1 N sodium hydroxide, 1 N hydrochloric acid, and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography eluting with a gradient of 0–30% ethyl acetate / hexane to afford tert-butyl 4-(4-(methoxycarbonylphenyl)piperazine-1-carboxylate) (285 mg, 17% yield) as a white solid. 17 H 25 N2O4[M+H] + LCMS calculated for: m / z=321.2; found: 321.1.

[0636] Step 2: 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid [ka]

[0637] Sodium hydroxide (1 M in water, 7.8 mL, 7.8 mmol), THF / methanol (1:1, 10 mL), and tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate (250 mg, 0.78 mmol) were added to a 40 mL vial. The vial was sealed with a cap, and the mixture was stirred at 45° C. overnight. After cooling to room temperature, the mixture was acidified with 1N HCl and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (240 mg, 100% yield) as a white solid. 16 H 23 N2O4[M+H] + LCMS calculated for: m / z=307.2; found: 307.1.

[0638] Step 3: N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide [ka]

[0639] 4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)benzoic acid (100.0 mg, 0.33 mmol), 3-amino-piperidine-2,6-dione hydrochloride (107.45 mg, 0.65 mmol), N,N-diisopropylethylamine (227.42 μL, 1.31 mmol), and ethyl acetate (2 mL) were added to a 20 mL vial, followed by propyl-phosphonic anhydride (0.49 mL, 1.63 mmol). The mixture was stirred overnight at room temperature. Additional propylphosphonic anhydride (0.49 mL, 1.63 mmol) was added, and the mixture was stirred for another day. The mixture was diluted with chloroform / isopropanol (3:1, 50 mL) and brine (30 mL). The phases were separated. The aqueous phase was extracted with chloroform / isopropanol (3:1, 2 x 30 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative (Waters CSH C-18, 5 μm particle size, 30 x 100 mm) HPLC (36.2 to 56.2% CHCN in HO with 0.1% TFA in 5 min) to give a white solid. The solid was then stirred with hydrochloric acid (2.45 mL, 9.79 mmol, 4 M in dioxane) in a 20 mL vial at room temperature for 2 hours. Volatiles were removed under reduced pressure to give N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide (59 mg, 51% yield as the hydrochloride salt) as a white solid. C 16 H 21 N4O3[M+H] + LCMS calculated for: m / z=317.2; found: 317.1.

[0640] Step 4: N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)benzamide

[0641] This example was synthesized by a procedure similar to that described in Example 9, using N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide hydrochloride instead of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride in step 5 to give N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)benzamide (3.1 mg, 7% yield). 39 H 44 N9O5[M+H] + LCMS calculated for: m / z=718.3; found: 718.2.

[0642] Example 13. N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide [ka] Step 1: tert-Butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ka]

[0643] This example was synthesized by a procedure similar to that described in Example 12, using methyl 2,4-difluorobenzoate instead of methyl 4-fluorobenzoate in Step 1 to afford tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (595 mg, 53% yield) as a white solid. 17 H24 FN2O4[M+H] + LCMS calculated for: m / z=339.2; found: 339.1.

[0644] Step 2: 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid [ka]

[0645] This example was synthesized by a procedure similar to that described in Example 12, using tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate instead of tert-butyl 4-(4-methoxycarbonylphenyl)piperazine-1-carboxylate in Step 2 to afford 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (100% yield) as a white solid. 16 H 22 FN2O4[M+H] + LCMS calculated for: m / z=325.2; found: 325.1.

[0646] Step 3: N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide [ka]

[0647] This example was synthesized by a procedure similar to that described in Example 12, using 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid instead of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid in Step 3 to afford N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (47% yield as the hydrochloride salt) as a white solid. 16 H 20 FN4O3[M+H] +LCMS calculated for: m / z=335.2; found: 335.1.

[0648] Step 4: N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide

[0649] This example was synthesized by a procedure similar to that described in Example 9, using N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide hydrochloride instead of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride in step 5 to give N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide (3.5 mg, 7% yield). 39 H 43 FN9O5[M+H] + LCMS calculated for: m / z=736.3; found: 736.3.

[0650] Example 14. 3-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione [ka] Step 1: tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate [ka]

[0651] 3-(4-Bromophenyl)piperidine-2,6-dione (150.0 mg, 0.56 mmol), tert-butyl-1-piperazinecarboxylate (145.88 mg, 0.78 mmol), cesium carbonate (365 mg, 1.12 mmol), and 1,4-dioxane (6 mL) were added to a 20 mL vial equipped with a stir bar. The mixture was sparged with nitrogen for 5 minutes. Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (SPhos Pd G2) (40 mg, 0.06 mmol) was added. The vial was sealed with a septum cap and purged with nitrogen for 5 minutes. The mixture was stirred at 90 °C overnight. After cooling to room temperature, the mixture was diluted with acetonitrile, filtered, and purified by preparative (Waters CSH C-18, 5 μm particle size, 30 × 100 mm) HPLC (21.2 to 41.2% CHCN in HO containing 0.1% TFA in 5 min) to give tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (13 mg, 6% yield) as a colorless film. 20 H 28 N3O4[M+H] + LCMS calculated for: m / z=374.2; found: 374.1.

[0652] Step 2: 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione [ka]

[0653] tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (13.0 mg, 0.03 mmol), 2,2,2-trifluoroacetic acid (0.13 mL, 1.74 mmol), and acetonitrile (0.5 mL) were stirred in a 2-dram vial at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (11 mg, 82% yield as the TFA salt) as a light yellow film. 15 H 20 N3O2[M+H] + LCMS calculated for: m / z=274.2; found: 274.0.

[0654] Step 3: 3-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0655] This example was synthesized by a procedure similar to that described in Example 9, using 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (TFA salt) instead of 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride in step 5 to give 3-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (1.1 mg, 5% yield). 38 H 43 N8O4[M+H] + LCMS calculated for: m / z=675.3; found: 675.3.

[0656] Example 15. 3-(4-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione [ka] Step 1: (6aR,8R)-2-chloro-6a-(difluoromethyl)-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine [ka]

[0657] This example was repeated in step 2, except that (6aR,8R)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-ol was substituted with (6aR,8R)-2-chloro-6a-(difluoromethyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino-[2, Synthesis of this compound using a procedure similar to that described in Example 9 using [3-c]pyridazin-8-ol gave (6aR,8R)-2-chloro-6a-(difluoromethyl)-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino-[2,3-c]pyridazine (110 mg, 93% yield). 17 H 17 ClF2N5O[M+H] + LCMS calculated for: m / z=380.1; found: 380.0.

[0658] Step 2: 2-((6aR,8R)-6a-(difluoromethyl)-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol [ka]

[0659] This example was modified by substituting (6aR,8R)-2-chloro-6a-(difluoromethyl)-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine for (6aS,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine in step 3. Synthesis was carried out using a procedure similar to that described in Example 9 using 2-((6aR,8R)-6a-(difluoromethyl)-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (42 mg, 100% yield) using 2-[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl]pyridazine. 23 H 22 F2N5O2[M+H] + LCMS calculated for: m / z=438.2; found: 438.1.

[0660] Step 3: 6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde [ka]

[0661] This example was modified in step 4 by substituting 2-((6aR,8R)-6a-(difluoromethyl)-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol for 2-((6aS,8R)-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol. Synthesized by a procedure similar to that described in Example 9 using [1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol to give 6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde (estimated quantitative yield). 22 H 20 F2N5O3[M+H] + LCMS calculated for: m / z=440.2; found: 440.1.

[0662] Step 4: tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,6-dihydro-pyridine-1(2H)-carboxylate [ka]

[0663] 3-(4-Bromophenyl)piperidine-2,6-dione (300.0 mg, 1.12 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (449.79 mg, 1.45 mmol), potassium carbonate (463.91 mg, 3.36 mmol), 1,4-dioxane (10 mL), and water (1 mL) were added to a 20 mL vial equipped with a stir bar. The mixture was sparged with nitrogen for 5 minutes. Next, chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (SPhos Pd G2) (80.56 mg, 0.11 mmol) was added. The vial was sealed with a septum cap and purged with nitrogen for 5 minutes. The mixture was stirred at 75°C for 3 hours. After cooling to room temperature, the mixture was diluted with a 3:1 mixture of chloroform / isopropanol (30 mL) and brine (20 mL). The phases were separated. The aqueous phase was extracted with chloroform / isopropanol (2 x 30 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography eluting with 0-100% ethyl acetate / hexane to give tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (294 mg, 71% yield). 17 H 19 N2O4[M-tBu+2H] + LCMS calculated for: m / z=315.1; found: 315.1.

[0664] Step 5: tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate (Intermediate 17) [ka]

[0665] tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (269.1 mg, 0.73 mmol), 10 wt% palladium on carbon (38.65 mg), tetrahydrofuran (6 mL), and ethanol (6 mL) were added to a 40 mL vial. The vial was sealed with a septum cap and purged with hydrogen. The mixture was stirred overnight at room temperature under an atmosphere of hydrogen (balloon). The mixture was passed through Celite eluting with dichloromethane (50 mL) and concentrated under reduced pressure to give tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate (263 mg, 97% yield) as a white solid. C 17 H 21 N2O4[M-tBu+2H] + LCMS calculated for: m / z=317.2; found: 317.1.

[0666] Step 6: 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione [ka]

[0667] tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidine-1-carboxylate (200.0 mg, 0.54 mmol), 1,4-dioxane (2 mL), and hydrochloric acid (1.35 mL, 5.37 mmol, 4 M in 1,4-dioxane) were added to a 2-dram vial. The mixture was stirred at room temperature for 4 hours. Volatiles were removed under reduced pressure to give 3-(4-(piperidin-4-yl)phenyl)piperidine-2,6-dione (as the HCl salt) (158 mg, 0.5116 mmol, 95% yield) as a white solid. 16 H 21 N2O2[M-tBu+2H] + LCMS calculated for: m / z=273.2; found: 273.0.

[0668] Step 7: 3-(4-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione

[0669] In this example, instead of 6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde and 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride in step 5, 6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine C was synthesized by a procedure similar to that described in Example 9 using 3-(4-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione (17.6 mg, 25% yield). 38 H 40 F2N7O4[M+H] + LCMS calculated for: m / z=696.3; found: 696.2.

[0670] Example 16. 3-(4-(1-((6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione [ka] Step 1: (6aR,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (Intermediate 19) [ka]

[0671] This example was repeated in step 2, except that (6aR,8R)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino-[2,3-c]pyridazin-8-ol was replaced with (6aR,8R)-2-chloro-6a-ethyl-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino-[2 ,3-c]pyridazin-8-ol was used to synthesize (6aR,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine (69 mg, 65% yield). 18 H 21 ClNO[M+H] + LCMS calculated for: m / z=358.1; found: 358.0.

[0672] Step 2: 2-((6aR,8R)-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol [ka]

[0673] This example was modified by substituting (6aR,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine with (6aR,8R)-2-chloro-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazine in step 3. Synthesis was carried out using a procedure similar to that described in Example 9 using 2-((6aR,8R)-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (27 mg, 100% yield) using 4-[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl]pyridazine. 24 H 26 NO2[M+H] + LCMS calculated for: m / z=416.2; found: 416.2.

[0674] Step 3: 6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde [ka]

[0675] This example can be synthesized by substituting 2-((6aR,8R)-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Intermediate 20) with 2-((6aR,8R)-6a-ethyl-8-((5-vinylpyridin-2-yl)oxy)-5,6,6a,7,8,9-hexahydropyrrolo[1' ,2':4,5]pyrazino[2,3-c]pyridazin-2-yl)phenol (Intermediate 3) was synthesized by a procedure similar to that described in Example 9 to give 6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde (Intermediate 21) (estimated quantitative yield). 23 H 24 N5O3[M+H] + LCMS calculated for: m / z=418.2; found: 418.1.

[0676] Step 4: 3-(4-(1-((6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione

[0677] In this example, instead of 6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)nicotinaldehyde and 1-(4-(piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride in step 5, 6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo-[1',2':4,5]pyrazino[2,3-c]pyridazine C was synthesized by a procedure similar to that described in Example 9 using 3-(4-(1-((6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]-pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione (10.8 mg, 18% yield). 39 H 44 N7O4[M+H] + LCMS calculated for: m / z=674.3; found: 674.2.

[0678] Example A. SMARCA2 HiBiT and SMARCA4 HiBiT Degradation Assays Preparation of SMARCA2 / 4-HiBiT knock-in cells HiBiT peptide knock-in of SMARCA2 in LgBiT-expressing HEK293T cells was performed using the CRISPR-mediated tagging system described by Promega. Homozygous HiBiT knock-in on the c-terminal SMARCA2 was confirmed by Sanger sequencing. SMARCA2-HiBiT knock-in Hela monoclonal cells (CS302366) and SMARCA4-HiBiT knock-in Hela monoclonal cells (CS3023226) were purchased from Promega. Heterozygous HiBiT knock-in was confirmed by Sanger sequencing in both SMARCA2-HiBiT and SMARCA4-HiBiT monoclonal cells.

[0679] SMARCA2 HiBiT and SMARCA4 HiBiT degradation assay in HeLa cells Dispense a 10 μl aliquot of the prepared Hela-SMARCA2-HiBiT cells or Hela-SMARCA4-HiBiT cells (at a 1:1 ratio of cells to trypan blue (#1450013, Bio-Rad)) onto a cell counting slide (#145-0011, Bio-Rad) and obtain cell density and cell viability using a cell counter (TC20, Bio-Rad). Remove the appropriate volume of resuspended cells from the culture flask to accommodate 2500 cells / well at 20 μL / well. Transfer the Hela-HiBiT cells to a 50 mL conical (#430290, Corning). Spin down at 1000 rpm for 5 minutes using a tabletop centrifuge (SPINCHRON 15, Beckman). The supernatant was discarded, and the cell pellet was resuspended in modified EMEM (#30-2003, ATCC) cell culture medium containing 10% FBS (F2422-500ML, Sigma) and 1x penicillin / streptomycin (200 g / L) (30-002-CI, Corning) to a cell density of 125,000 cells / mL. 20 μL of resuspended Hela-HiBiT cells were dispensed per well into a 384-well TC-treated plate (#12-565-343, Thermo Scientific) using a standard cassette (#50950372, Thermo Scientific) on a Multidrop Combi (#5840310, Thermo Scientific) in a laminar flow cabinet.

[0680] The compound was dissolved in DMSO to prepare a 10 mM stock, and further serial 3-fold dilutions were performed while maintaining a maximum concentration of 10 μM. Using a digital liquid dispenser (D300E, Tecan), the test compounds were dispensed onto plates. The plates were incubated at 37 °C for 18 hours in a humidified tissue culture incubator. Using a Multidrop Combi with a small tube cassette (#24073295, Thermo Scientific), 20 μL of prepared Nano-Glo® HiBiT Lysis Detection Buffer (N3050, Promega) was added to each well of a 384-well plate and incubated at room temperature for 30 - 60 minutes. Using the 384-well ultra-high sensitivity luminescence mode, the plates were read on a microplate reader (Envision 2105, PerkinElmer). Raw data files and compound information reports were swept into a central data lake and deconvolved using an automated script designed by TetraScience, Inc. Data analysis, curve fitting, and reporting were performed in the Dotmatics Informatics Suite using the Screening Ultra module.

[0681] The results are summarized in Table 1 below. In Table 1, A = DC50 < 0.1 μM, B = 0.1 μM ≤ DC50 < 1 μM, and C = DC50 > 1 μM. In Table 4, A = Dmax > 75%, B = 50% < Dmax ≤ 75%, and C = Dmax < 50%.

Table 1

[0682] Although numerous embodiments of the present invention have been described, it will be apparent that our basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present invention. Accordingly, it will be understood that the scope of the present invention is defined not by the specific embodiments shown as examples, but by the appended claims.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof, wherein PTM is of formula IA: 【Chemistry 2】 is part of the formula R １ is a covalent bond or chemical moiety linking the PTM and ULM; * is the point of attachment to the ULM; n=0 to 3; Each W is independently an optionally substituted —CH ２ -, -C(O)-, -S(O)-, or -S(O) ２ -, and when n=2 or 3, only one W is -C(O)-, -S(O)-, or -S(O) ２ - and other W is -CH ２ - or substituted -CH ２ - and R ｃ１ and R ｄ１ are independently H, D, halo, C １－６ Alkyl, C １－６ Cycloalkyl, C １－３ haloalkyl, or C １－４ is alkoxyl, R ｅ３ is H, -C(O)R ｆ , or -P(O)(OR ｇ ) ２ and R ｆ and R ｇ are independently H, C １－４ Alkyl, C １－４ Substituted alkyl, C ３－８ Cycloalkyl, C ３－８ Substituted cycloalkyl, C ３－８ heterocycloalkyl, or C ３－８ is a substituted heterocycloalkyl; Z and Y are each independently N, CR ｈ wherein R ｈ = H, D, Halo, C １－６ Alkyl, C １－６ Cycloalkyl, C １－３ haloalkyl, or absent, or R １ is attached to Z, Z is C and Y is N or CR ｈ wherein R ｈ is H, or R １ is attached to Y, Y is C and Z is N or CR ｈ wherein R ｈ is H, B is an optionally substituted 5- to 7-membered cycloalkyl ring, an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocycle, ring B is fused to ring G via Y and Z, and ULM is 【Transformation 3】 and In the formula, X １ represents a bond, —C(O)—, —C(S)—, —CH ２ -, -CHCF ３ -, SO ２ -, -S(O), P(O)R ｂ -or-P(O)OR ｂ - and R ｂ are H, D, and -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each X ２ are independently N or CR ｂ However, there is one X ２ is a C atom having a point of attachment to the PTM.

2. R １ The compound of claim 1 , wherein is a covalent bond.

3. R １ But the formula: -(A) ｑ - is a chemical moiety represented by During the ceremony, q is an integer from 1 to 14; Each A is independently a bond, CR １ａ R １ｂ ,O,S,SO,SO ２ , N.R. １ｃ , S.O. ２ NR １ｃ , SONR １ｃ , SO (= NR １ｃ ), SO(=NR １ｃ ) NR １ｄ , C.O.R. １ｃ , N.R. １ｃ CONR １ｄ , N.R. １ｃ C(O)O, NR １ｃ SO ２ NR １ｄ , CO, CR １ａ =CR １ｂ , C≡C, SiR １ａ R １ｂ , P(O)R １ａ , P(O)OR １ａ , (CR １ａ R １ｂ ) １－４ , -(CR １ａ R １ｂ ) １－４ O (CR １ａ R １ｂ ) １－４ , -(CR １ａ R １ｂ ) １－４ S (CR １ａ R １ｂ ) １－４ , -(CR １ａ R １ｂ ) １－４ NR (CR １ａ R １ｂ ) １－４ , N.R. １ｃ C(=NCN)NR １ｄ NR １ｃ C (=NCN), NR １ｃ C (= CNO ２ ) NR １ｄ , 0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl optionally substituted with a group, 0-6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group, 0-6 R １ａ and / or R １ｂ aryl optionally substituted with a group, 0 to 6 R １ａ and / or R １ｂ heteroaryl optionally substituted with a group; R １ａ , R １ｂ , R １ｃ , R １ｄ and R １ｅ are each independently -H, D, -halo, -C １ -C ８ Alkyl, —O—C １ -C ８ Alkyl, -C １ -C ６ Haloalkyl, —S—C １ -C ８ Alkyl, -NHC １ -C ８ Alkyl, —N(C １ -C ８ alkyl) 2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, —O—(3- to 11-membered cycloalkyl), —S—(3- to 11-membered cycloalkyl), NH—(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl) ２ , N-(3- to 11-membered cycloalkyl)(C １ -C ８ alkyl), —OH, —NH ２ , -SH, -SO ２ C １ -C ８ Alkyl, SO(NH)C １ -C ８ Alkyl, P(O)(OC １ -C ８ alkyl) (C １ -C ８ alkyl), -P(O)(OC １ -C ８ alkyl) ２ , -C≡C-C １ -C ８ Alkyl, -C≡CH, -CH=CH(C １ -C ８ alkyl), -C(C １ -C ８ alkyl)=CH(C １ -C ８ alkyl), -C(C １ -C ８ alkyl)=C(C １ -C ８ alkyl) ２ , —Si(OH) ３ , -Si(C １ -C ８ alkyl) ３ , -Si(OH)(C １ -C ８ alkyl) ２ , -C(O)C １ -C ８ Alkyl, —CO ２ H, —CN, —CF ３ , -CHF ２ , -CH ２ F, -NO ２ , -SF ５ , -SO ２ NHC １ -C ８ Alkyl, —SO ２ N (C １ -C ８ alkyl) ２ , -SO(NH)NHC １ -C ８ Alkyl, —SO(NH)N(C １ -C ８ alkyl) ２ , -SONHC １ -C ８ Alkyl, -SON(C １ -C ８ alkyl) ２ , -CONHC １ -C ８ Alkyl, -CON(C １ -C ８ alkyl) ２ , -N(C １ -C ８ alkyl)CONH(C １ -C ８ alkyl), -N(C １ -C ８ alkyl)CON(C １ -C ８ alkyl) ２ , -NHCONH(C １ -C ８ alkyl), -NHCON(C １ -C ８ alkyl) ２ , -NHCONH ２ , -N(C １ -C ８ alkyl)SO ２ NH (C １ -C ８ alkyl), -N(C １ -C ８ alkyl)SO ２ N (C １ -C ８ alkyl) ２ , -NHSO ２ NH (C １ -C ８ alkyl), -NHSO ２ N (C １ -C ８ alkyl) ２ , or -NHSO ２ NH ２ and In the formula, R １ａ or R １ｂ are each independently optionally linked to other groups and each independently represent 0 to 4 R １ｅ 2. The compound of claim 1, wherein the cycloalkyl and / or heterocyclyl moieties may be optionally substituted with groups.

4. q=5 and R １ is represented by the formula: -A １ -A ２ -A ３ -A ４ -A ５ - is a chemical moiety represented by the formula: A １ , A ３ , and A ５ each independently represents a bond, -(CR １ａ R １ｂ ) ０－４ O (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ S (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ NR １ｃ (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ SO (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ SO ２ (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ SO ２ NR １ｃ (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ SONR １ｃ (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ SO (= NR １ｃ ) (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ SO (= NR １ｃ ) NR １ｄ (CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ CONR １ｃ (CR １ａ R １ｂ ) ０－４， -(CR １ａ R １ｂ ) ０－４ C(O)O(CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ NR １ｃ CONR １ｄ (CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ NR １ｃ C(O)O(CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ NR １ｃ SO ２ NR １ｄ (CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ C(O)(CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ CR １ａ =CR １ｂ (CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ C≡C(CR １ａ R １ｂ ) ０－４ ,-(CR １ａ R １ｂ ) ０－４ SiR １ａ R １ｂ (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ P(O)R １ａ (CR １ａ R １ｂ ) ０－４ , -(CR １ａ R １ｂ ) ０－４ P(O)OR １ａ (CR １ａ R １ｂ ) ０－４ , (CR １ａ R １ｂ ) １－４ , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl; A ２ and A ４ each independently represents a bond, (CR １ａ R １ｂ ) １－４ , optionally substituted 3- to 11-membered cycloalkyl, 3- to 11-membered heterocyclyl, aryl, and heteroaryl; R １ａ and R １ｂ are each independently -H, D, -halo, -C １ -C ８ Alkyl, —O—C １ -C ８ Alkyl, -C １ -C ６ Haloalkyl, —S—C １ -C ８ Alkyl, -NHC １ -C ８ Alkyl, —N(C １ -C ８ alkyl) 2, 3- to 11-membered cycloalkyl, aryl, heteroaryl, 3- to 11-membered heterocyclyl, —O—(3- to 11-membered cycloalkyl), —S—(3- to 11-membered cycloalkyl), NH—(3- to 11-membered cycloalkyl), N(3- to 11-membered cycloalkyl) ２ , N-(3- to 11-membered cycloalkyl)(C １ -C ８ alkyl), —OH, —NH ２ , -SH, -SO ２ C １ -C ８ Alkyl, SO(NH)C １ -C ８ Alkyl, P(O)(OC １ -C ８ alkyl) (C １ -C ８ alkyl), -P(O)(OC １ -C ８ alkyl) ２ , -C≡C-C １ -C ８ Alkyl, -C≡CH, -CH=CH(C １ -C ８ alkyl), -C(C １ -C ８ alkyl)=CH(C １ -C ８ alkyl), -C(C １ -C ８ alkyl)=C(C １ -C ８ alkyl) ２ , —Si(OH) ３ , -Si(C １ -C ８ alkyl) ３ , -Si(OH)(C １ -C ８ alkyl) ２ , -C(O)C １ -C ８ Alkyl, —CO ２ H, -CN, -NO ２ , -SF ５ , -SO ２ NHC １ -C ８ Alkyl, —SO ２ N (C １ -C ８ alkyl) ２ , -SO(NH)NHC １ -C ８ Alkyl, —SO(NH)N(C １ -C ８ alkyl) ２ , -SONHC １ -C ８ Alkyl, -SON(C １ -C ８ alkyl) ２ , -CONHC １ -C ８ Alkyl, -CON(C １ -C ８ alkyl) ２ , -N(C １ -C ８ alkyl)CONH(C １ -C ８ alkyl), -N(C １ -C ８ alkyl)CON(C １ -C ８ alkyl) ２ , -NHCONH(C １ -C ８ alkyl), -NHCON(C １ -C ８ alkyl) ２ , -NHCONH ２ , -N(C １ -C ８ alkyl)SO ２ NH (C １ -C ８ alkyl), -N(C １ -C ８ alkyl)SO ２ N-(C １ -C ８ alkyl) ２ , -NHSO ２ NH (C １ -C ８ alkyl), -NHSO ２ N (C １ -C ８ alkyl) ２ , or -NHSO ２ NH ２ is selected from the group consisting of R １ｃ and R １ｄ are each independently H, D, optionally substituted C １－４ Alkyl, C ３－８ Cycloalkyl, C ３－８ The compound of claim 3 , wherein the compound is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

5. R １ is 0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl optionally substituted with a group, 0-6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted by a -(CR １ａ R １ｂ ) １－５ , -(CR １ａ =CR １ｂ ) -, -(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A-(CR １ａ R １ｂ ) １－５ -, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (CR １ａ =CR １ｂ )-(CR １ａ R １ｂ ) １－５ -, - (CR １ａ R １ｂ ) １－５ - (CR １ａ =CR １ｂ )-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -(C≡C)-(CR １ａ R １ｂ ) １－５ -, - (CR １ａ R １ｂ ) １－５ -(C≡C)-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(C≡C)-(CR １ａ R １ｂ ) １－５ -A-(CR １ａ R １ｂ ) １－５ -, where A is O, S, or NR １ｃ and -(C≡C)-(CR １ａ R １ｂ ) １－５ , -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl optionally substituted with a group)-, -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with 0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ -, - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR １ａ R １ｂ ) １－５ -, - (CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3 to 11-membered cycloalkyl)-A-, -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-A-, -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ , -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A- (0 to 6 R １ａ and / or R １ｂ A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR １ａ R １ｂ ) １－５ , -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A- (0 to 6 R １ａ and / or R １ｂ A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A- (0 to 6 R １ａ and / or R １ｂ A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A- (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ -A-, where each A is independently O, S, or NR １ｃ and -(CR １ａ R １ b) １－５ -A- (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR １ａ R １ｂ ) １－５ -A-, where each A is independently O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A-(CR １ａ R １ｂ ) １－５ -A-(CR １ａ R １ｂ ) １－５ -A-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A-(CO), where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (CR １ａ =CR １ｂ )-(CR １ａ R １ｂ ) １－５ -A-(CO)-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -(C≡C)-(CR １ａ R １ｂ ) １－５ -A-(CO)-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ -A-(CO)-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A-(CO)-(0 to 6 R １ａ and / or R １ｂ A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR １ａ R １ｂ ) １－５ -A-(CO)-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A-(CO)-(0 to 6 R １ａ and / or R １ｂ A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ -A- (0 to 6 R １ａ and / or R １ｂ and (3- to 11-membered cycloalkyl)-A-(CO)-, optionally substituted with a group, wherein each A is independently O, S, or NR １ｃ and -(0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-CO-(CR １ａ R １ｂ ) １－５ -A-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ -A-(CO)-, where A is O, S, or NR １ｃ and -(CR １ａ R １ｂ ) １－５ - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR １ａ R １ｂ ) １－５ -A-(CO)-, where A is O, S, or NR １ｃ and -(0 to 6 R １ａ and / or R １ｂ 3- to 11-membered cycloalkyl)-(CR １ａ R １ｂ ) １－５ - or - (0 to 6 R １ａ and / or R １ｂ 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR １ａ R １ｂ ) １－５ The compound according to any one of claims 1 or 3, wherein

6. The compound of formula IA may be represented by formula IA-1: 【Chemistry 4】 The compound according to any one of claims 1 to 5,

7. The compound of formula IA may be represented by formula IA-2: 【Transformation 5】 The compound according to any one of claims 1 to 5,

8. The compound of formula IA may be represented by formula IA-3: 【Transformation 6】 is a compound of the formula m=1 to 3; X is an optionally substituted —CH ２ - or NH, or R １ is attached to X, then X is —CH— or N, and Q is an optionally substituted —CH ２ -, optionally substituted -(CH ２ ) ２ -, -C(O)-, optionally substituted -CH ２ C(O)-, -S(O)-, -S(O) ２ -, optionally substituted -CH ２ S (O) ２ - or optionally substituted -CH ２ The compound according to any one of claims 1 to 5 or 7, which is S(O)-.

9. The compound of formula IA may be represented by formula IA-4: 【Transformation 7】 is a compound of the formula m=1 to 3; Each R ｋ But independently, H, D, F, C １－６ Alkyl, C １－６ Cycloalkyl, C １－３ Haloalkyl, C １－４ Alkoxyl, substituted C １－３ Alkyl, substituted C １－３ Cycloalkyl, substituted C １－３ Haloalkyl, or substituted C １－４ is alkoxyl, 9. The compound of any one of claims 1 to 5 or 7 to 8, wherein s=0, 1, 2, 3, 4, 5, 6 or 7.

10. The compound of formula IA-4 may be a compound of formula IA-5: 【Transformation 8】 10. The compound of claim 9, wherein

11. The compound according to any one of claims 8 to 10, wherein m=2.

12. At least one W is optionally substituted —CH ２ When n=2 or 3, only one W is —C(O)—, —S(O)—, or —S(O) ２ - and other W is -CH ２ or substituted —CH ２ The compound according to any one of claims 8 to 11, wherein

13. The compound according to any one of claims 8 to 11, wherein at least one W is -C(O)-.

14. The compound of formula IA-5 may be represented by formula IA-6, IA-6a, or IA-6b: 【Chemistry 9】 12. The compound of claim 11,

15. R ｅ３ The compound of any one of claims 1 to 14, wherein is H.

16. R ｄ１ The compound of any one of claims 1 to 15, wherein is H.

17. R ｃ１ The compound of any one of claims 1 to 13, wherein is H.

18. 18. The compound of any one of claims 1 to 17, wherein ULM is: 【Chemistry 10】

19. 18. The compound of any one of claims 1 to 17, wherein ULM is: 【Chemistry 11】

20. 18. The compound of any one of claims 1 to 17, wherein ULM is: 【Chemistry 12】

21. 18. The compound of any one of claims 1 to 17, wherein ULM is: 【Chemistry 13】

22. 18. The compound of any one of claims 1 to 17, wherein ULM is: 【Chemistry 14】

23. 18. The compound of any one of claims 1 to 17, wherein ULM is: 【Chemistry 15】

24. ULM 【Chemistry 16】 The compound according to any one of claims 1 to 17,

25. ULM 【Chemistry 17】 The compound according to any one of claims 1 to 17,

26. 18. The compound of any one of claims 1 to 17, wherein ULM is: [Chemistry 18]

27. 18. The compound of any one of claims 1 to 17, wherein ULM is: 【Chemistry 19】

28. Each X ２ is CH, but one X ２ The compound of any one of claims 18 to 27, provided that is the C atom having the point of attachment to the PTM.

29. X １ But CH ２ 29. The compound of claim 27 or 28, wherein:

30. [0023] The compound of formula I is of formula IA-7, formula IA-8, formula IA-9, formula IA-10, formula IA-11, formula IA-12, formula IA-13, formula IA-14, formula IA-15, or formula IA-16: 【Chemistry 20】 【change】 【change】 30. The compound according to any one of claims 1 to 29, which is a compound of formula:

31. Each X ２ is CH and X １ is CH ２ 31. The compound of claim 30, wherein:

32. [0023] The compound of formula I is of formula IA-7a, formula IA-8a, formula IA-9a, formula IA-10a, formula IA-11a, formula IA-12a, formula IA-13a, formula IA-14a, formula IA-15a, or formula IA-16a: 【Chemistry 21】 【change】 is a compound of During the ceremony, Each R ｋ are independently H, D, F, C １－６ Alkyl, C １－６ Cycloalkyl, C １－３ Haloalkyl, C １－４ Alkoxyl, substituted C １－３ Alkyl, substituted C １－３ Haloalkyl, or substituted C １－４ is alkoxyl, 32. The compound of claim 30 or claim 31, wherein s is 0, 1, 2, 3 or 4.

33. Each X ２ is CH and X １ is CH ２ 33. The compound of claim 32, wherein:

34. wherein the compound of formula I is formula IA-7b, formula IA-8b, formula IA-9b, formula IA-10b, formula IA-11b, formula IA-12b, formula IA-13b, formula IA-14b, formula IA-15b, or formula IA-16b: 【Chemistry 22】 【change】 is a compound of During the ceremony, Each R ｋ are independently H, D, F, C １－６ Alkyl, C １－６ Cycloalkyl, C １－３ Haloalkyl, C １－４ Alkoxyl, substituted C １－３ Alkyl, substituted C １－３ Haloalkyl, or substituted C １－４ is alkoxyl, s is 0, 1, 2, 3 or 4; A １ is a bond, O, S, S(O), S(O) ２ , N.R. １ , -(CR １ R ２ ) ｎ , -O(CR １ R ２ ) ｎ , -S(CR １ R ２ ) ｎ , -C=O, -C(=O)O, -C(=O)NR ３ , -SO ２ , —SO, heteroaryl, cycloalkyl, or heterocycloalkyl; A ２ is a bond, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; A ３ is a bond, -(CR １ R ２ ) ｎ , -(O-(CR １ R ２ ) ｎ , -S(CR １ R ２ ) ｎ , —C═O, —SO ２ , SO, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; A ４ is a bond, alkyl, cycloalkyl, heteroaryl, or heterocycloalkyl; A １ , A ２ , A ３ and A ４ each of which is D, halo, alkyl, haloalkyl, —CN, —OR ３ , N.R. ｃ R ｄ , NO ２ , -SR ３ , -C=OR ｂ , -C(=O)OR ｂ , —C(═O)NR ３ R ３ , -SO ２ R ｂ , -SOR ｂ , -S(=O)(=NR ｂ ) optionally substituted with N, cycloalkyl, or heterocycloalkyl; Each A １ , A ２ , A ３ , A ４ 49. The compound of claim 48, wherein the two substituents are optionally joined to form a further 3- to 8-membered ring.

35. Each X ２ is CH and X １ is CH ２ 35. The compound of claim 34, wherein:

36. A １ is O, S, -CR １ R ２ , —C(═O)O, or —C(═O)NR ３ and A ２ is D, halo, alkyl, haloalkyl, —CN or OR ３ aryl, heterocycloalkyl, heteroaryl or cycloalkyl optionally substituted with A ３ is -(CR １ R ２ ) ｎ and A ４ is D, halo, alkyl, haloalkyl, —CN or OR ３ 36. The compound of claim 34 or claim 35, wherein the heterocycloalkyl or heteroaryl is optionally substituted with

37. [0023] The compound of formula I is of formula IA-7c, formula IA-8c, formula IA-9c, formula IA-10c, formula IA-11c, formula IA-12c, formula IA-13c, formula IA-14c, formula IA-15c, or formula IA-16c: 【Chemistry 23】 【change】 is a compound of In the formula, each R ｋ are independently H or C １－６ is alkyl, s is 0, 1, 2, 3 or 4; R ｄ１ is H or F, A １ is O, S, -CR １ R ２ or -C=O, A ２ is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl; A ３ is -CR １ R ２ or -C=O, A ４ The compound of any one of claims 34 to 36, wherein is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

38. 10. The compound of formula I, wherein the compound is a compound of formula IA-7d1, formula IA-7d2, formula IA-8d1, formula IA-8d2, formula IA-9d1, formula IA-9d2, formula IA-10d1, formula IA-10d2, formula IA-11d1, formula IA-11d2, formula IA-12d1, formula IA-12d2, formula IA-13d1, formula IA-13d2, formula IA-14d1, formula IA-14d2, or formula IA-15d1, formula IA-15d2, formula IA-16d1, or formula IA-16d2: 【Chemistry 24】 【change】 【change】 【change】 is a compound of In the formula, each R ｋ are independently H or C １－６ is alkyl, s is 0, 1, 2, 3 or 4; R ｄ１ is H or F, A １ is O, S, -CR １ R ２ or -C=O, A ２ is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl; A ３ is -CR １ R ２ or -C=O, A ４ The compound of claim 37, wherein is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

39. [0023] When the compound of Formula I is of Formula IA-7e, Formula IA-8e, Formula IA-9e, Formula IA-10e, Formula IA-11e, Formula IA-12e, Formula IA-13e, Formula IA-14e, Formula IA-15e, or Formula IA-16e: 【Chemistry 25】 【change】 【change】 is a compound of During the ceremony, Each R ｋ are independently H, D, F, C １－６ Alkyl, C １－６ Cycloalkyl, C １－３ Haloalkyl, C １－４ Alkoxyl, substituted C １－３ Alkyl, substituted C １－３ Haloalkyl, or substituted C １－４ is alkoxyl, 32. The compound of claim 30 or claim 31, wherein s is 0, 1, 2, 3 or 4.

40. Each X ２ is CH and X １ is CH ２ 40. The compound of claim 39, wherein:

41. wherein the compound of Formula I is of Formula IA-7f, Formula IA-8f, Formula IA-9f, Formula IA-10f, Formula IA-11f, Formula IA-12f, Formula IA-13f, Formula IA-14f, Formula IA-15f, or Formula IA-16f: 【Chemistry 26】 【change】 is a compound of During the ceremony, Each R ｋ are independently H, D, F, C １－６ Alkyl, C １－６ Cycloalkyl, C １－３ Haloalkyl, C １－４ Alkoxyl, substituted C １－３ Alkyl, substituted C １－３ Haloalkyl, or substituted C １－４ is alkoxyl, s is 0, 1, 2, 3 or 4; A １ is a bond, O, S, S(O), S(O) ２ , N.R. １ , -(CR １ R ２ ) ｎ , -O(CR １ R ２ ) ｎ , -S(CR １ R ２ ) ｎ , -C=O, -C(=O)O, -C(=O)NR ３ , -SO ２ , —SO, heteroaryl, cycloalkyl, or heterocycloalkyl; A ２ is a bond, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; A ３ is a bond, -(CR １ R ２ ) ｎ , -(O-(CR １ R ２ ) ｎ , -S(CR １ R ２ ) ｎ , —C═O, —SO ２ , SO, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; A ４ is a bond, alkyl, cycloalkyl, heteroaryl, or heterocycloalkyl; A １ , A ２ , A ３ and A ４ each of which is D, halo, alkyl, haloalkyl, —CN, —OR ３ , N.R. ｃ R ｄ , NO ２ , -SR ３ , -C=OR ｂ , -C(=O)OR ｂ , —C(═O)NR ３ R ３ , -SO ２ R ｂ , -SOR ｂ , -S(=O)(=NR ｂ ) optionally substituted with N, cycloalkyl, or heterocycloalkyl; Each A １ , A ２ , A ３ , A ４ Compounds wherein the above two substituents are optionally joined to form an additional 3- to 8-membered ring.

42. Each X ２ is CH and X １ is CH ２ 42. The compound of claim 41, wherein:

43. A １ is O, S, -CR １ R ２ , —C(═O)O, or —C(═O)NR ３ and A ２ is D, halo, alkyl, haloalkyl, —CN or OR ３ aryl, heterocycloalkyl, heteroaryl or cycloalkyl optionally substituted with A ３ is -(CR １ R ２ ) ｎ and A ４ is D, halo, alkyl, haloalkyl, —CN or OR ３ 42. The compound of claim 40 or claim 41, wherein the compound is a heterocycloalkyl or heteroaryl optionally substituted with

44. [0023] The compound of formula I is formula IA-7g, formula IA-8g, formula IA-9g, formula IA-10g, formula IA-11g, formula IA-12g, formula IA-13g, formula IA-14g, formula IA-15g, or formula IA-16g: 【Chemistry 27】 【change】 【change】 is a compound of In the formula, each R ｋ are independently H or C １－６ is alkyl, s is 0, 1, 2, 3 or 4; R ｄ１ is H or F, A １ is O, S, -CR １ R ２ or -C=O, A ２ is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl; A ３ is -CR １ R ２ or -C=O, A ４ The compound of any one of claims 41 to 43, wherein is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

45. [0023] The compound of formula I is of formula IA-7h, formula IA-8h, formula IA-9h, formula IA-10h, formula IA-11h, formula IA-12h, formula IA-13h, formula IA-14h, formula IA-15h, or formula IA-16h: 【Chemistry 28】 【change】 【change】 is a compound of In the formula, each R ｋ are independently H or C １－６ is alkyl, s is 0, 1, 2, 3 or 4; R ｄ１ is H or F, A １ is O, S, -CR １ R ２ or -C=O, A ２ is a 3- to 8-membered aryl, heteroaryl, heterocycloalkyl, or 3- to 8-membered cycloalkyl; A ３ is -CR １ R ２ or -C=O, A ４ is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered cycloalkyl.

46. A １ The compound of any one of claims 33 to 38 or 41 to 45, wherein is O.

47. A １ is S.

48. A ３ Ga-CR １ R ２ The compound according to any one of claims 33 to 38 or 41 to 47,

49. A ３ Ga-CH ２ The compound according to any one of claims 33 to 38 or 41 to 48,

50. A ２ 50. The compound of any one of claims 33-38 or 41-49, wherein is piperidine.

51. A ２ 50. The compound of any one of claims 33-38 or 41-49, wherein is piperazine.

52. A ２ The compound of any one of claims 33 to 38 or 41 to 49, wherein is pyrrolidine.

53. A ２ 50. The compound of any one of claims 33-38 or 41-49, wherein is azetidine.

54. A ４ The compound of any one of claims 33-38 or 41-53, wherein is piperidine.

55. A ４ 54. The compound of any one of claims 33-38 or 41-53, wherein is piperazine.

56. A ４ The compound of any one of claims 33 to 38 or 41 to 53, wherein is pyrrolidine.

57. A ４ The compound of any one of claims 33-38 or 41-53, wherein is azetidine.

58. The compound is selected from the group consisting of: N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)benzamide, 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-4-oxoquinazoline-3(4H)-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1-oxophthalazine-2(1H)-yl)piperidine-2,6-dione, 3-(6-(4-(((3S,5R)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-2H-indazol-2-yl)piperidine-2,6-dione, 3-(6-(4-(((3R,5S)-4-((S)-2-(2-hydroxyphenyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazine-8-carbonyl)-3,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione, 3-(6-(4-(((1R,5S,6r)-6-(((S)-2-(2-hydroxyphenyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)piperidin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione, N-(2,6-dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethylpiperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide, N-(2,6-dioxopiperidin-3-yl)-4-[4-[[(3R,5S)-4-[(10S)-4-(2-hydroxyphenyl)-1,5,6,8,12-pentaazatricyclo[8.4.0.02,7]tetradeca-2,4,6-triene-12-carbonyl]-3,5-dimethylpiperazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carboxamide, 58. The compound of claim 1 or any one of claims 3 to 57, selected from:

59. The compound is selected from the group consisting of: 1-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione, 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione, 3-((4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione, N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)benzamide, N-(2,6-dioxopiperidin-3-yl)-4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)-2-fluorobenzamide, 3-(4-(4-((6-(((6aS,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione, 3-(4-(1-((6-(((6aR,8R)-6a-(difluoromethyl)-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydropyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione, 3-(4-(1-((6-(((6aR,8R)-6a-ethyl-2-(2-hydroxyphenyl)-5,6,6a,7,8,9-hexahydro-pyrrolo[1',2':4,5]pyrazino[2,3-c]pyridazin-8-yl)oxy)pyridin-3-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6-dione, 58. The compound of claim 1 or any one of claims 3 to 57, selected from:

60. 60. A pharmaceutical composition comprising a compound according to any one of claims 1 to 59 and a pharmaceutically acceptable excipient.

61. 61. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 59 or a pharmaceutical composition of claim 60.

62. 62. The method of claim 61, wherein the cancer is a SMARCA4 deficient cancer.

63. The cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemia; benign and malignant lymphoma, in particular Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, 63. The method of claim 61 or 62, wherein the cancer is selected from the group consisting of sarcomas, including ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma.

64. 64. The method of claim 62 or 63, wherein the cancer is T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, B-cell precursor ALL, B-cell precursor lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

65. 65. The method of claim 64, wherein the lung cancer is a SMARCA4-deficient non-small cell lung cancer.

66. A method for degrading a SMARCA protein, the method comprising contacting the SMARCA protein with a compound according to any one of claims 1 to 59 or a pharmaceutical composition according to claim 60.

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