KAT6-targeting compounds with biquitin ligase-binding moieties

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] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 366,484, filed June 16, 2022, which is incorporated herein by reference in its entirety.

[0002] 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 target KAT6 proteins that are degraded and / or inhibited by the bifunctional compounds in accordance with the present disclosure. [Background technology]

[0003] Epigenetic control of transcription through chromatin remodeling is a critical regulatory mechanism that ultimately influences the functional expression of many proteins. Abnormalities in epigenetic regulators are a cause of human disease and are considered a major oncogenic driver in many cancers. Histone regulation plays a key role in this process. Epigenetic regulators modify histone proteins through various post-translational modifications, such as acetylation and methylation, which alter chromatin accessibility, for example. Histone acetylation is catalyzed by histone acetyltransferases (HATs), and dysregulation of this class of epigenetic regulators is associated with transcriptional alterations and cancer (1, 2).

[0004] The MYST family of acetyltransferases is associated with several types of cancer and contains a conserved catalytic domain (MYST domain). Lysine acetyltransferase 6a (KAT6A, MOZ, MYST3), a member of this family, promotes histone acetylation and is homologous to lysine acetyltransferase 6b (KAT6B) (3, 4). KAT6A has been reported to acetylate lysine 9 (H3K9ac), lysine 14 (H3K14ac) (4), and lysine 23 (H3K23ac) (5) of histone H3, but its functional dependence on these sites and other potential substrates remains poorly understood. In addition to histone proteins, KAT6A has been reported to acetylate nonhistone proteins, such as p53 (6), although its role in regulating nonhistone substrates is unclear. KAT6A can form protein complexes with inhibitor of growth family member 5 (ING5), bromodomain and PHD finger containing 1, 2, or 3 (e.g., BRPF1, BRPF2, BRPF3), and myst / Esa1-associated factor 6 (EAF6), which may enhance its gene regulatory capabilities (4, 7). Mechanistically, KAT6A has been implicated in the control of cellular processes such as senescence, cell cycle progression, and hematopoietic stem cell maintenance (4, 7, 8).

[0005] More recently, KAT6A has been shown to epigenetically regulate estrogen receptor alpha (ER alpha) expression via its HAT domain in KAT6A-amplified breast cancer cell lines. Loss of KAT6A is associated with reduced proliferation in vitro and tumor growth in vivo, and its overexpression correlates with worse clinical outcomes in estrogen receptor-positive (ER+) breast cancer (9). KAT6A inhibitors have been reported to show higher sensitivity in the ER+ luminal subtype (ER / PR+ / HER2-) (10). KAT6A has been implicated as an oncogenic factor in breast, brain, hematological, gynecological, and other cancers (5, 9, 11, 12).

[0006] KAT6A is frequently altered in many types of cancer, often by copy number amplification or recurrent chromosomal translocations. KAT6A amplifications, located within the recurrently amplified chromosome 8p11-12 amplicon, have been observed in numerous cancers, including breast, lung, prostate, hematological, bladder, uterine, endometrial, ovarian, esophageal, head and neck, gastric, colon, and other cancers (9, 13, 14). Particularly in hematological cancers, recurrent rearrangements result in several fusion proteins, including KAT6A-CBP, KAT6A-p300, KAT6A-TIF2, KAT6A-NcoA3, and KAT6A-LEUTX (7). Recently, KAT6A has been suggested to be important for the development of MLL-rearranged AML (11).

[0007] To date, only one KAT6A-targeting small molecule inhibitor is currently in clinical trials (PF04606446, Phase 1, Pfizer) to study its efficacy in locally advanced or metastatic ER+ / HER2- breast cancer, castration-resistant prostate cancer, and non-small cell lung cancer, either as a single agent or in combination with either fulvestrant or letrozole plus palbociclib (NCT-07248144) (15). It remains unclear whether conventional small molecule inhibitors of KAT6A can fully realize their potential to selectively target these or other cancers. Therefore, exploring targeted protein degradation (TPD) approaches to develop potent and selective KAT6A degraders may enhance the therapeutic window for cancers that depend on KAT6A for growth, proliferation, or survival.

[0008] Given the established role of KATs in diseases such as cancer, there is a need for new regulators of these proteins.

[0009] References: 1.Nair SS,Kumar R.Chromatin remodeling in cancer: a gateway to regulate gene transcription.Mol Oncol.2012;6(6):611-9. 2.Farria A,Li W,Dent SY.KATs in cancer:functions and therapies.Oncogene.2015;34(38):4901-13. 3.Avvakumov N,Cote J.The MYST family of histone acetyltransferases and their intimate links to cancer.Oncogene.2007;26(37):5395-407. 4.Su J,Wang X,Bai Y,Sun M,Yao Y,Duan Y.The role of MOZ / KAT6A in hematological malignancies and advances in MOZ / KAT6A inhibitors.Pharmacol Res.2021;174:105930. 5.Lv D,Jia F,Hou Y,Sang Y,Alvarez AA,Zhang W,et al.Histone Acetyltransferase KAT6A Upregulates PI3K / AKT Signaling through TRIM24 Binding.Cancer Res.2017;77(22):6190-201. 6.Rokudai S,Laptenko O,Arnal SM,Taya Y,Kitabayashi I,Prives C.MOZ increases p53 acetylation and premature senescence through its complex formation with PML.Proc Natl Acad Sci U S A.2013;110(10):3895-900. 7.Huang F,Abmayr SM,Workman JL.Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression,Stem Cell Maintenance,and Human Disease.Mol Cell Biol.2016;36(14):1900-7. 8.Sheikh BN,Phipson B,El-Saafin F,Vanyai HK,Downer NL,Bird MJ,et al.MOZ(MYST3,KAT6A)inhibits senescence via the INK4A-ARF pathway.Oncogene.2015;34(47):5807-20. 9.Yu L,Liang Y,Cao X,Wang X,Gao H,Lin SY,et al.Identification of MYST3 as a novel epigenetic activator of ERα frequently amplified in breast cancer.Oncogene.2017;36(20):2910-8. 10.Sharma S,Chung J,Uryu S,Rickard A,Nady N,Khan S,et al.Abstract 1130:First-in-class KAT6A / KAT6B inhibitor CTx-648(PF-9363)demonstrates potent anti-tumor activity in ER+ breast cancer with KAT6A dysregulation.Cancer Research.2021;81(13_Supplement):1130-. 11.Yan F,Li J,Milosevic J,Petroni R,Liu S,Shi Z,et al.KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs.Cancer Discov.2022;12(3):792-811. 12.Liu W,Zhan Z,Zhang M,Sun B,Shi Q,Luo F,et al.KAT6A,a novel regulator of β-catenin,promotes tumorigenicity and chemoresistance in ovarian cancer by acetylating COP1.Theranostics.2021;11(13):6278-92. 13.Saglam O,Tang Z,Tang G,Medeiros LJ,Toruner GA.KAT6A amplifications are associated with shorter progression-free survival and overall survival in patients with endometrial serous carcinoma.PLoS One.2020;15(9):e0238477. 14.Cerami E,Gao J,Dogrusoz U,Gross BE,Sumer SO,Aksoy BA,et al.The cBio cancer genomics portal:an open platform for exploring multidimensional cancer genomics data.Cancer Discov.2012;2(5):401-4. 15.ClinicalTrials.gov.NCT04606446:Study of PF-07248144 in Advanced or Metastatic Solid Tumors(KAT6)Bethesda(MD):National Library of Medicine(US);2020[Available from:https: / / clinicaltrials.gov / ct2 / show / NCT04606446. Summary of the Invention

[0010] The present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein PTM is of formula IA [ka] is part of the formula Y is a covalent bond or chemical moiety that connects the PTM and ULM; * is the attachment point to ULM, Ring A is C6-C 10 a 5- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, R 1 is a 5-6 membered heteroaryl optionally substituted with H, D, or methyl; R 2 is H, D, or —(C(R 8 )2) n -(5- to 9-membered heteroaryl), R 3 is H, D, or halogen, C1-C4 alkyl, cyclopropyl, haloalkyl, C1-C4 alkoxy, or haloalkoxy, R 4is H, D, or halogen, C-C alkyl, cyclopropyl, C-C alkoxy, or —O-cyclopropyl; Each R 5 are independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- Calk-aryl, C 0- C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R a , -C(O)OR a , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR d )(OR c ) or -S(O)R b and Each R a are independently H, -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b )NR b R c 、 -C(=NOR b )NR b R c 、 -C(=NCN)NR b R c 、 -P(OR c )2, -P(O)Rc R b , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)NR c R d , SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R c or R d are independently H, -C1-C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or R c and R d together with the atom to which they are both attached form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocyclo-alkenyl group, Each R 8 are independently H, D, halogen, or C1-C4 alkyl; m is 0, 1, 2, 3, or 4; n is 0 or 1, and ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to cereblon E3 ubiquitin ligase.

[0011] 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

[0012] 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.

[0013] 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 limit 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 including 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.

[0014] 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.

[0015] 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.

[0016] 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 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 the same time, to some extent, preferably in effective amounts. 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, particularly, anti-cancer agents. In particularly preferred embodiments, co-administration of the compounds results in synergistic activity and / or therapy, including anti-cancer activity.

[0017] 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. Deuterated small molecules contemplated are those in which one or more hydrogen atoms contained in a drug molecule have been replaced by deuterium.

[0018] Within its use in context, the term compound generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures), as well 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.

[0019] 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 with 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. This is the lysine used to create polyubiquitin, which is recognized by the proteasome.

[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 one to eight 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 a range of carbon atoms is used herein, such as C1-C6, all ranges as well as individual numbers of carbon atoms are included. For example, "C1-C3" refers to C 1- C3, C 1- C2, C 2- Includes C3, C1, C2, and C3.

[0022] When used in combination with a substituent defined herein, the term "optionally substituted" means that the substituent may, but need not, be replaced with one or more suitable functional groups or other substituents provided herein. For example, the substituent may be halo, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo(C 1-6 ) Alkyl, C 1-6 Alkoxy, Halo(C 1-6 Alkoxy), C 1-6 Alkylthio, C 1-6 Alkylamino, NH2, NH(C 1-6 alkyl), N(C 1-6 alkyl)2, NH(C 1-6 Alkoxy), N(C 1-6 Alkoxy)2, -C(O)NHC 1-6 Alkyl, -C(O)N(C 1-6 alkyl)2, -C(O)NH2, -C(O)C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -NHCO(C 1-6alkyl), -N(C 1-6 alkyl)CO(C 1-6 alkyl), -S(O)C 1-6 Alkyl, -S(O)C 1-6 It may be optionally substituted with one or more alkyl, oxo, 6- to 12-membered aryl, benzyl, pyridinyl, pyrazolyl, thiazolyl, isothiazolyl, or other 5- to 12-membered heteroaryl groups. In some embodiments, each of the above optional substituents may itself be optionally substituted with one or two groups.

[0023] The term "cycloalkyl," as used herein, refers to a 3- to 12-membered cyclic alkyl group, including bridged (e.g., adamantine) and spirocyclic (e.g., spiro[3.5]nonane) rings. 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), where a single cycloalkyl ring (as defined above) can be fused with 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 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. It is also understood that the point of attachment (as defined above for cycloalkyl) of multiple fused ring systems 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.

[0024] As used herein, the term "alkenyl" refers to a C alkyl group containing at least one carbon-carbon double bond. 2- C 12 In some embodiments, an alkenyl group is optionally substituted. In some embodiments, an alkenyl group is a C 2- It is a C6 alkenyl.

[0025] 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 2- It is a C6 alkynyl.

[0026] 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.

[0027] The terms "halo" or "halogen," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0028] 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.

[0029] 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-tetrahydronaphthyl, and the like.

[0030] 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. Polyfused 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 polyfused 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 polyfused ring system may be connected to each other in any order. It is also understood that the point of attachment of a polyfused ring system (as defined above for heteroaryl) may be at any position on the heteroaryl ring. It is also understood that the point of attachment of a heteroaryl or heteroaryl polyfused ring system may be at any suitable atom of the heteroaryl ring, including carbon atoms and heteroatoms (e.g., 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.

[0031] 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, imidazolidin-2-one, 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, 2,7-diazaspiro[3.5]nonane, (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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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 a composition 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.

[0036] 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.

[0037] "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.

[0038] "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.

[0039] 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.

[0040] "Solvate" refers to a physical association of a compound of Formula I with one or more solvent molecules.

[0041] "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.

[0042] In one embodiment, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein PTM is of formula IA [ka] is part of the formula Y is a covalent bond or chemical moiety that connects the PTM and ULM; * is the attachment point to ULM, Ring A is C6-C 10 a 5- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, R 1 is a 5-6 membered heteroaryl optionally substituted with H, D, or methyl; R 2 is H, D, or —(C(R 8 )2) n -(5- to 9-membered heteroaryl), R 3 is H, D, or halogen, C1-C4 alkyl, cyclopropyl, haloalkyl, C1-C4 alkoxy, or haloalkoxy, R 4 is H, D, or halogen, C-C alkyl, cyclopropyl, C-C alkoxy, or —O-cyclopropyl; Each R 5 are independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- Calk-aryl, C 0- C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R a , -C(O)OR a , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b), -B(OR d )(OR c ) or -S(O)R b and Each R a are independently H, -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b )NR b R c 、 -C(=NOR b )NR b R c 、 -C(=NCN)NR b R c 、 -P(OR c )2, -P(O)R c R b , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)NR c R d , SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R c or R d are independently H, -C1-C 10alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or R c and R d together with the atom to which they are both attached form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocyclo-alkenyl group, Each R 8 are independently H, D, halogen, or C1-C4 alkyl; m is 0, 1, 2, 3, or 4; n is 0 or 1, and ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to cereblon E3 ubiquitin ligase.

[0043] In some embodiments, the compound of Formula I comprises a protein targeting moiety (PTM). In some embodiments, the PTM of the compound of Formula I is represented by Formula IA: [ka] is part of.

[0044] According to the present disclosure, Y of formula IA is a covalent bond or a chemical moiety that links a PTM and a ULM. In some embodiments, Y of formula IA is a chemical moiety that links a PTM and a ULM. In other embodiments, Y of formula IA is a covalent bond.

[0045] According to the present disclosure, ring A of formula IA is C6-C 10 In some embodiments, ring A of formula IA is a C6-C 10 In some embodiments, ring A of formula IA is a phenyl group. In other embodiments, ring A of formula IA is a 5-10 membered heteroaryl group.

[0046] According to the present disclosure, R of formula IA 1 is a 5-6 membered heteroaryl optionally substituted with H, D, or methyl. In some embodiments, R of formula IA 1 is H. In some embodiments, R in formula IA 1 is D. In other embodiments, R in formula IA 1 is a 5-6 membered heteroaryl optionally substituted with methyl.

[0047] According to the present disclosure, R of formula IA 2 is H, D, or —(C(R 8 )2) n -(5- to 9-membered heteroaryl). In some embodiments, R of formula IA 2 is H. In some embodiments, R of formula IA 2 is D. In other embodiments, R of formula IA 2 is —(C(R) optionally substituted by halogen, C1-C3 alkyl, —CH2OH, or —OH; 8 )2) n -(5- to 9-membered heteroaryl).

[0048] In yet other embodiments, R of formula IA 2 is —(C(R) optionally substituted with halogen, C1-C3 alkyl, —CH2OH, or —OH; 8 )2) n -(5-6 membered heteroaryl). In some embodiments, R of formula IA 2 -(C(R 8 )2) n When R is -(5- to 6-membered heteroaryl), the 5- to 6-membered heteroaryl is pyrazole, pyrrole, pyridine, or pyridazine. 2 -(C(R 8 )2) n When it is -(5-6 membered heteroaryl), the 5-6 membered heteroaryl is pyrazole.

[0049] According to the present disclosure, R of formula IA 8 is H, D, halogen, or C-C alkyl. In some embodiments, R of formula IA 8 is H. In some embodiments, R of formula IA 8 is D. In other embodiments, R of formula IA 8 is halogen. In another embodiment, R of formula IA 8 is C1-C4 alkyl.

[0050] In accordance with the present disclosure, n of formula IA is 0 or 1. In some embodiments, n of formula IA is 0. In other embodiments, n of formula IA is 1.

[0051] According to the present disclosure, R of formula IA 3 is H, D, halogen, C-C alkyl, cyclopropyl, haloalkyl, C-C alkoxy, or haloalkoxy. In some embodiments, R of formula IA 3 is H. In some embodiments, R of formula IA 3 is D. In some embodiments, R of formula IA 3 is halogen. In some embodiments, R of formula IA 3 is C1-C4 alkyl. In other embodiments, R of formula IA 3 is cyclopropyl. In another embodiment, R of formula IA 3 is C1-C4 haloalkyl. In other embodiments, R of formula IA 3 is C1-C4 alkoxy. In other embodiments, R of formula IA 3 is haloalkoxy.

[0052] According to the present disclosure, R of formula IA 4 is H, D, halogen, C-C alkyl, cyclopropyl, C-C alkoxy, or —O-cyclopropyl. 4 is H. In some embodiments, R of formula IA 4 is D. In some embodiments, R of formula IA 4is halogen. In some embodiments, R of formula IA 4 is C1-C4 alkyl. In other embodiments, R of formula IA 4 is cyclopropyl. In another embodiment, R of formula IA 4 is C1-C4 alkoxy. In other embodiments, R 4 is -O-cyclopropyl. In another embodiment, R of formula IA 4 is methoxy.

[0053] According to the present disclosure, R of formula IA 5 are each independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- Calk-aryl, C 0- C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R a , -C(O)OR a , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR d )(OR c ) or -S(O)R b and Each R a are independently H, -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b)NR b R c 、 -C(=NOR b )NR b R c 、 -C(=NCN)NR b R c 、 -P(OR c )2, -P(O)R c R b , -P(O)OR c OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)NR c R d , SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b are independently H, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R c or R d are independently H, -C1-C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or R c and R d together with the atom to which they are both attached form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocyclo-alkenyl group;

[0054] According to the present disclosure, R of formula IA5 is independently H, D, halogen, cyano, C-C alkyl, haloalkyl, cyclopropyl, C-C alkoxy, haloalkoxy, -O-cyclopropyl, -CH-O-CH, -C(O)OCH, or -C(O)N(H)CH. In some embodiments, at least one R of formula IA is 5 is H. In some embodiments, each R of formula IA 5 is D. In some embodiments, at least one R of formula IA 5 is halogen. In some embodiments, each R of formula IA is C-C alkoxy. In some embodiments, at least one R of formula IA is 5 is C1-C4 alkoxy.

[0055] In other embodiments, at least one R of formula IA 5 is fluoro. In another embodiment, at least one R of formula IA 5 is cyano. In another embodiment, at least one R of formula IA is 5 is C1-C4 alkyl. In another embodiment, at least one R 5 is haloalkyl. In another embodiment, at least one R of formula IA 5 is cyclopropyl. In another embodiment, at least one R 5 is haloalkoxy. In another embodiment, at least one R of formula IA is 5 is -O-cyclopropyl. In another embodiment, at least one R of formula IA is 5 is —CH—O—CH. In another embodiment, at least one R of formula IA is —CH—O—CH. 5 is —C(O)OCH 3 . In another embodiment, at least one R 5 is -C(O)N(H)CH3.

[0056] In accordance with the present disclosure, m of formula IA is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m of formula IA is 1. In other embodiments, m of formula IA is 2. In other embodiments, m of formula IA is 3. In other embodiments, m of formula IA is 4.

[0057] According to the present disclosure, ULM is a small molecule E3 ubiquitin ligase-binding moiety that binds to cereblon E3 ubiquitin ligase. In some embodiments, ULM is a moiety described herein.

[0058] 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, Y of formula IA is a chemical moiety used to link PTM and ULM that is known in the art.

[0059] In some embodiments, Y of Formula IA 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 by reference herein in its entirety.

[0060] In other embodiments, Y of Formula IA 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.

[0061] In other embodiments, Y of formula IA is a chemical moiety used to conjugate a PTM and a ULM, as described in WO 2019 / 084030, which is incorporated by reference in its entirety.

[0062] In other embodiments, Y of formula IA is a chemical moiety used to conjugate a PTM and a ULM, as described in WO 2019 / 084026, which is incorporated by reference in its entirety.

[0063] In some embodiments, Y of formula IA is of the formula: -(A) q -, is a chemical structural unit represented by the formula: q is an integer from 1 to 14, Each A is independently 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 1c (CR 1a R 1b ) 1-4 , N.R. 1c C(=NCN)NR 1d NR 1c C(=NCN), NR 1c C(=CNO2)NR 1d , 0 to 6 R 1a or R 13-11 membered cycloalkyl optionally substituted with b groups, 0-6 R 1a or R 1 3-11 membered heteocyclyl optionally substituted with b groups, 0-6 R 1a or R 1b aryl optionally substituted with a group, 0 to 6 R 1a or R 1b heteroaryl optionally substituted with a group; and 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); -aryl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, -SO2-aryl, -SO2-heteroaryl, 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 -C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -C(O)OC1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -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)SON2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SON(C1-C8 alkyl)2, -NHSON2NH(C1-C8 alkyl), -NHSON2N(C1-C8 alkyl)2, or -NHSON2NH2, or, where the context permits, R 1a or R 1b may be bonded to other groups or to each other and may be bonded to 0 to 4 R 1eThe groups form optionally substituted cycloalkyl and / or heterocyclyl moieties.

[0064] In these embodiments, q represents the number of A groups connected. For example, when q=1, -(A) q - is -A1-; if q=2, -(A) q - is -A1-A2-; when q=3, -(A) q - is -A1-A2-A3-; when q=4, -(A) q - is -A1-A2-A3-A4-; if q=5, -(A) q - is -A1-A2-A3-A4-A5-; when q=6, -(A) q - is -A1-A2-A3-A4-A5-A6-; if q=7, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-; if = 8, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-; if q=9, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-A9-; if q=10, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 - and; if q=11, -(A) q -A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 - and; if q=12, -(A) q -A-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 - and; if q=13, -(A) q -A-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 and when q=14, -(A) q -A-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10 -A 11 -A 12 -A 13 -A 14 -It is.

[0065] In some embodiments, q=4 and Y of formula IA is a chemical moiety represented by the formula: -A1-A2-A3-A4-, wherein each A 1-4 are independently O, S, SO, SO2, and 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 1c (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)(C1- C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, -SO2-aryl, -SO2-heteroaryl, 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, -S i(C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -C(O)OC1-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(C -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; and R 1c and R 1d are each independently H, D, optionally substituted C 1-4 Alkyl, C3-8 Cycloalkyl, C 3-8 It is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0066] In other embodiments, q=3 and Y of formula IA is a chemical moiety represented by the formula: -A1-A2-A3-, wherein A 1-3 each independently represents 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 1c (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)(C1- C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, -SO2-aryl, -SO2-heteroaryl, 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, -S i(C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -C(O)OC1-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(C -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; and R 1c and R 1d are each independently H, D, optionally substituted C 1-4 Alkyl, C3-8 Cycloalkyl, C 3-8 It is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0067] In other embodiments, q=2 and Y of formula IA 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 , 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 1c (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)(C1- C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, -SO2-aryl, -SO2-heteroaryl, 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, -S i(C1-C8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -C(O)OC1-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(C -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; and R 1c and R 1d are each independently H, D, optionally substituted C 1-4 Alkyl, C3-8 Cycloalkyl, C 3-8 It is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0068] In other embodiments, q=1 and Y of formula IA 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 , 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 1c (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), 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), N-(3- to 11-membered cycloalkyl) (C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, -SO2-aryl, 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-C 8 alkyl)3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -C(O)OC1-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-C -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; and R 1c and R 1d are each independently H, D, optionally substituted C 1-4 Alkyl, C 3-8Cycloalkyl, C 3-8 It is selected from the group consisting of heterocycloalkyl, aryl, or heteroaryl.

[0069] In some embodiments, Y of formula IA is a covalent bond, 0 to 6 R 1a or R 1b 3-11 membered cycloalkyl optionally substituted with a group, 0-6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with 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 , -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c , -(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 , -(CR 1a R 1b ) 1-5 -(C≡C)-(CR1a 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 , -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S, or NR 1c , -(C≡C)-(CR 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-, -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with a -(0-6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -, (0 to 6 R 1a 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 or R 1b 3 to 11-membered cycloalkyl optionally substituted with a group)-A-, -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b3- to 11-membered heterocyclyl optionally substituted with a group)-A-, -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-A-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a 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 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 , -(CR1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-A-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-, where A is independently O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-, where A is independently O, S, or NR 1c , -(CR1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c , -(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 , -(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c , -(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 , -(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(CO)-(0 to 6 R 1a or R 1bA is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a 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 , -(CR 1a R 1b ) 1-5 -A-(CO)-(0 to 6 R 1a or R 1b A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-A-(CO)-, where A is O, S, or NR 1c , -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-CO-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c , -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1aR 1b ) 1-5 -A-(CO)-, where A is O, S, or NR 1c , -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 - or (0 to 6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5- is.

[0070] In some embodiments, Y of formula IA is -CR 1a =CR 1b For example, -CH=CH-.

[0071] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 For example, -(CH2) 1-5 -, -CH2-, -CH2CH2CH2-, etc.

[0072] In some embodiments, Y of formula IA is -(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-.

[0073] In other embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR1c For example, -(CH2) 1-5 -O-(CH2) 1-5 -, -(CH2) 1-5 -S-(CH2) 1-5 -, -(CH2) 1-5 -NH-(CH2) 1-5 -It is.

[0074] In some embodiments, Y of formula IA is —(C≡C)—(CR 1a R 1b ) 1-5 For example, -(C≡C)-(CH2)2-.

[0075] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b and optionally substituted 3- to 11-membered cycloalkyl)-, for example, -CH2-cyclobutyl-.

[0076] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 For example, -CH2-cyclobutyl-CH2-.

[0077] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 For example, -CH2-azetidinyl-CH2-.

[0078] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b A 3- to 11-membered heterocyclyl optionally substituted with a group, such as -CH2-azetidinyl-.

[0079] In some embodiments, Y of formula IA is -(0-6 R 1a or R 1b 3- to 11-membered heterocyclyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -, for example, -azetidinyl-CH2-, -pyrolidnyl-CH2-, -piperidinyl-CH2-, and the like.

[0080] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b 3- to 11-membered cycloalkyl optionally substituted with a group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S, or NR 1c For example, -CH2-cyclopropyl-CH2-O-.

[0081] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -(0 to 6 R 1a 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-.

[0082] In some embodiments, Y of formula IA is -(CR1a R 1b ) 1-5 -(0 to 6 R 1a or R 1b A is O, S, or NR 1c For example, -CH2-azetidinyl-O-.

[0083] In some embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b A is O, S, or NR 1c For example, -CH2-O-azetidinyl-, -CH2-NH-azetidinyl-, etc.

[0084] In other embodiments, Y of formula IA is -(CR 1a R 1b ) 1-5 -A-(0 to 6 R 1a or R 1b A is O, S, or NR 1c For example, -CH2-O-cyclobutylene-, -CH2-NH-cyclobutylene-, etc.

[0085] In some embodiments, Y of formula IA 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—.

[0086] In some embodiments, Y of formula IA is [ka] wherein: ** is the point of attachment to the PTM, L1, L2, and L3 each independently represent 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 1c (CR 1a R 1b ) 1-4、 NR 1c C(=NCN)NR 1d , N.R. 1c C(=NCN), NR 1c C(=CNO2)NR 1d and Ring A1 and ring A2 each independently represent 0 to 6 R 1a or R 1b 3-11 membered cycloalkyl optionally substituted with a group, 0-6 R 1a or R 1b3-11 membered heterocyclyl optionally substituted with a group, 0-6 R 1a or R 1b aryl optionally substituted with a group, or 0 to 6 R 1a or R 1b is a heteroaryl optionally substituted with a group; R 1a , R 1b , R 1c , R 1d and R 1eare 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)(C1-C8 alkyl), -OH, -NH2, -SH, -SO2C1-C8 alkyl, -SO2-aryl, -SO2-heteroaryl, 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, -C(O)OC1-C8 alkyl, -CO2H, -CN, -CF3, -CHF2, -CH2F, -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-C 8 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)SON2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SON(C1-C8 alkyl)2, -NHSON2NH(C1-C8 alkyl), -NHSON2N(C1-C8 alkyl)2, or -NHSON2NH2, and R 1a or R 1b each independently optionally bonded to other groups, and 1eGroups may form optionally substituted cycloalkyl and / or heterocyclyl moieties.

[0087] In some embodiments, Y of formula IA is [ka] wherein: ** is the point of attachment to the PTM, L1 is a bond, (C(R 10 )2) p or CO, L2 is a bond, (C(R 10 )2) p or CO, L3 is a bond, (C(R 10 )2) p or CO, each p is independently 1, 2, 3, or 4; Each R 10 are independently H, D, or C1-C4 alkyl; Ring A1 is a 3- to 7-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, an aryl group, or a heteroaryl group, and Ring A2 is a 3- to 7-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0088] According to the present disclosure, L1 is a bond, (C(R 10 )2) p or CO. In some embodiments, L is a bond. In some embodiments, L is (C(R 10 )2) p In other embodiments, L1 is CO.

[0089] According to the present disclosure, L2 is a bond, (C(R 10 )2) p or CO. In some embodiments, L2 is a bond. In some embodiments, L2 is (C(R 10 )2) p In other embodiments, L2 is CO.

[0090] According to the present disclosure, L3 is a bond, (C(R 10 )2) p or CO. In some embodiments, L3 is a bond. In some embodiments, L3 is (C(R 10 )2) p In other embodiments, L3 is CO.

[0091] In accordance with the present disclosure, each p is independently 1, 2, 3, or 4. In some embodiments, p is 1. In some embodiments, at least one p is 1. In some embodiments, each p is 2. In some embodiments, at least one p is 2. In other embodiments, each p is 3. In other embodiments, at least one p is 3. In other embodiments, each p is 4. In other embodiments, at least one p is 4.

[0092] According to the present disclosure, each R 10 is independently H, D, or C1-C4 alkyl. In some embodiments, each R 10 is H. In some embodiments, at least one R 10 is H. In some embodiments, each R 10 is D. In some embodiments, at least one R 10 is D. In other embodiments, each R 10 is C1-C4 alkyl. In other embodiments, at least one R 10 is C1-C4 alkyl. In other embodiments, each R 10 is methyl or ethyl. In other embodiments, at least one R 10 is methyl or ethyl.

[0093] According to the present disclosure, ring A1 is a 3- to 7-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, an aryl group, or a heteroaryl group. In some embodiments, ring A1 is a 3- to 7-membered cycloalkyl group. In some embodiments, ring A1 is a 4- to 10-membered heterocycloalkyl group. In other embodiments, ring A1 is an aryl group. In other embodiments, ring A1 is a heteroaryl group.

[0094] In some embodiments, ring A1 is a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, or an azabicyclo-alkyl group. In other embodiments, ring A1 is a piperidine or pyrrolidine group.

[0095] According to the present disclosure, ring A2 is a 3- to 7-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, an aryl group, or a heteroaryl group. In some embodiments, ring A2 is a 3- to 7-membered cycloalkyl group. In some embodiments, ring A2 is a 4- to 10-membered heterocycloalkyl group. In other embodiments, ring A2 is an aryl group. In other embodiments, ring A2 is a heteroaryl group.

[0096] In some embodiments, ring A2 is a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, a diazaspiroalkyl group, or an azabicycloalkyl group. In other embodiments, ring A2 is a piperazine group or a diazaspirononane group.

[0097] In some embodiments, Y of formula IA is [ka] wherein: L1, L2, and ring A1 are as defined herein; r is 0, 1, or 2; s is 0, 1, or 2, and Z is N or CR 10 and R 10is as defined herein.

[0098] In accordance with the present disclosure, r is 0, 1, or 2. In some embodiments, r is 0. In some embodiments, r is 1. In other embodiments, r is 2.

[0099] In accordance with the present disclosure, s is 0, 1, or 2. In some embodiments, s is 0. In some embodiments, s is 1. In other embodiments, s is 2.

[0100] According to the present disclosure, Z is N or CR 10 In some embodiments, Z is N. In other embodiments, Z is CR 10 is.

[0101] According to the present disclosure, a ULM of formula I is [ka] wherein: [ka] is the point of attachment to Y or the PTM, Ring A3 is a monocyclic, bicyclic or tricyclic aryl, heteroaryl or heterocyclic group; L4 is a bond, -O-, -S-, or -NR a -, -C(R a )2--C(O)NR a - and X1 is CH2, CO, CH=CH (when X2=CO), or N=CH (when X2=CO), X2 is CH2, CO, CH=CH (when X1=CO), or N=CH (when X1=CO); R 12 is H, D, optionally substituted C 1-4 Alkyl, C 1-4 Alkoxyl, C 1-4 Haloalkyl, -CN, -OR a , -OR bor -SR b and Each R 15 are independently H, D, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- Calk-aryl, C 0- C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R a , -C(O)OR a , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR d )(OR c ) or -S(O)R b and Each R a are independently H, D, -C(O)R b , -C(O)OR c , -C(O)NR c R d , -C(=NR b )NR b R c 、 -C(=NOR b )NR b R c 、 -C(=NCN)NR b R c 、 -P(OR c )2, -P(O)R c R b , -P(O)ORc OR b , -S(O)R b , -S(O)NR c R d , -S(O)2R b , -S(O)NR c R d , SiR b 3. -C1-C 10 Alkyl, -C2-C 10 Alkenyl, -C2-C 10 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; Each R c or R d are independently H, D, -C1-C 10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -O-C1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or R c and R d together with the atom to which they are both attached form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocyclo-alkenyl group, and o is 1, 2, 3, 4 or 5.

[0102] According to the present disclosure, ring A3 is a monocyclic, bicyclic, or tricyclic aryl, heteroaryl, or heterocyclic group. In some embodiments, ring A3 is a monocyclic, bicyclic, or tricyclic aryl group. In other embodiments, ring A3 is a monocyclic, bicyclic, or tricyclic heteroaryl group. In other embodiments, ring A3 is a monocyclic, bicyclic, or tricyclic heterocyclic group.

[0103] In some embodiments, Ring A3 is a bicyclic heterocyclic group. In some embodiments, Ring A3 is an isoindoline group. In other embodiments, Ring A3 is an isoindolin-1-one group. In other embodiments, Ring A3 is an isoindolin-3-one group. In other embodiments, Ring A3 is an isoindolin-1,3-dione group.

[0104] According to the present disclosure, each R 15 are independently H, D, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- Calk-aryl, C 0- C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R a , -C(O)OR a , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR d )(OR c ) or -S(O)R b is.

[0105] In some embodiments, each R 15 is H. In some embodiments, at least one R 15 is H. In some embodiments, each R 15 is D. In some embodiments, at least one R 15is D. In some embodiments, each R 15 is C1-C6 alkyl. In some embodiments, at least one R 15 is C1-C6 alkyl. In some embodiments, each R 15 is methyl or ethyl. In some embodiments, at least one R 15 is methyl or ethyl.

[0106] In other embodiments, each R 15 are independently selected from halogen, oxo, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- Calk-aryl, C 0- C1alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a , -SR a , -NR c R d , -NR a R c , -C(O)R b , -OC(O)R a , -C(O)OR a , -C(O)NR c R d , -S(O)R b , -S(O)NR c R d , -S(O)(=NR b )R b , -SF5, -P(O)R b R b , -P(O)(OR b )(OR b ), -B(OR d )(OR c ), or -S(O)R b is selected from.

[0107] In accordance with the present disclosure, o is 1, 2, 3, 4, or 5. In some embodiments, o is 1. In some embodiments, o is 2. In other embodiments, o is 3. In other embodiments, o is 4. In other embodiments, o is 5.

[0108] According to the present disclosure, L4 is a bond, -O-, -S-, -NR a -, -C(R a )2-, -C(O)NR a In some embodiments, L4 is -. In some embodiments, L4 is a bond. In some embodiments, L4 is -O-. In other embodiments, L4 is -S-. In other embodiments, L4 is -NR a In other embodiments, L4 is -C(R a In other embodiments, L4 is -C(O)NR a -It is.

[0109] According to the present disclosure, X1 is CH2, CO, CH=CH (when X2=CO), or N=CH (when X2=CO). In some embodiments, X1 is CH2. In some embodiments, X1 is CO. In other embodiments, X1 is CH=CH (when X2=CO). In other embodiments, X1 is N=CH (when X2=CO).

[0110] According to the present disclosure, X2 is CH2, CO, CH=CH (when X1=CO), or N=CH (when X1=CO). In some embodiments, X2 is CH2. In some embodiments, X2 is CO. In other embodiments, X2 is CH=CH (when X1=CO). In other embodiments, X2 is N=CH (when X1=CO).

[0111] According to this disclosure, R 12 H, D, optionally substituted C 1-4 Alkyl, C 1-4 Alkoxyl, C 1-4 Haloalkyl, -CN, -OR a , -OR b or -SR b In some embodiments, R 12 is H. In some embodiments, R 12 is D. In some embodiments, R 12 is an optionally substituted C1-4 In another embodiment, R 12 is C 1-4 In another embodiment, R 12 is C 1-4 In another embodiment, R 12 is -CN. In other embodiments, R 12 -OR a In other embodiments, R 12 -OR b In other embodiments, R 12 -SR b is.

[0112] According to the present disclosure, a ULM of formula I is [ka] wherein: [ka] is the point of attachment to Y or the PTM, R 15 is as defined herein; X3 is CH2, CO, CH=CH (when X4=CO), or N=CH (when X4=CO), and X4 is CH2, CO, CH=CH (when X3=CO), or N=CH (when X3=CO).

[0113] According to the present disclosure, X3 is CH2, CO, CH=CH (when X4=CO), or N=CH (when X4=CO). In some embodiments, X3 is CH2. In some embodiments, X3 is CO. In other embodiments, X3 is CH=CH (when X4=CO). In other embodiments, X3 is N=CH (when X4=CO).

[0114] According to the present disclosure, X4 is CH2, CO, CH=CH (when X3=CO), or N=CH (when X3=CO). In some embodiments, X4 is CH2. In some embodiments, X4 is CO. In other embodiments, X4 is CH=CH (when X3=CO). In other embodiments, X4 is N=CH (when X3=CO).

[0115] According to the present disclosure, the PTM is represented by formula IA-1 [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , (R 5 ) m , and Y are as defined herein.

[0116] According to the present disclosure, the PTM is represented by formula IA-2 [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , (R 5 ) m , and Y are as defined herein.

[0117] According to the present disclosure, the PTM is represented by formula IA-3 [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , (R 5 ) m , L1, L2, L3, ring A1, and ring A2 are as defined herein.

[0118] According to the present disclosure, the PTM is represented by formula IA-4 [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , (R 5 ) m , L1, L2, Z, r, s, and ring A1 are as defined herein.

[0119] According to the present disclosure, the PTM is represented by formula IA-5 [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , (R 5 ) m , L1, L2, L4, Z, r, s, ring A1, ring A3, (R 15 ) o , R 12 , X1, and X2 are as defined herein.

[0120] According to the present disclosure, the PTM is represented by formula IA-6 [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 4 , (R 5 ) m , L2, L4, Z, r, s, ring A1, R 15 , X3, and X4 are as defined herein.

[0121] According to the present disclosure, the PTM is represented by formula IA-7 [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 , R 5 ,L2,Z,r,s,R 15 , X3, and X4 are as defined herein; and t is 1 or 2.

[0122] In accordance with the present disclosure, t is 1 or 2. In some embodiments, t is 1. In other embodiments, t is 2.

[0123] In some embodiments, the claimed compounds comprise: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)benzene-sulfonamide, 3-[4-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-7-azaspiro[3.5]nonan-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide, 3-[7-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide, 3-[3-[[4-[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]piperazin-1-yl]methyl]pyrrolidin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide, 3-[4-[[1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl]piperidin-4-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide, 3-[4-[6-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-6-azaspiro[3.4]octan-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide, 3-[4-[2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]ethyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide, 3-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrrolidin-3-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide, 3-[6-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the claimed compounds comprise: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-methylpyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoropyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(2-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-7-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(8-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,8-diazaspiro[4.5]decan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)ethyl)piperazin-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)morpholin-2-yl)methyl)piperazin-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]nonan-2-yl)methyl)piperazin-1-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(9-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-3,3-dimethylpiperazin-1-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-6-azaspiro[3.4]octan-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbonyl)piperazin-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6-dimethoxybenzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, 5-(4-((4-(3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide, 3-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)amino)piperidin-1-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)(methyl)amino)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)amino)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(9-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((3aS,6aS)-5-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)hexahydro-pyrrolo[3,4-c]pyrrol-2(1H)-yl)benzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide, N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

[0125] 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.

[0126] 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.

[0127] Isotopic variations of the compounds of the present disclosure (including all subgenera described herein) are also contemplated by the present disclosure. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen are tritium and deuterium.

[0128] 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.

[0129] 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. 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%, 0.05%, 0.10%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65 %, 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 any number in a range defined by and inclusive of any two of the foregoing numbers) w / w, w / v or v / v.

[0130] 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%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 15.75 ... 0%, 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%, 0.05%, 0.04%, 0.03%, 0.02%, or greater than 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 in a range defined by and including any two of the above numbers) w / w, w / v, or v / v.

[0131] 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 0.08% to about 10%, from about 0.09% to about 12%, from about 0.10% to about 13%, from about 0.11% to about 14%, from about 0.12% to about 15%, from about 0.13% to about 16%, from about 0.14% to about 17%, from about 0.15% to about 18%, from about 0.16% to about 19%, from about 0.17% to about 20%, from about 0.18% to about 22%, from about 0.19% to about 23%, from about 0.19% to about 24%, from about 0.19% to about 25%, from about 0.19% to about 26%, from about 0.19% to about 27%, from about 0.19% to about 28%, from about 0.19% to about 29%, from about 0.19% to about 26%, from about 0.19% to about 25%, from about 0.19% to about 26%, from about 0.19% to about 28%, from about 0.19% to about 29%, from about 0.19% to about 29%, from about 0.19% to about 25%, from about 0.19% to about 24%, from about % 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.

[0132] 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.

[0133] In some embodiments, the amount of one or more compounds of the present invention is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or any number in a range defined by and including any two of the foregoing numbers).

[0134] 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, 0.003 ... 5g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0 .0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045 g, 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, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or any number in a range bounded by and including any two of the foregoing numbers).

[0135] 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.

[0136] 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.

[0137] 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.

[0138] Non-limiting exemplary pharmaceutical compositions and methods for preparing them are described below.

[0139] Pharmaceutical composition for oral administration In some embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0140] 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.

[0141] 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 a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0142] 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.

[0143] 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 pharmaceutical medium can be used as a carrier, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., 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, and in some embodiments, lactose can be used for oral solid preparations. 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.

[0144] 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.

[0145] 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.

[0146] 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 disintegrate in the bottle. Using too little can result in insufficient disintegration, which can alter 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 those skilled 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.

[0147] 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.

[0148] 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.

[0149] Tablets may be uncoated, or 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).

[0150] 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.

[0151] 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.

[0152] 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.

[0153] The hydrophilic surfactant may be either ionic or nonionic. Suitable ionic surfactants include 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.

[0154] 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.

[0155] 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, succinic acid, hydroxypropyl methylcellulose ... 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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-acetylglucosamine, methyl ... 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, but not limited to, dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0161] 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.

[0162] 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 skilled 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 biologically acceptable 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.

[0163] 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.

[0164] In addition, 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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, and the like.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] Other pharmaceutical compositions Pharmaceutical compositions can 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.

[0178] 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.

[0179] In some embodiments, the compounds or pharmaceutical compositions of the present invention are administered by intravenous injection.

[0180] 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.

[0181] In some embodiments, the compounds of the invention are administered in a single dose. 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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 can be a polymer matrix and can 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.

[0186] 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.

[0187] 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.

[0188] 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 compounds of the invention may be adjusted accordingly. 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.

[0189] 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, such as 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 reduced proliferation or down-regulation 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.

[0190] In certain embodiments, the present invention provides pharmaceutical compositions comprising a bispecific compound or a pharmaceutically acceptable salt thereof.

[0191] In certain embodiments, the present invention provides pharmaceutical compositions comprising bispecific compounds for use in degrading target proteins in cells.

[0192] 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.

[0193] As used herein, unless otherwise indicated, "abnormal cell growth" or "cancer" refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that grow due to the expression of mutant tyrosine kinases or the overexpression of receptor tyrosine kinases; (2) benign and malignant cells of other proliferative diseases with aberrant tyrosine kinase activation; (3) any tumors that grow due to receptor tyrosine kinases; (4) any tumors that grow due to aberrant serine / threonine kinase activation; (5) benign and malignant cells of other proliferative diseases with aberrant serine / threonine kinase activation; (6) any tumors that grow due to aberrant signal transduction, metabolic epigenetic, and transcriptional mechanisms; and (7) benign and malignant cells of other proliferative diseases with aberrant signal transduction, metabolic epigenetic, and transcriptional mechanisms.

[0194] For convenience, certain well-known abbreviations may be used herein, including estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), non-small cell lung cancer (NSCLC), and castration-resistant prostate cancer (CRPC).

[0195] Further embodiments relate to methods of treating abnormal cell growth in a patient. Additional embodiments relate to methods of treating abnormal cell growth in a patient, the method comprising administering to the patient a compound described herein in an amount effective to treat the abnormal cell growth.

[0196] In another embodiment, the abnormal cell growth is cancer.

[0197] In some embodiments, the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, renal pelvic cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, glioblastoma, brain stem glioma, pituitary adenoma, or a combination of two or more of the foregoing cancers.

[0198] Additional embodiments relate to methods of treating a solid tumor in a patient, wherein some embodiments relate to treating a solid tumor in a patient, the treatment comprising administering to the patient a compound described herein in an amount effective to treat the solid tumor.

[0199] In one embodiment, the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder.

[0200] In one embodiment, the solid tumor is breast, lung, prostate, pancreatic, or ovarian.

[0201] In one embodiment, the cancer is breast cancer.

[0202] In one embodiment, the breast cancer is ER+ breast cancer.

[0203] In one embodiment, the breast cancer is ER+HER2- breast cancer.

[0204] In one embodiment, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0205] In one embodiment, the lung cancer is non-small cell lung cancer.

[0206] In one embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0207] In one embodiment, the prostate cancer is castration-resistant prostate cancer. In one embodiment, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0208] Additional embodiments relate to methods of treating a hematological tumor in a patient, including administering to the patient a compound described herein in an amount effective to treat the hematological tumor.

[0209] In one embodiment, the hematological tumor is leukemia, lymphoma, or multiple myeloma.

[0210] In one embodiment, the hematological tumor is leukemia or lymphoma.

[0211] An additional embodiment relates to a method of treating cancer in a patient, the method comprising administering to the patient an amount of a compound described herein effective to treat the cancer, hi one embodiment, the cancer is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, bladder, or blood.

[0212] In one embodiment, the cancer is breast, lung, prostate, pancreatic, ovarian, or blood.

[0213] In one embodiment, the cancer is breast, lung, prostate, pancreatic, or ovarian, hi one embodiment, the cancer is breast cancer.

[0214] In one embodiment, the breast cancer is ER+ breast cancer.

[0215] In one embodiment, the breast cancer is ER+HER2- breast cancer.

[0216] In one embodiment, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0217] In one embodiment, the lung cancer is non-small cell lung cancer.

[0218] In one embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0219] In one embodiment, the prostate cancer is castration-resistant prostate cancer. In one embodiment, the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

[0220] In one embodiment, the cancer is hematogenous.

[0221] In one embodiment, the hematological tumor is leukemia or lymphoma.

[0222] Further embodiments relate to methods of treating cancer in a patient, comprising administering to the patient a cancer-treating amount of a compound described herein in combination with an anti-tumor agent selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, antihormones, and antiandrogens.

[0223] A further embodiment relates to a pharmaceutical composition for treating cancer in a patient, comprising a compound described herein in an amount effective to treat the cancer, and a pharmaceutically acceptable carrier.

[0224] An additional embodiment relates to a method of treating cancer in a patient, particularly a human, comprising administering to the patient an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, effective to treat the cancer. In one embodiment of this method, the cancer includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, renal pelvic cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, glioblastoma, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.

[0225] In one embodiment, the method comprises administering to the patient a compound described herein in an amount effective to treat the aforementioned cancer solid tumor. In a preferred embodiment, the solid tumor is breast cancer, lung cancer, colon cancer, brain cancer, prostate cancer, gastric cancer, pancreatic cancer, ovarian cancer, skin cancer (melanoma), endocrine cancer, uterine cancer, testicular cancer, and bladder cancer.

[0226] In another embodiment of the aforementioned method, the aforementioned cancer is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hyperplasia, or restinosis.

[0227] Some embodiments relate to a method of treating cancer in a patient, the method comprising administering to the patient an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, effective to treat the cancer, in combination with an anti-tumor agent selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, antihormones, and antiandrogens.

[0228] An additional embodiment relates to a pharmaceutical composition for treating cancer in a patient, particularly a human, comprising an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, effective to treat cancer, and a pharmaceutically acceptable carrier. In one embodiment of the foregoing compositions, the cancer includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, sarcoma of soft tissue, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, renal pelvic cancer, tumors of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, glioblastoma, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hyperplasia, or restinosis.

[0229] Further embodiments relate to methods of treating cancer in a patient, the method comprising administering to the patient an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, effective to treat the cancer, in combination with another anti-tumor agent selected from the group consisting of an antimitotic agent, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an antihormonal agent, and an anti-androgen. Some embodiments contemplate pharmaceutical compositions for treating abnormal cell proliferation, the composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, effective to treat abnormal cell proliferation, and another anti-tumor agent selected from the group consisting of an antimitotic agent, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an antibody, a cytotoxic agent, an antihormonal agent, and an anti-androgen.

[0230] Still further embodiments relate to methods of treating angiogenesis-related disorders in a patient, including a human, comprising administering to the patient an amount of a compound described herein, as defined above, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, which is effective in combination with one or more anti-tumor agents listed above to treat the disorder. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular histoplasmosis, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget's disease, humoral hypercalcemia of malignant tumors, hypercalcemia from tumors metastasizing to bone, and osteoporosis induced by glucocorticoid treatment; coronary artery restenosis; and certain microbial infections, including those associated with microbial pathogens selected from adenovirus, hantavirus, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and Group A Streptococcus.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] Some embodiments relate to methods of treating cancer in a patient (and pharmaceutical compositions therefor) comprising an amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with an amount of one or more agents selected from an anti-angiogenic agent, a signal transduction inhibitor (e.g., that inhibits the means by which regulatory molecules communicate intracellularly that govern fundamental processes of cell proliferation, differentiation, and survival), and an anti-proliferative agent, which amounts together are effective to treat the aforementioned abnormal cell proliferation.

[0238] Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with the compounds described herein in the methods and pharmaceutical compositions described herein.

[0239] Tyrosine kinase inhibitors can also be combined with the compounds described herein.

[0240] VEGF inhibitors, such as sutent and axitinib, may also be combined with the compounds described herein.

[0241] ErbB2 receptor inhibitors can be administered in combination with the compounds described herein.Various other compounds, such as styrene derivatives, have also been shown to have tyrosine kinase inhibitory properties, and some tyrosine kinase inhibitors have been identified as ErbB2 receptor inhibitors.

[0242] Epidermal growth factor receptor (EGFR) inhibitors may be administered in combination with the compounds of the present invention. PI3K inhibitors, such as PI3K alpha or PI3K beta inhibitors, may also be administered in combination with the compounds of the present invention.

[0243] Mammalian target of rapamycin (mTOR) inhibitors may also be administered in combination with the compounds of the present invention.

[0244] A c-Met inhibitor may be administered in combination with a compound of the present invention.

[0245] CDK inhibitors may be administered in combination with the compounds of the present invention.

[0246] MEK inhibitors may be administered in combination with the compounds of the present invention.

[0247] PARP inhibitors may be administered in combination with the compounds of the present invention.

[0248] JAK inhibitors may be administered in combination with the compounds of the present invention.

[0249] Antagonists of programmed death 1 protein (PD-1) may be administered in combination with the compounds of the invention.

[0250] Antagonists of programmed death-ligand 1 (PD-L1) may also be administered in combination with the compounds of the invention.

[0251] Other anti-proliferative agents that may be used in conjunction with the compounds described herein include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr.

[0252] The compounds described herein may also be used with other agents useful in the treatment of abnormal cell growth or cancer, including, but not limited to, agents that can enhance anti-tumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents that can block CTLA4, as well as anti-proliferative agents, such as other farnesyl protein transferase inhibitors, e.g., farnesyl protein transferase.

[0253] The compounds described herein may be applied as the sole therapy or may include one or more other anti-tumor agents, such as those selected from antimitotic agents, alkylating agents, antimetabolites, growth factor inhibitors, cell cycle inhibitors, intercalating antibiotics, enzymes, and antihormonal agents.

[0254] The compounds described herein can be used alone or in combination with one or more of a variety of anti-cancer or supportive care agents. For example, the compounds described herein can be used with cytotoxic agents. Some embodiments also contemplate the use of the compounds described herein with hormone therapy. Additionally, some embodiments provide the compounds described herein alone or in combination with one or more supportive care products, such as products selected from the group consisting of filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such combination therapy can be achieved by simultaneous, sequential, or separate administration of the individual components of the therapy.

[0255] The compounds described herein may be used in conjunction with anti-tumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived anti-tumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and / or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that may be used in conjunction with the compounds described herein:

[0256] 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 they can use their general knowledge of organic chemistry to modify or optimize the preparations shown in the schemes 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.

[0257] 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]

[0258] General synthetic procedure The compounds of the invention can be prepared using the general procedures described below.The compounds described herein can be prepared according to the following synthetic schemes and general synthetic procedures.

[0259] Compounds of formula (I) can be synthesized, for example, using the procedure shown in Scheme I. Using suitable synthetic methods (such as, but not limited to, S N Ar reaction, Suzuki coupling, Stille coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling, or reductive amination) to obtain an optionally protected compound 1-1, wherein RG 1 is an optionally protected compound 1-2, where RG is, but is not limited to, a halogen (e.g., F, Cl, Br, I), a hydroxy, an aldehyde, a boronic acid, a boronate ester, a trialkyltin, a carboxylic acid, or an amine. 2 and R.G. 3are each independently a halogen (e.g., F, Cl, Br, I), hydroxy, aldehyde, boronic acid, boronate ester, trialkyltin, carboxylic acid, or amine, to give compounds 1-3. N and optionally protecting compound 1-4, wherein RG is a methyl group, and the optionally protecting compound 1-5 is a methyl group, and the optionally protecting compound 1-6 is a methyl group, and the optionally protecting compound 1-7 is a methyl group, and the optionally protecting compound 1-8 is a methyl group, and the optionally protecting compound 1-9 is a methyl group, and the optionally protecting compound 1-10 is a methyl group, and the optionally protecting compound 1-110 is a methyl group, and 4 is a reactive group such as halogen (e.g., F, Cl, Br, I), hydroxy, aldehyde, boronic acid, boronate ester, trialkyltin, carboxylic acid, or amine, to provide compounds of formula (I).

[0260] Alternatively, synthesis can be achieved by coupling optionally protected compound 1-4 with optionally protected compound 1-2 using the appropriate synthetic method described above to give compound 1-6, and then reacting 1-6 with optionally protected compound 1-1 using the appropriate synthetic method described above to give the compound of formula (I). Scheme I [ka]

[0261] Intermediates for the synthesis of compounds of formula (I) can be prepared as described in Scheme II. Reaction of nitrile 2-1 with N-hydroxyacetamide in the presence of a base such as K2CO3 can provide benzo[d]isoxazole 2-2. Amine 2-2 can be converted to sulfonyl halide 2-3, where X, under standard sulfonylation conditions (e.g., in the presence of a base such as K0tBu, LiHMDS, or pyridine). a is sulfonylated with a halogen (eg, F, Cl, or Br) to give compound 1-4. Scheme II [ka]

[0262] Compounds of formula (I) can be prepared as described in Scheme III. N Optionally protected compound 1-1 can be converted to compound 2-1, wherein RG is a methyl group, by a method using a methyl group (e.g., Ar reaction, Suzuki coupling, Stille coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling, or reductive amination) to afford compound 2-1, wherein RG is a methyl group, 5 and R.G. 6 are each independently a reactive group such as, but not limited to, halogen (e.g., F, Cl, Br, I), hydroxy, aldehyde, boronic acid, boronate ester, trialkyltin, carboxylic acid, or amine, and y is an integer from 0 to 14, can be coupled with an appropriate synthetic method (e.g., but not limited to, S N Ar reaction, Suzuki coupling, Stille coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling, or reductive amination) to combine optionally protected 1-4 with compound 2-3, where RG 7 and R.G. 8 are each independently a reactive group such as, but not limited to, halogen (e.g., F, Cl, Br, I), hydroxy, aldehyde, boronic acid, boronate ester, trialkyltin, carboxylic acid, or amine, and z is an integer from 0 to 14, and the sum of y and z is an integer from 1 to 14, to give compounds 2-4. N Coupling of compounds 2-2 and 2-4 using Ar reaction, Suzuki coupling, Stille coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling, or reductive amination) can give compounds 2-5. Scheme III [ka]

[0263] Intermediates for the preparation of compounds of formula I can be synthesized according to the route described in Scheme IV. N Under Ar conditions, optionally in the presence of a base (e.g., DIPEA), X b is a halogen (e.g., F or Cl) or a pseudohalogen (e.g., OTf or OMs), to compound 4-2, 1a is an optionally protected, nitrogen-containing, 3-11 membered heterocyclyl optionally substituted with a reactive group such as, but not limited to, halogen (e.g., F, Cl, Br, I), hydroxy, aldehyde, boronic acid, boronate ester, trialkyltin, carboxylic acid, or amine, to provide compound 4-3. Scheme IV [ka]

[0264] Intermediates for the preparation of compounds of formula I can be synthesized according to the route depicted in Scheme V. Standard S- N X can be prepared under Ar conditions or under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G2 or BrettPhos Pd G3, and a base, such as K3PO4 or sodium tert-butoxide). c is a halogen (e.g., F, Cl, or Br) or a pseudohalogen (e.g., OTf or OMs) and R zCoupling of compound 5-1, where 5-1 is a C1-C4 alkyl group, with compound 4-2 can give compound 5-2. Reduction of nitrile 5-2 under appropriate conditions (e.g., Raney nickel) can give aldehyde 5-3. Reductive amination and cyclization of compound 5-3 with amine 5-4 under standard conditions, such as the addition of an appropriate acid (e.g., AcOH) and a reducing agent (e.g., sodium triacetoxyborohydride), followed by a base (e.g., DIPEA), can give compound 5-5. Scheme V [ka]

[0265] Intermediates for the preparation of compounds of formula I can be synthesized according to the route described in Scheme VI. N X can be prepared under Ar conditions or under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst, such as XPhos Pd G2 or BrettPhos Pd G3, and a base, such as K3PO4 or sodium tert-butoxide). d is a halogen (e.g., F, Cl, or Br) or a pseudohalogen (e.g., OTf or OMs), and R y Coupling of compound 6-1, where R is a C1-C4 alkyl group, with compound 4-2 can give compound 6-2. Reduction of nitrile 6-2 under appropriate conditions (e.g., Raney nickel) can give aldehyde 6-3. Reductive amination and cyclization of compound 6-3 with amine 5-4 under standard conditions, such as the addition of an appropriate acid (e.g., AcOH) and a reducing agent (e.g., sodium triacetoxyborohydride), followed by a base (e.g., DIPEA), can give compound 6-4. Scheme VI [ka]

[0266] Compounds of formula (I) can be prepared as described in Scheme VII. Under standard conditions, such as in the presence of an oxidizing agent (e.g., Dess-Martin periodinane, 2-iodoxybenzoic acid, or SO3·pyridine), and optionally in the presence of a base (e.g., NaHCO3 or Et3N), R x Oxidation of alcohol 7-1, where is H or C1-C4 alkyl, can provide compound 7-2. N X can be obtained under Ar conditions, optionally in the presence of a base (e.g., DIPEA), or under standard Buchwald-Hartwig amination conditions (e.g., in the presence of a palladium catalyst such as BrettPhos Pd G3 and a base such as sodium tert-butoxide). e Compound 7-4 of Compound 7-3, wherein A is a halogen (e.g., F, Cl, Br, or I) or a pseudohalogen (e.g., OMs or OTf). 2a is a 3- to 11-membered diazaheterocyclyl, and P 1 is a suitable nitrogen protecting group (e.g., Boc, Cbz, Bn, PMB, or acetyl), followed by deprotection to give compound 7-5. Reaction of compound 7-2 and amine 7-5 under standard conditions for reductive amination (e.g., in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, and optionally in the presence of an acid such as acetic acid) can give compound 7-6. Scheme VII [ka]

[0267] Intermediates for the preparation of compounds of Formula I can be synthesized according to the route described in Scheme VIII. Under standard conditions, such as in the presence of a suitable acid (e.g., acetic acid) and a reducing agent (e.g., sodium triacetoxyborohydride), followed by a base (e.g., N,N-diisopropylethylamine), compound 5-3 can be converted to compound 8-2 via reductive amination and cyclization with optionally enantiomerically enriched compound 8-1. Cyclization of 8-2 in the presence of a base (e.g., potassium tert-butoxide) can provide compound 5-5. Scheme VIII [ka]

[0268] Intermediates for the preparation of compounds of Formula I can be synthesized according to the route described in Scheme IX. Under standard conditions, such as in the presence of a suitable acid (e.g., acetic acid) and a reducing agent (e.g., sodium triacetoxyborohydride), followed by a base (e.g., N,N-diisopropylethylamine), compound 6-3 can be converted to compound 9-1 via reductive amination and cyclization with optionally enantiomerically enriched compound 8-1. Cyclization of 9-1 in the presence of a base (e.g., potassium tert-butoxide) can provide compound 6-4. Scheme IX [ka]

[0269] Example 1 N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide [ka]

[0270] Step 1: 1-(methylsulfonyl)-1H-pyrazole [ka]

[0271] To a solution of pyrazole (10.0 g, 147 mmol) in DCM (100 mL) was added triethylamine (41.0 mL, 294 mmol) and methanesulfonyl chloride (17.1 mL, 220 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride (50 mL) and water (50 mL). The layers were separated, and the aqueous layer was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a pale yellow oil (21.4 g, 146 mmol, 99.3% yield). 1 H NMR (300MHz, CDCl3) δ8.06(d,J=2.7Hz,1H),7.85(d,J=1.7Hz,1H),6.48(dd,J=2.6,1.7Hz,1H),3.34(s,3H).

[0272] Step 2: 2,6-Difluoro-4-(hydroxymethyl)benzonitrile [ka]

[0273] To a solution of 2,6-difluoro-4-formylbenzonitrile (5.00 g, 29.9 mmol) in ethanol (100 mL) was added sodium borohydride (1.13 g, 29.9 mmol) at 0° C. The reaction was stirred at 0° C. for 2 hours. Water (10 mL) and 1N HCl (60 mL) were added. The mixture was partially concentrated under reduced pressure and then diluted with EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a pale yellow solid (5.2 g, 31 mmol, quantitative yield). This material was used directly in the next step without further purification. 1 H NMR (300MHz, DMSO-d6) δ7.32 (d, J = 9.3 Hz, 2H), 5.67 (t, J = 5.7 Hz, 1H), 4.59 (d, J = 5.7 Hz, 2H).

[0274] Step 3: 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile [ka]

[0275] To a solution of 2,6-difluoro-4-(hydroxymethyl)benzonitrile (4.7 g, 28 mmol) in methanol (100 mL) was added sodium methoxide (6.01 g, 111 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified to pH 3 with 1N HCl at 0° C. The mixture was concentrated and extracted with EtOAc (100 mL × 3). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-80% EtOAc / heptane) to afford the title compound (4.3 g, 24 mmol, 84% yield) as a pale yellow solid. 1 H NMR (300MHz, CDCl3) δ6.90~6.69 (m, 2H), 4.75 (d, J=4.7Hz, 2H), 3.96 (s, 3H).

[0276] Step 4: 2-Fluoro-6-methoxy-4-(pyrazol-1-ylmethyl)benzonitrile [ka]

[0277] To a stirred solution of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (4.1 g, 23 mmol) in acetonitrile (80 mL) was added CsCO (14.75 g, 45.26 mmol) and 1-methylsulfonyl-pyrazole (4.96 g, 33.9 mmol). The resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered through a pad of Celite and concentrated. The crude material was purified by silica gel chromatography (20-70% EtOAc / heptane) to afford the title compound (4.1 g, 18 mmol, 79% yield) as a yellow solid. 1 H NMR (300MHz, CDCl3) δ7.61(d,J=1.7Hz,1H),7.47(d,J=2.3Hz,1H),6.57~6.51(m,2H),6.37(t,J=2.1Hz,1H),5.35(s,2H),3.90(s,3H). C 12 H 11 FN3O[M+H] + LCMS calculated for: m / z=232.1; found 232.2.

[0278] Step 5: 4-Methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-amine [ka]

[0279] To a stirred solution of 2-fluoro-6-methoxy-4-(pyrazol-1-ylmethyl)benzonitrile (3.9 g, 17 mmol) in DMF (45 mL) and water (15 mL) was added N-hydroxyacetamide (3.8 g, 51 mmol) and K2CO3 (14.0 g, 101 mmol). The resulting mixture was stirred at 70 °C overnight. The reaction mixture was cooled to room temperature and diluted with water (450 mL) and EtOAc (450 mL). The layers were separated, and the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (20-70% EtOAc / heptane) to afford the title compound (2.9 g, 12 mmol, 70% yield) as a white solid. 1 H NMR(300MHz,CDCl3)δ7.57(d,J=1.7Hz,1H),7.43(d,J=2.3Hz,1H),6.78(s,1H ),6.39(s,1H),6.32(t,J=2.1Hz,1H),5.38(s,2H),4.65(s,2H),3.89(s,3H). C 12 H 13 N4O2[M+H] + LCMS calculated for: m / z=245.1; found: 245.1.

[0280] Step 6: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-bromo-benzenesulfonamide [ka]

[0281] To a solution of 4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-amine (210 mg, 0.86 mmol) and 3-bromobenzenesulfonyl chloride (548 mg, 2.14 mmol) in THF (10 mL) was added potassium tert-butoxide (578 mg, 5.15 mmol). After heating at 60 °C for 1 h, the mixture was cooled to room temperature and 1 N HCl (15 mL) was added. The organic phase was separated, and the aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over NaSO, concentrated, and purified by silica gel chromatography (0–8% MeOH / DCM) to give the title compound (400 mg, 0.87 mmol, quantitative) as a brown solid. 18 H 16 BrN4O4S[M+H] + LCMS calculated for: m / z=463.0; found: 462.8.

[0282] Step 7: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(piperazin-1-yl)benzenesulfonamide [ka]

[0283] A solution of 3-bromo-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide (62.0 mg, 0.134 mmol), tert-butyl 1-piperazinecarboxylate (29.9 mg, 0.161 mmol), BrettPhos Pd G3 (18.2 mg, 0.0201 mmol, CAS 1470372-59-8), and sodium tert-butoxide (77.1 mg, 0.803 mmol) in 1,4-dioxane (1 mL) was stirred at 100° C. for 3 hours under a nitrogen atmosphere. Upon cooling to room temperature, the mixture was concentrated, and TFA (3 mL) was added. The mixture was concentrated and purified by preparative HPLC on a C18 column (2-40% MeCN / 0.1% TFA (aq)) to give the title compound as a colorless solid TFA salt (30 mg, 0.064 mmol, 48% yield). 1 H NMR(300MHz,DMSO-d6)δ10.86(s,1H),8.73(s,2H),7.88(d,J=2.3Hz,1H),7.57~7.40(m,4H),7.29(dt,J=7.9,2.1Hz, 1H),6.84(s,1H),6.76(s,1H),6.30(t,J=2.1Hz,1H),5.45(s,2H),3.88(s,3H),3.42~3.34(m,4H),3.29~3.21(m,3H). C 22 H 25 N6O4S[M+H] + LCMS calculated for: m / z=469.2; found: 468.9.

[0284] Step 8: 2-(2,6-dioxopiperidin-3-yl)-5-[3-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione [ka]

[0285] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (12.0 g, 43.4 mmol) and pyrrolidin-3-ylmethanol (4.39 g, 43.4 mmol) in NMP (120 mL) was added diisopropylethylamine (21.5 mL, 130 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with water (150 mL) and EtOAc (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×150 mL) and concentrated. The crude material was purified by silica gel chromatography (EtOA) to afford the title compound (10.4 g, 28.4 mmol, 65.3%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.64(d,J=8.4Hz,1H),6.89(d,J=2.0Hz,1H),6.80(m,1H),5.05(m,1H),4.75( m,1H),3.51~3.37(m,5H),3.19m,1H),2.94~2.81(m,1H),2.59(m,2H),2.45(m,1H),2.04(m,2H),1.87~1.74(m,1H). C 18 H 20 N3O5[M+H] + LCMS calculated for: m / z=358.1; found: 358.3.

[0286] Step 9: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde [ka]

[0287] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[3-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione (5.2 mg, 0.015 mmol) in DCM (0.5 mL) was added NaHCO (2.44 mg, 0.0291 mmol) and Dess-Martin periodinane (12.3 mg, 0.0291 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM (2 mL) and washed with a 1:1 NaHCO / NaSO solution (3 mL). The organic phase was separated, and the aqueous phase was extracted with DCM (3 × 3 mL). The combined organic phases were dried over NaSO and concentrated to the title compound (5.1 mg, 0.015 mmol, quantitative) as a yellow solid, which was used directly in the next step without further purification. 18 H 18 N3O5[M+H] + LCMS calculated for: m / z=356.1; found: 355.9.

[0288] Step 10: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide

[0289] To a solution of N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]-3-piperazin-1-ylbenzenesulfonamide (6.84 mg, 0.0117 mmol, from step 7) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidine-3-carbaldehyde (4.69 mg, 0.0132 mmol) in methanol (1 mL) was added acetic acid (5 drops) and sodium cyanoborohydride (7.38 mg, 0.117 mmol). The mixture was stirred at room temperature for 1 h, diluted with water (0.5 mL) and MeCN (3 mL), and purified by preparative HPLC on a C18 column (5-50% MeCN / 0.1% TFA (aq)) to afford the title compound as a yellow solid TFA salt (3.0 mg, 0.0037 mmol, 32% yield). 1 H NMR(300MHz,DMSO-d6)δ11.09(s,1H),10.89(s,1H),7.88(d,J=2.3Hz,1H),7.70(d,J=8.4Hz,1H),7.62~7.56( m,1H),7.54~7.43(m,3H),7.34(dd,J=7.9,2.5Hz,1H),6.95(d,J=2.1Hz,1H),6.89~6.82(m,2H),6.77(s,1H),6 .31(t,J=2.1Hz,1H),5.45(s,2H),5.07(dd,J=12.7,5.3Hz,1H),3.97~3.83(m,5H),3.80~3.63(m,6H),3.24(t ,J=8.8Hz,7H),2.98~2.77(m,2H),2.65~2.54(m,1H),2.35~2.19(m,1H),2.09~1.94(m,1H),1.94~1.75(m,1H). C 40 H 42 N9O8S[M+H] + LCMS calculated for: m / z=808.2; found: 808.2.

[0290] Example 2 N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)benzenesulfonamide [ka]

[0291] Step 1: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)piperidin-4-yl)propanal [ka]

[0292] The title compound was synthesized following a procedure similar to Example 1, steps 8 and 9. 21 H 24 N3O5[M+H] + LCMS calculated for: m / z=398.2; found: 398.0.

[0293] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin-1-yl)benzenesulfonamide

[0294] The title compound was synthesized following a procedure similar to Example 1, Step 10. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H),10.87(s,1H),9.55(s,1H),7.88(d,J=2.3Hz,1H),7.66(d,J=8.5Hz,1H ),7.58~7.54(m,1H),7.52~7.42(m,3H),7.35~7.21(m,3H),6.84(d,J=0.9Hz,1H),6.77(s,1H),6.30(t,J=2. 1Hz,1H),5.45(s,2H),5.07(dd,J=12.7,5.4Hz,1H),4.13~4.03(m,2H),3.88(s,3H),3.67~3.57(m,3H),3.21 ~2.81(m,9H),2.64~2.54(m,1H),2.06~1.96(m,1H),1.85~1.67(m,4H),1.67~1.49(m,1H),1.33~1.10(m,5H). C 43 H 48 N9O8S[M+H] + LCMS calculated for: m / z=850.3; found: 850.4.

[0295] Example 3 N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)benzenesulfonamide [ka]

[0296] Step 1: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde [ka]

[0297] The title compound was synthesized according to a procedure similar to Steps 8 and 9 of Example 1 to give the title compound (7.3 mg, 0.019 mmol, quantitative) as a yellow solid, which was used directly in the next step without further purification. 20 H 22 N3O5[M+H] + LCMS calculated for: m / z=384.1; found: 383.9.

[0298] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin-1-yl)benzenesulfonamide

[0299] The title compound was synthesized following a procedure similar to Example 1, Step 10. 1 H NMR(300MHz,DMSO-d6)δ11.08(s,1H),10.87(s,1H),9.59(s,1H),7.88(d,J=2.2Hz,1H),7.67(d,J=8.5Hz,1H) ,7.58~7.53(m,1H),7.52~7.42(m,3H),7.37~7.21(m,3H),6.83(s,1H),6.76(s,1H),6.30(t,J=2.1Hz,1H),5. 45(s,2H),5.07(dd,J=12.7,5.4Hz,1H),4.08(d,J=13.0Hz,3H),3.88(s,4H),3.63(d,J=11.3Hz,2H),3.29~2. 78(m,8H),2.64~2.54(m,1H),2.10~1.96(m,1H),1.78(d,J=12.6Hz,2H),1.70~1.57(m,3H),1.34~1.11(m,3H). C 42 H 46 N9O8S[M+H] + LCMS calculated for: m / z=836.3; found: 836.3.

[0300] Example 4 3-[4-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-7-azaspiro[3.5]nonan-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0301] Step 1: 7-Azaspiro[3.5]nonan-2-ol [ka]

[0302] To a solution of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (134 mg, 0.554 mmol) in DCM (1.6 mL) was added trifluoroacetic acid (0.40 mL, 5.2 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 7-azaspiro[3.5]nonan-2-ol as the TFA salt, which was carried forward without further purification. CH 16 NO[M+H] + LCMS calculated for: m / z=142.1; found: 142.1.

[0303] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)isoindole-1,3-dione [ka]

[0304] A solution of 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-1H-isoindole-1,3(2H)-dione (163 mg, 0.590 mmol), 7-azaspiro[3.5]nonan-2-ol (188 mg, from Step 1), and N,N-diisopropyl-ethylamine (0.411 mL, 2.36 mmol) in NMP (2 mL) was stirred at 100 °C for 24 h. The reaction was cooled to room temperature and diluted with water (20 mL) and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The crude material was purified by silica gel chromatography (20-100% EtOAc / heptane) to afford the title compound (231 mg, 0.581 mmol, 98.5% yield) as a yellow, viscous oil. 21 H 24 N3O5[M+H] + LCMS calculated for: m / z=398.2; found: 398.1.

[0305] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)isoindole-1,3-dione [ka]

[0306] The title compound was synthesized following a procedure similar to Example 1, Step 9. 21 H 22 N5O5[M+H] + LCMS calculated for: m / z=396.2; found: 395.9.

[0307] Step 4: 3-[4-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-7-azaspiro[3.5]nonan-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0308] To a solution of N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]-3-piperazin-1-ylbenzenesulfonamide (6.0 mg, 0.010 mmol, from Example 1, Step 7) and 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)isoindole-1,3-dione (4.07 mg, 0.0103 mmol) in DMSO (1 mL) was added sodium triacetoxyborohydride (4.37 mg, 0.0206 mmol). The mixture was stirred at room temperature overnight. Purification by preparative HPLC on a C18 column (5-50% MeCN / 0.1% TFA (aq)) afforded the title compound (8.5 mg, 0.010 mmol, 97% yield) as a yellow solid TFA salt. 1 H NMR(300MHz,DMSO-d6)δ11.09(s,1H),10.91(s,1H),9.94(s,1H),7.88(d,J=2.2Hz,1H),7.67(d,J=8.5Hz,1H) ,7.59~7.55(m,1H),7.53~7.41(m,3H),7.38~7.22(m,3H),6.84(s,1H),6.77(s,1H),6.30(t,J=2.1Hz,1H),5.4 5(s,2H),5.07(dd,J=12.8,5.4Hz,1H),3.91~3.85(m,6H),3.58~3.47(m,4H),3.47~3.36(m,3H),3.10~2.92(m C 43 H 46 N9O8S[M+H] + LCMS calculated for: m / z=848.3; found: 848.3.

[0309] Example 5 3-[7-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0310] Step 1: 3-(2,7-diazaspiro[3.5]nonan-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0311] The title compound was synthesized following a procedure similar to Example 1, Step 7. 25 H 29 N6O4S[M+H] + LCMS calculated for: m / z=509.2; found: 509.1.

[0312] Step 2: 3-[7-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0313] The title compound was synthesized following a procedure similar to Example 4, Step 4. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H),10.83(s,1H),9.18(s,1H),7.88(d,J=2.3Hz,1H),7.70(d,J=8.4Hz,1H),7.50(d,J=1.8Hz,1H), 7.39(t,J=7.9Hz,1H),7.31~7.22(m,1H),7.00~6.92(m,2H),6.85(d,J=6.6Hz,2H),6.76(s,1H),6.67(dd,J=8.0,2.4Hz,1H),6.31(t,J =2.1Hz,1H),5.45(s,2H),5.07(dd,J=12.7,5.4Hz,1H),3.87(s,3H),3.75~3.69(m,4H),3.42(d,J=8.6Hz,3H),3.32~3.16(m,4H),3.1 3~2.96(m,2H),2.96~2.75(m,2H),2.66~2.54(m,2H),2.34~2.21(m,1H),2.15(d,J=13.6Hz,2H),2.08~1.88(m,4H),1.87~1.71(m,1H). C 43 H 46 N9O8S[M+H] + LCMS calculated for: m / z=848.3; found: 848.5.

[0314] Example 6 3-[3-[[4-[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]piperazin-1-yl]methyl]pyrrolidin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0315] Step 1: N-[(4-methoxyphenyl)methyl]-5-oxoxolane-2-carboxamide [ka]

[0316] To 5-oxoxolane-2-carboxylic acid (1.00 g, 7.69 mmol) was slowly added thionyl chloride (3.5 mL, 48 mmol) at 0 °C. The mixture was stirred at 85 °C for 3 hours and then at room temperature for 16 hours. The mixture was concentrated. The resulting residue was dissolved in DCM (10 mL) at 10 °C, and a solution of 4-methoxybenzylamine (1.60 g, 11.7 mmol) and triethylamine (0.950 g, 9.39 mmol) in DCM (4 mL) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. Water (5.0 mL) was added, and the mixture was extracted with DCM (3 × 3.0 mL). The combined organic layers were washed with 0.5 M HCl (5.0 mL) and brine (5.0 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 petroleum ether / ethyl acetate) to give the title compound as a white solid (0.850 g, 3.41 mmol, 44.4% yield). 13 H 16 NO4[M+H] + LCMS calculated for: m / z=250.1; found: 250.1.

[0317] Step 2: 3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione [ka]

[0318] To a solution of N-[(4-methoxyphenyl)methyl]-5-oxoxolane-2-carboxamide (2.60 g, 10.4 mmol) in THF (30 mL) was added dropwise a solution of potassium tert-butoxide (1.18 g, 10.5 mmol) in THF (15 mL) at −78° C. The reaction was stirred at −78° C. for 1 h and then at −40° C. for 1.5 h. The reaction was quenched with saturated NH4Cl (aq) and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0–100% EtOAc / hexanes) to afford the title compound (1.65 g, 6.62 mmol, 63.4% yield) as a white solid.1 H NMR(400MHz,CDCl3)δ7.37~7.29(m,2H),6.87~6.78(m,2H),4.88(s,2H),4.20(dd,J=5.6,12.6Hz,1H),3.78(s,3H),3.54(d,J=43.4Hz,1H),2. 89(ddd,J=2.6,4.8,18.0Hz,1H),2.64(ddd,J=5.4,13.7,18.1Hz,1H),2.32(dtd,J=2.5,5.5,12.9Hz,1H),1.88(dtd,J=4.8,12.8,13.8Hz,1H).

[0319] Step 3: 1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]trifluoromethanesulfonate [ka]

[0320] To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (300 mg, 1.20 mmol) in DCM (6 mL) was added pyridine (300 μL, 3.71 mmol) at 0° C. Triflic anhydride (330 μL, 1.55 mmol) was added dropwise. The reaction was stirred at 0° C. for 1.5 h. The reaction mixture was warmed to room temperature and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound (300 mg, 0.787 mmol, 65.4% yield). 1 H NMR (400MHz, CDCl3) δ7.39~7.31(m,2H),6.86~6.78(m,2H),5.29(dd,J=11.5,5.6Hz,1H),4.89(s,2H),3.78(s ,3H),2.99(dt,J=18.0,4.5Hz,1H),2.73(ddd,J=18.0,12.4,5.6Hz,1H),2.47~2.36(m,1H),2.39~2.25(m,1H).

[0321] Step 4: 6-Bromo-9H-pyrido[2,3-b]indole [ka]

[0322] To a solution of 9H-pyrido[2,3-b]indole (5.00 g, 29.7 mmol) in THF (30 mL) was added N-bromosuccinimide (5.56 g, 31.2 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (20% EtOAc / hexanes) to afford the title compound (6.80 g, 27.5 mmol, 92.6% yield) as a white solid. C 11 H8BrN2[M+H] + LCMS calculated for: m / z=247.0; found: 247.0.

[0323] Step 5: 2-[(6-bromopyrido[2,3-b]indol-9-yl)methoxy]ethyl-trimethylsilane [ka]

[0324] To a solution of 6-bromo-9H-pyrido[2,3-b]indole (4.10 g, 16.6 mmol) in DMF (50 mL) was added sodium hydride (1.33 g, 33.2 mmol) at 0 °C. The reaction was stirred for 10 minutes, after which 2-(trimethylsilyl)ethoxymethyl chloride (5.53 g, 33.2 mmol) was added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc (30 mL) and washed with water (3 x 30 mL). The organic layer was dried over NaSO, filtered, and concentrated. The crude material was purified by preparative TLC (25% EtOAc / petroleum ether) to give the title compound (5.20 g, 13.8 mmol, 83.0%) as a yellow oil. 17 H 22 BrN2OSi[M+H] + LCMS calculated for: m / z=377.1; found: 377.1.

[0325] Step 6: tert-Butyl 4-[9-(2-trimethylsilylethoxymethyl)pyrido[2,3-b]indol-6-yl]piperazine-1-carboxylate [ka]

[0326] To a solution of tert-butyl 1-piperazinecarboxylate (4.94 g, 26.5 mmol), 1,1'-binaphthyl-2,2'-diphenylphosphine (632 mg, 1.33 mmol), cesium carbonate (16.5 mL, 39.8 mmol), and 2-[(6-bromopyrido[2,3-b]indol-9-yl)methoxy]ethyl-trimethylsilane (5.00 g, 13.3 mmol) in toluene (50 mL) was added palladium(II) acetate (1.21 g, 1.33 mmol). The reaction was stirred at 80° C. for 16 hours. The reaction was cooled to room temperature and concentrated. The crude material was purified by silica gel chromatography to afford the title compound (3.80 g, 7.42 mmol, 56.0%) as a yellow oil. 26 H 39 N4O3Si[M+H] + LCMS calculated for: m / z=483.3; found: 483.3.

[0327] Step 7: tert-Butyl 4-(9H-pyrido[2,3-b]indol-6-yl)piperazine-1-carboxylate [ka]

[0328] To a solution of tert-butyl 4-[9-(2-trimethylsilylethoxymethyl)pyrido[2,3-b]indol-6-yl]piperazine-1-carboxylate (4.00 g, 8.29 mmol) in THF (3 mL) was added tetrabutylammonium fluoride (4.72 g, 41.4 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was diluted with brine (50 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were concentrated and purified by silica gel chromatography (50% EtOAc / petroleum ether) to give the title compound (1.90 g, 4.85 mmol, 58.6%). 20 H 25 N4O2[M+H] + LCMS calculated for: m / z=353.2; found: 353.3.

[0329] Step 8: tert-Butyl 4-[9-[1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]pyrido[2,3-b]indol-6-yl]piperazine-1-carboxylate [ka]

[0330] To a solution of tert-butyl 4-(9H-pyrido[2,3-b]indol-6-yl)piperazine-1-carboxylate (1.50 g, 4.26 mmol) and 18-crown-6 (1.69 g, 6.38 mmol) in THF (10 mL) was added sodium bis(trimethylsilyl)amide (1.56 g, 8.51 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour. [1-[(4-Methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]trifluoromethanesulfonate (3.25 g, 8.51 mmol, from Step 3) was added, and the reaction was stirred at 0° C. for 3 hours. The reaction was warmed to room temperature and concentrated. The crude material was purified by preparative HPLC on a C18 column to give the title compound (1.10 g, 1.88 mmol, 44.3%). 33 H 38 N5O5[M+H]+ LCMS calculated for: m / z=584.3; found: 584.4.

[0331] Step 9: 3-(6-piperazin-1-ylpyrido[2,3-b]indol-9-yl)piperidine-2,6-dione [ka]

[0332] To a solution of tert-butyl 4-[9-[1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]pyrido[2,3-b]indol-6-yl]piperazine-1-carboxylate (1.00 g, 1.71 mmol) in toluene (5 mL) was added methanesulfonic acid (1.00 mL, 1.71 mmol) dropwise. The reaction was stirred at 110° C. for 3 hours. The reaction was cooled to room temperature and concentrated. The crude material was purified by preparative HPLC to give the title compound (98.3 mg, 0.237 mmol, 13.8%). 1 H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.45~8.43(m,2H),7.80(s,1H),7.48(s,1H),7.2 3(s,2H),5.99(s,1H),3.11~3.04(m,10H),2.68(s,1H),2.31~2.29(m,1H),2.09(s,1H). C 20 H 22 NO2[M+H] + LCMS calculated for: m / z=364.2; found: 364.3.

[0333] Step 10: 3-[3-(hydroxymethyl)pyrrolidin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0334] The title compound was synthesized following a procedure similar to Example 1, Step 7.23 H 26 N5O5S[M+H] + LCMS calculated for: m / z=484.2; found: 484.0.

[0335] Step 11: 3-[3-[[4-[9-(2,6-dioxopiperidin-3-yl)pyrido[2,3-b]indol-6-yl]piperazin-1-yl]methyl]pyrrolidin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide

[0336] To a solution of 3-[3-(hydroxymethyl)pyrrolidin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide (16.0 mg, 0.0331 mmol) and EtN (0.0415 mL, 0.331 mmol) in DMSO (0.4 mL) was added a solution of sulfur trioxide pyridine (15.8 mg, 0.0993 mmol) in DMSO (0.4 mL). The reaction was stirred at room temperature for 1 hour. A solution of 3-(6-piperazin-1-ylpyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (13.6 mg, 0.0331 mmol) in MeCN (0.4 mL) and acetic acid (0.0284 mL, 0.496 mmol) was added. The reaction was stirred for 0.5 hours. Sodium triacetoxyborohydride (28.1 mg, 0.132 mmol) was added and the reaction continued to stir for 1 hour. The reaction was diluted with MeCN, filtered, and purified by preparative HPLC (20.5-40.5% MeCN / 0.1% TFA (aq)) to give the title compound as a yellow solid TFA salt (5.90 mg, 0.00700 mmol, 21.3% yield). 43 H 45 N 10 O6S[M+H] + LCMS calculated for: m / z=829.3; found: 828.9.

[0337] Example 7 3-[4-[[1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl]piperidin-4-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0338] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindole-1,3-dione [ka]

[0339] The title compound was synthesized following a procedure similar to Example 1, Step 8. 1 H NMR(400MHz,DMSO-d6):δ11.06(s,1H),7.64(d,J=8.6Hz,1H),7.44~7.01(m,2H),5.06(dd,J=12.9,5.4Hz,1H),4.06(d,J=13.0Hz,2H),3.2 8~3.14(m,3H),2.90(ddd,J=19.3,18.6,8.4Hz,3H),2.70~2.54(m,2H),2.01(dd,J=8.9,3.7Hz,1H),1.78~1.60(m,3H),1.26~1.09(m,2H). C 19 H 22 N3O5[M+H] + LCMS calculated for: m / z=372.2; found: 372.3.

[0340] Step 2: 1-[2-(2,6-dioxoipiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde [ka]

[0341] To a solution of EtN (0.702 mL, 5.04 mmol) in DMSO (5.6 mL) was added sulfur trioxide pyridine (267 mg, 1.68 mmol). Then, a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[4-(hydroxymethyl)piperidin-1-yl]isoindole-1,3-dione (208 mg, 0.560 mmol) in DMSO (0.5 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. The material was purified by silica gel chromatography (0-4% MeOH / DCM) to give the title compound (200 mg, 0.542 mmol, 96.8%). 19 H 20 N3O5[M+H] + LCMS calculated for: m / z=370.2; found: 370.1.

[0342] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]piperidin-1-yl]isoindole-1,3-dione [ka]

[0343] The title compound was synthesized following a procedure similar to Example 4, Step 4 and isolated as the TFA salt. 1 H NMR(300MHz,DMSO-d6)δ11.08(s,1H),8.83(s,1H),7.68(d,J=8.6Hz,1H),7.36(d,J=2. 3Hz,1H),7.27(dd,J=8.7,2.3Hz,1H),5.09(d,J=5.3Hz,1H),4.09(d,J=13.2Hz,2H),3.5 3(d,J=11.9Hz,2H),3.28(d,J=5.7Hz,2H),3.12~2.75(m,7H),2.66~2.53(m,1H),2.24~ 1.93(m,2H),1.82(d,J=13.4Hz,4H),1.60(s,2H),1.54~1.35(m,2H),1.34~1.13(m,2H). C 25 H 33 N4O5[M+H]+ LCMS calculated for: m / z=469.2; found: 469.3.

[0344] Step 4: 1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl]piperidine-4-carbaldehyde [ka]

[0345] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]piperidin-1-yl]isoindole-1,3-dione (10.0 mg, 0.0172 mmol, from Step 3) in DMSO (0.5 mL) was added 2-iodoxybenzoic acid (16.0 mg, 0.0257 mmol). The reaction was stirred at 50° C. for 0.5 hours. The mixture was used directly as a solution in the next step without further purification. 25 H 31 N4O5[M+H] + LCMS calculated for: m / z=467.2; found: 467.1.

[0346] Step 5: 3-[4-[[1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl]piperazin-4-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0347] The title compound was synthesized following a procedure similar to Example 4, Step 4. 1H NMR(300MHz,DMSO-d6)δ11.09(s,1H),10.89(s,1H),9.89(s,1H),9.17(s,1H),7.88(d,J=2.2Hz,1H),7.68(d, J=8.5Hz,1H),7.55(s,1H),7.54~7.41(m,2H),7.39~7.23(m,3H),6.83(s,1H),6.76(s,1H),6.30(t,J=2.1Hz,1 H),5.45(s,2H),5.07(dd,J=12.8,5.4Hz,1H),4.10(d,J=12.8Hz,2H),3.88(s,3H),3.73~3.51(m,8H),3.36~3. 07(m,8H),3.06~2.80(m,7H),2.64~2.52(m,1H),2.30~1.92(m,3H),1.84(d,J=12.8Hz,2H),1.63~1.36(m,2H). C 47 H 55 N 10 O8S[M+H] + LCMS calculated for: m / z=919.4; found: 919.7.

[0348] Example 8 3-[4-[6-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-6-azaspiro[3.4]octan-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0349] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxy-6-azaspiro[3.4]octan-6-yl)isoindole-1,3-dione [ka]

[0350] The title compound was synthesized following a procedure similar to Example 1, Step 8. 20 H22 N3O5[M+H] + LCMS calculated for: m / z=384.2; found: 384.1.

[0351] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-6-azaspiro[3.4]octan-6-yl)isoindole-1,3-dione [ka]

[0352] The title compound was synthesized following a procedure similar to Example 4, Step 7. 20 H 20 N3O5[M+H] + LCMS calculated for: m / z=382.1; found: 382.0.

[0353] Step 3: 3-[4-[6-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-6-azaspiro[3.4]octan-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0354] The title compound was synthesized following a procedure similar to Example 4, Step 4. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H),10.85(s,1H),10.12(s,1H),7.88(d,J=2.3Hz,1H),7.68(d,J=8.4Hz,1H) ,7.57(s,1H),7.53~7.42(m,3H),7.33(d,J=7.5Hz,1H),6.92(d,J=2.2Hz,1H),6.84(s,1H),6.81(dd,J=8.9,2.4 Hz,1H),6.77(s,1H),6.31(t,J=2.1Hz,1H),5.45(s,2H),5.06(dd,J=12.6,5.4Hz,1H),4.01~3.82(m,5H),3.51~ 3.37(m,8H),3.20~2.98(m,4H),2.97~2.81(m,1H),2.64~2.54(m,1H),2.36(d,J=8.1Hz,4H),2.14~1.94(m,2H). C 42 H 44 N9O8S[M+H] + LCMS calculated for: m / z=834.3; found: 834.6.

[0355] Example 9 3-[4-[2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]ethyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide [ka]

[0356] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-[3-(2-hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione [ka]

[0357] The title compound was synthesized following a procedure similar to Example 1, Step 8. 19 H 22N3O5[M+H] + LCMS calculated for: m / z=372.2; found: 372.1.

[0358] Step 2: 2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]acetaldehyde [ka]

[0359] The title compound was synthesized following a procedure similar to Example 1, Step 9. 19 H 20 N3O5[M+H] + LCMS calculated for: m / z=370.1; found: 370.1.

[0360] Step 3: 3-[4-[2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]ethyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide

[0361] The title compound was synthesized following a procedure similar to Example 1, Step 10. 41 H 44 N9O8S[M+H] + LCMS calculated for: m / z=822.3; found: 822.2.

[0362] Example 10 3-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrrolidin-3-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0363] Step 1: 3-[6-[3-(hydroxymethyl)pyrrolidin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione [ka]

[0364] A solution of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (40.0 mg, 0.124 mmol), pyrrolidin-3-ylmethanol (14.4 mg, 0.142 mmol), BrettPhos Pd G3 (8.98 mg, 0.00991 mmol, CAS 1470372-59-8), and sodium tert-butoxide (59.5 mg, 0.619 mmol) in 1,4-dioxane (1 mL) was stirred at 90° C. for 1 h. The mixture was cooled to room temperature, and TFA (5 drops), HO (0.5 mL), and MeOH (3 mL) were added. The mixture was filtered and purified by preparative HPLC on a C18 column (5-50% MeCN / 0.1% TFA (aq)) to afford the title compound as a colorless solid TFA salt (22.7 mg, 0.0661 mmol, 53.4% yield). 18 H 22 N3O4[M+H] + LCMS calculated for: m / z=344.2; found: 344.1.

[0365] Step 2: 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrrolidine-3-carbaldehyde [ka]

[0366] The title compound was synthesized following a procedure similar to Example 4, Step 7. 18 H 20 N3O4[M+H] + LCMS calculated for: m / z=342.1; found: 342.1.

[0367] Step 3: 3-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrrolidin-3-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide

[0368] The title compound was synthesized following a procedure similar to Example 4, Step 4. 40 H 44 N9O7S[M+H] + LCMS calculated for: m / z=794.3; found: 794.2.

[0369] Example 11. 3-[6-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0370] Step 1: 3-(2,6-diazaspiro[3.3]heptan-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0371] The title compound was synthesized following a procedure similar to Example 1, Step 7. 23 H 25 N6O4S[M+H] + LCMS calculated for: m / z=481.2; found: 480.9.

[0372] Step 2: 3-[6-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0373] The title compound was synthesized following a procedure similar to Example 1, Step 10. 41 H 42 N9O8S[M+H] + LCMS calculated for: m / z=820.3; found: 820.2.

[0374] Example 12 N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-methylpyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0375] Step 1. 2-(2,6-Dioxopiperidin-3-yl)-5-[3-(hydroxymethyl)-3-methylpyrrolidin-1-yl]isoindoline-1,3-dione [ka]

[0376] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 8. 19 H 22 N3O5[M+H] + LCMS calculated for: m / z=372.2; found: 372.0.

[0377] Step 2. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-methylpyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0378] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[3-(hydroxymethyl)-3-methyl-pyrrolidin-1-yl]isoindole-1,3-dione (21.9 mg, 0.0590 mmol) and triethylamine (74.0 μL, 0.531 mmol) in DMSO (0.8 mL) was added a solution of sulfur trioxide pyridine complex (28.2 mg, 0.177 mmol) (CAS 26412-87-3) in DMSO (0.8 mL). The reaction mixture was stirred for 1 h. A solution of 3-(2,7-diazaspiro[3.5]nonan-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide (30.0 mg, 0.0590 mmol) (from Example 5, Step 1) in MeCN (0.8 mL) was added, followed by acetic acid (50.6 μL, 0.885 mmol), and the reaction mixture was stirred for 0.5 h. Sodium triacetoxyborohydride (50.0 mg, 0.236 mmol) was added, and the reaction was stirred for 1 h. The reaction was diluted with MeCN, filtered, and purified by preparative HPLC on a C18 column (24.5-44.5% MeCN / 0.1% TFA (aq)) to give the title compound as a yellow solid TFA salt (0.90 mg, 0.0011 mmol, 1.7% yield). 44 H 48 N9O8S[M+H] + LCMS calculated for: m / z=862.3; found: 862.2.

[0379] Examples 13 to 22 Examples 13-22 listed in Tables 1 and 2 were synthesized following procedures similar to Example 1, Steps 7-8 and Example 12, Step 2. All examples in Tables 1 and 2 were prepared as TFA salts. In Table 1 below: * represents binding to ULM, [ka] represents the attachment of the PTM to ring A. [ka]

[0380] Table 1. Examples 13 to 22 [Table 1] TIFF2025525339000081.tif119124

[0381] Table 2. Examples 13-22 [Table 2] TIFF2025525339000083.tif250162 TIFF2025525339000084.tif250162 TIFF2025525339000085.tif103162

[0382] Example 23. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzenesulfonamide [ka]

[0383] Step 1. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3-(hydroxymethyl)pyrrolidin-1-yl)benzenesulfonamide [ka]

[0384] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 7, using pyrrolidin-3-ylmethanol. 23 H 26 N5O5S[M+H] + LCMS calculated for: m / z=484.2; found: 483.9.

[0385] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3-formylpyrrolidin-1-yl)benzenesulfonamide [ka]

[0386] The title compound was synthesized by a procedure similar to that outlined in Example 31, Step 2. 23 H 24 N5O5S[M+H] + LCMS calculated for: m / z=482.1; found: 482.0.

[0387] Step 3: tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)oxy)piperidine-1-carboxylate [ka]

[0388] To a mixture of triphenylphosphine (8.05 g, 30.7 mmol) in THF (150 mL) was added diisopropyl azodicarboxylate (7.38 g, 36.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (5.00 g, 18.2 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (3.68 g, 18.5 mmol) were added, and the reaction mixture was stirred for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL × 3), dried over Na SO , filtered, and concentrated. Purification by silica gel chromatography (30-50% EtOAc / petroleum ether) afforded the title compound as a white solid (20.0 g, 43.7 mmol, 88.2% yield). 23 H 28 N3O7[M+H] + LCMS calculated for: m / z=458.2; found: 458.3.

[0389] Step 4. 2-(2,6-Dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione [ka]

[0390] To a mixture of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy-piperidine-1-carboxylate (5.00 g, 10.9 mmol), HCl (55.0 mL, 220 mmol, 4 N in 1,4-dioxane) was added. The reaction mixture was stirred for 16 hours. The mixture was concentrated to give the title compound as a white solid HCl salt (3.78 g, 9.78 mmol, 97.0% yield). 1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.74(s,1H),7.87~7.85(d,J=8.4Hz,1H),7.57~7.56(m,1H),7.43~7.41(m,1H),5.15 ~5.10(m,1H),4.98~4.94(m,1H),3.10(m,2H),2.94~2.85(m,1H),2.62~2.55(m,3H),2.16~2.03(m,4H),1.92~1.86(m,2H). C 18 H 20 N3O5[M+H] + LCMS calculated for: m / z=358.1; found: 358.5.

[0391] Step 5: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzenesulfonamide

[0392] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-piperidin-4-yloxyisoindole-1,3-dione (9.83 mg, 0.0198 mmol) (from Step 4) in DMSO (0.5 mL) was added triethylamine (7 mL, 0.05 mmol) and acetic acid (7.5 mL, 0.13 mmol). The resulting mixture was added to a solution of 3-(3-formylpyrrolidin-1-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzene-sulfonamide (10.0 mg, 0.0198 mmol) in DMSO (0.5 mL) and sodium triacetoxyborohydride (29 mg, 0.14 mmol). The reaction mixture was stirred for 15 min. The mixture was diluted with water (0.5 mL) and MeCN (3 mL) and purified by preparative HPLC on a C18 column (5-50% MeCN / 0.1% TFA (aq)) to afford the title compound as a colorless solid TFA salt (3.5 mg, 0.0043 mmol, 20% yield). 1H NMR(300MHz,DMSO-d6)δ11.12(s,1H),10.79(s,1H),9.28(s,1H),7.95~7.84(m,1H),7.59(d,J=2.2Hz,1H),7.49(d,J=1.8Hz,1 H),7.48~7.42(m,1H),7.38(t,J=8.0Hz,1H),7.20(d,J=7.7Hz,1H),7.11(s,1H),6.83(s,1H),6.81~6.76(m,1H),6.75(s,1H), 6.30(t,J=2.1Hz,1H),5.44(s,2H),5.13(dd,J=12.9,5.4Hz,1H),3.86(s,3H),3.77~3.60(m,1H),3.57~3.48(m,2H),3.36~3.1 5(m,7H),3.07(t,J=8.4Hz,1H),2.97~2.70(m,2H),2.66~2.53(m,2H),2.43~2.18(m,2H),2.16~1.96(m,3H),1.95~1.70(m,2H). C 41 H 43 N8O9S[M+H] + LCMS calculated for: m / z=823.3; found: 823.4.

[0393] Example 24. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbonyl)piperazin-1-yl)benzenesulfonamide [ka]

[0394] Step 1: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carboxylic acid [ka]

[0395] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[3-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione (10.9 mg, 0.0299 mmol) in 1,2-dichloroethane (1 mL) was added 2-iodoxybenzoic acid (55.9 mg, 0.0901 mmol). The reaction mixture was stirred at 80 °C for 3 h. The mixture was diluted with DCM (2 mL), filtered, and washed with 1:1 saturated NaHCO / saturated NaSO (aq) (3 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 × 3 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude material was dissolved in DMF (1 mL), and oxone (18.4 mg, 0.0299 mmol) was added. The mixture was stirred for 0.5 h. The mixture was diluted with water and DMSO and purified by preparative HPLC on a C18 column (5-50% MeCN / 0.1% TFA (aq)) to give the title compound (2.0 mg, 0.0054 mmol, 18% yield) as a yellow solid TFA salt. 18 H 18 N3O6[M+H] + LCMS calculated for: m / z=372.1; found: 371.8.

[0396] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbonyl)piperazin-1-yl)benzenesulfonamide

[0397] To a solution of 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidine-3-carboxylic acid (2 mg, 0.01 mmol) in DMF (1 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (5.3 mg, 0.011 mmol) and N,N-diisopropylethylamine (6 mL, 0.03 mmol). The reaction mixture was stirred for 15 minutes. N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]-3-piperazin-1-ylbenzene-sulfonamide (3.8 mg, 0.011 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with water and DMSO and purified by preparative HPLC on a C18 column (5-40% MeCN / 0.1% TFA (aq)) to give the title compound as a yellow solid TFA salt (1.4 mg, 0.0017 mmol, 32% yield). 1 H NMR(300MHz,DMSO-d6)δ11.08(s,1H),10.83(s,1H),7.87(d,J=2.3Hz,1H),7.65(d,J=8.5Hz,1H),7.53~7 .34(m,4H),7.31~7.22(m,1H),6.95(d,J=2.0Hz,1H),6.87~6.81(m,2H),6.75(s,1H),6.30(t,J=2.1Hz,1H ),5.44(s,2H),5.06(dd,J=12.5,5.2Hz,1H),3.86(s,3H),3.80~3.71(m,2H),3.70~3.60(m,2H),3.60~3. 50(m,3H),3.29~3.15(m,5H),2.97~2.80(m,1H),2.57~2.53(m,1H),2.31~2.11(m,3H),2.07~1.94(m,2H). C 40 H 40 N9O9S[M+H] + LCMS calculated for: m / z=822.3; found: 822.2.

[0398] Example 25. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6-dimethoxybenzenesulfonamide [ka]

[0399] Step 1. 2-(2,6-Dioxopiperidin-3-yl)-5-((R)3-(hydroxymethyl)pyrrolidin-1-yl)isoindole-1,3-dione [ka]

[0400] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 8, using (R)-pyrrolidin-3-ylmethanol. 18 H 20 N3O5[M+H] + LCMS calculated for: m / z=358.1; found: 358.0.

[0401] Step 2. 3-Bromo-2,6-dimethoxybenzenesulfonyl chloride [ka]

[0402] To a solution of 2,6-dimethoxybenzene-1-sulfonyl chloride (490 mg, 2.07 mmol) in MeCN (10 mL) was added N-bromosuccinimide (405 mg, 2.28 mmol) at 0 °C. The resulting mixture was stirred at 35 °C for 3 h. The reaction was quenched with water (20 mL). The resulting layers were separated, and the aqueous layer was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (653 mg, 2.07 mmol, >99% yield). C8H8BrO4S [M+H] + LC-MS calculated for: m / z=278.9; found: 279.2.

[0403] Step 3. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-bromo-2,6-dimethoxybenzenesulfonamide [ka]

[0404] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 6. 20 H 20 BrN4O6S[M+H] + LCMS calculated for: m / z=523.0; found: 523.4.

[0405] Step 4. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxy-3-(2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0406] The title compound was synthesized using a procedure similar to that outlined in Step 7 of Example 1 using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate. 27H 33 N6O6S[M+H] + LCMS calculated for: m / z=569.2; found: 569.0.

[0407] Step 5. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6-dimethoxybenzenesulfonamide

[0408] The title compound was synthesized by a procedure similar to that outlined in Example 12, Step 2. 45 H 50 N9O 10 S[M+H] + LCMS calculated for: m / z=908.3; found: 908.1.

[0409] Example 26. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide [ka]

[0410] Step 1. Benzyl(3-bromo-2-methoxyphenyl)sulfane [ka]

[0411] To a solution of 1,3-dibromo-2-methoxybenzene (2000 mg, 7.52 mmol) in 1,4-dioxane (40 mL) was added benzyl mercaptan (0.89 mL, 7.6 mmol), Pd2(dba)3 (180 mg, 0.261 mmol), Xantphos (220 mg, 0.38 mmol, CAS 161265-03-8), and diisopropylethylamine (1.96 g, 15.2 mmol). The resulting mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to room temperature, and water (40 mL) was added. The mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound, which was carried forward without further purification. TLC R f =0.5 (petroleum ether).

[0412] Step 2. 3-Bromo-2-methoxybenzenesulfonyl chloride [ka]

[0413] To a solution of benzyl(3-bromo-2-methoxyphenyl)sulfane (2.33 g, 7.54 mmol) in acetic acid (21 mL) and water (7 mL) was added N-chlorosuccinimide (4.02 g, 30.1 mmol) at 0° C. The reaction was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound, which was used without further purification. TLC R f =0.4 (10% EtOAc / hexane).

[0414] Step 3. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-bromo-2-methoxybenzenesulfonamide [ka]

[0415] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 6. 19 H 18 BrN4O5S[M+H] + LCMS calculated for: m / z=493.0; found: 493.6.

[0416] Step 4. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy-3-(2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0417] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 7. 26 H 31 N6O5S[M+H] + LCMS calculated for: m / z=539.2; found: 539.0.

[0418] Step 5. Methyl (R)-2-cyano-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate [ka]

[0419] To a solution of methyl 2-cyano-4-fluorobenzoate (600 mg, 3.35 mmol) and (R)-pyrrolidin-3-ylmethanol (508 mg, 5.02 mmol) in DMSO (8 mL) was added N,N-diisopropyl-ethylamine (2.33 mL, 13.4 mmol). The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water (15 mL) and EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound as a tan oil (820 mg, 3.2 mmol, 94% yield). C 14 H 17 N2O3[M+H] + LCMS calculated for: m / z=261.1; found: 261.0.

[0420] Step 6. Methyl (R)-2-formyl-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate [ka]

[0421] To a solution of methyl (R)-2-cyano-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate (870 mg, 3.34 mmol) in acetic acid (3.82 mL, 66.9 mmol) and pyridine (8.11 mL, 100 mmol), sodium hypophosphite monohydrate (3.54 g, 33.4 mmol) was added in two portions. Raney nickel (589 mg, slurry in water) was added, and the reaction mixture was stirred at 75° C. for 2 h. An additional portion of Raney nickel (589 mg, slurry in water) was added, and the reaction mixture was stirred at 75° C. for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite, and diluted with water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to give the title compound, which was carried forward without further purification. C 14 H 18 NO4[M+H]+ LC-MS calculated value: m / z = 264.1, found value: 264.1.

[0422] Step 7. 3-(5-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0423] Methyl (R)-2-formyl-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate in DCM (11 mL) and DMF (3.75 mL) To a solution of 3-aminopiperidine-2,6-dione hydrochloride (660 mg, 4.01 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (880 mg, 3.34 mmol) was added N,N-diisopropylethylamine (1.16 mL, 6.68 mmol). The reaction mixture was stirred at 35° C. for 10 minutes. Acetic acid (1.91 mL, 33.4 mmol) was added, and the reaction mixture was stirred at 35° C. for 15 minutes. The reaction mixture was cooled to 0° C., sodium triacetoxyborohydride (2.13 g, 10.0 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with saturated NaHCO (aq) (50 mL) and DCM (30 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated. Purification by silica gel chromatography (0-10% MeOH / DCM) afforded the title compound as a white solid (384 mg, 1.12 mmol, 33.5% yield). 18 H 22 N3O4[M+H] + LCMS calculated for: m / z=344.2; found: 344.1.

[0424] Step 8. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide

[0425] The title compound was synthesized by a procedure similar to that outlined in Example 12, Step 2. 44 H 50 N9O8S[M+H] + LCMS calculated for: m / z=864.3; found: 864.4.

[0426] Example 27. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide [ka]

[0427] The title compound was synthesized by a procedure similar to that outlined in Example 26. 44 H 50 N9O8S[M+H] + LCMS calculated for: m / z=864.3; found: 864.4.

[0428] Example 28 N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0429] Step 1. Methyl (R)-2-cyano-4-(3-formylpyrrolidin-1-yl)benzoate [ka]

[0430] To a solution of methyl 2-cyano-4-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]benzoate (15.7 g, 60.1 mmol) in DCM (160 mL) was added Dess-Martin periodinane (28.1 g, 66.1 mmol). The reaction mixture was stirred at 30 °C for 2 h. The mixture was quenched with 10% sodium thiosulfate / 8% sodium bicarbonate (aq) (160 mL) and stirred for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (150 mL). The aqueous layer was filtered and extracted with DCM (120 mL × 2). The combined organic layers were washed with saturated NaHCO (aq) (200 mL × 2) and brine (200 mL), dried over NaSO, filtered, and concentrated to give the title compound as an orange oil (1.10 g, 4.26 mmol, >99% yield). 14 H 15 N2O3[M+H] + LCMS calculated for: m / z=259.1; found: 259.5.

[0431] Step 2. Methyl (R)-2-cyano-4-(3-(dimethoxymethyl)pyrrolidin-1-yl)benzoate [ka]

[0432] To a solution of methyl (R)-2-cyano-4-(3-formylpyrrolidin-1-yl)benzoate (17.4 g, 67.4 mmol) in methanol (100 mL) was added trimethyl orthoformate (36.9 mL, 337 mmol) and p-toluenesulfonic acid (1.28 g, 6.74 mmol). The resulting mixture was stirred at 60 °C for 1 h. The reaction was quenched with 10% Na2CO3 (aq) (170 mL), and the mixture was stirred for 15 min. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (0-20% EtOAc / hexane) afforded the title compound as an orange oil (14.1 g, 46.3 mmol, 68.8% yield). C 16 H 21 N2O4[M+H] + LC-MS calculated value: m / z = 305.1, found value: 305.6.

[0433] Step 3. Methyl (R)-4-(3-(dimethoxymethyl)pyrrolidin-1-yl)-2-formylbenzoate [ka]

[0434] The title compound was synthesized by a procedure similar to that outlined in Example 26, Step 4. 16 H 22 NO5[M+H] + LCMS calculated for: m / z=308.1; found: 308.6.

[0435] Step 4. Methyl (S)-5-amino-4-(5-((R)-3-(dimethoxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate [ka]

[0436] To a mixture of methyl (4S)-4,5-diamino-5-oxopentanoate hydrochloride (0.77 g, 3.9 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (1.26 g, 9.76 mmol). The reaction mixture was stirred for 10 minutes. A solution of methyl 4-[(3R)-3-(dimethoxymethyl)-pyrrolidin-1-yl]-2-formylbenzoate (1.00 g, 3.25 mmol) in DCM (10 mL) was added, followed by acetic acid (0.98 g, 16 mmol). The reaction mixture was stirred at 40°C for 1 hour. Sodium triacetoxyborohydride (1.38 g, 6.51 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated NaHCO3 (aq) (30 mL) and diluted with DCM (30 mL x 3). The combined organic layers were washed with brine (25 mL × 3), dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (0-75% EtOAc / hexanes) afforded the title compound (900 mg, 2.15 mmol, 65.9% yield) as a pale yellow solid. 21 H 30 N3O6[M+H] + LCMS calculated for: m / z=420.2; found: 420.6.

[0437] Step 5. (S)-3-(5-((R)-3-(dimethoxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0438] To a solution of (S)-5-amino-4-(5-((R)-3-(dimethoxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate (900 mg, 2.15 mmol) in THF (18 mL) was added dropwise a solution of potassium tert-butoxide (253 mg, 2.25 mmol) in THF (5 mL) at −78° C. The resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was quenched with 1N HCl (9 mL) and stirred at room temperature for 10 minutes. The mixture was adjusted to pH ∼6 with saturated NaHCO3 (aq). The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound as a pale yellow oil (770 mg, 1.99 mmol, 92.6% yield). C 20 H 26 N3O5[M+H] + LCMS calculated for: m / z=388.2; found: 388.7.

[0439] Step 6. (R)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde [ka]

[0440] To a mixture of (S)-3-(5-((R)-3-(dimethoxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg, 0.774 mmol) in acetone (5 mL) was added 2N HCl (4.50 mL, 9.00 mmol) at 0° C. The resulting mixture was stirred for 5 hours. The reaction mixture was adjusted to pH ∼8 with saturated NaHCO (aq), diluted with water (30 ml), and extracted with EtOAc (30 ml × 5). The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound as a pale yellow oil (280 mg, 0.820 mmol, >99% yield). 18 H 20 N3O4[M+H] +LCMS calculated for: m / z=342.1; found: 342.6.

[0441] Step 7. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0442] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. 43 H 48 N9O7S[M+H] + LCMS calculated for: m / z=834.3; found: 834.1.

[0443] Example 29. 5-(4-((4-(3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide [ka]

[0444] Step 1. Methyl 5-(4-(hydroxymethyl)piperidin-1-yl)picolinate [ka]

[0445] To a solution of methyl 5-fluoropyridine-2-carboxylate (0.44 mL, 3.2 mmol) in DMSO (1.6 mL) was added potassium carbonate (535 mg, 3.87 mmol) and 4-piperidine-methanol (445 mg, 3.87 mmol). The reaction was stirred at 110° C. for 0.75 h. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with DCM (3×5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound, which was carried forward without further purification. 13 H 19 N2O3[M+H] + LCMS calculated for: m / z=251.1; found: 251.0.

[0446] Step 2. 5-(4-(hydroxymethyl)piperidin-1-yl)picolinic acid [ka]

[0447] To a solution of methyl 5-[4-(hydroxymethyl)piperidin-1-yl]pyridine-2-carboxylate (807 mg, 3.22 mmol) in THF (5 mL) was added sodium hydroxide (653 mg, 16.3 mmol) in water (10 mL). The reaction was stirred for 0.5 h. HCl (aq) (3.30 mL, 19.8 mmol, 6N) was added and the reaction mixture was stirred for 5 min. The reaction mixture was concentrated to give the title compound as the HCl salt, which was carried forward without further purification. 12 H 17 N2O3[M+H] + LCMS calculated for: m / z=237.1; found: 237.0.

[0448] Step 3. N-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)picolinamide [ka]

[0449] To a solution of 5-[4-(hydroxymethyl)piperidin-1-yl]pyridine-2-carboxylic acid (1.50 g, 5.50 mmol) (from Step 2) in DCM (55 mL) was added triethylamine (5.50 mL, 39.5 mmol). The mixture was sonicated to produce a fine suspension. 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (3.14 g, 8.25 mmol) was added, and the reaction mixture was stirred for 2 minutes. 3-Aminopiperidine-2,6-dione hydrochloride (1.81 g, 11.0 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was filtered and concentrated. Purification by silica gel chromatography (0-10% MeOH / DCM) afforded the title compound as a white solid (476 mg, 1.37 mmol, 25.0% yield). 17 H 23 N4[M+H] + LCMS calculated for: m / z=347.2; found: 347.1.

[0450] Step 4. 5-(4-((4-(3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide

[0451] The title compound was synthesized by a procedure similar to that outlined in Example 12, Step 2. 39 H 45 N 10 O7S[M+H] + LCMS calculated for: m / z=797.3; found: 797.2.

[0452] Example 30. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide [ka]

[0453] The title compound was synthesized by a procedure similar to that outlined in Step 2 of Example 12 using 3-(2,7-diazaspiro[3.5]nonan-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide (from Step 1 of Example 5) and 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione (from Step 1 of Example 6). 44 H 48 N9O9S[M+H] + LCMS calculated for: m / z=878.3; found: 878.2.

[0454] Example 31. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide [ka]

[0455] Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione [ka]

[0456] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 8, using 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione. 18 H 20 N3O5[M+H] + LCMS calculated for: m / z=358.1; found: 358.1.

[0457] Step 2: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pyrrolidine-3-carbaldehyde [ka]

[0458] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione (8.0 mg, 0.018 mmol) in 1,2-dichloroethane (1 mL) was added 2-iodoxybenzoic acid (41.8 mg, 0.0675 mmol). The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was diluted with DCM (2 mL), filtered, and washed with 1:1 saturated NaHCO / saturated NaSO (aq) (3 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 × 3 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound (7.95 mg, 0.0224 mmol, >99% yield) as a yellow solid, which was used directly in the next step without further purification. 18 H 18 N3O5[M+H] + LCMS calculated for: m / z=356.1; found: 356.0.

[0459] Step 3. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pyrrolidin-3-yl)methyl)piperazine-1- (yl)benzenesulfonamide

[0460] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. 1 H NMR(300MHz,DMSO-d6)δ11.09(s,1H),10.89(s,1H),9.61(s,1H),7.88(d,J=2.2Hz,1H),7.61(dd,J=8.6,7.0Hz,1H), 7.58~7.55(m,1H),7.53~7.42(m,3H),7.36~7.28(m,1H),7.18(dd,J=6.9,1.7Hz,1H),7.12(d,J=8.7Hz,1H),6.83(s,1 H),6.76(s,1H),6.30(t,J=2.1Hz,1H),5.44(s,2H),5.07(dd,J=12.8,5.4Hz,1H),3.97~3.82(m,5H),3.78~3.54(m,5 H),3.33~3.01(m,7H),2.96~2.71(m,2H),2.65~2.53(m,1H),2.31~2.13(m,1H),2.08~1.90(m,1H),1.86~1.68(m,1H). C 40 H 42 N9O8S[M+H] + LCMS calculated for: m / z=808.2; found: 808.2.

[0461] Example 32. 3-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide [ka]

[0462] Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-[4-(hydroxymethyl)piperidin-1-yl]isoindole-1,3-dione [ka]

[0463] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 8. 1 H NMR(300MHz,CDCl3)δ8.10(s,1H),7.57(dd,J=8.4,7.1Hz,1H),7.37(dd,J=7.2,0.8Hz,1H),7.18(dd,J=8.5,0.9Hz,1H),5.05~4.88(m,1H),3 .87~3.68(m,2H),3.58(t,J=5.0Hz,2H),2.98~2.61(m,5H),2.18~2.06 (m,1H),1.89(d,J=12.6Hz,2H),1.74~1.68(m,1H),1.58~1.40(m,3H). C 19 H 22 N3O5[M+H] + LCMS calculated for: m / z=372.2; found: 372.1.

[0464] Step 2: 3-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]piperidin-4-yl]methyl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0465] The title compound was synthesized by a procedure similar to that outlined in Example 12, Step 2. 1H NMR(300MHz,DMSO-d6)δ11.09(s,1H),10.89(s,1H),9.44(s,1H),7.88(d,J=2.2Hz,1H),7.71(dd,J=8.5,7.1H z,1H),7.57(d,J=2.4Hz,1H),7.54~7.43(m,3H),7.38~7.31(m,3H),6.84(d,J=0.9Hz,1H),6.77(d,J=1.0Hz,1H ),6.30(t,J=2.1Hz,1H),5.45(s,1H),5.09(dd,J=12.8,5.4Hz,1H),3.90~3.84(m,5H),3.79~3.58(m,4H),3.2 0~3.13(m,6H),3.01~2.77(m,3H),2.66~2.51(m,2H),2.07~2.01(m,2H),1.91~1.88(m,2H),1.52~1.45(m,2H). C 41 H 44 N9O8S[M+H] + LCMS calculated for: m / z=822.3; found: 822.5.

[0466] Example 33. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0467] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. 1H NMR(300MHz,DMSO-d6)δ10.95(s,1H),10.83(s,1H),9.13(s,1H),7.88(d,J=2.3Hz,1H),7.57~7.47(m,1H),7.39(t,J=7.9Hz,1H),7.31~7 .22(m,1H),6.97(t,J=2.0Hz,1H),6.84(s,1H),6.76(s,1H),6.68~6.62(m,3H),6.30(t,J=2.1Hz,1H),5.45(s,2H),5.04(dd,J=13.1,5.1H z,1H),4.32(d,J=16.8Hz,1H),4.19(d,J=16.9Hz,1H),3.86(s,3H),3.72(s,2H),3.68~3.62(m,3H),3.36~3.21(m,5H),3.18~2.94(m,4H), 2.94~2.70(m,2H),2.64~2.55(m,1H),2.45~2.31(m,1H),2.30~2.20(m,1H),2.14(d,J=13.6Hz,2H),2.03~1.88(m,3H),1.86~1.71(m,1H). C 43 H 48 N9O7S[M+H] + LCMS calculated for: m / z=834.3; found: 834.4.

[0468] Example 34. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0469] Step 1. 3-(6-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka]

[0470] To a solution of pyrrolidin-3-ylmethanol (8.49 mg, 0.0812 mmol) and 3-(6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20.0 mg, 0.0812 mmol) in NMP (1 mL) was added N,N-diisopropylethylamine (0.040 mL, 0.23 mmol). The reaction mixture was stirred at 120 °C overnight. The reaction was cooled to room temperature and diluted with water (30 mL) and EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (50–100% EtOAc / hexanes) afforded the title compound (26 mg, 0.076 mmol, 99% yield) as a clear oil. 18 H 22 N3O4[M+H] + LCMS calculated for: m / z=344.2; found: 344.1.

[0471] Step 2: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde [ka]

[0472] The title compound was synthesized by a procedure similar to that outlined in Example 31, Step 2. 18 H 20 N3O4[M+H] + LCMS calculated for: m / z=342.1; found: 341.9.

[0473] Step 3: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0474] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10. 1 H NMR(300MHz,DMSO-d6)δ10.98(s,1H),10.83(s,1H),9.22(s,1H),7.88(d,J =2.2Hz,1H),7.50(d,J=1.8Hz,1H),7.39(t,J=8.2Hz,2H),7.27(d,J=8.3Hz ,1H),6.97(t,J=2.0Hz,1H),6.89~6.80(m,3H),6.76(s,1H),6.72~6.62(m, 1H),6.31(t,J=2.1Hz,1H),5.45(s,2H),5.09(dd,J=13.2,5.1Hz,1H),4.33 (d,J=16.6Hz,1H),4.20(d,J=16.5Hz,1H),3.87(s,3H),3.72(s,2H),3.65( s,1H),3.63~3.48(m,3H),3.47~3.37(m,1H),3.36~3.20(m,3H),3.18~3.00 (m,3H),2.99~2.71(m,2H),2.60(d,J=16.4Hz,1H),2.47~2.30(m,1H),2.30 ~2.20(m,1H),2.15(d,J=13.8Hz,2H),2.04~1.89(m,3H),1.86~1.71(m,1H). C 43 H 48 N9O7S[M+H] + LCMS calculated for: m / z=834.3; found: 834.4.

[0475] Example 35. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0476] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione [ka]

[0477] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 8, using (S)-pyrrolidin-3-ylmethanol. 18 H 20 N3O5[M+H] + LCMS calculated for: m / z=358.1; found: 358.0.

[0478] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(7-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide

[0479] The title compound was synthesized by a procedure similar to that outlined in Example 12, Step 2, using 3-(2,7-diazaspiro[3.5]nonan-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide (from Example 5, Step 1).1 H NMR(300MHz,DMSO-d6)δ11.08(s,1H),10.82(s,1H),9.18(s,1H),7.88(d,J=2.3Hz,1H),7.69(d,J=8.5Hz,1H),7.50(d,J=1.8Hz,1H),7.3 9(t,J=7.9Hz,1H),7.26(d,J=7.8Hz,1H),7.00~6.92(m,2H),6.88~6.81(m,2H),6.75(s,1H),6.67(dd,J=8.0,2.3Hz,1H),6.30(t,J=2.1Hz) ,1H),5.45(s,2H),5.06(dd,J=12.7,5.4Hz,1H),3.86(s,3H),3.73~3.70(m,3H),3.56~3.49(m,4H),3.48~3.36(m,1H),3.34~3.15(m,3H), 3.14~2.96(m,2H),2.95~2.75(m,2H),2.66~2.54(m,2H),2.34~2.21(m,1H),2.14(d,J=13.5Hz,2H),2.05~1.88(m,3H),1.87~1.73(m,1H). C 43 H 46 N9O8S[M+H] + LCMS calculated for: m / z=848.3; found: 848.5.

[0480] Example 36. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)amino)piperidin-1-yl)benzenesulfonamide [ka]

[0481] Step 1: tert-butyl (1-(3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)phenyl)piperidin-4-yl)carbamate [ka]

[0482] To a solution of 3-bromo-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide (20 mg, 0.043 mmol) in 1,4-dioxane (2 mL) was added 4-(N-boc-amino)piperidine (17 mg, 0.085 mmol), CsCO (35.0 mg, 0.108 mmol), and RuPhos Pd G (7.00 mg, 8.36 μmol) (CAS 1445085-77-7). The mixture was sparged with N and heated to 110° C. for 12 hours. The mixture was concentrated to provide the title compound, which was used without further purification. 28 H 35 N6O6S[M+H] + LCMS calculated for: m / z=583.2; found: 583.8.

[0483] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-aminopiperidin-1-yl)benzenesulfonamide [ka]

[0484] To a mixture of tert-butyl N-[1-[3-[[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]sulfamoyl]phenyl]piperidin-4-yl]carbamate (90 mg, 0.15 mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred for 1 h. The mixture was concentrated, diluted with methanol (3 mL), and purified by preparative HPLC on a C18 column (5-100% MeCN / 0.1% TFA (aq)) to afford the title compound as a colorless solid TFA salt (30 mg, 0.062 mmol, 40% yield). 23 H 27 N6O4S[M+H] +LCMS calculated for: m / z=483.2; found: 483.6.

[0485] Step 3: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)amino)piperidin-1-yl)benzenesulfonamide

[0486] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10, using (R)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (from Example 28, Step 6). 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.81(brs,2H),8.48(s,2H),7.85(d,J=4.0Hz,1H),7.52~7.48(m,2H),7.42(t,J=8.0Hz,1H),7.34(d,J=8.0 Hz,1H),7.25(dd,J=8.0,2.0Hz,1H),6.82(s,1H),6.74(s,1H),6.62~6.61 (m,1H),6.28(t,J=2.0Hz,1H),5.43(s,2H),5.02(dd,J=12.0,4.0Hz,1H), 4.30(d,J=16.0Hz,1H),4.18(d,J=16.0Hz,1H),3.86~3.84(m,4H),3.54~3 .50(m,1H),3.32~3.30(m,1H),3.15~3.09(m,2H),2.93~2.87(m,2H),2.83 ~2.80(m,2H),2.66~2.56(m,2H),2.39~2.28(m,2H),2.24~2.16(m,1H),2. 10~2.07(m,2H),1.96~1.93(m,2H),1.86~1.77(m,2H),1.63~1.54(m,2H). C 41 H 46 N9O7S[M+H] + LCMS calculated for: m / z=808.3; found: 809.0.

[0487] Example 37. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)(methyl)amino)benzenesulfonamide [ka]

[0488] Step 1: tert-butyl 4-((3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)phenyl)amino)piperidine-1-carboxylate [ka]

[0489] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 7. 28 H 35 N6O6S[M+H] + LCMS calculated for: m / z=583.2; found: 583.8.

[0490] Step 2: tert-butyl 4-((3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)phenyl)(methyl)amino)piperidine-1-carboxylate [ka]

[0491] To a solution of tert-butyl 4-[3-[[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]sulfamoyl]anilino]piperidine-1-carboxylate (50 mg, 0.086 mmol) in methanol (1.5 mL) was added acetic acid (0.1 mL) and paraformaldehyde (200 mg, 2.66 mmol). The mixture was stirred at 30° C. for 1 hour, and then sodium triacetoxyborohydride (90 mg, 0.43 mmol) was added. The resulting mixture was stirred at 30° C. for 2 hours. The solution was diluted with water (15 mL) and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated. Preparative TLC (20:1 DCM / MeOH, R f =0.70) to afford the title compound (15 mg, 0.025 mmol, 29% yield) as a pale yellow solid. 29 H 37 N6O6S[M+H] + LCMS calculated for: m / z=597.2; found: 597.8.

[0492] Step 3: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(methyl(piperidin-4-yl)amino)benzenesulfonamide [ka]

[0493] To a solution of tert-butyl 4-[3-[[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]sulfamoyl]-N-methylanilino]piperidine-1-carboxylate (100 mg, 0.168 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL). The resulting mixture was stirred for 1 h. The mixture was concentrated, dissolved in DMSO (2 mL), filtered, and purified by preparative HPLC on a C18 column (5-100% MeCN / 0.1% TFA (aq)) to afford the title compound as a white solid TFA salt (70 mg, 0.12 mmol, 68% yield). 24 H 29 N6O4S[M+H] + LCMS calculated for: m / z=497.2; found: 497.6.

[0494] Step 4: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)(methyl)amino)benzenesulfonamide

[0495] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10, using (R)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (from Example 28, Step 6). 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.76(s,1H),9.34(s,1H),7.86(d,J=4 .0Hz,1H),7.51(d,J=12.0Hz,1H),7.48(d,J=1.2Hz,1H),7.39(t,J=8.0Hz,1H ),7.35(s,1H),7.25(d,J=8.0Hz,1H),7.12(dd,J=12.0,4.0Hz,1H),6.82(s,1 H),6.73(s,1H),6.65~6.63(m,2H),6.28(t,J=4.0Hz,1H),5.43(s,2H),5.02( dd,J=12.0,4.0Hz,1H),4.30(d,J=16.0Hz,1H),4.18(d,J=16.0Hz,1H),4.06~ 4.00(m,1H),3.84(s,3H),3.68~3.60(m,3H),3.45(d,J=8.0Hz,1H),3.36~3.2 6(m,3H),3.17~3.09(m,3H),2.93~2.78(m,2H),2.74(s,3H),2.59~2.55(m,1H ),2.40~2.35(m,1H),2.30~2.23(m,1H),2.09~1.92(m,3H),1.83~1.80(m,2H). C 42 H 48 N9O7S[M+H] + LCMS calculated for: m / z=822.3; found: 822.9.

[0496] Example 38. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)amino)benzenesulfonamide [ka]

[0497] Step 1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(piperidin-4-ylamino)benzenesulfonamide [ka]

[0498] To a mixture of tert-butyl 4-((3-(N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)phenyl)amino)piperidine-1-carboxylate (from Example 37, Step 1) (101 mg, 0.173 mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred for 1 h. The mixture was concentrated, dissolved in methanol (3 ml), filtered, and purified by preparative HPLC on a C18 column (5-100% MeCN / 0.1% TFA (aq)) to afford the title compound as an off-white solid TFA salt (40 mg, 0.067 mmol, 39% yield). 23 H 27 N6O4S[M+H] + LCMS calculated for: m / z=483.2; found: 483.6.

[0499] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperidin-4-yl)amino)benzenesulfonamide

[0500] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10, using (R)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (from Example 28, Step 6). 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.72(s,1H),9.42~9.35(m,1H),7. 86(dd,J=2.0,0.4Hz,1H),7.52~7.48(m,2H),7.30~7.26(m,1H),7.23~7.18 (m,1H),7.16~7.11(m,1H),6.88~6.84(m,1H),6.81(s,1H),6.74(s,1H),6 .65~6.64(m,2H),6.29(t,J=4.0Hz,1H),5.44(s,2H),5.03(dd,J=12.0,4.0 Hz,1H),4.31(d,J=20.0Hz,1H),4.19(d,J=16.0Hz,1H),3.85(s,3H),3.72 ~3.61(m,3H),3.53~3.43(m,3H),3.35~3.31(m,1H),3.14~3.09(m,3H),2.9 4~2.85(m,1H),2.84~2.76(m,1H),2.60~2.56(m,1H),2.40~2.33(m,1H),2 .29~2.22(m,1H),2.14~2.11(m,1H),2.04~1.76(m,4H),1.68~1.58(m,2H). C 41 H 46 N9O7S[M+H] + LCMS calculated for: m / z=808.3; found: 809.0.

[0501] Example 39. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(9-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)benzenesulfonamide [ka]

[0502] Step 1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3,9-diazaspiro[5.5]undecan-3-yl)benzenesulfonamide [ka]

[0503] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 8. 27 H 33 N6O4S[M+H] + LCMS calculated for: m / z=537.2; found: 537.1.

[0504] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(9-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)benzenesulfonamide

[0505] The title compound was synthesized by a procedure similar to that outlined in Example 12, Step 2, using 3-(5-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (from Example 26, Step 5). 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.70(s,1H),9.15(s,1H),7.80(d,J=2.2Hz,1H),7.47~7.40(m ,3H),7.34(t,J=8.0Hz,1H),7.25(d,J=7.6Hz,1H),7.16(dd,J=8.4,2.4Hz,1H),6.73(d,J=36.2Hz,2H) ,6.58(dq,J=4.1,2.2Hz,2H),6.23(t,J=2.1Hz,1H),5.38(s,2H),4.97(dd,J=13.2,5.1Hz,1H),4.33~4 .08(m,2H),3.79(s,3H),3.59~2.69(m,17H),2.60~2.46(m,1H),2.34~2.06(m,2H),1.94~1.40(m,8H). C 45 H 52 N9O7S[M+H]+ LCMS calculated for: m / z=862.4; found: 862.6.

[0506] Example 40. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((3aS,6aS)-5-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzenesulfonamide [ka]

[0507] Step 1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((3aS,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzenesulfonamide [ka]

[0508] The title compound was synthesized by a procedure similar to that outlined in Steps 1-2 of Example 36 using tert-butyl (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. 24 H 27 N6O4S[M+H] + LCMS calculated for: m / z=495.2; found: 495.6.

[0509] Step 3: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-((3aS,6aS)-5-(((S)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzenesulfonamide

[0510] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10, using (R)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (from Example 28, Step 6). 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.82(dd,J=1.2,0.4Hz,1H),7.48(d,J=8.0Hz,1H),7.46(dd,J=2.0,0.4Hz,1H),7.17(t,J=8.0Hz,1 H),7.06(d,J=8.0Hz,1H),7.02(s,1H),6.62~6.60(m,3H),6.54~6.51(m,2H),6.26(t,J=4.0Hz,1H),5.36(s,2H),5.01(dd,J=12.0,4.0Hz, 1H),4.29(d,J=16.0Hz,1H),4.17(d,J=16.0Hz,1H),3.79(s,3H),3.55~3.49(m,2H),3.43~3.37(m,6H),3.26~3.24(m,1H),3.14~3.03(m, 5H),2.93~2.84(m,1H),2.66~2.63(m,1H),2.59~2.55(m,1H),2.45~2 .28(m,4H),2.20~2.17(m,1H),1.97~1.92(m,1H),1.81~1.74(m,1H). C 42 H 46 N9O7S[M+H] + LCMS calculated for: m / z=820.3; found: 820.0.

[0511] Example 41. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide [ka]

[0512] Step 1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-bromo-2-methoxybenzenesulfonamide [ka]

[0513] The title compound was synthesized using 5-bromo-2-methoxybenzenesulfonyl chloride following a procedure similar to that outlined in Example 1, Step 6. 19 H 18 BrN4O5S[M+H] + LCMS calculated for: m / z=493.0; found: 493.3.

[0514] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxy-5-(2,7-diazaspiro[3.5]nonan-2-yl)benzenesulfonamide [ka]

[0515] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 7. 26 H 31 N6O5S[M+H] + LCMS calculated for: m / z=539.2; found: 539.0.

[0516] Step 3: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-(7-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methoxybenzenesulfonamide

[0517] The title compound was synthesized by a procedure similar to that outlined in Example 1, Step 10 using 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (from Example 1, Step 9). 1 H NMR(300MHz,DMSO-d6)δ11.09(s,1H),9.98(s,1H),9.19(s,1H),7.88(d,J=2.2Hz,1H),7.70(d,J=8.4Hz,1H),7.50(d,J=1.8Hz,1H),7.09(d ,J=9.0Hz,1H),6.95(d,J=2.1Hz,1H),6.88~6.81(m,3H),6.77(d,J=0.9Hz,1H),6.69(dd,J=8.8,2.9Hz,1H),6.30(t,J=2.1Hz,1H),5.45(s,2 H),5.07(dd,J=12.7,5.4Hz,1H),3.87(s,3H),3.82~3.73(m,2H),3.71(s,3H),3.66(s,2H),3.59(s,2H),3.57~3.47(m,3H),3.47~3.36(m,1H) ),3.35~3.16(m,3H),2.92~2.72(m,2H),2.65~2.55(m,2H),2.33~2.19 (m,1H),2.13(d,J=13.7Hz,2H),2.06~1.89(m,3H),1.88~1.74(m,1H). C 44 H 48 N9O9S[M+H] + LCMS calculated for: m / z=878.3; found: 878.4.

[0518] Example 42. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide [ka]

[0519] The title compound was synthesized by procedures similar to those outlined in Example 1, Steps 7-8 and Example 12, Step 2. 39 H 40 N9O8S[M+H] + LCMS calculated for: m / z=794.2; found: 794.4.

[0520] Example A. Western Blot KAT6A Degradation Assessment The activity of compounds was assessed by measuring KAT6A protein levels using Western blot as a readout of KAT6A degradation ability. These tests were performed on the HCC1954 cell line, which harbors KAT6A copy number amplification. Cells were maintained in an incubator at 37°C with 5% CO2 in the following medium: RPMI 1640, ATCC (copyright) modified (Gibco, A10491-01) supplemented with 10% v / v FBS (Gibco, 26140-079) and 1% penicillin-streptomycin (Gibco, 15140-122). Cells were seeded into 6-well plates at a density of 300,000 cells / well and allowed to attach overnight in the incubator. Compounds dissolved in DMSO were prepared at 1000x the desired final concentration, with the final DMSO concentration being 0.1%. After 24 hours of treatment, cells were washed with phosphate-buffered saline (PBS) (Corning, 21-040-CV), detached with trypsin-EDTA (Gibco, #25200-056), and pelleted in complete RPMI medium in a microcentrifuge at 1500 rpm for 5 minutes. Protein was extracted from the cell pellet by resuspending in 15 μL of PBS before adding 45 μL of lysis buffer consisting of 4% SDS, 1× protease and phosphatase inhibitors, and 1 mM PMSF (Cell Signaling Technology, #8553S). The lysate was transferred to a homogenizer column (Omega Biotek, #HCR003) and centrifuged at 12,000 rpm for 1.5 minutes.

[0521] Homogenized lysates were quantified by BCA assay (ThermoScientific, Pierce BCA Protein Assay, #23223, #23224) according to the manufacturer's instructions. Samples were then diluted to 1x in 4x Laemmli buffer (Biorad, #1610747) and boiled at 95°C for 5 minutes. To assess KAT6A protein expression, samples were run on a 26-well gel (Biorad, 4-15% Criterion TGX Precast Gel, #5671085) at 120V for approximately 1 hour. Proteins were transferred to a low-fluorescence PVDF membrane (Millipore, Sigma, #IPFL00010) using a Trans-Blot Turbo Transfer System (Biorad). The membranes were then probed with KAT6A (Cell Signaling Technology, #78462) and GAPDH (Cell Signaling Technology, #5174S) primary antibodies and fluorescently labeled secondary antibodies (LI-COR, IRDye 800CW goat anti-rabbit #926-32211, IRDye 680RD goat anti-mouse #926-68070) using an iBind Flex Western device (Thermofisher, SLF2000) according to the manufacturer's recommended conditions. The membranes were washed briefly in water and scanned on a LI-COR Odyssey CLx. Band quantification was assessed using Image Studio Ver. 5.2. KAT6A expression was normalized to the GAPDH loading control, and KAT6A expression is then expressed as a percentage of that observed in DMSO.

[0522] The results are summarized in Table 3 below.

[0523] Table 3 - KAT6A degradation at 0.1 μM [Table 3]

[0524] In Table 3, "+" indicates a % degradation value of 0<% degradation≦50, "++" indicates a % degradation value of 50<% degradation≦75, and "+++" indicates a % degradation value >75.

[0525] Example B. HiBit KAT6A Decomposition Evaluation The degradation activity of compounds was evaluated by measuring KAT6A protein levels using the HiBiT system. These tests were performed on HeLa cells carrying HiBit-tagged KAT6A. Cells were maintained in an incubator at 37°C with 5% CO2 in EMEM (ATCC, 30-2003) supplemented with 10% v / v FBS (Gibco, 26140-079) and 1% penicillin-streptomycin. Cells were seeded into 384-well plates at a density of 2,000 cells / well. Compounds dissolved in DMSO were added in nine-point serial dilutions. After 18 hours of treatment, KAT6A levels were measured using the Nano-Glo® HiBiT Lytic Detection System (Promega, Cat. No. N3030) according to the manufacturer's instructions. Luminescence signals were measured using a multimode plate reader (Envision 2105, Perkin Elmer). Luminescence values were normalized to background and DMSO controls to quantify KAT6A for each condition. Results were analyzed and DC 50 and D max Values were obtained using a four-parameter logistic curve fit, and the results are summarized in Table 4 below.

[0526] Table 4 HiBit KAT6A decomposition [Table 4]

[0527] In Table 4, column DC 50 "A" is DC 50 <10 nM, "B" indicates 10 nM ≤ DC 50 <100nM, "C" indicates 100nM ≤ DC 50 <1000nM, D indicates DC 50 In Table 4, column D indicates that was not calculated for the screening parameter. max "A" is D max >75%, and "B" indicates 50% <Dmax ≦75%, and "C" indicates 25% <D max ≦50%, and D is D max ≦25%.

[0528] While several embodiments of the present invention have been described, it will be apparent that the basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present invention. It will therefore be understood that the scope of the present invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. Equation (I): 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt or solvate thereof, In the formula, PTM is in formula IA 【Chemistry 2】 It is part of the formula, Y is a covalent bond, or a chemical moiety that bonds PTM and ULM. ＊ This is the connection point to ULM, Ring A is C ６ -C １０ It is a 5-10 member aryl group or a 5-10 member heteroaryl group. R １ This is a 5-6 member heteroaryl compound optionally substituted with H or methyl. R ２ is H or halogen, C １ -C ３ alkyl, -CH ２ OH, or -(C(R ８ )) ２ )) ｎ -(5- to 9-membered heteroaryl), and R ３ H or halogen, C １ -C ４ Alkyl, cyclopropyl, haloalkyl, C １ -C ４ Alkoxy, or It is a haloalkoxy, R ４ H or halogen, C １ -C ４ Alkyl, cyclopropyl, C １ -C ４ It is an alkoxy or -O-cyclopropyl, Each R ５ These are independently H, halogen, oxo, -OH, -CN, and -NO. ２ , -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, C ０－ C １ alk-aryl, C ０－ C １ alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR ａ , -SR ａ , -NR ｃ R ｄ , -NR ａ R ｃ , -C(O)R ｂ , -OC(O)R ａ , -C(O)OR ａ , -C(O)NR ｃ R ｄ , -S(O)R ｂ , -S(O) ２ NR ｃ R ｄ , -S(O)(=NR ｂ ) R ｂ , -SF ５ ,-P(O)R ｂ R ｂ , -P(O)(OR ｂ ) ( OR ｂ ), -B (OR ｄ ) ( OR ｃ ) or -S(O) ２ R ｂ And, Each R ａ is independently H, -C(O)R ｂ -C(O)OR ｃ -C(O)NR ｃ R ｄ -C(=NR ｂ )NR ｂ R ｃ 、 -C(=NOR ｂ )NR ｂ R ｃ 、 -C(=NCN)NR ｂ R ｃ 、 -P(OR ｃ ) ２ -P(O)R ｃ R ｂ -P(O)OR ｃ OR ｂ -S(O)R ｂ -S(O)NR ｃ R ｄ -S(O) ２ R ｂ -S(O) ２ NR ｃ R ｄ SiR ｂ ３ -C １ -C １０ alkyl, -C ２ -C １０ alkenyl, -C ２ -C １０ alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, Each R ｂ H and -C are independent of each other. １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, Each R ｃ Or R ｄ H and -C are independent of each other. １ -C １０ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkinyl, -OC １ -C ６ Alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, R ｃ and R ｄ These, together with the atoms to which they are bonded, form a monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocyclo-alkenyl group. Each R ８ These are independently H, halogen, or C １ -C ４ It is alkyl, m is 0, 1, 2, 3, or 4. n is 0 or 1, and ULM is 【Transformation 3】 And in the formula, 【Chemistry 4】 This is a connection point to Y or PTM, Ring A3 is a monocyclic, bicyclic, or tricyclic aryl, heteroaryl, or heterocyclic group. L4 is a bond, -O-, -S-, -NR a-, -C(Ra a) 2-, -C(O)NR a-, X1 is CH2, CO, CH=CH (when X2 = CO), or N=CH (when X2 = CO), X2 is CH2, CO, CH=CH (when X1 = CO), or N=CH (when X1 = CO), R12 is H, optionally substituted C1-4 alkyl, C1-4 alkoxyl, C1-4 haloalkyl, -CN, -OR a, -OR b, or -SR b. Each R15 is independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C0-C1 alk-aryl, C0-C1 alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a, -SR a, -NR c R d, -NR a R c, -C(O)R b, -OC(O)R a, -C(O)OR a, -C(O)NR c R d, -S(O)R b, -S(O)2 NR c R d, -S(O)(=NR b)R b -SF 5, -P(O)R b R b, -P(O)(OR b)(OR b), -B(OR d)(OR c) or -S(O) 2 R b, Each R a is independently H, -C(O)R b, -C(O)OR c, -C(O)NR c R d, -C(=NR b)NR b R c, -C(=NOR b)NR b R c, -C(=NCN)NR b R c, -P(OR c) 2, -P(O)R c R b, -P(O)OR c OR b, -S(O)R b, -S(O)NR c R d, -S(O) 2 R b, -S(O) 2 NR c R d, SiR b 3, -C 1 -C 10 alkyl, -C 2 -C 10 alkenyl, -C 2 -C10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, Each R b is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. Each R c or R d is independently H, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, or R c and R d, together with the atoms to which they are both bonded, form monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocyclo-alkenyl groups, and o is 1, 2, 3, 4, or 5. Optionally, Y is the chemical moiety that binds PTM and ULM. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

2. R １ H is and / or R2 is H, or R2 is a -(C(R8)2)n-(5- to 9-membered heteroaryl) which is optionally substituted with a halogen, C1-C3 alkyl, -CH2OH, or -OH, or R2 is a -(C(R8)2)n-(5-6 member heteroaryl) which is optionally substituted with a halogen, C1-C3 alkyl, -CH2OH, or -OH. The 5-6 member heteroaryl is optionally pyrazole, pyrrole, pyridine, or pyridazine. Furthermore, optionally, the 5-6 member heteroaryl is a pyrazole, and / or Each R8 is H. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. n is 0, or n is 1, The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. R ３ However, is H, or R3 is halogen, or R3 is a C1-C4 alkyl group, and / or R4 is H, or R4 is either a C1-C4 alkyl group, or R4 is a C1-C4 alkoxy, or R4 is methoxy. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

5. Ring A is C ６ -C １０ It is Ariel, If ring A is optionally phenyl, The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

6. Each R ５ However, is H, or At least one R5 is H, or Each R5 is either a C1-C4 alkoxy or At least one R5 is a C1-C4 alkoxy, or Each R5 is independently H, halogen, cyano, C1-C4 alkyl, haloalkyl, cyclopropyl, C1-C4 alkoxy, haloalkoxy, -O-cyclopropyl, -CH2-O-CH3, -C(O)OCH3, or -C(O)N(H)CH3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. m is 0, or m is 1, or m is 2, or m is 3, or m is 4. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

8. Y is given by the formula: -(A) ｑ -、 And in the formula, q is an integer from 1 to 14. Each A is independent of CR １ａ R １ｂ ,O,S,SO,SO ２ , NR １ｃ SO ２ NR １ｃ , SONR １ｃ , SO (=NR １ｃ ), SO (=NR １ｃ ) NR １ｄ CONR １ｃ , NR １ｃ CONR １ｄ , NR 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 １ｃ (CR １ａ R １ｂ ) １－４、 NR １ｃ C(=NCN)NR １ｄ , NR １ｃ C (=NCN), NR １ｃ C(=CNO) ２ ) NR １ｄ , 0 to 6 R １ａ Or R １ 3- to 11-membered cycloalkyl groups optionally substituted with a b group, with 0-6 R groups. １ａ Or R １ 3- to 11-membered heterocyclines with optional substitution of b groups, 0-6 R groups １ａ Or R １ｂ Aryls optionally substituted in the base, or 0 to 6 R １ａ Or R １ｂ Selected from the group consisting of heteroaryls that have been optionally substituted in the base, R １ａ , R １ｂ , R １ｃ , R １ｄ and R １ｅ These are, independently, -H, -Halo, and -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, 3-11 member cycloalkyl, aryl, heteroaryl, 3-11 member heterocyclyl, -O- (3-11 member cycloalkyl), -S- (3-11 member cycloalkyl), NH- (3-11 member cycloalkyl), N (3-11 member cycloalkyl) ２ , N-(3-11 member cycloalkyl)(C １ -C ８ Alkyl), -OH, -NH ２ , -SO ２ C １ -C ８ Alkyl, -SO ２ -Aryl, -SO ２ - Heteroaryl, 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, -C(O)OC １ -C ８ Alkyl, -CO ２ H, -CN, -CF ３ ,-CHF ２ ien-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 R １ａ Or R １ｂ Each of these groups can independently and optionally bind to other groups, forming 0 to 4 R groups. １ｅ The group may optionally be substituted to form cycloalkyl and / or heterocyclyl moieties. Optional q is an integer between 1 and 5. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

9. Y, 【Transformation 5】 And in the formula, ＊＊ This is the junction point to the PTM, L １ , L ２ , and L ３ Each is independent, combined, CR １ａ R １ｂ ,O,S,SO,SO ２ , NR １ｃ SO ２ NR １ｃ , SONR １ｃ , SO (=NR １ｃ ), SO (=NR １ｃ ) NR １ｄ CONR １ｃ , NR １ｃ CONR １ｄ , NR 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 ,-(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 １ｃ (CR １ａ R １ｂ ) １－４、 NR １ｃ C(=NCN)NR １ｄ , NR １ｃ C (=NCN), NR １ｃ C(=CNO) ２ ) NR １ｄ And, Ring A １ and ring A ２ Each of these independently comprises 0 to 6 R １ａ or R １ｂ 3- to 11-membered cycloalkyl groups, 0-6 R groups, optionally substituted with a base. １ａ or R １ｂ A 3- to 11-membered heterocycline with optional substitutions at the base, and 0-6 R １ａ or R １ｂ Aryls optionally substituted in the base, or 0 to 6 R １ａ or R １ｂ A heteroaryl compound that has been optionally substituted with the base compound. R １ａ , R １ｂ , R １ｃ , R １ｄ and R １ｅ These are, independently, -H, -Halo, and -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, 3-11 member cycloalkyl, aryl, heteroaryl, 3-11 member heterocyclyl, -O- (3-11 member cycloalkyl), -S- (3-11 member cycloalkyl), NH- (3-11 member cycloalkyl), N (3-11 member cycloalkyl) ２ , N-(3-11 member cycloalkyl)(C １ -C ８ Alkyl), -OH, -NH ２ ,-SH,SO ２ C １ -C ８ Alkyl, -SO ２ -Aryl, -SO ２ - Heteroaryl, 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, -C(O)OC １ -C ８ Alkyl, -CO ２ H, -CN, -CF ３ ,-CHF ２ ien-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 R １ａ Or R １ｂ Each of these groups can independently and optionally bind to other groups, forming 0 to 4 R groups. １ｅ The group may optionally be substituted to form cycloalkyl and / or heterocyclyl moieties, or Y, 【Transformation 6】 ** is the connection point to the PTM, L1 is a bond, (C(R10)2)p, or CO, L2 is a bond, (C(R10)2)p, or CO, L3 is a bond, (C(R10)2)p, or CO, p is 1, 2, 3, or 4. Each R10 is independently H or C1-C4 alkyl, Ring A1 is a 3-7 membered cycloalkyl group, a 4-10 membered heterocycloalkyl group, an aryl group, or a heteroaryl group, and Ring A2 is a 3-7 membered cycloalkyl group, a 4-10 membered heterocycloalkyl group, an aryl group, or a heteroaryl group. Optionally, L3 is a combination, and / or L1 is a bond, and / or L2 is (C(R10)2)p and / or Ring A1 is a 4- to 10-membered heterocycloalkyl group, Ring A1 may optionally be a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, or an azabicycloalkyl group, or Ring A1 is a piperidine group or a pyrrolidine group, and / or Ring A2 is a 4- to 10-membered heterocycloalkyl group. Ring A2 may optionally be a piperazine group, a morpholine group, a piperidine group, a pyrrolidine group, an azetidine group, a diazaspiroalkyl group, or an azabicycloalkyl group. Ring A2 is a piperazine group or a diazaspirononane group. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

10. Y, 【Transformation 7】 And in the formula, r is 0, 1, or 2. s is 0, 1, or 2, and Z is N or CR １０ And, r is optionally 1 and / or s is 1 and / or Z is N. The compound according to claim 9, or a pharmaceutically acceptable salt or solvate thereof.

11. Ring A ３ However, it is a bicyclic heterocyclic group, and / or L4 is a bond, and / or R 12 is H, and / or Each R 15 is H, and / or X1 is CO and / or X2 is CH2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

12. ULM 【Transformation 8】 And in the formula, 【Chemistry 9】 This is a connection point to Y or PTM, X ３ CH ２ , CO, CH=CH(X ４ =CO case), or N=CH(X ４ = (in the case of CO), and X ４ CH ２ , CO, CH=CH(X ３ =CO case), or N=CH(X ３ = (In the case of CO) Optionally, X 3 is CH 2, or X3 is CO, or X4 is CH2, or X4 is CO. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

13. PTM is formula IA-1 【Chemistry 10】 A compound of, or a pharmaceutically acceptable salt thereof, or PTM is formula IA-2 【Chemistry 11】 A compound of, or a pharmaceutically acceptable salt thereof, or PTM is formula IA-3 【Chemistry 12】 A compound of, or a pharmaceutically acceptable salt thereof, in the formula L1 is a bond, (C(R10)2)p, or CO, L2 is a bond, (C(R10)2)p, or CO, L3 is a bond, (C(R10)2)p, or CO, p is 1, 2, 3, or 4. Each R10 is independently H or C1-C4 alkyl, Ring A1 is a 3-7 membered cycloalkyl group, a 4-10 membered heterocycloalkyl group, an aryl group, or a heteroaryl group, and Ring A2 is a 3-7 membered cycloalkyl group, a 4-10 membered heterocycloalkyl group, an aryl group, or a heteroaryl group, or PTM is formula IA-4 【Chemistry 13】 A compound of, or a pharmaceutically acceptable salt thereof, in the formula L1 is a bond, (C(R10)2)p, or CO, L2 is a bond, (C(R10)2)p, or CO, p is 1, 2, 3, or 4. Each R10 is independently H or C1-C4 alkyl, Ring A1 is a 3-7 membered cycloalkyl group, a 4-10 membered heterocycloalkyl group, an aryl group, or a heteroaryl group. r is 0, 1, or 2. s is 0, 1, or 2, and Z is either N or CR 10, or PTM-ULM is formula IA-5 【Chemistry 14】 A compound of, or a pharmaceutically acceptable salt thereof, in the formula L1 is a bond, (C(R10)2)p, or CO, L2 is a bond, (C(R10)2)p, or CO, p is 1, 2, 3, or 4. Each R10 is independently H or C1-C4 alkyl, Ring A1 is a 3-7 membered cycloalkyl group, a 4-10 membered heterocycloalkyl group, an aryl group, or a heteroaryl group. r is 0, 1, or 2. s is 0, 1, or 2, and Z is N or CR 10, Ring A3 is a monocyclic, bicyclic, or tricyclic aryl, heteroaryl, or heterocyclic group. L4 is a bond, -O-, -S-, -NR a-, -C(Ra a) 2 --C(O)NR a-, X1 is CH2, CO, CH=CH (when X2 = CO), or N=CH (when X2 = CO), X2 is CH2, CO, CH=CH (when X1 = CO), or N=CH (when X1 = CO), R 12 is H, D, optionally substituted C 1-4 alkyl, C 1-4 alkoxyl, C 1-4 haloalkyl, -CN, -OR a, -OR b, or -SR b, Each R15 is independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C0-C1 alk-aryl, C0-C1 alk-heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, -OR a, -SR a, -NR c R d, -NR a R c, -C(O)R b, -OC(O)R a, -C(O)OR a, -C(O)NR c R d, -S(O)R b, -S(O)2 NR c R d, -S(O)(=NR b)R b -SF 5, -P(O)R b R b, -P(O)(OR b)(OR b), -B(OR d)(OR c) or -S(O) 2 R b, Each R a is independently H, -C(O)R b, -C(O)OR c, -C(O)NR c R d, -C(=NR b)NR b R c, -C(=NOR b)NR b R c, -C(=NCN)NR b R c, -P(OR c) 2, -P(O)R c R b, -P(O)OR c OR b, -S(O)R b, -S(O)NR c R d, -S(O) 2 R b, -S(O) 2 NR c R d, SiR b 3, -C 1 -C 10 alkyl, -C 2 -C 10 alkenyl, -C 2 -C10 Alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, Each R b is independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl. Each R c or R d is independently H, -C1-C10 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, or R c and R d, together with the atoms to which they are both bonded, form monocyclic or polycyclic heterocycloalkyl or monocyclic or polycyclic heterocyclo-alkenyl groups, and o is 1, 2, 3, 4 or 5, or PTM-ULM is formula IA-6 【Chemistry 15】 A compound of, or a pharmaceutically acceptable salt thereof, in the formula X3 is CH2, CO, CH=CH (when X4 = CO), or N=CH (when X4 = CO), and X4 is CH2, CO, CH=CH (when X3=CO), or N=CH (when X3=CO), or PTM-ULM is formula IA-7 【Chemistry 16】 A compound of, or a pharmaceutically acceptable salt thereof, in the formula The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein t is 1 or 2.

14. N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperazine-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-(3-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)propyl)piperazine-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-(2-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)ethyl)piperazine-1-yl)benzene-sulfonamide, 3-[4-[7-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]-7-azaspiro[3.5]nonane-2-yl]piperazine-1-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, 3-[7-[[1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]pyrrolidine-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, 3-[3-[[4-[9-(2,6-dioxopiperidine-3-yl)pyrido[2,3-b]indole-6-yl]piperazine-1-yl]methyl]pyrrolidine-1-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, 3-[4-[[1-[[1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]piperidine-4-yl]methyl]piperidine-4-yl]methyl]piperazine-1-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, 3-[4-[6-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]-6-azaspiro[3.4]octan-2-yl]piperazine-1-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, 3-[4-[2-[1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]pyrrolidine-3-yl]ethyl]piperazine-1-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, 3-[4-[[1-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-3H-isoindole-5-yl]pyrrolidine-3-yl]methyl]piperazine-1-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, 3-[6-[[1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-5-yl]pyrrolidine-3-yl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof, or N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-methylpyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-3-fluoropyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(2-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-7-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(8-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,8-diazaspiro[4.5]decane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-(2-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)piperidine-4-yl)oxy)ethyl)piperazine-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-((4-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindoline-5-yl)morpholine-2-yl)methyl)piperazine-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-((7-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-7-azaspiro[3.5]nonane-2-yl)methyl)piperazine-1-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(9-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-3,3-dimethylpiperazine-1-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(6-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)-6-azaspiro[3.4]octan-2-yl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(3-((4-((2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)oxy)piperidine-1-yl)methyl)pyrrolidine-1-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-(1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-carbonyl)piperazine-1-yl)benzene-sulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-2,6-dimethoxybenzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-methoxybenzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-methoxybenzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((S)-1-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, 5-(4-((4-(3-(N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)sulfamoyl)phenyl)piperazine-1-yl)methyl)piperidine-1-yl)-N-(2,6-dioxopiperidine-3-yl)picolinamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-methoxybenzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-methoxybenzenesulfonamide, 3-[4-[[1-[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]piperidine-4-yl]methyl]piperazine-1-yl]-N-[4-methoxy-6-(pyrazole-1-ylmethyl)-1,2-benzoxazole-3-yl]benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-((1-(2-(2,6-dioxopiperidine-3-yl)-3-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(7-(((3R)-1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-((((S)-1-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)amino)piperidine-1-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)(methyl)amino)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-((1-(((S)-1-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)piperidine-4-yl)amino)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(9-(((3S)-1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-3,9-diazaspiro[5.5]undecane-3-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-((3aS,6aS)-5-(((S)-1-(2-((S)-2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)benzenesulfonamide, N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-5-(7-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)pyrrolidine-3-yl)methyl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-methoxybenzenesulfonamide, The compound according to claim 1, which is N-(6-((1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-3-(4-((1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-yl)methyl)piperazine-1-yl)benzenesulfonamide, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition according to claim 15 for treating cancer or solid tumors in a subject requiring the same, The cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, liver cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemia, lymphoblastic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal-pelvic cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axial tumor, glioblastoma, brainstem glioma, pituitary adenoma, and two or more combinations of the aforementioned cancers, or The solid tumor is selected from the group consisting of breast, lung, colon, brain, prostate, stomach, pancreas, ovary, melanoma, endocrine tumor, uterus, testis, hematologic tumor, and bladder tumor, or The solid tumor is selected from the group consisting of breast, lung, prostate, pancreas, blood, and ovary, or The aforementioned cancer is breast cancer. Optionally, whether the breast cancer is ER+ breast cancer, or The breast cancer in question is either ER+HER2-breast cancer or Whether the breast cancer is locally advanced or metastatic ER+HER2- breast cancer, The aforementioned cancer is lung cancer. At the discretion of the user, whether the lung cancer is non-small cell lung cancer, Whether the lung cancer is locally advanced or metastatic non-small cell lung cancer, The aforementioned cancer is prostate cancer. Optionally, whether the prostate cancer is castration-resistant prostate cancer, or The aforementioned prostate cancer is locally advanced or metastatic castration-resistant prostate cancer. Pharmaceutical composition.

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