KAT6 targeting compounds with ubiquitin ligase binding moieties

Abstract

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

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 366,484, filed on June 16, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present specification provides bifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of use. The bifunctional compounds can be used as modulators targeting KAT6 protein, which are degraded and / or otherwise inhibited by the bifunctional compounds according to the present disclosure. Background Art

[0004] Epigenetic control of transcription by chromatin remodeling is an important regulatory mechanism that ultimately affects the functional expression of many proteins. Abnormalities of epigenetic regulatory factors are the cause of human diseases and are considered to be the main carcinogenic factors of many cancers. The regulation of histones plays a vital role in this process, and epigenetic regulatory factors modify histones by various post-translational modifications such as acetylation and methylation, thereby changing, for example, chromatin accessibility. Histone acetylation is catalyzed by histone acetyltransferases (HATs), and the dysregulation of such epigenetic regulatory factors is associated with transcriptional changes and cancer (1,2).

[0005] 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) is a member of this family that promotes histone acetylation and is paralogous to lysine acetyltransferase 6b (KAT6B) (3, 4). KAT6A has been reported to acetylate histone H3 at lysine 9 (H3K9ac), lysine 14 (H3K14ac) (4), and lysine 23 (H3K23ac) (5), although little is known about the functional dependence of these sites and other potential substrates. In addition to histones, KAT6A has been reported to acetylate non-histone proteins, such as p53 (6), but its role in regulating non-histone substrates is unclear. KAT6A can form protein complexes with inhibitor of growth family member 5 (ING5), bromodomain-containing 1, 2, or 3 and PHD finger (BRPF1, BRPF2, BRPF3), and myst / Esa1-associated factor 6 (EAF6), which may enhance its gene regulatory capacity (4, 7). Mechanistically, KAT6A has been implicated in the regulation of cellular processes such as senescence, cell cycle progression, and hematopoietic stem cell maintenance (4, 7, 8).

[0006] More recently, KAT6A was shown to epigenetically regulate estrogen receptor α (ERα) 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 is associated with poor clinical outcome 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 is considered a carcinogen in breast cancer, brain cancer, hematological cancer, gynecological cancer, and other cancers (5, 9, 11, 12).

[0007] KAT6A is frequently altered in many types of cancer, most commonly through copy number amplification or recurrent chromosomal translocations. Located within the recurrently amplified chromosome 8p11-12 amplicon, KAT6A amplification has been observed in many cancers, including breast cancer, lung cancer, prostate cancer, blood cancer, bladder cancer, uterine cancer, endometrial cancer, ovarian cancer, esophageal cancer, head and neck cancer, gastric cancer, colon cancer, and other cancers (9, 13, 14). Particularly in hematologic cancers, recurrent redistribution can lead to several fusion proteins, such as KAT6A-CBP, KAT6A-p300, KAT6A-TIF2, KAT6A-NcoA3, and KAT6A-LEUTX (7). Recently, KAT6A has been implicated as important for the growth of MLL-rearranged AML (11).

[0008] To date, only one small molecule inhibitor targeting KAT6A (PF-07248144, Phase 1, Pfizer) is in clinical trials to investigate its efficacy as a single agent or in combination with fulvestrant or letrozole + palbociclib (NCT04606446) for locally advanced or metastatic ER+ / HER2- breast cancer, castration-resistant prostate cancer, and non-small cell lung cancer (15). It is currently unclear whether conventional KAT6A small molecule inhibitors can unlock the full potential of targeting these or other cancers in a selective manner. Therefore, exploring targeted protein degradation (TPD) approaches to develop potent and selective KAT6A degraders could enhance the therapeutic window for cancers that rely on KAT6A for growth, proliferation, or survival.

[0009] Given the established role of KATs in diseases such as cancer, new regulators of these proteins are needed.

[0010] References:

[0011] 1.Nair SS,Kumar R.Chromatin remodeling in cancer:a gateway toregulate gene transcription.Mol Oncol.2012;6(6):611-9.

[0012] 2.Farria A,Li W,Dent SY.KATs in cancer:functions andtherapies.Oncogene.2015;34(38):4901-13.

[0013] 3.Avvakumov N, J.The MYST family of histone acetyltransferasesand their intimate links to cancer.Oncogene.2007;26(37):5395-407.

[0014] 4.Su J,Wang X,Bai Y,Sun M,Yao Y,Duan Y.The role of MOZ / KAT6A inhematological malignancies and advances in MOZ / KAT6A inhibitors.PharmacolRes.2021;174:105930.

[0015] 5.Lv D,Jia F,Hou Y,Sang Y,Alvarez AA,Zhang W,et al.HistoneAcetyltransferase KAT6A Upregulates PI3K / AKT Signaling through TRIM24Binding.Cancer Res.2017;77(22):6190-201.

[0016] 6.Rokudai S,Laptenko O,Arnal SM,Taya Y,Kitabayashi I,Prives C.MOZincreases p53 acetylation and premature senescence through its complexformation with PML.Proc Natl Acad Sci U S A.2013;110(10):3895-900.

[0017] 7.Huang F,Abmayr SM,Workman JL.Regulation of KAT6 Acetyltransferasesand Their Roles in Cell Cycle Progression,Stem Cell Maintenance,and HumanDisease.Mol Cell Biol.2016;36(14):1900-7.

[0018] 8.Sheikh BN,Phipson B,El-Saafin F,Vanyai HK,Downer NL,Bird MJ,etal.MOZ(MYST3,KAT6A)inhibits senescence via the INK4A-ARFpathway.Oncogene.2015;34(47):5807-20.

[0019] 9.Yu L,Liang Y,Cao X,Wang X,Gao H,Lin SY,et al.Identification ofMYST3 as a novel epigenetic activator of ERα frequently amplified in breastcancer.Oncogene.2017;36(20):2910-8.

[0020] 10.Sharma S,Chung J,Uryu S,Rickard A,Nady N,Khan S,et al.Abstract1130:First-in-class KAT6A / KAT6B inhibitor CTx-648(PF-9363)demonstrates potentanti-tumor activity in ER+breast cancer with KAT6A dysregulation.CancerResearch.2021;81(13_Supplement):1130-.

[0021] 11.Yan F,Li J,Milosevic J,Petroni R,Liu S,Shi Z,et al.KAT6A and ENLForm an Epigenetic Transcriptional Control Module to Drive CriticalLeukemogenic Gene-Expression Programs.Cancer Discov.2022;12(3):792-811.

[0022] 12.Liu W,Zhan Z,Zhang M,Sun B,Shi Q,Luo F,et al.KAT6A,a novelregulator ofβ-catenin,promotes tumorigenicity and chemoresistance in ovariancancer by acetylating COP1.Theranostics.2021;11(13):6278-92.

[0023] 13.Saglam O,Tang Z,Tang G,Medeiros LJ,Toruner GA.KAT6A amplificationsare associated with shorter progression-free survival and overall survival inpatients with endometrial serous carcinoma.PLoS One.2020;15(9):e0238477.

[0024] 14.Cerami E,Gao J,Dogrusoz U,Gross BE,Sumer SO,Aksoy BA,et al.ThecBio cancer genomics portal:an open platform for exploring multidimensionalcancer genomics data.Cancer Discov.2012;2(5):401-4.

[0025] 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

[0026] The present disclosure relates to compounds of formula (I):

[0027] ULM-PTM (I)

[0028] or a pharmaceutically acceptable salt or solvate thereof,

[0029] Wherein PTM is a portion of Formula IA:

[0030]

[0031] in

[0032] Y is a covalent bond or a chemical moiety connecting the PTM and the ULM;

[0033] * is the connection point with ULM;

[0034] Ring A is C6-C 10 aryl or 5-10 membered heteroaryl;

[0035] R 1 is H, D or a 5-6 membered heteroaryl group optionally substituted by methyl;

[0036] R 2 is H, D or -(C(R 8 )2) n -(5-9 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH;

[0037] R 3 is H, D or halogen, C1-C4 alkyl, cyclopropyl, haloalkyl, C1-C4 alkoxy or

[0038] Haloalkoxy;

[0039] R 4 is H, D or halogen, C1-C4 alkyl, cyclopropyl, C1-C4 alkoxy or -O-cyclopropyl;

[0040] Each R 5are independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b ;

[0041] 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)2NR 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;

[0042] Each R b are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0043] Each R c or R d are independently H, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; or

[0044] R c and R d together with the atoms to which they are both attached, form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl;

[0045] Each R 8 are independently H, D, halogen or C1-C4 alkyl;

[0046] m is 0, 1, 2, 3 or 4;

[0047] n is 0 or 1; and

[0048] ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to the Cereblon E3 ubiquitin ligase.

[0049] Stereoisomers of the compounds of Formula I and pharmaceutically acceptable salts and stereoisomers thereof are also contemplated, described and encompassed herein. Methods of using the compounds of Formula I and pharmaceutical compositions comprising the compounds of Formula I are described. DETAILED DESCRIPTION

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the art to which the present disclosure relates. The terms used in this specification are only used to describe specific embodiments and are not intended to limit the present disclosure.

[0051] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise (e.g., in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the range is provided), between the upper and lower limits of the range, and any other stated or intervening value within the stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges, which may be independently included in smaller ranges, are also encompassed within the disclosure, subject to any specifically excluded limitations within the stated range. When the stated range includes one or both of the limitations, ranges excluding either of the two included limitations are also included in the disclosure.

[0052] The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, the term is given the art-recognized meaning as applied by ordinary skilled artisans in the context of describing its use in the present disclosure.

[0053] As used herein and in the claims, the articles "a" and "an" are used herein to refer to one or more than one (e.g., at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. For example, "an element" means one element or more than one element.

[0054] The terms "co-administration" and "co-administering" or "combination therapy" can refer to both simultaneous administration (administering two or more therapeutic agents at the same time) and chronotropic administration (administering one or more therapeutic agents at a different time than the administration of the other therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent simultaneously, preferably in an effective amount. In certain preferred aspects, one or more of the compounds of the invention described herein are co-administered in combination with at least one additional biologically active agent, particularly a biologically active agent including an anticancer agent. In particularly preferred aspects, the co-administration of the compounds produces synergistic activity and / or therapy, including anticancer activity.

[0055] In the context, unless otherwise indicated, as used herein, the term "compound" refers to any specific compound disclosed herein, and includes tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), and pharmaceutically acceptable salts and derivatives thereof, including prodrugs and / or deuterated forms thereof (where applicable). Deuterated small molecules contemplated are those in which one or more hydrogen atoms contained in the drug molecule have been replaced by deuterium.

[0056] In its use in this 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) and specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds. In this context, the term also refers to a prodrug form of a compound that has been modified to facilitate administration and delivery of the compound to the active site. It should be noted that in describing the compounds herein, many substituents and variables associated therewith are described, among others. It will be understood by those of ordinary skill that the molecules described herein are stable compounds as generally described below.

[0057] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins to target substrate proteins for degradation. For example, E3 ubiquitin ligase proteins, which cause ubiquitin to attach to lysine on the target protein alone or in combination with E2 ubiquitin conjugating enzymes, and then target specific protein substrates for degradation by proteasomes. Therefore, E3 ubiquitin ligases alone or in combination with E2 ubiquitin conjugating enzymes are responsible for transferring ubiquitin to the targeted protein. In general, ubiquitin ligases involve polyubiquitination, so that the second ubiquitin is attached to the first ubiquitin; the third ubiquitin is attached to the second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by proteasomes. However, there are some ubiquitination events, which are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by ubiquitin ligases. Monoubiquitinated proteins are not targeted for degradation of the proteasome, but can, for example, be combined with other proteins with domains capable of binding ubiquitin to change their cellular location or function. To complicate matters further, different lysines of ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0058] As used herein, unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon group having up to twelve carbon atoms. In some embodiments, the number of carbon atoms (i.e., C 1- C8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-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, alkyl groups are C 1- C6 alkyl; in some embodiments, it is C 1- C4 alkyl.

[0059] When a carbon atom range is used herein, such as C1-C6, all ranges as well as individual carbon atom numbers are contemplated. For example, "C1-C3" includes C 1- C3, C 1- C2, C2- C3, C1, C2 and C3.

[0060] As used in conjunction with substituents defined herein, the term "optionally substituted" means that the substituent may, but need not, be substituted with one or more suitable functional groups or other substituents as provided herein. For example, the substituent may be optionally substituted with one or more of the following: 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, halogenated (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)2C 1-6 Alkyl, -NHCO(C 1-6 Alkyl), —N(C 1-6 alkyl)CO(C 1-6 Alkyl), —S(O)C 1-6 Alkyl, -S(O)2C 1-6 Alkyl, oxo, 6-12 membered aryl, benzyl, pyridyl, pyrazolyl, thiazolyl, isothiazolyl or other 5 to 12 membered heteroaryl. In some embodiments, each of the above optional substituents is itself optionally substituted with one or two groups.

[0061] As used herein, the term "cycloalkyl" refers to a 3-12 membered cycloalkyl, and includes bridges (e.g., adamantane) and spiro rings (e.g., spiro [3.5] nonane). Cycloalkyl can be fully saturated or partially unsaturated. The term "cycloalkyl" also includes multiple condensed ring systems (e.g., a ring system comprising 2, 3 or 4 rings), wherein a single cycloalkyl ring (as defined above) can be fused with one or more groups selected from the following to form multiple condensed ring systems: heterocycle, carbocycle, aryl or heteroaryl. Such multiple condensed ring systems can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocyclic moieties of multiple condensed rings. When the valence requirements allow, the rings of multiple condensed ring systems can be connected to each other by fusion, spiro rings and bridge bonds. It should be understood that the individual rings of multiple condensed ring systems can be connected in any order relative to each other. It should also be understood that the connection point of multiple condensed ring systems (as defined above for cycloalkyl) can be at any position of the cycloalkyl ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.1.0]heptyl, spiro[3.3]heptyl, and spiro[3.4]octyl. In some embodiments, the cycloalkyl group is a 3-7 membered cycloalkyl group.

[0062] As used herein, the term "alkenyl" refers to a C-carbon group containing at least one carbon-carbon double bond. 2- C 12 In some embodiments, alkenyl is optionally substituted. In some embodiments, alkenyl is C 2- C6 alkenyl.

[0063] As used herein, the term "alkynyl" refers to a C- 2- C 12 In some embodiments, alkenyl is optionally substituted. In some embodiments, alkynyl is C 2- C6 alkynyl.

[0064] The terms "alkoxy", "alkylamino" and "alkylthio" are used in their conventional sense and refer to those alkyl groups attached to the rest of the molecule via an oxygen atom ("oxy"), an amino group ("amino") or a thio group. The term "alkylamino" includes monoalkylamino / dialkylamino groups, and the alkyl moieties may be the same or different.

[0065]

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0066] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a heteroatom selected from S, O, P and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, alkylamides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. As used herein, a normal 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.

[0067] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a plurality of fused all-carbon ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, the aryl has 6 to 12 carbon atoms. The aryl includes a phenyl. The aryl also includes a plurality of condensed ring systems (for example, a ring system comprising 2, 3 or 4 rings) having about 9 to 12 carbon atoms, wherein at least one ring is aromatic and wherein other rings may be aromatic or non-aromatic. Such a plurality of condensed ring systems are optionally substituted by one or more (for example 1, 2 or 3) oxo groups on any carbocyclic moiety of the plurality of condensed ring systems. When the valence requirement allows, the rings of the plurality of condensed ring systems may be connected to each other by fusion, spirocycles and bridge bonds. It should be understood that the connection point of the plurality of condensed ring systems (as defined above) may be at any position of the aromatic ring. Examples of aryl include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, etc.

[0068] As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple fused 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. If the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized form. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl or furanyl. "Heteroaryl" also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings), wherein, as defined above, heteroaryl is fused to one or more rings selected from the following to form multiple fused ring systems: heteroaryl (to form, for example, naphthyridinyl, such as 1,8-naphthyridinyl), heterocycle (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycle (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazolyl). Thus, heteroaryl (single aromatic ring or multiple fused ring systems) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Heteroaryl (single aromatic ring or multiple fused ring systems) can also have about 5 to 12 or about 5 to 10 members within the heteroaryl ring. Multiple fused ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic moieties of the fused rings. When valence requirements permit, the rings of multiple fused ring systems can be connected to each other by fusion, spirocycles, and bridge bonds. It should be understood that the individual rings of multiple fused ring systems can be connected in any order relative to each other. It should also be understood that the connection point of multiple fused ring systems (as defined above for heteroaryl) can be at any position of the heteroaryl ring. It should also be understood that the connection point of heteroaryl or heteroaryl multiple fused ring systems can be at any suitable atom of the heteroaryl ring, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolyl, benzofuranyl, benzimidazolyl, thianthrandenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole, and 3b,4,4a,5-tetrahydro-1H-cyclopropyl[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, the term includes 5- and 6-membered monocyclic aromatic rings that include one or more heteroatoms.Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiazole, pyrimidine, oxazole, and thiadiazole.

[0069] As used herein, the term "heterocyclyl" or "heterocycle" refers to a single saturated or partially unsaturated ring having at least one atom other than carbon, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes a plurality of condensed ring systems having at least one such saturated or partially unsaturated ring, which will be further described below. Therefore, the term includes a single saturated or partially unsaturated ring (e.g., 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 by one or more (e.g., 1, 2 or 3) oxo groups, and sulfur and nitrogen atoms may also exist in their oxidized form. Exemplary heterocycles include, but are not limited to, azetidinyl, tetrahydrofuranyl and piperidinyl. The term "heterocycle" also includes multiple fused ring systems (e.g., ring systems containing 2, 3 or 4 rings), wherein a single heterocyclic ring (as defined above) can be fused with one or more groups selected from the following to form multiple fused ring systems: heterocyclic (to form, for example, 1,8-decahydronaphthyridinyl), carbocyclic (to form, for example, decahydroquinolinyl) and aryl. Thus, the heterocyclic ring (single saturated or single partially unsaturated ring or multiple fused ring systems) has about 2-20 carbon atoms and 1-6 heteroatoms within the heterocyclic ring. Such multiple fused ring systems can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocyclic or heterocyclic moieties of the multiple fused rings. When the valence requirements allow, the rings of the multiple fused ring systems can be interconnected by fusion, spirocyclic and bridge bonds. It should be understood that the individual rings of the multiple fused ring systems can be connected in any order relative to each other. Thus, a heterocycle (single saturated or single partially unsaturated ring or multiple fused ring systems) has about 3-20 atoms, including about 1-6 heteroatoms, within the heterocyclic ring system. It is also understood that the point of attachment of multiple fused ring systems (as defined above for heterocyclyl) can be at any position of the heterocyclic ring. It is also understood that the point of attachment of a heterocycle or heterocyclic multiple fused 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 includes 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 2-4Heterocycle. Exemplary heterocycles include, but are not limited to, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydroxyoxazolyl, 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 3-8 membered ring having at least one heteroatom. The term "heterocyclic ring" refers to a saturated or partially unsaturated 4, 5, 6 or 7 ring with at least one heteroatom. The non-limiting examples of heterocycle include aziridine, azetidine, pyrrolidine, piperidine, piperidine, piperazine, oxirane, morpholine and thiomorpholine. As used herein, the term "9 or 10 yuan heterocycle" refers to a partially unsaturated or aromatic fused bicyclic ring system with at least one heteroatom. For example, the term 9 or 10 yuan heterocycle includes a bicyclic ring system with a benzo ring fused with a 5 yuan or 6 yuan saturated, partially unsaturated or aromatic ring containing one or more heteroatoms.

[0070] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). Where feasible, nitrogen and sulfur may be present in oxidized form.

[0071] As used herein, the term "chiral" refers to molecules that have the property that their mirror image partner is non-superimposable, while the term "achiral" refers to molecules that are superimposable on their mirror image partner.

[0072] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space, eg, enantiomers, diastereomers, tautomers.

[0073] The term "patient" or "subject" is used throughout this specification to describe an animal, preferably a human or domesticated animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. For treatment of those infections, conditions, or disease states that are specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domesticated animals such as dogs or cats or farm animals such as horses, cattle, sheep, etc. In general, in this disclosure, the term patient refers to a human patient unless otherwise specified or implied by the context in which the term is used.

[0074] The term "effective" is used to describe an amount of a compound, composition, or component that, when used in the context of its intended use, achieves the intended result. The term effective encompasses all other effective amount or effective concentration terms otherwise described or used in this application.

[0075] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or state governments or their counterparts in countries outside the United States, or listed in the US Pharmacopoeia or other generally recognized pharmacopeia for use in animals (e.g., in humans).

[0076] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, which are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or from 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-ethane-disulfonic 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, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when: the 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 coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. By way of example only, salts further include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc.

[0077] "Pharmaceutically acceptable excipient" refers to a non-toxic, biologically tolerable, and otherwise biologically suitable substance, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a medicament and compatible therewith for administration to a subject. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0078] "Solvate" means a physical association of a compound of Formula I with one or more solvent molecules.

[0079] In one embodiment, "treating" or "treatment" of any disease or condition refers to ameliorating the disease or condition (i.e., preventing or reducing the development of at least one of the disease or its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to regulating the disease or condition physically (e.g., stabilization of indiscernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of a disease or condition.

[0080] In one embodiment, the present disclosure relates to compounds of formula (I):

[0081] ULM-PTM (I)

[0082] or a pharmaceutically acceptable salt or solvate thereof,

[0083] Wherein PTM is a portion of Formula IA:

[0084]

[0085] in

[0086] Y is a covalent bond or a chemical moiety connecting the PTM and the ULM;

[0087] * is the connection point with ULM;

[0088] Ring A is C6-C 10 aryl or 5-10 membered heteroaryl;

[0089] R 1 is H, D or a 5-6 membered heteroaryl group optionally substituted by methyl;

[0090] R 2is H, D or -(C(R 8 )2) n -(5-9 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH;

[0091] R 3 is H, D or halogen, C1-C4 alkyl, cyclopropyl, haloalkyl, C1-C4 alkoxy or

[0092] Haloalkoxy;

[0093] R 4 is H, D or halogen, C1-C4 alkyl, cyclopropyl, C1-C4 alkoxy or -O-cyclopropyl;

[0094] Each R 5 are independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b ;

[0095] 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 Rc 、-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)2NR 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;

[0096] Each R b are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0097] Each R c or R d are independently H, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; or

[0098] R c and R d together with the atoms to which they are both attached, form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl;

[0099] Each R 8 are independently H, D, halogen or C1-C4 alkyl;

[0100] m is 0, 1, 2, 3 or 4;

[0101] n is 0 or 1; and

[0102] ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to the Cereblon E3 ubiquitin ligase.

[0103] In some embodiments, the compound of Formula I includes a protein targeting moiety (PTM). In some embodiments, the PTM in the compound of Formula I is a moiety of Formula IA

[0104]

[0105] According to the present disclosure, Y in Formula IA is a covalent bond or a chemical moiety that connects PTM and ULM. In some embodiments, Y in Formula IA is a chemical moiety that connects PTM and ULM. In other embodiments, Y in Formula IA is a covalent bond.

[0106] According to the present disclosure, Ring A in Formula IA is C6-C 10 In some embodiments, ring A in formula IA is C6-C 10 In some embodiments, Ring A in Formula IA is phenyl. In other embodiments, Ring A in Formula IA is a 5-10 membered heteroaryl.

[0107] According to the present disclosure, R in Formula IA 1 is H, D or a 5-6 membered heteroaryl optionally substituted with methyl. In some embodiments, R in 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 group optionally substituted by a methyl group.

[0108] According to the present disclosure, R in Formula IA 2 is H, D or -(C(R 8 )2) n -(5-9 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH. In some embodiments, R in Formula IA 2 is H. In some embodiments, R in Formula IA 2 is D. In other embodiments, R in Formula IA 2 is -(C(R 8 )2) n -(5-9 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH.

[0109] In yet other embodiments, R in Formula IA 2 is H or -(C(R 8 )2) n -(5-6 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH. In some embodiments, when R in Formula IA 2 -(C(R8 )2) n -(5-6 membered heteroaryl), the 5-6 membered heteroaryl is pyrazole, pyrrole, pyridine or pyridazine. In some embodiments, when R in Formula IA 2 -(C(R 8 )2) n -(5-6 membered heteroaryl), the 5-6 membered heteroaryl is pyrazole.

[0110] According to the present disclosure, R in Formula IA 8 is H, D, halogen or C1-C4 alkyl. In some embodiments, R in Formula IA 8 is H. In some embodiments, R in Formula IA 8 is D. In other embodiments, R in Formula IA 8 In other embodiments, R in Formula IA 8 It is a C1-C4 alkyl group.

[0111] According to the present disclosure, n in Formula IA is 0 or 1. In some embodiments, n in Formula IA = 0. In other embodiments, n in Formula IA = 1.

[0112] According to the present disclosure, R in Formula IA 3 is H, D, halogen, C1-C4 alkyl, cyclopropyl, haloalkyl, C1-C4 alkoxy or haloalkoxy. In some embodiments, R in Formula IA 3 is H. In some embodiments, R in Formula IA 3 is D. In some embodiments, R in Formula IA 3 In some embodiments, R in Formula IA 3 is a C1-C4 alkyl group. In other embodiments, R in Formula IA 3 In other embodiments, R in Formula IA 3 is a C1-C4 haloalkyl group. In other embodiments, R 3 is C1-C4 alkoxy. In other embodiments, R in Formula IA 3 It is a halogenated alkoxy group.

[0113] According to the present disclosure, R in Formula IA 4 is H, D, halogen, C1-C4 alkyl, cyclopropyl, C1-C4 alkoxy or -O-cyclopropyl. In some embodiments, R in Formula IA 4 is H. In some embodiments, R in Formula IA 4 is D. In some embodiments, R in Formula IA 4 In some embodiments, R in Formula IA 4is a C1-C4 alkyl group. In other embodiments, R in Formula IA 4 In other embodiments, R in Formula IA 4 is C1-C4 alkoxy. 4 In other embodiments, R in Formula IA 4 It is a methoxy group.

[0114] According to the present disclosure, each R in Formula IA 5 are independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b ;

[0115] 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(ORc )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)2NR 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;

[0116] Each R b are independently H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0117] Each R c or R d are independently H, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; or

[0118] R c and R d together with the atoms to which they are both attached, form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl;

[0119] According to the present disclosure, each R in Formula IA 5 is independently H, D, 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. In some embodiments, at least one R in Formula IA 5 is H. In some embodiments, each R in Formula IA 5 is D. In some embodiments, at least one R in Formula IA 5 In some embodiments, each R5 in Formula IA is C1-C4 alkoxy. In some embodiments, at least one R in Formula IA is 5 It is a C1-C4 alkoxy group.

[0120] In other embodiments, at least one R in Formula IA 5In other embodiments, at least one R in Formula IA 5 In other embodiments, at least one R in Formula IA 5 is a C1-C4 alkyl group. In other embodiments, at least one R in Formula IA 5 In other embodiments, at least one R in Formula IA 5 In other embodiments, at least one R in Formula IA 5 In other embodiments, at least one R in Formula IA 5 In other embodiments, at least one R in Formula IA 5 In other embodiments, at least one R in Formula IA 5 In other embodiments, at least one R in Formula IA 5 It is -C(O)N(H)CH3.

[0121] According to the present disclosure, m in Formula IA is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m in Formula IA = 1. In other embodiments, m in Formula IA = 2. In other embodiments, m in Formula IA = 3. In other embodiments, m in Formula IA = 4.

[0122] According to the present disclosure, a ULM is a small molecule E3 ubiquitin ligase binding moiety that binds to a Cereblon E3 ubiquitin ligase. In some embodiments, a ULM is a moiety as described herein.

[0123] Chemical moieties for linking PTM and ULM moieties are known in the art. These moieties are sometimes referred to as "linkers" in the art. In some embodiments, Y in Formula IA is a chemical moiety known in the art for linking PTM and ULM.

[0124] In some embodiments, Y in Formula IA is a chemical moiety for linking a PTM and a ULM, as described in U.S. Patent Application Publication No. 2019 / 0300521, the entire contents of which are incorporated herein by reference.

[0125] In other embodiments, Y in Formula IA is a chemical moiety for linking a PTM and a ULM, as described in U.S. Patent Application Publication No. 2019 / 0255066, the entire contents of which are incorporated herein by reference.

[0126] In other embodiments, Y in Formula IA is a chemical moiety used to link a PTM and a ULM, as described in WO 2019 / 084030, the entire contents of which are incorporated herein by reference.

[0127] In other embodiments, Y in Formula IA is a chemical moiety used to link a PTM and a ULM, as described in WO 2019 / 084026, the entire contents of which are incorporated herein by reference.

[0128] In some embodiments, Y in Formula IA is a chemical structural unit represented by the following formula:

[0129] -(A) q -,

[0130] in:

[0131] q is an integer from 1 to 14;

[0132] Each A is independently selected from the group consisting of: CR 1a R 1b 、O、S、SO、SO2、NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d ,CO,CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a , (CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b )1-4 NR 1c (CR 1a R 1b ) 1-4 NR 1c C(=NCN)NR 1d NR 1c C(=NCN),NR 1c C(=CNO2)NR 1d , optionally 0-6 R 1a or R 1b 3-11 membered cycloalkyl substituted with 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group, optionally substituted by 0-6 R 1a or R 1b The aryl group is optionally substituted with 0-6 R 1a or R 1b a substituted heteroaryl group,

[0133] And R 1a , R 1b , R 1c , R 1d and R 1eeach independently represents -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, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH2, -S H, -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, -SO2NHC1-C8 alkyl, -SO2N(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 -N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH 2； or, where the context permits, R 1a or R 1b is connected to other groups or to each other to form a group optionally with 0-4 R 1e The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

[0134] In these examples, q represents the number of attached A groups. For example, when q=1, -(A) q - is -A1-; when 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-; when q=5, -(A) q - is -A1-A2-A3-A4-A5-; when q=6, -(A) q - is -A1-A2-A3-A4-A5-A6-; when q=7, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-; when q=8, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-; when q=9, -(A) q - is -A1-A2-A3-A4-A5-A6-A7-A8-A9-; when q=10, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -; when q=11, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -; When q = 12, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -; When q = 13, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 -; and when q = 14, -(A) q -for-A1-A2-A3-A4-A5-A6-A7-A8-A9-A 10 -A 11 -A 12 -A 13 -A 14 -.

[0135] In some embodiments, q=4, and Y in Formula IA is a chemical moiety represented by the formula: -A1-A2-A3-A4-, wherein A 1-4 Each of which is independently selected from the group consisting of: O, S, SO, SO2, NR 1c 、SO2NR 1c ,SONR 1c、SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d ,CO,CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a , (CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR 1c (CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0136] Where R 1a and R 1bEach is independently selected from the group consisting of: -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, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -O H, -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, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0137] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0138] In other embodiments, q=3, and Y in Formula IA is a chemical moiety represented by the formula: -A1-A2-A3-, wherein A 1-3Each of which is independently selected from the group consisting of: O, S, SO, SO2, NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d ,CO,CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a , (CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR 1c (CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0139] Where R 1a and R 1beach independently selected from the group consisting of: -H, D, halogen, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -O H, -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, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0140] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0141] In other embodiments, q=2, and Y in Formula IA is a chemical moiety represented by the formula: -A1-A2-, wherein A 1-2Each of which is independently selected from the group consisting of: O, S, SO, SO2, NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d ,CO,CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a , (CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR 1c (CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0142] Where R 1a and R 1beach independently selected from the group consisting of: -H, D, halogen, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -O H, -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, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0143] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0144] In other embodiments, q=1, and Y in Formula IA is a chemical moiety represented by the formula: -A1-, wherein A1 is selected from the group consisting of: O, S, SO, SO2, NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d ,CO,CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a , (CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR 1c (CR 1a R 1b ) 1-4 , optionally substituted 3-11 membered cycloalkyl, 3-11 membered heterocyclyl, aryl and heteroaryl;

[0145] Where R 1a and R 1beach independently selected from the group consisting of: -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, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 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-C8 alkyl )3, -Si(OH)(C1-C8 alkyl)2, -C(O)C1-C8 alkyl, -C(O)OC1-C8 alkyl, -CO2H, -CN, -NO2, -SF5, -SO2NHC1-C8 alkyl, -SO2N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and

[0146] R 1c and R 1d are each independently selected from the group consisting of: H, D, optionally substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, aryl or heteroaryl.

[0147] In some embodiments, Y in Formula IA is a covalent bond, optionally substituted by 0-6 R 1a or R 1b3-11 membered cycloalkyl substituted with 0-6 R 1a or R 1b 3-11 membered heterocyclic group substituted by a group, -(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)-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(C≡C)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c 、-(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 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group)-, -(optionally substituted by 0-6 R 1a or R 1b 3-11-membered cycloalkyl substituted with a group)-(CR 1a R 1b ) 1-5 -, -(optionally with 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 -、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group)-A-, -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl substituted with a group)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-A-, wherein A is O, S or NR1c 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl 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-(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-, wherein A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group)-A-, wherein A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group)-, wherein A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl substituted with a group)-(CR 1a R1b ) 1-5 -A-, where A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-, wherein A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl substituted with a group)-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 -A-, wherein each A is independently 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 -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 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl 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)-(optionally with 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-, wherein A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by 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)-(optionally with 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group)-, wherein A is O, S or NR 1c 、-(CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-A-(CO)-, wherein each A is independently O, S or NR 1c, -(optionally 0-6 R 1a or R 1b 3-11-membered cycloalkyl 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 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl 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 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 -A-(CO)-, where A is O, S or NR 1c , -(optionally 0-6 R 1a or R 1b 3-11-membered cycloalkyl substituted with a group)-(CR 1a R 1b ) 1-5 -or-(optionally with 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5- .

[0148] In some embodiments, Y in Formula IA is -CR 1a =CR 1b -, for example, -CH=CH-.

[0149] In some embodiments, Y in Formula IA is (CR 1a R 1b ) 1-5 , for example (CH2) 1-5 -, -CH2-, -CH2CH2CH2-, etc.

[0150] In some embodiments, Y in Formula IA is -(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR1c , 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-.

[0151] In other embodiments, Y in Formula IA is -(CR 1a R 1b ) 1-5 -A-(CR 1a R 1b ) 1-5 -, where A is O, S or NR 1c , for example, -(CH2) 1-5 -O-(CH2) 1-5 -、-(CH2) 1-5 -S-(CH2) 1-5 -、-(CH2) 1-5 -NH-(CH2) 1-5 -.

[0152] In some embodiments, Y in Formula IA is -(C≡C)-(CR 1a R 1b ) 1-5 , for example, -(C≡C)-(CH2)2-, etc.

[0153] In some embodiments, Y in Formula IA is -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-, for example, -CH2-cyclobutyl-.

[0154] In some embodiments, Y in Formula IA is -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl substituted with a group)-(CR 1a R 1b ) 1-5 , for example, -CH2-cyclobutyl-CH2-, etc.

[0155] In some embodiments, Y in Formula IA is -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 , for example, -CH2-azetidinyl-CH2-.

[0156] In some embodiments, Y in Formula IA is -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b substituted 3-11 membered heterocyclyl)-, for example, -CH2-azetidinyl-.

[0157] In some embodiments, Y in Formula IA is -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 -, for example, -azetidinyl-CH2-, -pyrrolidinyl-CH2- and -piperidinyl-CH2- and the like.

[0158] In some embodiments, Y in Formula IA is (CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered cycloalkyl 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-, etc.

[0159] In some embodiments, Y in Formula IA is -(CR 1a R 1b ) 1-5 -(optionally replaced by 0-6 R 1a or R 1b 3-11-membered heterocyclic group substituted by a group)-(CR 1a R 1b ) 1-5 -A-, where A is O, S or NR 1c , for example, -CH2-piperidinyl-CH2CH2-O-, etc.

[0160] In some embodiments, Y in Formula IA is (CR 1a R 1b ) 1-5-(optionally replaced by 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group)-A-, wherein A is O, S or NR 1c , for example, -CH2-azetidinyl-O-, and the like.

[0161] In some embodiments, Y in Formula IA is (CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group)-, wherein A is O, S or NR 1c , for example, -CH2-O-azetidinyl-, -CH2-NH-azetidinyl-, and the like.

[0162] In other embodiments, Y in Formula IA is (CR 1a R 1b ) 1-5 -A-(optionally replaced by 0-6 R 1a or R 1b substituted 3-11-membered cycloalkyl)-, wherein A is O, S or NR 1c , such as -CH2-O-cyclobutene-, -CH2-NH-cyclobutene-, etc.

[0163] In some embodiments, Y in 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-.

[0164] In some embodiments, Y in Formula IA is

[0165] in

[0166] ** is the connection point with PTM;

[0167] L1, L2, and L3 are each independently a bond, CR 1a R 1b 、O、S、SO、SO2、NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d ,CO,CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a , (CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR 1c (CR 1a R 1b ) 1-4 NR 1c C(=NCN)NR 1d NR 1c C(=NCN),NR 1c C(=CNO2)NR 1d ;

[0168] Ring A1 and Ring A2 are each independently optionally substituted with 0-6 R 1a or R 1b 3-11 membered cycloalkyl substituted with 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group, optionally substituted by 0-6 R 1a or R 1b The aryl group is optionally substituted with 0-6 R 1a or R 1b a substituted heteroaryl group,

[0169] Where R 1a , R 1b , R 1c , R 1d and R 1eEach is 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, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 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, -SO2NHC1-C8 alkyl, -SO2N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and wherein R 1a or R 1b Each independently may be optionally linked to other groups to form a group optionally with 0-4 R 1e The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

[0170] In some embodiments, Y in Formula IA is

[0171] in

[0172] ** is the connection point with PTM;

[0173] L1 is a bond, (C(R 10 )2) p or CO;

[0174] L2 is a bond, (C(R 10 )2) p or CO;

[0175] L3 is a bond, (C(R 10 )2) p or CO;

[0176] Each p is independently 1, 2, 3 or 4;

[0177] Each R 10 are independently H, D or C1-C4 alkyl;

[0178] Ring A1 is 3-7 membered cycloalkyl, 4-10 membered heterocycloalkyl, aryl or heteroaryl; and

[0179] Ring A2 is a 3- to 7-membered cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, an aryl group or a heteroaryl group.

[0180] According to the present disclosure, L1 is a bond, (C(R 10 )2) p or CO. In some embodiments, L1 is a bond. In some embodiments, L1 is (C(R 10 )2) p In other embodiments, L1 is CO.

[0181] 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.

[0182] 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.

[0183] According to the present disclosure, each p is independently 1, 2, 3, or 4. In some embodiments, each 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.

[0184] 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 a C1-C4 alkyl group. In other embodiments, at least one R 10 is a C1-C4 alkyl group. In other embodiments, each R 10 is methyl or ethyl. In other embodiments, at least one R 10 It is methyl or ethyl.

[0185] According to the present disclosure, Ring A1 is a 3-7 membered cycloalkyl, a 4-10 membered heterocycloalkyl, an aryl or a heteroaryl. In some embodiments, Ring A1 is a 3-7 membered cycloalkyl. In some embodiments, Ring A1 is a 4-10 membered heterocycloalkyl. In other embodiments, Ring A1 is an aryl. In other embodiments, Ring A1 is a heteroaryl.

[0186] In some embodiments, Ring A1 is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, or azabicycloalkyl. In other embodiments, Ring A1 is piperidine or pyrrolidinyl.

[0187] According to the present disclosure, Ring A2 is a 3-7 membered cycloalkyl, a 4-10 membered heterocycloalkyl, an aryl or a heteroaryl. In some embodiments, Ring A2 is a 3-7 membered cycloalkyl. In some embodiments, Ring A2 is a 4-10 membered heterocycloalkyl. In other embodiments, Ring A2 is an aryl. In other embodiments, Ring A2 is a heteroaryl.

[0188] In some embodiments, ring A2 is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, diazaspiroalkyl or azabicycloalkyl. In other embodiments, ring A2 is piperazinyl or diazaspironanyl.

[0189] In some embodiments, Y in Formula IA is

[0190] in

[0191] L1, L2 and Ring A1 are as defined herein;

[0192] r is 0, 1, or 2;

[0193] s is 0, 1, or 2; and

[0194] Z is N or CR 10 ;and

[0195] R 10 As defined herein.

[0196] According to 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.

[0197] According to 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.

[0198] According to the present disclosure, Z is N or CR 10 In some embodiments, Z is N. In other embodiments, Z is CR 10 .

[0199] According to the present disclosure, ULM in Formula I is

[0200]

[0201] in:

[0202] is the connection point with Y or PTM;

[0203] Ring A3 is a monocyclic, bicyclic or tricyclic aryl, heteroaryl or heterocyclic group,

[0204] L4 is a bond, -O-, -S-, -NR a -、-C(R a )2-、-C(O)NR a -;

[0205] X1 is CH2, CO, CH=CH (when X2=CO) or N=CH (when X2=CO);

[0206] X2 is CH2, CO, CH=CH (when X1=CO) or N=CH (when X1=CO);

[0207] R 12 is H, D, optionally substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -CN, -OR a 、-ORb or -SR b ;

[0208] Each R 15 are independently H, D, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b ;

[0209] 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)OR c OR b 、-S(O)R b 、-S(O)NRc R d 、-S(O)2R b 、-S(O)2NR 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;

[0210] Each R b are independently H, D, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl or heterocycloalkenyl;

[0211] Each R c or R d H, D, -C1-C 10 Alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -OC1-C6 alkyl, -O-cycloalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; or

[0212] R c and R d together with the atoms to which they are both attached, form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl; and

[0213] o is 1, 2, 3, 4, or 5.

[0214] 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.

[0215] In some embodiments, Ring A3 is a bicyclic heterocyclic group. In some embodiments, Ring A3 is isoindolinyl. In other embodiments, Ring A3 is isoindolin-1-onyl. In other embodiments, Ring A3 is isoindolin-3-onyl. In other embodiments, Ring A3 is isoindolin-1,3-dione.

[0216] 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- C1 alkylaryl, C 0- C1 alkylheteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, -ORa 、-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)2NR 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)2R b .

[0217] 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 15 is D. In some embodiments, each R 15 is a C1-C6 alkyl group. In some embodiments, at least one R 15 is a C1-C6 alkyl group. In some embodiments, each R 15 is methyl or ethyl. In some embodiments, at least one R 15 It is methyl or ethyl.

[0218] In other embodiments, each R 15 independently selected from halogen, oxo, -OH, -CN, -NO2, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b .

[0219] According to 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.

[0220] 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 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 -.

[0221] 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).

[0222] 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).

[0223] According to the present disclosure, R 12 is H, D, optionally substituted C 1-4 Alkyl, C 1-4Alkoxy, 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 C 1-4 In other embodiments, R 12 C 1-4 In other embodiments, R 12 C 1-4 In other embodiments, R 12 In other embodiments, R 12 For-OR a In other embodiments, R 12 For-OR b In other embodiments, R 12 For-SR b .

[0224] According to the present disclosure, ULM in Formula I is

[0225]

[0226] in:

[0227] is the connection point with Y or PTM;

[0228] R 15 As defined herein;

[0229] X3 is CH2, CO, CH=CH (when X4=CO) or N=CH (when X4=CO); and

[0230] X4 is CH2, CO, CH=CH (when X3=CO) or N=CH (when X3=CO).

[0231] 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).

[0232] 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).

[0233] According to the present disclosure, PTM is a compound of formula IA-1

[0234]

[0235] or a pharmaceutically acceptable salt thereof; wherein R 2 , R 4 , (R 5 ) m and Y are as defined herein.

[0236] According to the present disclosure, PTM is a compound of formula IA-2

[0237]

[0238] or a pharmaceutically acceptable salt thereof; wherein R 2 , R 4 , (R 5 ) m and Y are as defined herein.

[0239] According to the present disclosure, PTM is a compound of formula IA-3

[0240]

[0241] 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.

[0242] According to the present disclosure, PTM is a compound of formula IA-4

[0243]

[0244] 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.

[0245] According to the present disclosure, PTM is a compound of formula IA-5

[0246]

[0247] 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.

[0248] According to the present disclosure, PTM is a compound of formula IA-6

[0249]

[0250] 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.

[0251] According to the present disclosure, PTM is a compound of formula IA-7

[0252]

[0253] 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 wherein t is 1 or 2.

[0254] According to the present disclosure, t is 1 or 2. In some embodiments, t is 1. In other embodiments, t is 2.

[0255] In some embodiments, the compound according to claim is

[0256] 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;

[0257] 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;

[0258] 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;

[0259] 3-[4-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-7-azaspiro[3.5]non-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide;

[0260] 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-benzooxazol-3-yl]benzenesulfonamide;

[0261] 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-benzooxazol-3-yl]benzenesulfonamide;

[0262] 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;

[0263] 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-benzooxazol-3-yl]benzenesulfonamide;

[0264] 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-benzooxazol-3-yl]benzenesulfonamide;

[0265] 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-benzooxazol-3-yl]benzenesulfonamide;

[0266] 3-[6-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,6-diazaspiro[3.3]hept-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide;

[0267] or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the compound according to claim is

[0269] 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;

[0270] 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;

[0271] 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;

[0272] 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]dec-2-yl)benzenesulfonamide;

[0273] 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;

[0274] 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)benzenesulfonamide;

[0275] 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)benzenesulfonamide;

[0276] 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;

[0277] 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]undec-3-yl)benzenesulfonamide;

[0278] 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;

[0279] 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]non-2-yl)benzenesulfonamide;

[0280] 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;

[0281] 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;

[0282] 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;

[0283] 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;

[0284] 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;

[0285] 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;

[0286] 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;

[0287] 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;

[0288] 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;

[0289] 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-benzooxazol-3-yl]benzenesulfonamide;

[0290] 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;

[0291] 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;

[0292] 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;

[0293] 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;

[0294] 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;

[0295] 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;

[0296] 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]undec-3-yl)benzenesulfonamide;

[0297] 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;

[0298] 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;

[0299] 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;

[0300] or a pharmaceutically acceptable salt thereof.

[0301] It will be apparent that the compounds of the present invention, including all subclasses described herein, can have multiple stereocenters. Thus, there are multiple stereoisomers (enantiomers and diastereomers) of the compounds (and subclasses described herein). The present disclosure contemplates and encompasses every stereoisomer of any compound encompassed by the present disclosure, as well as mixtures of such stereoisomers.

[0302] Pharmaceutically acceptable salts and solvates of the compounds of the present disclosure, including all subgenuses described herein, are also within the scope of the present disclosure.

[0303] The present disclosure also contemplates isotopic variants of the compounds of the present disclosure (including all subclasses described herein). Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen are tritium and deuterium.

[0304] Pharmaceutical compositions and methods of administration

[0305] The pharmaceutical composition of the present invention is usually formulated to provide a therapeutically effective amount of the disclosed compound in the form of an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where necessary, the pharmaceutical composition contains a pharmaceutically acceptable salt and / or coordination complex thereof and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants.

[0306] Pharmaceutical composition of the present invention can be used alone or in combination with one or more other medicaments, and described other medicaments are also usually used in the form of pharmaceutical composition. When necessary, one or more compounds of the present invention and other medicaments can be mixed into preparations, or two components can be formulated into independent preparations so that they can be used in combination alone or simultaneously.

[0307] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the invention is less than 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%, 0.1% or less. 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v or v / v.

[0308] In some embodiments, the concentration of one or more compounds of the invention is greater than 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%, 14.5 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%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or a number within a range defined by and including any two of the above numbers) w / w, w / v or v / v.

[0309] In some embodiments, the concentration of one or more compounds of the invention is between about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 26%, about 0.09% to about 27%, about 0.10% to about 28%, about 0.11% to about 29%, about 0.12% to about 29%, about 0.13% to about 29%, about 0.14% to about 29%, about 0.15% to about 29%, about 0.16% to about 29%, about 0.17% to about 29%, about 0.18% to about 29%, about 0.19% to about 29%, about 0.20% to about 29%, about 0.21% to about 29%, about 0.22% to about 29%, about 0.23% to about 29%, about 0.24% to about 29%, about 0.25% to about 29%, about 0.26% to about 29%, about 0.27% to about 29%, about 0.28% to about 29%, about 0. In the range of 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%, about 1% to about 10% w / w, w / v or v / v.

[0310] In some embodiments, the concentration of one or more compounds of the invention is in 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%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0311] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 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. 0.002g, 0.001g, 0.0009g, 0.0008g, 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 a number within a range defined by and including any two of the above numbers).

[0312] In some embodiments, the amount of one or more compounds of the invention is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 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 .045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095 g, 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, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or numbers within the range defined by and including any two of the above numbers).

[0313] In some embodiments, the amount of one or more compounds of the invention ranges from 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.

[0314] Compounds according to the present invention are effective in a wide range of dosages. For example, when treating adults, 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used. An exemplary dosage is 10 to 30 mg per day. Exact dosage will depend on route of administration, compound administration form, subject to be treated, subject to be treated, weight, and preference and experience of the attending physician.

[0315] The pharmaceutical compositions of the present invention generally contain 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, penetration enhancers, solubilizers and adjuvants.

[0316] Non-limiting exemplary pharmaceutical compositions and methods for their preparation are described below.

[0317] Pharmaceutical compositions for oral administration .

[0318] In some embodiments, the present invention provides a pharmaceutical composition for oral administration, which contains a compound of the present invention and a pharmaceutical excipient suitable for oral administration.

[0319] In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration, which contains: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[0320] In some embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical composition of the present invention suitable for oral administration can be presented in discrete dosage forms, such as capsules, cachets or tablets, or each containing a predetermined amount of active ingredients in the form of powders or granules in a liquid or aerosol spray, solution, or suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or an oil-in-water liquid emulsion. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier, which constitutes one or more essential ingredients. Typically, the composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely powdered solid carrier or both, and then forming the product into a desired presentation form when necessary. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine an active ingredient in a free-flowing form (such as a powder or granule) optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent and / or a surfactant or a dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0321] The present invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water may promote the degradation of some compounds. For example, in the pharmaceutical field, water (e.g., 5%) may be added as a means of simulating long-term storage to determine the properties of the formulation over time, such as shelf life or stability. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. If substantial contact with moisture and / or moisture is expected during manufacture, packaging and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made water-free. Anhydrous pharmaceutical compositions can be prepared and stored in a manner that maintains the anhydrous nature of the anhydrous pharmaceutical composition. Therefore, anhydrous compositions can be packaged using materials known to prevent exposure to water so that the composition can be included in a suitable prescribed kit. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, etc., unit dose containers, blister packs, and strip packs.

[0322] According to conventional pharmaceutical compounding techniques, the active ingredient can be closely mixed with a pharmaceutical carrier. The carrier can be in various forms depending on the desired preparation form for administration. When preparing a composition of an oral dosage form, in the case of an oral liquid preparation (such as a suspension, solution, and elixir) or an aerosol, any commonly used pharmaceutical medium can be used as a carrier, such as water, ethylene glycol, oil, alcohol, flavoring agent, preservative, colorant, etc.; or in the case of an oral solid preparation, carriers such as starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binder, and disintegrant can be used, and lactose is not used in some embodiments. For example, in the case of a solid oral preparation, suitable carriers include powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0323] 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 (e.g., acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum), cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0324] 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 powders), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0325] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that may disintegrate in the bottle. Too little disintegrant may not be enough to cause disintegration to occur, and may therefore change the rate and extent of release of one or more active ingredients from the dosage form. Therefore, a sufficient amount of disintegrant (which will not adversely change the release of one or more active ingredients due to too little or too much) can be used to form a dosage form of the compound disclosed herein. The amount of disintegrant used can vary based on the type of formulation and the mode of administration and can be easily discerned by a person of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant or about 1 to about 5% by weight 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.

[0326] Lubricants that can be used to form pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talcum, 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 a mixture thereof. Additional lubricants include, for example, a condensed aerosol of synthetic silica, synthetic silicon dioxide or a mixture thereof. Optionally, a lubricant can be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0327] When aqueous suspensions and / or elixirs are required for oral administration, the active ingredient therein may be mixed with various sweetening or flavoring agents, coloring agents or dyes and, if desired, emulsifying and / or suspending agents and such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0328] Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0329] 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. That is, 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.

[0330] Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. 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 more soluble in oils, while surfactants with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions.

[0331] Hydrophilic surfactants are generally considered to be those 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 equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide that is commonly used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0332] The hydrophilic surfactant can be an ionic or nonionic surfactant. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidates; 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 their derivatives; lysolecithin and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylates; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0333] Within the above group, ionic surfactants include, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acyl lactylations; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citric acid esters of monoglycerides and diglycerides; and mixtures thereof.

[0334] The ionic surfactant can be an ionized form of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactates, stearoyl-2-lactate, stearoyl lactylate, succinylated monoglycerides, monoacetylated / diacetylated tartaric acid esters of monoglycerides / diglycerides, citrate esters of monoglycerides / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linolenate, stearate, dodecyl sulfate, tetradecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0335] The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauric acid polyethylene glycol glyceride; 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 transesterification products of polyols having 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 transesterification products of polyols having 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.

[0336] Other hydrophilic nonionic surfactants include, but are not limited to, 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, PEG-20 dilaurate, PEG-25 triolein, 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 capric / caprylic glycerides, PEG-8 capric / caprylic glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleate, PEG-40 behenate Sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series and poloxamer.

[0337] By way of example only, suitable lipophilic surfactants include: 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; lactic acid derivatives of mono- and diglycerides; hydrophobic transesterification products of polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols having at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0338] In one embodiment, the composition can include a solubilizing agent to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This is particularly important for compositions for non-oral use (e.g., compositions for injection). A solubilizing agent can also be added to increase the solubility of hydrophilic drugs and / or other components such as surfactants or to keep the composition as a stable or uniform solution or dispersion.

[0339] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, oxyalkylene glycols, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycogen) or methoxy PEG; amides and other nitrogen-containing compounds, such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, 2-caprolactam ... pyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters 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 solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, caprylic acid monoglyceride, diethylene glycol monoethyl ether and water.

[0340] Mixtures of solubilizing agents can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methyl pyrrolidone, N-hydroxyethyl pyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycogen, oxydiol, propylene glycol and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen and propylene glycol.

[0341] The amount of the solubilizing agent that can be included is not particularly limited.The amount of a given solubilizing agent can be limited to the biologically acceptable amount that can be easily determined by those skilled in the art.In some cases, it may be advantageous to include a solubilizing agent that exceeds the biologically acceptable amount by an amount, for example, to maximize the concentration of the medicine, wherein before providing compositions to the experimenter, conventional techniques such as distillation or evaporation are used to remove excessive solubilizing agents.Therefore, by the combined weight of medicine and other excipients, the weight ratio of solubilizing agent (if present) can be 10 % by weight, 25 % by weight, 50 % by weight, 100 % by weight or at most about 200 % by weight.If desired, a very small amount of solubilizing agent can also be used, such as 5%, 2%, 1% or even less.Typically, a solubilizing agent can exist with an amount of about 1 % by weight to about 100 % by weight, more typically about 5 % by weight to about 25 % by weight.

[0342] The composition may further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adherents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicifiers, flavoring agents, colorants, flavor enhancers, opacifiers, suspending agents, adhesives, fillers, plasticizers, lubricants, and mixtures thereof.

[0343] In addition, acids or bases can be incorporated into the composition to facilitate processing, enhance stability or achieve other purposes. 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 as salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, methanesulfonic 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, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc. Salts of polyprotic acids can also be used, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, etc. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0344] Suitable acid is a pharmaceutically acceptable organic acid or inorganic acid. 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, methanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinonesulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, etc.

[0345] Pharmaceutical composition for injection .

[0346] In some embodiments, the present invention provides a pharmaceutical composition for injection, which contains a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the pharmaceutical agents in the composition are as described herein.

[0347] Forms into which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0348] Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. Can be, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of a dispersant and by using a surfactant to maintain appropriate fluidity. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0349] Sterile injectable solutions are prepared by incorporating the compound of the present invention in a suitable solvent as required with the various other ingredients listed above, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other ingredients required from the ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, some desirable preparation methods are vacuum drying and freeze drying techniques, which produce powders of active ingredients and produce any additional desired ingredients from their previously sterile filtered solutions.

[0350] Pharmaceutical compositions for topical (eg, transdermal) delivery .

[0351] In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery, which contains a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0352] The composition of the present invention can be formulated into a solid, semi-solid or liquid preparation suitable for local or topical application, such as gel, water-soluble jelly, cream, lotion, suspension, foam, powder, slurry, ointment, solution, oil, paste, suppository, spray, emulsion, saline solution, dimethyl sulfoxide (DMSO)-based solution. Generally, a carrier with a higher density can provide an area exposed to the active ingredient for a long time. In contrast, a solution formulation can expose the active ingredient more directly to the selected area.

[0353] The pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient, which is a compound that increases the penetration of the therapeutic molecule across the stratum corneum permeability barrier of the skin or aids in delivering the therapeutic molecule across the stratum corneum permeability barrier of the skin. There are many such penetration enhancing molecules available to those trained in the art of topical formulations.

[0354] Examples of such carriers and excipients include, but are not limited to, wetting agents (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), pyrrolidones, glyceryl 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 glycols.

[0355] Another exemplary formulation for use in the methods of the present invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, with or without another agent.

[0356] The construction and use of transdermal patches for delivering medicaments are well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches can be configured for continuous, pulsatile, or on-demand delivery of medicaments.

[0357] Pharmaceutical compositions for inhalation .

[0358] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by oral or nasal respiratory route to produce local or systemic effects. Compositions preferably in pharmaceutically acceptable solvents may be atomized by the use of an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be attached to a mask tampons or intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be preferably administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0359] Other pharmaceutical compositions .

[0360] 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. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G., eds., Handbook of Clinical Drug Data, 10th ed., McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, 3rd ed., Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, 9th ed., McGraw-Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, 10th ed., McGraw-Hill, 2001; Remingtons Pharmaceutical Sciences, 13th ed., Sciences, 20th ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, 32nd ed. (The Pharmaceutical Press, London, 1999); all references are incorporated herein by reference in their entirety.

[0361] The administration of the compound or pharmaceutical composition of the present invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), local (e.g., transdermal application), rectal administration, local delivery by catheter or stent, or by inhalation. The compound can also be administered intrafatally or intrathecally.

[0362] In some embodiments, the compounds or pharmaceutical compositions of the invention are administered by intravenous injection.

[0363] The amount of the compound administered will depend on the severity of the subject being treated, the disease or condition, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. However, whether in a single dose or in divided doses, the effective dose is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day. For a 70 kg person, this will be equivalent to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some cases, the dosage level below the lower limit of the above range may exceed a sufficient amount, and in other cases, still larger dosages can be used without causing any harmful side effects, such as by dividing such larger doses into several small doses for full-day administration.

[0364] In some embodiments, compounds of the invention are administered in a single dose.

[0365] Typically, such administration will be by injection, such as intravenous injection, to quickly introduce the agent. However, other routes may be used as appropriate. Single doses of the compounds of the invention may also be used to treat acute conditions.

[0366] In some embodiments, the compounds of the present invention are administered in multiple doses. It can be administered about once a day, twice a day, three times a day, four times a day, five times a day, six times a day, or more than six times a day. It can be administered about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compounds of the present invention and another medicament are administered together about once a day to about 6 times a day. In another embodiment, the administration of the compounds of the present invention and the medicament continues to be less than about 7 days. In another embodiment, the administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, six months, or one year. In some cases, continuous administration is achieved, and continuous administration continues for the required duration.

[0367] The administration of the compounds of the present invention can continue for the desired duration. In some embodiments, the administration of the compounds of the present invention continues for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the administration of the compounds of the present invention continues for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the present invention continue to be administered for a long time, for example to treat chronic effects.

[0368] An effective amount of the compounds of the present invention may be administered in single or multiple doses by any recognized mode of administration having similar utility, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically or as an inhalant.

[0369] The composition of the present invention can also be delivered by impregnation or coating device (for example, stent) or arterial insertion cylindrical polymer. Such application methods can, for example, help prevent or improve restenosis after surgery such as balloon angioplasty. Without being bound by theory, the compound of the present invention can slow down or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that help restenosis. The compound of the present invention can be applied, for example, by local delivery from the cover or sheath of the support, stent graft, graft or support of the support. In certain embodiments, the compound of the present invention is mixed with a matrix. Such a matrix can be a polymer matrix and can be used to combine the compound with the support. Polymer matrices suitable for such purposes include, for example, lactone polyesters or copolyesters, such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA), polydimethylsiloxane, poly(ethylene-vinyl acetate), acrylate polymers or copolymers (e.g., polyhydroxyethyl methyl methacrylate, polyvinyl pyrrolidone), fluorinated polymers (e.g., polytetrafluoroethylene and cellulose esters). Suitable matrices may be non-degradable or may degrade over time, thereby releasing one or more compounds. The compounds of the present invention may be applied to the surface of the stent by various methods (e.g., dip / spin coating, spray coating, dip coating and / or brush coating). The compound may be applied in a solvent, and the solvent may be allowed to evaporate, thereby forming a compound layer on the stent. Alternatively, the compound may be positioned in the body of the stent or graft, such as in a microchannel or micropore. When implanted, the compound diffuses from the body of the stent to contact the arterial wall. Such stents can be prepared by immersing a stent made to contain such micropores or microchannels in a solution of the compound of the present invention in a suitable solvent and then evaporating the solvent. Excess drugs on the surface of the stent can be removed by additional short solvent washings. In yet other embodiments, the compounds of the present invention can be covalently attached to a stent or graft. Covalent linkers can be used, which degrade in vivo to release the compounds of the present invention. Any biologically unstable connection, such as ester, amide or anhydride connection, can be used for such purposes. In addition, the compounds of the present invention can be administered intravascularly from the balloon used during angioplasty. Extravascular administration of the compound can also be performed by pericardial or adventitial application of the formulation of the present invention to reduce restenosis.

[0370] For example, various stent devices that can be used as described are disclosed in the following references, all of which are hereby incorporated 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; U.S. Patent No. 6,344,053.

[0371] The compounds of the present invention can be administered in doses. It is known in the art that due to the variability of compound pharmacokinetics between subjects, individualization of dosing regimens is necessary for optimal therapy. The administration of the compounds of the present invention can be found by routine experimentation based on the present disclosure.

[0372] When the compound of the invention is administered as a composition comprising one or more agents, and the half-life of said agent is shorter than that of the compound of the invention, the unit dosage form of said agent and the compound of the invention may be adjusted accordingly.

[0373] The pharmaceutical composition of the present invention can be, for example, suitable for oral administration in the form of tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions, suitable for parenteral injection in the form of sterile solutions, suspensions or emulsions, suitable for topical administration in the form of ointments or creams, or suitable for rectal administration in the form of suppositories. The pharmaceutical composition can be in a unit dosage form suitable for single administration of precise doses. The pharmaceutical composition will include conventional pharmaceutical carriers or excipients and compounds according to the present invention as active ingredients. In addition, the pharmaceutical composition can include other medicaments (medicinal agent or pharmaceutical agent), carriers, adjuvants, etc.

[0374] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous propylene glycol or aqueous dextrose. Such dosage forms can be suitably buffered, if necessary.

[0375] How to use

[0376] The method generally comprises administering a therapeutically effective amount of the compound of the present invention to the subject. The therapeutically effective amount of the compound combination of the present invention can change according to the intended application (in vitro or in vivo) or the subject being treated and the condition (e.g., the subject's weight and age, the severity of the condition, the mode of administration, etc.) that can be easily determined by a person of ordinary skill in the art. The term is also applicable to the dosage that will induce a specific response (e.g., the proliferation of the target protein is reduced or the activity is downregulated) in the target cell. The specific dosage will change according to the specific compound selected, the dosage regimen followed, whether it is administered in combination with other compounds, the timing of administration, the administration tissue, and the physical delivery system carried by it.

[0377] In a certain embodiment, the present invention provides a pharmaceutical composition comprising a bispecific compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0378] In one embodiment, the present invention provides a pharmaceutical composition comprising a bispecific compound for degrading a target protein in a cell.

[0379] In a certain embodiment, a method of degrading a target protein comprises administering to a cell a therapeutically effective amount of a bispecific compound or a pharmaceutically acceptable salt thereof, wherein the compound is effective for degrading the target protein.

[0380] As used herein, unless otherwise indicated, "abnormal cell growth" or "cancer" refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the following abnormal growths: (1) tumor cells (tumors) that proliferate by expressing mutant tyrosine kinases or overexpression of receptor tyrosine kinases; (2) benign and malignant cells of other proliferative diseases with abnormal tyrosine kinase activation; (3) any tumor that proliferates through receptor tyrosine kinases; (4) any tumor that proliferates through abnormal serine / threonine kinase activation; (5) benign and malignant cells of other proliferative diseases with abnormal serine / threonine kinase activation; (6) any tumor that proliferates through abnormal signaling, metabolism, epigenetic and transcriptional mechanisms; and (7) benign and malignant cells of other proliferative diseases with abnormal signaling, metabolism, epigenetic and transcriptional mechanisms.

[0381] 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).

[0382] Additional embodiments are directed to methods of treating abnormal cell growth in a patient. Additional embodiments are directed to a method of treating abnormal cell growth in a patient, the method comprising administering to the patient an amount of a compound described herein that is effective in treating abnormal cell growth.

[0383] In other embodiments, the abnormal cell growth is cancer.

[0384] 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 cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemias, lymphocytic lymphomas, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphomas, spinal axis tumors, glioblastomas, brain stem gliomas, pituitary adenomas, or a combination of two or more of the foregoing cancers.

[0385] Additional embodiments relate to methods of treating a solid tumor in a patient. Some embodiments relate to treating a solid tumor in a patient, comprising administering to the patient an amount of a compound described herein that is effective in treating the solid tumor.

[0386] In one embodiment, the solid tumor is breast, lung, colon, brain, prostate, stomach, pancreas, ovary, melanoma, endocrine, uterine, testicular, or bladder.

[0387] In one embodiment, the solid tumor is breast, lung, prostate, pancreas, or ovary.

[0388] In one embodiment, the cancer is breast cancer.

[0389] In one embodiment, the breast cancer is ER+ breast cancer.

[0390] In one embodiment, the breast cancer is ER+HER2- breast cancer.

[0391] In one embodiment, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0392] In one embodiment, the lung cancer is non-small cell lung cancer.

[0393] In one embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0394] 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.

[0395] Additional embodiments relate to methods of treating a hematological neoplasm in a patient. Some embodiments relate to treating a hematological neoplasm in a patient, the method comprising administering to the patient an amount of a compound described herein that is effective in treating a hematological neoplasm.

[0396] In one embodiment, the hematological tumor is leukemia, lymphoma or multiple myeloma.

[0397] In one embodiment, the hematological tumor is a leukemia or a lymphoma.

[0398] Additional embodiments relate to methods of treating cancer in a patient, the methods comprising administering to the patient an amount of a compound described herein that is effective for treating cancer. In one embodiment, the cancer is breast, lung, colon, brain, prostate, stomach, pancreas, ovary, melanoma, endocrine, uterine, testicular, bladder, or hematologic.

[0399] In one embodiment, the cancer is breast, lung, prostate, pancreatic, ovarian, or hematologic.

[0400] In one embodiment, the cancer is breast, lung, prostate, pancreas or ovary. In one embodiment, the cancer is breast cancer.

[0401] In one embodiment, the breast cancer is ER+ breast cancer.

[0402] In one embodiment, the breast cancer is ER+HER2- breast cancer.

[0403] In one embodiment, the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

[0404] In one embodiment, the lung cancer is non-small cell lung cancer.

[0405] In one embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0406] 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.

[0407] In one embodiment, the cancer is hematological.

[0408] In one embodiment, the hematological tumor is a leukemia or a lymphoma.

[0409] Additional embodiments relate to methods of treating cancer in a patient, the methods comprising administering to the patient an amount of a compound described herein that is effective in treating cancer in combination with an anti-neoplastic agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

[0410] Further embodiments relate to pharmaceutical compositions for treating cancer in a patient, the pharmaceutical compositions comprising an amount of a compound described herein that is effective in treating cancer and a pharmaceutically acceptable carrier.

[0411] Additional embodiments relate to methods 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 cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.

[0412] In one embodiment, the method comprises administering to the patient an amount of a compound described herein that is effective in treating the cancer solid tumor. In a preferred embodiment, the solid tumor is breast cancer, lung cancer, colon cancer, brain cancer, prostate cancer, stomach cancer, pancreatic cancer, ovarian cancer, skin cancer (melanoma), endocrine cancer, uterine cancer, testicular cancer and bladder cancer.

[0413] In another embodiment of the method, the cancer is a benign proliferative disease, including but not limited to psoriasis, benign prostatic hypertrophy, or restenosis.

[0414] 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, which is effective for treating cancer in combination with an anti-tumor agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

[0415] Another embodiment relates to a pharmaceutical composition for treating cancer in a patient (and particularly a human), comprising an amount of a compound described herein that is effective in treating cancer or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and a pharmaceutically acceptable carrier. In one embodiment of the composition, the cancer includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal region cancer, 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 cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord axis tumor, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of the pharmaceutical composition, the abnormal cell growth is a benign proliferative disease, including but not limited to psoriasis, benign prostatic hypertrophy or restenosis.

[0416] Additional 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, or hydrate thereof, which is effective in treating cancer in combination with another anti-tumor agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens. Some embodiments contemplate a pharmaceutical composition for treating abnormal cell growth, wherein the composition comprises a compound described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which is effective in treating abnormal cell growth, and another anti-tumor agent selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxins, anti-hormones, and anti-androgens.

[0417] Still further embodiments relate to a method 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 treating the disorder in combination with one or more anti-tumor agents listed above. Such conditions include malignancies, such as melanoma; ocular conditions, such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization caused by proliferative diabetic retinopathy; rheumatoid arthritis; bone loss conditions, such as osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, hypercalcemia from tumor metastases to bone, and osteoporosis caused by glucocorticoid therapy; coronary artery restenosis; and certain microbial infections, including those associated with a microbial pathogen selected from the group consisting of adenovirus, hantavirus, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and group A Streptococcus.

[0418] The compounds of the present disclosure and pharmaceutical compositions comprising the compounds can be administered alone or in combination with medical therapy to treat any of the described diseases. Medical therapy includes, for example, surgery and radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, systemic radioisotopes).

[0419] In other aspects, the compounds of the present disclosure and pharmaceutical compositions comprising the compounds may be administered alone or in combination with one or more other agents to treat any of the described diseases.

[0420] In other methods, the compounds of the disclosure and pharmaceutical compositions comprising the compounds may be administered in combination with agonists of nuclear receptor agents.

[0421] In other methods, the compounds of the disclosure and pharmaceutical compositions comprising the compounds may be administered in combination with antagonists of nuclear receptor agents.

[0422] In other methods, the compounds of the disclosure and pharmaceutical compositions comprising the compounds may be administered in combination with an anti-proliferative agent.

[0423] Combination therapy

[0424] For the treatment of cancer and other proliferative diseases, the compounds of the present invention can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors or other antiproliferative agents. The compounds of the present invention can also be used in combination with medical therapies such as surgery or radiotherapy, for example gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy and systemic radioisotopes. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, all-trans retinoic acid, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, intravenous busulfan, intravenous, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate acetate), levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin CC), mitotane, mitoxantrone, nandrolone, phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase, pegfilgrastim m), pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinstat, and zoledronate.

[0425] Some embodiments are directed to a method of treating cancer in a patient (and to a pharmaceutical composition for treating cancer), 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 selected from the group consisting of an anti-angiogenic agent, a signal transduction inhibitor (e.g., a method that inhibits the intracellular transmission of regulatory molecules that control fundamental processes of cell growth, differentiation and survival), and an anti-proliferative agent, said amounts being together effective to treat said abnormal cell growth.

[0426] 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.

[0427] Tyrosine kinase inhibitors can also be combined with the compounds described herein.

[0428] VEGF inhibitors (eg, sutent and axitinib) may also be used in combination with the compounds described herein.

[0429] ErbB2 receptor inhibitors may 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 several tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors.

[0430] Epidermal growth factor receptor (EGFR) inhibitors may be administered in combination with the compounds of the present invention.PI3K inhibitors (such as PI3Kα or PI3Kβ inhibitors) may be administered in combination with the compounds of the present invention.

[0431] Mammalian target of rapamycin (mTOR) inhibitors may be administered in combination with the compounds of the present invention.

[0432] c-Met inhibitors may be administered in combination with the compounds of the present invention.

[0433] CDK inhibitors may be administered in combination with the compounds of the present invention.

[0434] MEK inhibitors may be administered in combination with the compounds of the present invention.

[0435] PARP inhibitors may be administered in combination with the compounds of the present invention.

[0436] JAK inhibitors may be administered in combination with the compounds of the present invention.

[0437] Antagonists of programmed death 1 (PD-1) may be administered in combination with the compounds of the present invention.

[0438] Antagonists of programmed death-ligand 1 (PD-L1) may be administered in combination with the compounds of the invention.

[0439] Other antiproliferative agents that may be used with the compounds described herein include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr.

[0440] The compounds described herein may also be used with other agents useful for treating 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; and anti-proliferative agents, such as other farnesyl protein transferase inhibitors, e.g., farnesyl protein transferase.

[0441] The compounds described herein may be used as a monotherapy or may be combined with one or more other anti-tumor substances, such as substances selected from, for example, mitotic inhibitors, alkylating agents, antimetabolites, growth factor inhibitors, cell cycle inhibitors, intercalating antibiotics, enzymes and anti-hormones.

[0442] The compounds described herein can be used alone or in combination with one or more of a variety of anticancer agents 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. In addition, some embodiments provide the compounds described herein alone or in combination with one or more supportive care products, for example, a product selected from the group consisting of: filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or a combination thereof. Such combined therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

[0443] The compounds described herein can be used with antineoplastic agents, alkylating agents, antimetabolites, antibiotics, botanical antineoplastic 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 can be used with the compounds described herein.

[0444] The compounds of the present invention can be prepared using a variety of preparative reactions known in the literature. The following scheme provides general guidance on the preparation of the compounds of the present invention. It will be appreciated by those skilled in the art that the preparations shown in the schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the present invention. Example synthetic methods for preparing compounds of the present invention are provided in the schemes below.

[0445] The following examples are provided to illustrate some of the concepts described within this disclosure. While the examples are considered to provide embodiments, they should not be considered to limit the more general embodiments described herein.

[0446] Examples

[0447] General synthesis procedure

[0448] The compounds of the present 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.

[0449] Compounds of formula (I) can be synthesized using, for example, the sequence shown in Scheme I. Using appropriate 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 convert the optionally protected compound 1-1 (wherein RG 1 is a reactive group such as, but not limited to, a halogen (e.g., F, Cl, Br, I), a hydroxyl group, an aldehyde, a boronic acid, a boronate ester, a trialkyltin, a carboxylic acid or an amine) and an optionally protected compound 1-2 (wherein RG 2 and RG 3 Each is independently a reactive group, such as but not limited to a halogen (e.g., F, Cl, Br, I), a hydroxyl group, an aldehyde, a boronic acid, a boronate ester, a trialkyltin, a carboxylic acid or an amine) can be coupled to produce compounds 1-3. Using appropriate synthetic methods (such as but not limited to S N Ar reaction, Suzuki coupling, Steele coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling or reductive amination) to react compound 1-3 with an optionally protected compound 1-4 (wherein RG 4 Coupling with a reactive group such as a halogen (e.g., F, Cl, Br, I), a hydroxyl group, an aldehyde, a boronic acid, a boronate ester, a trialkyltin, a carboxylic acid or an amine can produce compounds of formula (I).

[0450] Alternatively, the synthesis can be achieved by coupling an optionally protected compound 1-4 with an optionally protected compound 1-2 using an appropriate synthetic method mentioned above to produce compound 1-6, and then reacting 1-6 with an optionally protected compound 1-1 using an appropriate synthetic method mentioned above to produce a compound of formula (I).

[0451] Scheme I

[0452]

[0453] 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 KCO can provide benzo[d]isoxazole 2-2. Amine 2-2 can be sulfonylated with sulfonyl halide 2-3 under standard sulfonylation conditions (e.g., in the presence of a base such as KOtBu, LiHMDS or pyridine), wherein X a is halogen (eg, F, Cl or Br) to produce compound 1-4.

[0454] Solution II

[0455]

[0456] The compounds of formula (I) can be prepared as described in Scheme III. Using appropriate synthetic methods (such as but not limited to S N Ar reaction, Suzuki coupling, Steele coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling or reductive amination) to react optionally protected compound 1-1 with compound 2-1 (wherein RG 5 and RG 6 Each independently is a reactive group, such as but not limited to a halogen (e.g., F, Cl, Br, I), a hydroxyl group, an aldehyde, a boronic acid, a boric acid ester, a trialkyltin, a carboxylic acid or an amine, and y is an integer from 0 to 14) can be coupled to produce compound 2-2. Using an appropriate synthetic method (such as but not limited to S N Ar reaction, Suzuki coupling, Steele coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling or reductive amination) and optionally protected 1-4 with compound 2-3 (wherein RG 7 and RG 8 Each independently is a reactive group such as, but not limited to, a halogen (e.g., F, Cl, Br, I), a hydroxyl group, an aldehyde, a boronic acid, a boric acid ester, a trialkyltin, a carboxylic acid, or an amine, and z is an integer from 0 to 14, and the sum of y and z is an integer from 1 to 14) can produce compound 2-4. Using appropriate synthetic methods (such as, but not limited to, S NAr reaction, Suzuki coupling, Steele coupling, Buchwald-Hartwig reaction, Mitsunobu reaction, Williamson ether synthesis, amide coupling or reductive amination) can produce compound 2-5 by coupling compound 2-2 with 2-4.

[0457] Scheme III

[0458]

[0459] Intermediates used to prepare compounds of Formula I can be synthesized according to the pathways described in Scheme IV. N Ar conditions, optionally in the presence of a base (eg, DIPEA), thalidomide 4-1 (wherein X b is a halogen (eg, F or Cl) or a pseudohalogen (eg, OTf or OMs)) and compound 4-2 (wherein ring A 1a is an optionally protected nitrogen-containing 3-11-membered heterocyclic group, which is optionally substituted with a reactive group, such as but not limited to a halogen (e.g., F, Cl, Br, I), a hydroxyl group, an aldehyde, a boronic acid, a boric acid ester, a trialkyltin, a carboxylic acid or an amine) which can react to produce compound 4-3.

[0460] Scheme IV

[0461]

[0462] Intermediates used to prepare compounds of Formula I can be synthesized according to the routes described in Scheme V. N 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 (e.g., XPhos Pd G2 or BrettPhos Pd G3) and a base (e.g., K3PO4 or sodium tert-butoxide)), compound 5-1 (wherein X c is a halogen (e.g., F, Cl, or Br) or a pseudohalogen (e.g., OTf or OMs) and R z For C1-C4 alkyl) with compound 4-2 can produce compound 5-2. Reduction of nitrile 5-2 under appropriate conditions (e.g., Raney nickel) can produce aldehyde 5-3. Under standard conditions, such as adding an appropriate acid (e.g., AcOH) and a reducing agent (e.g., sodium triacetoxyborohydride), and then adding a base (e.g., DIPEA), reductive amination and cyclization of compound 5-3 with amine 5-4 can produce compound 5-5.

[0463] Scheme V

[0464]

[0465] The intermediates used to prepare compounds of Formula I can be synthesized according to the pathways described in Scheme VI. N 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 (e.g., XPhos Pd G2 or BrettPhos Pd G3) and a base (e.g., K3PO4 or sodium tert-butoxide)), compound 6-1 (wherein X d is a halogen (e.g., F, Cl, or Br) or a pseudohalogen (e.g., OTf or OMs) and R y For C1-C4 alkyl) with compound 4-2 coupling can produce compound 6-2. Under appropriate conditions (e.g., Raney nickel) reduction of nitrile 6-2 can produce aldehyde 6-3. Under standard conditions, such as adding an appropriate acid (e.g., AcOH) and a reducing agent (e.g., sodium triacetoxyborohydride), and then adding a base (e.g., DIPEA), reductive amination and cyclization of compound 6-3 with amine 5-4 can produce compound 6-4.

[0466] Solution VI

[0467]

[0468] Compounds of formula (I) can be prepared as described in Scheme VII. Alcohol 7-1 (wherein R x is H or C1-C4 alkyl) can produce compound 7-2. N 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 (e.g., BrettPhos Pd G3) and a base (e.g., sodium tert-butoxide)), compound 7-3 (wherein X e is a halogen (eg, F, Cl, Br or I) or a pseudohalogen (eg, OMs or OTf)) and compound 7-4 (wherein A 2a is a 3-11 membered diazacyclic group, and P 1 Coupling with an appropriate nitrogen protecting group (e.g., Boc, Cbz, Bn, PMB or acetyl) and subsequent deprotection can produce compound 7-5. Compound 7-2 is reacted with 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 an acid such as acetic acid) to produce compound 7-6.

[0469] Scheme VII

[0470]

[0471] Intermediates for preparing compounds of formula I can be synthesized according to the pathways described in Scheme VIII. Compound 5-3 can be converted to compound 8-2 by reductive amination and cyclization with compound 8-1 (which is optionally enriched in enantiomers under standard conditions, such as in the presence of an appropriate acid (e.g., acetic acid) and a reducing agent (e.g., sodium triacetoxyborohydride), and then in the presence of a base (e.g., N,N-diisopropylethylamine). Cycling of 8-2 in the presence of a base (e.g., potassium tert-butoxide) can produce compound 5-5.

[0472] Scheme VIII

[0473]

[0474] Intermediates for preparing compounds of formula I can be synthesized according to the pathways described in Scheme IX. Compound 6-3 can be converted to compound 9-1 by reductive amination and cyclization with compound 8-1 (which is optionally enriched in enantiomers under standard conditions, such as in the presence of an appropriate acid (e.g., acetic acid) and a reducing agent (e.g., sodium triacetoxyborohydride), and then in the presence of a base (e.g., N,N-diisopropylethylamine). Cyclization of 9-1 in the presence of a base (e.g., potassium tert-butoxide) can produce compound 6-4.

[0475] Scheme IX

[0476]

[0477] 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

[0478]

[0479] Step 1: 1-(Methylsulfonyl)-1H-pyrazole

[0480]

[0481] 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 produce the title compound (21.4 g, 146 mmol, 99.3% yield) in the form of a light yellow oil. 1 H NMR (300MHz, CDCl3) δ 8.06 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 6.48 (dd, J = 2.6, 1.7 Hz, 1H), 3.34 (s, 3H).

[0482] Step 2: 2,6-Difluoro-4-(hydroxymethyl)benzonitrile

[0483]

[0484] Sodium borohydride (1.13 g, 29.9 mmol) was added to a solution of 2,6-difluoro-4-formylbenzonitrile (5.00 g, 29.9 mmol) in ethanol (100 mL) at 0 ° C. The reaction solution 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 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 produce the title compound (5.2 g, 31 mmol, quantitative yield) in the form of a light yellow solid. 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).

[0485] Step 3: 2-Fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile

[0486]

[0487] 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 about 3 with 1N HCl at 0 ° C. The mixture was concentrated and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (0–80% EtOAc / heptane) to give the title compound (4.3 g, 24 mmol, 84% yield) in the form of a light yellow solid. 1 H NMR (300MHz, CDCl3) δ6.90–6.69 (m, 2H), 4.75 (d, J = 4.7Hz, 2H), 3.96 (s, 3H).

[0488] Step 4: 2-Fluoro-6-methoxy-4-(pyrazol-1-ylmethyl)benzonitrile

[0489]

[0490] 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 hours. The reaction mixture was filtered through a celite pad and then concentrated. The crude material was purified by silica gel column chromatography (20–70% EtOAc / heptane) to produce the title compound (4.1 g, 18 mmol, 79% yield) in the form of 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 value: m / z = 232.1; found value: 232.2.

[0491] Step 5: 4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-amine

[0492]

[0493] N-hydroxyacetamide (3.8 g, 51 mmol) and K2CO3 (14.0 g, 101 mmol) are added 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). The resulting mixture is stirred overnight at 70 ° C. The reaction mixture is cooled to room temperature and diluted with water (450 mL) and EtOAc (450 mL). The layers are separated, and the organic layer is washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude material is purified by silica gel chromatography (20–70% EtOAc / heptane) to produce the title compound (2.9 g, 12 mmol, 70% yield) in the form of 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 value: m / z = 245.1; found value: 245.1.

[0494] Step 6: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-bromo-benzenesulfonamide

[0495]

[0496] 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 tert (578 mg, 5.15 mmol). After heating at 60 ° C for 1 hour, the mixture was cooled to room temperature and 1N 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 Na2SO4, 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 value: m / z = 463.0; found: 462.8.

[0497] Step 7: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(piperazin-1-yl)benzenesulfonamide

[0498]

[0499] A solution of 3-bromo-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-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, CAS1470372-59-8) and sodium tert-butoxide (77.1 mg, 0.803 mmol) in 1,4-dioxane (1 mL) was stirred at 100 ° C. under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was concentrated, and TFA (3 mL) was added. The mixture was concentrated and purified by preparative HPLC (2-40% MeCN / 0.1% TFA (aq)) on a C18 column to give the title compound (30 mg, 0.064 mmol, 48% yield) as a colorless solid TFA salt. 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 value: m / z = 469.2; found value: 468.9.

[0500] Step 8: 2-(2,6-dioxopiperidin-3-yl)-5-[3-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione

[0501]

[0502] 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 (EtOAc) to produce the title compound (10.4 g, 28.4 mmol, 65.3%) in the form of 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 value: m / z = 358.1; found value: 358.3.

[0503] Step 9: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde

[0504]

[0505] 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 1:1 NaHCO / NaS O 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) in the form of a yellow solid, which was used directly in the next step without any further purification. 18 H 18 N3O5[M+H] + LCMS calculated value: m / z = 356.1; found value: 355.9.

[0506] 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

[0507] To a solution of N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-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 hour, 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 give the title compound (3.0 mg, 0.0037 mmol, 32% yield) as a yellow solid TFA salt. 1H 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 value: m / z = 808.2; found value: 808.2.

[0508] 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

[0509]

[0510] Step 1: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanal

[0511]

[0512] The title compound was synthesized according to a procedure similar to Example 1, Steps 8 and 9. 21 H 24 N3O5[M+H] + LCMS calculated value: m / z = 398.2; found value: 398.0.

[0513] 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

[0514] The title compound was synthesized according to a procedure similar to Example 1, Step 10. 1 H 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 value: m / z = 850.3; found value: 850.4.

[0515] 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

[0516]

[0517] Step 1: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[0518]

[0519] The title compound was synthesized according to a procedure similar to that of Example 1, steps 8 and 9 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 any further purification. 20 H 22 N3O5[M+H] + LCMS calculated value: m / z = 384.1; found value: 383.9.

[0520] 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

[0521] The title compound was synthesized according to 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 value: m / z = 836.3; found value: 836.3.

[0522] Example 4. 3-[4-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-7-azaspiro[3.5]non-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide

[0523]

[0524] Step 1: 7-Azaspiro[3.5]nonan-2-ol

[0525]

[0526] 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 hours. The reaction mixture was concentrated to give 7-azaspiro[3.5]nonane-2-ol as a TFA salt, which was carried forward without further purification. CH 16 NO[M+H] + LCMS calculated value: m / z = 142.1; found value: 142.1.

[0527] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)isoindole-1,3-dione

[0528]

[0529] 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]nonane-2-ol (188 mg, from step 1) and N,N-diisopropylethylamine (0.411 mL, 2.36 mmol) in NMP (2 mL) was stirred at 100 ° C for 24 hours. The reaction solution 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 Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (20–100% EtOAc / heptane) to give the title compound (231 mg, 0.581 mmol, 98.5% yield) as a yellow viscous oil. C 21 H 24 N3O5[M+H] + LCMS calculated value: m / z = 398.2; found value: 398.1.

[0530] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-7-azaspiro[3.5]nonan-7-yl)isoindole-1,3-dione

[0531]

[0532] The title compound was synthesized according to a procedure similar to that of Example 1, Step 9. 21 H 22 N5O5[M+H] + LCMS calculated value: m / z = 396.2; found value: 395.9.

[0533] 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-benzooxazol-3-yl]benzenesulfonamide

[0534] To a solution of N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-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)) gave 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. 45(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,4H),2.91–2.80(m,1H),2.63–2.53(m,1H),2.30–2.17(m,2H),2.03(q,J=7.7,7.0Hz,3H),1.70–1.56(m,3H). C 43 H 46 N9O8S[M+H] +LCMS calculated value: m / z = 848.3; found value: 848.3.

[0535] 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-benzooxazol-3-yl]benzenesulfonamide

[0536]

[0537] Step 1: 3-(2,7-diazaspiro[3.5]nonan-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0538]

[0539] The title compound was synthesized according to a procedure similar to that of Example 1, Step 7. 25 H 29 N6O4S[M+H] + LCMS calculated value: m / z = 509.2; found value: 509.1.

[0540] 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-benzooxazol-3-yl]benzenesulfonamide

[0541] The title compound was synthesized according to 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 value: m / z = 848.3; found value: 848.5.

[0542] 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-benzooxazol-3-yl]benzenesulfonamide

[0543]

[0544] Step 1: N-[(4-methoxyphenyl)methyl]-5-oxooxolane-2-carboxamide

[0545]

[0546] Thionyl chloride (3.5mL, 48mmol) was slowly added to 5-oxooxacyclopentane-2-carboxylic acid (1.00g, 7.69mmol) at 0°C. The mixture was stirred at 85°C for 3 hours, and then stirred at room temperature for 16 hours. The mixture was concentrated. The obtained residue was dissolved in DCM (10mL) at 10°C, and a solution of 4-methoxybenzylamine (1.60g, 11.7mmol) and triethylamine (0.950g, 9.39mmol) in DCM (4mL) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. Water (5.0mL) was added, and the mixture was extracted with DCM (3×3.0mL). The combined organic layer was washed with 0.5M HCl (5.0mL) and brine (5.0mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (1:1 petroleum ether / ethyl acetate) to give the title compound (0.850 g, 3.41 mmol, 44.4% yield) as a white solid. 13 H 16 NO4[M+H] + LCMS calculated value: m / z = 250.1; found value: 250.1.

[0547] Step 2: 3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

[0548]

[0549] To a solution of N-[(4-methoxyphenyl)methyl]-5-oxooxacyclopentane-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 solution was stirred at -78 ° C for 1 hour, and then stirred at -40 ° C for 1.5 hours. The reaction solution was quenched with saturated NH4Cl (aqueous solution) 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 / hexane) to give the title compound (1.65 g, 6.62 mmol, 63.4% yield) as a white solid. 1H 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).

[0550] Step 3: 1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl]trifluoromethanesulfonate

[0551]

[0552] 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. Trifluoromethanesulfonic anhydride (330 μL, 1.55 mmol) was added dropwise. The reaction solution was stirred at 0°C for 1.5 hours. The reaction mixture was warmed to room temperature and concentrated. The crude material was purified by silica gel chromatography (0-100% EtOAc / hexanes) to give 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).

[0553] Step 4: 6-Bromo-9H-pyrido[2,3-b]indole

[0554]

[0555] 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 solution was stirred at room temperature for 2 hours. The reaction solution 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 / hexane) to give the title compound (6.80 g, 27.5 mmol, 92.6%) as a white solid. C 11 H8BrN2[M+H] + LCMS calculated value: m / z = 247.0; found value: 247.0.

[0556] Step 5: 2-[(6-Bromopyrido[2,3-b]indol-9-yl)methoxy]ethyl-trimethylsilane

[0557]

[0558] 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, and then 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 (3×30 mL). The organic layer was dried over Na2SO4, 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 value: m / z = 377.1; found value: 377.1.

[0559] Step 6: tert-Butyl 4-[9-(2-trimethylsilylethoxymethyl)pyrido[2,3-b]indol-6-yl]piperazine-1-carboxylate

[0560]

[0561] 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 solution was stirred at 80 ° C for 16 hours. The reaction solution was cooled to room temperature and concentrated. The crude material was purified by silica gel chromatography to give the title compound (3.80 g, 7.42 mmol, 56.0%) in the form of a yellow oil. 26 H 39 N4O3Si[M+H] + LCMS calculated value: m / z = 483.3; found value: 483.3

[0562] Step 7: tert-Butyl 4-(9H-pyrido[2,3-b]indol-6-yl)piperazine-1-carboxylate

[0563]

[0564] Tetrabutylammonium fluoride (4.72 g, 41.4 mmol) was added 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). The reaction solution was stirred at room temperature for 3 hours. The reaction solution 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 produce the title compound (1.90 g, 4.85 mmol, 58.6%). 20 H 25 N4O2[M+H] + LCMS calculated value: m / z = 353.2; found value: 353.3.

[0565] 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

[0566]

[0567] 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 value: m / z = 584.3; found value: 584.4.

[0568] Step 9: 3-(6-piperazin-1-ylpyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

[0569]

[0570] 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 N5O2[M+H] + LCMS calculated value: m / z = 364.2; found value: 364.3.

[0571] Step 10: 3-[3-(Hydroxymethyl)pyrrolidin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzoxazol-3-yl]benzenesulfonamide

[0572]

[0573] The title compound was synthesized according to a procedure similar to that of Example 1, Step 7. 23 H 26 N5O5S[M+H] + LCMS calculated value: m / z = 484.2; found value: 484.0.

[0574] 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-benzooxazol-3-yl]benzenesulfonamide

[0575] To a solution of 3-[3-(hydroxymethyl)pyrrolidin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide (16.0 mg, 0.0331 mmol) and Et3N (0.0415 mL, 0.331 mmol) in DMSO (0.4 mL) was added a solution of pyridine sulfur trioxide (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 was stirred for another 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 (5.90 mg, 0.00700 mmol, 21.3% yield) as a yellow solid TFA salt. 43 H 45 N 10 O6S[M+H] + LCMS calculated value: m / z = 829.3; found value: 828.9.

[0576] 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-benzooxazol-3-yl]benzenesulfonamide

[0577]

[0578] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-[4-(hydroxymethyl)piperidin-1-yl]isoindole-1,3-dione

[0579]

[0580] The title compound was synthesized according to 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 value: m / z = 372.2; found value: 372.3.

[0581] Step 2: 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidine-4-carbaldehyde

[0582]

[0583] To a solution of Et3N (0.702mL, 5.04mmol) in DMSO (5.6mL) was added pyridine sulfur trioxide (267mg, 1.68mmol). Then, a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[4-(hydroxymethyl)piperidin-1-yl]isoindole-1,3-dione (208mg, 0.560mmol) in DMSO (0.5mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. The material was directly purified by silica gel chromatography (0–4% MeOH / DCM) to give the title compound (200mg, 0.542mmol, 96.8%). C 19 H 20 N3O5[M+H] + LCMS calculated value: m / z = 370.2; found value: 370.1.

[0584] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]piperidin-1-yl]-isoindole-1,3-dione

[0585]

[0586] The title compound was synthesized according to a procedure analogous to Example 4, Step 4 and isolated as a 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 value: m / z = 469.2; found value: 469.3.

[0587] Step 4: 1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl]piperidine-4-carbaldehyde

[0588]

[0589] 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-iodooxybenzoic acid (16.0 mg, 0.0257 mmol). The reaction was stirred at 50 °C for 0.5 h. The mixture was used directly as a solution in the next step without any further purification. 25 H 31 N4O5[M+H] + LCMS calculated value: m / z = 467.2; found value: 467.1.

[0590] Step 5: 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

[0591] The title compound was synthesized according to a procedure similar to Example 4, Step 4. 1 H 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 value: m / z = 919.4; found value 919.7.

[0592] 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-benzooxazol-3-yl]benzenesulfonamide

[0593]

[0594] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(2-hydroxy-6-azaspiro[3.4]octan-6-yl)isoindole-1,3-dione

[0595]

[0596] The title compound was synthesized according to a procedure similar to that of Example 1, Step 8. 20 H 22 N3O5[M+H] + LCMS calculated value: m / z = 384.2; found value 384.1.

[0597] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(2-oxo-6-azaspiro[3.4]octan-6-yl)isoindole-1,3-dione

[0598]

[0599] The title compound was synthesized according to a procedure similar to Example 7, Step 4. 20 H 20 N3O5[M+H] + LCMS calculated value: m / z = 382.1; found value 382.0.

[0600] 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-benzooxazol-3-yl]benzenesulfonamide

[0601] The title compound was synthesized according to 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 value: m / z = 834.3; found 834.6.

[0602] 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-benzooxazol-3-yl]benzenesulfonamide

[0603]

[0604] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-[3-(2-hydroxyethyl)pyrrolidin-1-yl]isoindole-1,3-dione

[0605]

[0606] The title compound was synthesized according to a procedure similar to that of Example 1, Step 8. 19 H 22 N3O5[M+H] + LCMS calculated value: m / z = 372.2; found value 372.1.

[0607] Step 2: 2-[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]acetaldehyde

[0608]

[0609] The title compound was synthesized according to a procedure similar to that of Example 1, Step 9. 19 H 20 N3O5[M+H] + LCMS calculated value: m / z = 370.1; found value 370.1.

[0610] 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-benzooxazol-3-yl]benzenesulfonamide

[0611] The title compound was synthesized according to a procedure similar to Example 1, Step 10. 41 H 44 N9O8S[M+H] + LCMS calculated value: m / z = 822.3; found 822.2.

[0612] 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-benzooxazol-3-yl]benzenesulfonamide

[0613]

[0614] Step 1: 3-[6-[3-(Hydroxymethyl)pyrrolidin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione

[0615]

[0616] 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, CAS1470372-59-8) and sodium tert-butoxide (59.5 mg, 0.619 mmol) in 1,4-dioxane (1 mL) was stirred at 90 ° C for 1 hour. The mixture was cooled to room temperature, and TFA (5 drops), H2O (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 give the title compound (22.7 mg, 0.0661 mmol, 53.4% ​​yield) as a colorless solid TFA salt. 18 H 22 N3O4[M+H] + LCMS calculated value: m / z = 344.2; found value 344.1.

[0617] Step 2: 1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrrolidine-3-carbaldehyde

[0618]

[0619] The title compound was synthesized according to a procedure similar to Example 7, Step 4. 18 H 20 N3O4[M+H] + LCMS calculated value: m / z = 342.1; found value 342.1.

[0620] 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-benzooxazol-3-yl]benzenesulfonamide

[0621] The title compound was synthesized according to a procedure similar to Example 4, Step 4. 40 H 44 N9O7S[M+H] + LCMS calculated value: m / z = 794.3; found 794.2.

[0622] 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]hept-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide

[0623]

[0624] Step 1: 3-(2,6-diazaspiro[3.3]hept-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide

[0625]

[0626] The title compound was synthesized according to a procedure similar to that of Example 1, Step 7. 23 H 25 N6O4S[M+H] + LCMS calculated value: m / z = 481.2; found value 480.9.

[0627] 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]hept-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide

[0628] The title compound was synthesized according to a procedure similar to Example 1, Step 10. 41 H 42 N9O8S[M+H] + LCMS calculated value: m / z = 820.3; found value: 820.2.

[0629] 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

[0630]

[0631] Step 1. 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)isoindoline-1,3-dione

[0632]

[0633] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 8. 19 H 22 N3O5[M+H] + LC-MS calculated value: m / z = 372.2; found value: 372.0.

[0634] 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

[0635] 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 hour. A solution of 3-(2,7-diazaspiro[3.5]non-2-yl)-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide (30.0 mg, 0.0590 mmol) (from Example 5, Step 1) in MeCN (0.8 mL) was added, and then acetic acid (50.6 μL, 0.885 mmol) was added, and the reaction mixture was stirred for 0.5 hours. Sodium triacetoxyborohydride (50.0 mg, 0.236 mmol) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture 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 (0.90 mg, 0.0011 mmol, 1.7% yield) as a yellow solid. 44 H 48 N9O8S[M+H] + LC-MS calculated value: m / z = 862.3; found value: 862.2.

[0636] Example 13–22

[0637] Examples 13-22 listed in Tables 1 and 2 were synthesized according to 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, * indicates linkage to ULM, and Indicates the connection to ring A of the PTM.

[0638]

[0639] Table 1. Examples 13–22

[0640]

[0641]

[0642] Table 2. Examples 13-22

[0643]

[0644]

[0645]

[0646]

[0647]

[0648] 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

[0649]

[0650] Step 1. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3-(hydroxymethyl)pyrrolidin-1-yl)benzenesulfonamide

[0651]

[0652] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 7, using pyrrolidin-3-ylmethanol. 23 H 26 N5O5S[M+H] + LC-MS calculated value: m / z = 484.2; found value: 483.9.

[0653] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3-formylpyrrolidin-1-yl)benzenesulfonamide

[0654]

[0655] The title compound was synthesized by a procedure analogous to that outlined in Example 31, Step 2. 23 H 24 N5O5S[M+H] + LC-MS calculated value: m / z = 482.1; found value: 482.0.

[0656] Step 3. tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)piperidine-1-carboxylate

[0657]

[0658] 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 mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with brine (50 mL × 3), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (30-50% EtOAc / petroleum ether) gave the title compound (20.0 g, 43.7 mmol, 88.2% yield) as a white solid. 23 H 28 N3O7[M+H] + LC-MS calculated value: m / z = 458.2; found value: 458.3.

[0659] Step 4. 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-1,3-dione

[0660]

[0661] To a mixture of 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]oxy-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 10.9 mmol) was added HCl (55.0 mL, 220 mmol, 4N in 1,4-dioxane). The reaction mixture was stirred for 16 hours. The mixture was concentrated to give the title compound (3.78 g, 9.78 mmol, 97.0% yield) as a white solid HCl salt. 1 H 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] + LC-MS calculated value: m / z = 358.1; found value: 358.5.

[0662] 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

[0663] 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]benzenesulfonamide (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 minutes. 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 give the title compound (3.5 mg, 0.0043 mmol, 20% yield) as a colorless solid TFA salt. 1 HNMR (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, 1H),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] + LC-MS calculated value: m / z = 823.3; found value: 823.4.

[0664] 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

[0665]

[0666] Step 1: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carboxylic acid

[0667]

[0668] 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-iodooxybenzoic acid (55.9 mg, 0.0901 mmol). The reaction mixture was stirred at 80 ° C for 3 hours. The mixture was diluted with DCM (2 mL), filtered and washed with 1:1 saturated NaHCO3 / saturated Na2S2O3 (aqueous solution) (3 mL). The layers were separated and the aqueous layer was extracted with DCM (3×3 mL). The combined organic layers were dried over Na2SO4, 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 hours. 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] + LC-MS calculated value: m / z = 372.1; found value: 371.8.

[0669] 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

[0670] 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]pyridine 3-hexafluorophosphate oxide (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-benzooxazol-3-yl]-3-piperazin-1-ylbenzenesulfonamide (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 (1.4 mg, 0.0017 mmol, 32% yield) as a yellow solid TFA salt. 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] + LC-MS calculated value: m / z = 822.3; found value: 822.2.

[0671] 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

[0672]

[0673] Step 1. 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione

[0674]

[0675] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 8, using (R)-pyrrolidin-3-ylmethanol. 18 H 20 N3O5[M+H] + LC-MS calculated value: m / z = 358.1; found value: 358.0.

[0676] Step 2. 3-Bromo-2,6-dimethoxybenzenesulfonyl chloride

[0677]

[0678] N-bromosuccinimide (405 mg, 2.28 mmol) was added to a solution of 2,6-dimethoxybenzene-1-sulfonyl chloride (490 mg, 2.07 mmol) in MeCN (10 mL) at 0 ° C. The resulting mixture was stirred at 35 ° C for 3 hours. The reaction solution 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 produce the title compound (653 mg, 2.07 mmol,> 99% yield). C8H8BrO4S[M-Cl] + LC-MS calculated value: m / z = 278.9; found value: 279.2.

[0679] Step 3. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-bromo-2,6-dimethoxybenzenesulfonamide

[0680]

[0681] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 6. 20 H 20 BrN4O6S[M+H] + LC-MS calculated value: m / z = 523.0; found value: 523.4.

[0682] 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

[0683]

[0684] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 7, using tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate. 27 H 33 N6O6S[M+H] + LC-MS calculated value: m / z = 569.2; found value: 569.0.

[0685] 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

[0686] The title compound was synthesized by a procedure analogous to that outlined in Example 12, Step 2. 45 H 50 N9O 10 S[M+H] + LC-MS calculated value: m / z = 908.3; found value: 908.1.

[0687] 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

[0688]

[0689] Step 1. Benzyl(3-bromo-2-methoxyphenyl)sulfane

[0690]

[0691] 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, CAS161265-03-8) and diisopropylethylamine (1.96 g, 15.2 mmol). The resulting mixture was stirred at 110 °C for 2 hours. 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 on without further purification. TLC R f =0.5 (petroleum ether).

[0692] Step 2. 3-Bromo-2-methoxybenzenesulfonyl chloride

[0693]

[0694] 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 solution was stirred at room temperature for 16 hours. The reaction solution 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 produce the title compound, which was used without further purification. TLC R f = 0.4 (10% EtOAc / hexanes).

[0695] Step 3. N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-bromo-2-methoxybenzenesulfonamide

[0696]

[0697] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 6. 19 H 18 BrN4O5S[M+H] + LC-MS calculated value: m / z = 493.0; found value: 493.6.

[0698] 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

[0699]

[0700] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 7. 26 H 31 N6O5S[M+H] + LC-MS calculated value: m / z = 539.2; found value: 539.0.

[0701] Step 5. (R)-methyl 2-cyano-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate

[0702]

[0703] 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-diisopropylethylamine (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 (820 mg, 3.2 mmol, 94% yield) in the form of a tan oil. 14 H 17 N2O3[M+H] + LC-MS calculated value: m / z = 261.1; found value: 261.0.

[0704] Step 6. (R)-methyl 2-formyl-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate

[0705]

[0706] To (R) -2- cyano -4- (3- (hydroxymethyl) pyrrolidin-1-yl) benzoic acid methyl ester (870mg, 3.34mmol) in acetic acid (3.82mL, 66.9mmol) and pyridine (8.11mL, 100mmol) in a solution of sodium hypophosphite monohydrate (3.54g, 33.4mmol) was added in 2 batches. Raney nickel (589mg, slurry in water) was added, and the reaction mixture was stirred at 75 ° C for 2 hours. Another portion of Raney nickel (589mg, slurry in water) was added, and the reaction mixture was stirred at 75 ° C for 2 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and diluted with water (10mL) and EtOAc (10mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 15mL). The combined organic layers were washed with brine, dried over MgSO 4 , 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.

[0707] Step 7. 3-(5-((R)-3-(Hydroxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0708]

[0709] Methyl (R)-2-formyl-4-(3-(hydroxymethyl)pyrrolidin-1-yl)benzoate

[0710] (880 mg, 3.34 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (660 mg, 4.01 mmol)

[0711] N,N-diisopropylethylamine (1.16mL, 6.68mmol) was added to a solution in DCM (11mL) and DMF (3.75mL). The reaction mixture was stirred at 35°C for 10 minutes. Acetic acid (1.91mL, 33.4mmol) was added, and the reaction mixture was stirred at 35°C for 15 minutes. The reaction mixture was cooled to 0°C and sodium triacetoxyborohydride (2.13g, 10.0mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with saturated NaHCO3 (aqueous solution) (50mL) and DCM (30mL). The layers were separated, and the aqueous layer was extracted with DCM (3×20mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0–10% MeOH / DCM) gave the title compound (384mg, 1.12mmol, 33.5% yield) as a white solid. C 18 H 22 N3O4[M+H] + LC-MS calculated value: m / z = 344.2; found value: 344.1.

[0712] 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

[0713] The title compound was synthesized by a procedure analogous to that outlined in Example 12, Step 2. 44 H 50 N9O8S[M+H] + LC-MS calculated value: m / z = 864.3; found value: 864.4.

[0714] 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

[0715]

[0716] The title compound was synthesized by a procedure analogous to that outlined in Example 26. 44 H 50 N9O8S[M+H]+ LC-MS calculated value: m / z = 864.3; found value: 864.4.

[0717] 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

[0718]

[0719] Step 1. (R)-methyl 2-cyano-4-(3-formylpyrrolidin-1-yl)benzoate

[0720]

[0721] 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 hours. The mixture was quenched with 10% sodium thiosulfate / 8% sodium bicarbonate (aqueous solution) (160 ml) and stirred for 1 hour. The 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 NaHCO3 (aqueous solution) (200 ml×2) and brine (200 ml), dried over Na2SO4, filtered and concentrated to give the title compound (1.10 g, 4.26 mmol,>99% yield) in the form of an orange oil. 14 H 15 N2O3[M+H] + LC-MS calculated value: m / z = 259.1; found value: 259.5.

[0722] Step 2. (R)-methyl 2-cyano-4-(3-(dimethoxymethyl)pyrrolidin-1-yl)benzoate

[0723]

[0724] To a solution of (R)-2-cyano-4-(3-formylpyrrolidin-1-yl)benzoic acid methyl ester (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 hour. The reaction solution was quenched with 10% Na2CO3 (aqueous solution) (170 ml), and the mixture was stirred for 15 minutes. The reaction mixture was diluted with water (150 ml) and extracted with EtOAc (200 ml×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) gave the title compound (14.1 g, 46.3 mmol, 68.8% yield) in the form of an orange oil. 16 H 21 N2O4[M+H] + LC-MS calculated value: m / z = 305.1; found value: 305.6.

[0725] Step 3. Methyl (R)-4-(3-(dimethoxymethyl)pyrrolidin-1-yl)-2-formylbenzoate

[0726]

[0727] The title compound was synthesized by a procedure analogous to that outlined in Example 26, Step 4. 16 H 22 NO5[M+H] + LC-MS calculated value: m / z = 308.1; found value: 308.6.

[0728] Step 4. (S)-5-amino-4-(5-((R)-3-(dimethoxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid methyl ester

[0729]

[0730] N,N-diisopropylethylamine (1.26 g, 9.76 mmol) was added to a mixture of (4S)-4,5-diamino-5-oxopentanoic acid methyl ester hydrochloride (0.77 g, 3.9 mmol) in DMF (2 mL). The reaction mixture was stirred for 10 minutes. A solution of 4-[(3R)-3-(dimethoxymethyl)-pyrrolidin-1-yl]-2-formylbenzoic acid methyl ester (1.00 g, 3.25 mmol) in DCM (10 mL) was added, and then acetic acid (0.98 g, 16 mmol) was added. 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 NaHCO (aqueous solution) (30 ml) and extracted with DCM (30 ml × 3). The combined organic layers were washed with brine (25 mL x 3), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-75% EtOAc / hexanes) gave the title compound (900 mg, 2.15 mmol, 65.9% yield) as a pale yellow solid. 21 H 30 N3O6[M+H] + LC-MS calculated value: m / z = 420.2; found value: 420.6.

[0731] Step 5. (S)-3-(5-((R)-3-(dimethoxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0732]

[0733] To a solution of (S)-5-amino-4-(5-((R)-3-(dimethoxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid methyl ester (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 about 6 with saturated NaHCO3 (aqueous solution). The 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 (770 mg, 1.99 mmol, 92.6% yield) as a light yellow solid. 20 H 26 N3O5[M+H] +LC-MS calculated value: m / z = 388.2; found value: 388.7.

[0734] Step 6. (R)-1-(2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde

[0735]

[0736] 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 about 8 with saturated NaHCO3(aq), diluted with water (30 ml), and extracted with EtOAc (30 ml×5). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (280 mg, 0.820 mmol, >99% yield) as a light yellow solid. 18 H 20 N3O4[M+H] + LC-MS calculated value: m / z = 342.1; found value: 342.6.

[0737] 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

[0738] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 10. 43 H 48 N9O7S[M+H] + LC-MS calculated value: m / z = 834.3; found value: 834.1.

[0739] 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

[0740]

[0741] Step 1. Methyl 5-(4-(Hydroxymethyl)piperidin-1-yl)picolinate

[0742]

[0743] 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 hours. The reaction mixture was cooled to room temperature and poured into water. The mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound, which was carried on without further purification. C 13 H 19 N2O3[M+H] + LC-MS calculated value: m / z = 251.1; found value: 251.0.

[0744] Step 2. 5-(4-(Hydroxymethyl)piperidin-1-yl)picolinic acid

[0745]

[0746] 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 water (10 mL) containing sodium hydroxide (653 mg, 16.3 mmol). The reaction was stirred for 0.5 h. HCl (aq) (3.30 mL, 19.8 mmol, 6 N) 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] + LC-MS calculated value: m / z = 237.1; found value: 237.0.

[0747] Step 3. N-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)picolinamide

[0748]

[0749] 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]pyridine 3-hexafluorophosphoric acid oxide (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) gave the title compound (476 mg, 1.37 mmol, 25.0% yield) as a white solid. 17 H 23 N4[M+H] + LC-MS calculated value: m / z = 347.2; found value: 347.1.

[0750] 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

[0751] The title compound was synthesized by a procedure analogous to that outlined in Example 12, Step 2. 39 H 45 N 10 O7S[M+H] + LC-MS calculated value: m / z = 797.3; found value: 797.2.

[0752] 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

[0753]

[0754] The title compound was synthesized by a procedure analogous 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) and 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione (from Example 6, Step 1). 44 H 48 N9O9S[M+H] + LC-MS calculated value: m / z = 878.3; found value: 878.2.

[0755] 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

[0756]

[0757] Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione

[0758]

[0759] The title compound was synthesized by a procedure analogous 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] + LC-MS calculated value: m / z = 358.1; found value: 358.1.

[0760] Step 2: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)pyrrolidine-3-carbaldehyde

[0761]

[0762] 2-(2,6-dioxopiperidin-3-yl)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione (8.0 mg, 0.018 mmol) was added to a solution of 1,2-dichloroethane (1 mL) with 2-iodooxybenzoic 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 NaHCO3 / saturated Na2S2O3 (aqueous solution) (3 mL). The layers were separated and the aqueous layer was extracted with DCM (3×3 mL). The combined organic layers were dried over Na2SO4, 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 any further purification. C 18 H 18 N3O5[M+H] + LC-MS calculated value: m / z = 356.1; found value: 356.0.

[0763] 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)piperazin-1-yl)benzenesulfonamide

[0764] The title compound was synthesized by a procedure analogous 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 H42 N9O8S[M+H] + LC-MS calculated value: m / z = 808.2; found value: 808.2.

[0765] 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-benzooxazol-3-yl]benzenesulfonamide

[0766]

[0767] Step 1: 2-(2,6-dioxopiperidin-3-yl)-4-[4-(hydroxymethyl)piperidin-1-yl]isoindole-1,3-dione

[0768]

[0769] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step8. 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] + LC-MS calculated value: m / z = 372.2; found value: 372.1.

[0770] 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-benzooxazol-3-yl]benzenesulfonamide

[0771] The title compound was synthesized by a procedure analogous 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] + LC-MS calculated value: m / z = 822.3; found value: 822.5.

[0772] 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

[0773]

[0774] The title compound was synthesized by a procedure analogous 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] + LC-MS calculated value: m / z = 834.3; found value: 834.4.

[0775] 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

[0776]

[0777] Step 1. 3-(6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0778]

[0779] 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

[0780] N,N-diisopropylethylamine (0.040mL, 0.23mmol). The reaction mixture was stirred at 120°C overnight. The reaction solution was cooled to room temperature and diluted with water (30mL) and EtOAc (30mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×25mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (50–100% EtOAc / hexane) gave the title compound (26mg, 0.076mmol, 99% yield) in the form of a clear oil. 18 H 22 N3O4[M+H] + LC-MS calculated value: m / z = 344.2; found value: 344.1.

[0781] Step 2: 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde

[0782]

[0783] The title compound was synthesized by a procedure analogous to that outlined in Example 31, Step 2. 18 H 20 N3O4[M+H] + LC-MS calculated value: m / z = 342.1; found value: 341.9.

[0784] 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

[0785] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 10. 1H 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] + LC-MS calculated value: m / z = 834.3; found value: 834.4.

[0786] 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

[0787]

[0788] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione

[0789]

[0790] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 8, using (S)-pyrrolidin-3-ylmethanol. 18 H 20N3O5[M+H] + LC-MS calculated value: m / z = 358.1; found value: 358.0.

[0791] 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

[0792] The title compound was synthesized by a procedure analogous 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] + LC-MS calculated value: m / z = 848.3; found value: 848.5.

[0793] 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

[0794]

[0795] 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

[0796]

[0797] To a solution of 3-bromo N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-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), Cs2CO3 (35.0 mg, 0.108 mmol) and RuPhos Pd G3 (7.00 mg, 8.36 μmol) (CAS1445085-77-7). The mixture was heated to 110 °C with N2 purging for 12 hours. The mixture was concentrated to give the title compound, which was used without further purification. C 28 H 35 N6O6S[M+H] + LC-MS calculated value: m / z = 583.2; found value: 583.8.

[0798] Step 2: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(4-aminopiperidin-1-yl)benzenesulfonamide

[0799]

[0800] To a mixture of tert-butyl N-[1-[3-[[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-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 hour. The mixture was concentrated, diluted with methanol (3 ml), filtered and purified by preparative HPLC on a C18 column (5-100% MeCN / 0.1% TFA (aq)) to give the title compound (30 mg, 0.062 mmol, 40% yield) as a white solid TFA salt. 23 H 27 N6O4S[M+H] + LC-MS calculated value: m / z = 483.2; found value: 483.6.

[0801] 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

[0802] The title compound was synthesized by a procedure analogous 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),10.81(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] + LC-MS calculated value: m / z = 808.3; found value: 809.0.

[0803] 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

[0804]

[0805] 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

[0806]

[0807] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 7. 28 H 35 N6O6S[M+H]+ LC-MS calculated value: m / z = 583.2; found value: 583.8.

[0808] 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

[0809]

[0810] 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. The product was purified by preparative TLC (20:1 DCM / MeOH, R f =0.70) to give the title compound (15 mg, 0.025 mmol, 29% yield) as a pale yellow solid. 29 H 37 N6O6S[M+H] + LC-MS calculated value: m / z = 597.2; found value: 597.8.

[0811] Step 3: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(methyl(piperidin-4-yl)amino)benzenesulfonamide

[0812]

[0813] To a solution of tert-butyl 4-[3-[[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-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 hour. 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 give the title compound (70 mg, 0.12 mmol, 68% yield) as a white solid TFA salt. 24 H 29 N6O4S[M+H] + LC-MS calculated value: m / z = 497.2; found value: 497.6.

[0814] 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

[0815] The title compound was synthesized by a procedure analogous 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] + LC-MS calculated value: m / z = 822.3; found value: 822.9.

[0816] 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

[0817]

[0818] Step 1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(piperidin-4-ylamino)benzenesulfonamide

[0819]

[0820] 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 hour. 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 give the title compound (40 mg, 0.067 mmol, 39% yield) as an off-white solid TFA salt. 23 H 27 N6O4S[M+H] + LC-MS calculated value: m / z = 483.2; found value: 483.6.

[0821] 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

[0822] The title compound was synthesized by a procedure analogous 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] + LC-MS calculated value: m / z = 808.3; found value: 809.0.

[0823] 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]undec-3-yl)benzenesulfonamide

[0824]

[0825] Step 1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-3-(3,9-diazaspiro[5.5]undec-3-yl)benzenesulfonamide

[0826]

[0827] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 8. 27 H 33N6O4S[M+H] + LC-MS calculated value: m / z = 537.2; found value: 537.1.

[0828] 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]undec-3-yl)benzenesulfonamide

[0829] The title compound was synthesized by a procedure analogous 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] + LC-MS calculated value: m / z = 862.4; found value: 862.6.

[0830] 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

[0831]

[0832] 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

[0833]

[0834] The title compound was synthesized by a procedure analogous to that outlined in Example 36, Steps 1-2, using (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester. 24 H 27 N6O4S[M+H] + LC-MS calculated value: m / z = 495.2; found value: 495.6.

[0835] 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

[0836] The title compound was synthesized by a procedure analogous 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),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] + LC-MS calculated value: m / z = 820.3; found value: 820.0.

[0837] 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

[0838]

[0839] Step 1: N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-bromo-2-methoxybenzenesulfonamide

[0840]

[0841] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 6, using 5-bromo-2-methoxybenzenesulfonyl chloride. 19 H 18 BrN4O5S[M+H] +LC-MS calculated value: m / z = 493.0; found value: 493.3.

[0842] 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

[0843]

[0844] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Step 7. 26 H 31 N6O5S[M+H] + LC-MS calculated value: m / z = 539.2; found value: 539.0.

[0845] 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

[0846] The title compound was synthesized by a procedure analogous 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). 1HNMR (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] + LC-MS calculated value: m / z = 878.3; found value: 878.4.

[0847] 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

[0848]

[0849] The title compound was synthesized by a procedure analogous to that outlined in Example 1, Steps 7-8 and Example 12, Step 2. 39 H 40 N9O8S[M+H] + LC-MS calculated value: m / z = 794.2; found value: 794.4.

[0850] Example A. Western Blot KAT6A Degradation Assessment

[0851] The activity of the compounds was evaluated by measuring KAT6A protein levels using Western blot as a readout of KAT6A degradation capacity. These studies were performed in the HCC1954 cell line carrying KAT6A copy number amplification. Cells were maintained in a 37°C incubator under 5% CO2 in the following media: RPMI 1640, Modification (Gibco, A10491-01), supplemented with 10% v / v FBS (Gibco, 26140-079) and 1% penicillin streptomycin (Gibco, 15140-122). Cells were seeded in 6-well plates at a density of 300,000 cells / well and allowed to attach overnight in an incubator. Compounds dissolved in DMSO were prepared at 1000 times the desired final concentration, so that the final percentage of DMSO was 0.1%. After 24 hours of treatment, cells were washed with phosphate buffered saline (PBS) (Corning, 21-040-CV), separated with trypsin-EDTA (Gibco, No. 25200-056), and centrifuged at 1500 rpm for 5 minutes in complete RPMI medium in a microcentrifuge. Protein was extracted from the cell pellet by resuspending in 15uL PBS, followed by the addition of 45uL of lysis buffer consisting of 4% SDS, 1x protease and phosphatase inhibitors, and 1mM PMSF (Cell Signaling Technology, No. 8553S). The lysate was transferred to a homogenizer column (Omega Biotek, No. HCR003) and centrifuged at 12,000rpm for 1.5 minutes.

[0852] Homogenized lysates were quantified by BCA assay (ThermoScientific, PierceBCA protein assay, No. 23223, No. 23224) according to the manufacturer's instructions. The samples were then diluted to 1x solution in 4x Laemmli buffer (Laemmli buffer, Biorad, No. 1610747), and the solution was boiled at 95°C for 5 minutes. To evaluate KAT6A protein expression, the samples were run at 120V on a 26-well gel (Biorad, 4-15% standard TGX precast gel, No. 5671085) for approximately 1 hour. Proteins were transferred to a low-fluorescence PVDF membrane (Millipore Sigma, No. IPFL00010) using the Trans-Blot Turbo transfer system (Biorad). The membrane was then probed with KAT6A (Cell Signaling Technology, No. 78462) and GAPDH (Cell Signaling Technology, No. 5174S) primary antibodies and fluorescently labeled secondary antibodies (LI-COR, IRDye 800CW goat anti-rabbit No. 926-32211; IRDye 680RD goat anti-mouse No. 926-68070) using an iBind Flex Western blotting apparatus (Thermo Scientific, SLF2000) under the conditions recommended by the manufacturer. The membrane was briefly washed in water and scanned with a LI-COR Odyssey CLx. The quantification of the bands was evaluated using Image Studio version 5.2 to normalize KAT6A expression relative to the GAPDH loading control before expressing KAT6A expression as a percentage of expression observed in DMSO.

[0853] The results are summarized in Table 3 below.

[0854] Table 3 - KAT6A degradation at 0.1 μM

[0855] Examples degradation% 1 ++ 2 ++ 3 + 4 ++ 5 +++ 6 ++ 7 +++ 8 +++ 9 + 10 ++ 11 ++

[0856] In Table 3, "+" indicates a degradation % value of 0<degradation %≤50; "++" indicates a degradation % of 50<degradation %≤75; and "+++" indicates a degradation % value of >75.

[0857] Example B. HiBit KAT6A degradation assessment

[0858] The degradation activity of the compounds was evaluated by measuring the levels of KAT6A protein using the HiBiT system. These studies were performed in HeLa cells with HiBit-tagged KAT6A. Cells were maintained in an incubator at 37°C with 5% CO2 in EMEM (American Type Culture Collection (ATCC), 30-2003) supplemented with 10% v / v FBS (Gibco, 26140-079) and 1% penicillin-streptomycin. Cells were seeded in 384-well plates at a density of 2,000 cells / well. Compounds dissolved in DMSO were added in 9-point serial dilutions. After 18 hours of treatment, the cells were plated using 5% CO2 according to the manufacturer's instructions. KAT6A levels were measured using the HiBiT cleavage detection system (Promega catalog number N3030). 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 in each condition. Results were analyzed and DC was obtained using a four-parameter logistic curve fit. 50 and D max The results are summarized in Table 4.

[0859] Table 4. HiBit KAT6A degradation

[0860]

[0861]

[0862] In Table 4, the DC 50 In the column, "A" means DC 50 <10nM; "B" means 10nM≤DC 50 <100nM; "C" means 100nM≤DC 50 <1000nM; D means DC was not calculated due to screening parameters 50 In Table 4, D max In the column, "A" means D max >75%; "B" means 50% <D max ≤75%; "C" means 25% <D max ≤50%; D means D max ≤25%.

[0863] Although we have described several embodiments of the present invention, it is apparent that the basic examples can be altered to provide other embodiments utilizing the compounds and methods of the present invention. It will be understood, therefore, that the scope of the present invention will be defined by the claims rather than by the specific embodiments that have been shown by way of example.

Claims

1. A compound of formula (I): ULM-PTM (I) or a pharmaceutically acceptable salt or solvate thereof, Wherein PTM is the portion of Formula IA: in Y is a covalent bond or a chemical moiety connecting the PTM and the ULM; * is the connection point with ULM; Ring A is C6-C 10 aryl or 5-10 membered heteroaryl; R 1 is H or a 5-6 membered heteroaryl group optionally substituted by methyl; R 2 is H or -(C(R 8 )2) n -(5-9 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH; R 3 is H or halogen, C1-C4 alkyl, cyclopropyl, haloalkyl, C1-C4 alkoxy or haloalkoxy; R 4 is H or halogen, C1-C4 alkyl, cyclopropyl, C1-C4 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- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b ; 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)2NR 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, -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 attached, form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl; Each R 8 are independently H, 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 the Cereblon E3 ubiquitin ligase.

2. The compound of claim 1, wherein Y is a chemical moiety that links the PTM and the ULM.

3. The compound according to claim 1 or claim 2, wherein R 1 For H.

4. A compound according to any one of the preceding claims, wherein R 2 For H.

5. A compound according to any one of claims 1 to 3, wherein R 2 is -(C(R 8 )2) n -(5-9 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH.

6. The compound according to claim 5, wherein R 2 is -(C(R 8 )2) n -(5-6 membered heteroaryl): halogen, C1-C3 alkyl, -CH2OH or -OH. The compound according to claim 6 , wherein the 5-6 membered heteroaryl group is pyrazole, pyrrole, pyridine or pyridazine. The compound according to claim 6 , wherein the 5-6 membered heteroaryl is pyrazole.

9. A compound according to any one of the preceding claims, wherein n is 0.

10. The compound according to any one of claims 1 to 8, wherein n is 1.

11. A compound according to any one of the preceding claims, wherein R 3 For H.

12. A compound according to any one of claims 1 to 10, wherein R 3 It is a halogen.

13. A compound according to any one of claims 1 to 10, wherein R 3 It is a C1-C4 alkyl group.

14. A compound according to any one of the preceding claims, wherein R 4 For H.

15. A compound according to any one of claims 1 to 13, wherein R 4 It is a C1-C4 alkyl group.

16. A compound according to any one of claims 1 to 13, wherein R 4 It is a C1-C4 alkoxy group.

17. The compound according to claim 16, wherein R 4 It is a methoxy group.

18. A compound according to any one of the preceding claims, wherein Ring A is C6-C 10 Aryl. The compound according to claim 18 , wherein Ring A is phenyl.

20. A compound according to any one of the preceding claims, wherein each R 5 For H.

21. A compound according to any one of claims 1 to 19, wherein at least one R 5 For H.

22. A compound according to any one of claims 1 to 19, wherein each R5 is C1-C4 alkoxy.

23. A compound according to any one of claims 1 to 19, wherein at least one R5 is C1-C4 alkoxy.

24. A compound according to any one of the preceding claims, wherein m is 0.

25. The compound according to any one of claims 1 to 23, wherein m is 1.

26. A compound according to any one of claims 1 to 23, wherein m is 2.

27. A compound according to any one of claims 1 to 23, wherein m is 3.

28. A compound according to any one of claims 1 to 23, wherein m is 4.

29. A compound according to any one of the preceding claims, wherein each R 8 For H.

30. A compound according to any one of the preceding claims, wherein Y is represented by the formula: -(A) q -， in: q is an integer from 1 to 14; Each A is independently selected from the group consisting of: CR 1a R 1b 、O、S、SO、SO2、NR 1c 、SO2NR 1c ,SONR 1c 、SO(=NR 1c ), SO(=NR 1c )NR 1d ,CONR 1c NR 1c CONR 1d NR 1c C(O)O、NR 1c SO2NR 1d ,CO,CR 1a =CR 1b 、C≡C、SiR 1a R 1b 、P(O)R 1a 、P(O)OR 1a , (CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 S(CR 1a R 1b ) 1-4 、-(CR 1a R 1b ) 1-4 NR 1c (CR 1a R 1b ) 1-4、 NR 1c C(=NCN)NR 1d NR 1c C(=NCN),NR 1c C(=CNO2)NR 1d , optionally 0-6 R 1a or R 1b 3-11 membered cycloalkyl substituted with 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group, optionally substituted by 0-6 R 1a or R 1b The aryl group is optionally substituted with 0-6 R 1a or R 1b a substituted heteroaryl group, Where R 1a , R 1b , R 1c , R 1d and R 1e Each is independently -H, -halo, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH2, -SO2C C1-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, -SO2NHC1-C8 alkyl, -SO2N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and wherein R 1a or R 1b Each independently may be optionally linked to other groups to form a group optionally with 0-4 R 1e The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

31. The compound according to claim 30, wherein q is an integer from 1 to 5.

32. A compound according to any one of claims 1 to 29, wherein Y is in ** is the connection point with PTM; L1, L2, and L3 are each independently a key, CR 1a R 1b , O, S, SO, SO2, NR 1c , SO2NR 1c , SONR 1c , SO(=NR 1c ), SO(=NR 1c )NR 1d , CONR 1c , NR 1c CONR 1d , NR 1c , C(O)O, NR 1c SO2NR 1d , CO, CR 1a =CR 1b , C≡C, SiR 1a R 1b , P(O)R 1a , P(O)OR 1a , (CR 1a R 1b ) 1-4 , -(CR 1a R 1b ) 1-4 O(CR 1a R 1b ) 1-4 , -(CR 1a R 1b ) 1-4 , S(CR 1a R 1b ) 1-4 , -(CR 1a R 1b ) 1-4 , NR 1c (CR 1a R 1b ) 1-4、 , NR 1c , C(=NCN)NR 1d , NR 1c , C(=NCN), NR 1c , C(=CNO2)NR 1d ; Ring A1 and Ring A2 are each independently optionally substituted with 0-6 R 1a or R 1b 3-11 membered cycloalkyl substituted with 0-6 R 1a or R 1b substituted 3-11 membered heterocyclic group, optionally substituted by 0-6 R 1a or R 1b The aryl group is optionally substituted with 0-6 R 1a or R 1b a substituted heteroaryl group, Where R 1a , R 1b , R 1c , R 1d and R 1e Each is independently -H, halogen, -C1-C8 alkyl, -O-C1-C8 alkyl, -C1-C6 haloalkyl, -S-C1-C8 alkyl, -NHC1-C8 alkyl, -N(C1-C8 alkyl)2, 3-11 membered cycloalkyl, aryl, heteroaryl, 3-11 membered heterocyclyl, -O-(3-11 membered cycloalkyl), -S-(3-11 membered cycloalkyl), NH-(3-11 membered cycloalkyl), N(3-11 membered cycloalkyl)2, N-(3-11 membered cycloalkyl)(C1-C8 alkyl), -OH, -NH2, -SH, -S O2C1-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, -SO2NHC1-C8 alkyl, -SO2N(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)SO2NH(C1-C8 alkyl), -N(C1-C8 alkyl)SO2N(C1-C8 alkyl)2, -NHSO2NH(C1-C8 alkyl), -NHSO2N(C1-C8 alkyl)2, or -NHSO2NH2; and wherein R 1a or R 1b Each independently may be optionally linked to other groups to form a group optionally with 0-4 R 1e The cycloalkyl and / or heterocyclyl moieties are substituted by radicals.

33. A compound according to any one of claims 1 to 29, wherein Y is in ** is the connection point with 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; p is 1, 2, 3 or 4; Each R 10 are independently H or C1-C4 alkyl; Ring A1 is 3-7 membered cycloalkyl, 4-10 membered heterocycloalkyl, aryl or heteroaryl; 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.

34. The compound of claim 33, wherein L3 is a bond.

35. A compound according to claim 33 or claim 34, wherein L1 is a bond.

36. according to the compound described in any one of claims 33 to 35, wherein L2 is (C (R 10 )2) p .

37. The compound according to any one of claims 33 to 36, wherein Ring A1 is a 4-10 membered heterocycloalkyl.

38. The compound according to claim 37, wherein Ring A1 is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl or azabicycloalkyl. The compound according to claim 37 , wherein Ring A 1 is piperidinyl or pyrrolidinyl.

40. The compound according to any one of claims 33 to 39, wherein Ring A2 is a 4-10 membered heterocycloalkyl.

41. The compound according to claim 40, wherein Ring A2 is piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, diazaspiroalkyl or azabicycloalkyl.

42. The compound according to claim 40, wherein Ring A2 is piperazinyl or diazaspironanyl.

43. The compound according to claim 33, wherein Y is in r is 0, 1, or 2; s is 0, 1, or 2; and Z is N or CR 10 .

44. The compound of claim 43, wherein r is 1.

45. A compound according to claim 43 or claim 44, wherein s is 1.

46. ​​A compound according to any one of claims 43 to 45, wherein Z is N.

47. A compound according to any one of the preceding claims, wherein ULM is in: is the connection point with 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(R 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, optionally substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, -CN, -OR a 、-OR b or -SR b ; Each R 15 are independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b ; 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)2NR 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, -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 attached, form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl; and o is 1, 2, 3, 4, or 5.

48. The compound according to claim 47, wherein Ring A3 is a bicyclic heterocyclic group.

49. A compound according to claim 47 or claim 48, wherein L4 is a bond.

50. A compound according to any one of claims 47 to 49, wherein R 12 For H.

51. according to the compound described in any one of claims 47 to 50, wherein each R 15 For H.

52. A compound according to any one of claims 47 to 51, wherein X1 is CO.

53. A compound according to any one of claims 47 to 52, wherein X2 is CH2.

54. The compound of claim 47, wherein ULM is in: is the connection point with Y or PTM; 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).

55. The compound of claim 54, wherein X3 is CH2.

56. The compound of claim 54, wherein X3 is CO.

57. The compound of claim 54, wherein X4 is CH2.

58. The compound of claim 54, wherein X4 is CO.

59. The compound according to claim 1, wherein PTM is a compound of formula IA-1 or a pharmaceutically acceptable salt thereof.

60. The compound according to claim 1, wherein PTM is a compound of formula IA-2 or a pharmaceutically acceptable salt thereof.

61. The compound according to claim 1, wherein PTM is a compound of formula IA-3 or a pharmaceutically acceptable salt thereof; wherein 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; p is 1, 2, 3 or 4; Each R 10 are independently H or C1-C4 alkyl; Ring A1 is 3-7 membered cycloalkyl, 4-10 membered heterocycloalkyl, aryl or heteroaryl; 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.

62. The compound according to claim 1, wherein PTM is a compound of formula IA-4 or a pharmaceutically acceptable salt thereof; wherein L1 is a bond, (C(R 10 )2) p or CO; L2 is a bond, (C(R 10 )2) p or CO; p is 1, 2, 3 or 4; Each R 10 are 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 .

63. The compound according to claim 1, wherein PTM-ULM is a compound of formula IA-5 or a pharmaceutically acceptable salt thereof; wherein L1 is a bond, (C(R 10 )2) p or CO; L2 is a bond, (C(R 10 )2) p or CO; p is 1, 2, 3 or 4; Each R 10 are 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(R 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 Alkoxy, C 1-4 Haloalkyl, -CN, -OR a 、-OR b or -SR b ; Each R 15 are independently H, halogen, oxo, -OH, -CN, -NO2, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, C 0- C1 alkylaryl, C 0- C1 alkylheteroaryl, 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)2NR 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)2R b ; 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)2NR 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, -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 attached, form a monocyclic or polycyclic heterocycloalkyl, or a monocyclic or polycyclic heterocycloalkenyl; and o is 1, 2, 3, 4, or 5.

64. The compound of claim 63, wherein PTM-ULM is a compound of formula IA-6 or a pharmaceutically acceptable salt thereof; wherein 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).

65. The compound of claim 63 or claim 64, wherein PTM-ULM is a compound of formula IA-7 or a pharmaceutically acceptable salt thereof; wherein t is 1 or 2.

66. The compound according to claim 1, wherein each R 5 are 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.

67. The compound according to claim 1, which is: 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; 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; 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; 3-[4-[7-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]-7-azaspiro[3.5]non-2-yl]piperazin-1-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide; 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-benzooxazol-3-yl]benzenesulfonamide; 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-benzooxazol-3-yl]benzenesulfonamide; 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-benzooxazol-3-yl]benzenesulfonamide; 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-benzooxazol-3-yl]benzenesulfonamide; 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-benzooxazol-3-yl]benzenesulfonamide; 3-[6-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]pyrrolidin-3-yl]methyl]-2,6-diazaspiro[3.3]hept-2-yl]-N-[4-methoxy-6-(pyrazol-1-ylmethyl)-1,2-benzooxazol-3-yl]benzenesulfonamide; or a pharmaceutically acceptable salt thereof.

68. The compound according to claim 1, which is: 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]dec-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)benzenesulfonamide; 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)benzenesulfonamide; 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]undec-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]non-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)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)-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-benzooxazol-3-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-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]undec-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.

69. A compound according to any one of the preceding claims in the form of a pharmaceutically acceptable salt.

70. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

71. A method of treating cancer or a solid tumor in a subject in need thereof, the method comprising administering to the subject a compound according to any one of claims 1 to 69 or a pharmaceutical composition according to claim 70.

72. The method of claim 71, wherein 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, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, hematological malignancies, chronic or acute leukemias, lymphocytic lymphomas, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphomas, spinal axis tumors, glioblastomas, brain stem gliomas, pituitary adenomas, and combinations of two or more of the foregoing cancers.

73. The method of claim 71, wherein the solid tumor is selected from the group consisting of breast, lung, colon, brain, prostate, stomach, pancreas, ovary, melanoma, endocrine, uterine, testicular, hematologic, and bladder.

74. The method of claim 73, wherein the solid tumor is selected from the group consisting of breast, lung, prostate, pancreas, hematologic, and ovarian.

75. The method of claim 71, wherein the cancer is breast cancer.

76. The method of claim 75, wherein the breast cancer is ER+ breast cancer.

77. The method of claim 75, wherein the breast cancer is ER+HER2- breast cancer.

78. The method of claim 75, wherein the breast cancer is locally advanced or metastatic ER+HER2- breast cancer.

79. The method of claim 71, wherein the cancer is lung cancer.

80. The method of claim 79, wherein the lung cancer is non-small cell lung cancer.

81. The method of claim 79, wherein the lung cancer is locally advanced or metastatic non-small cell lung cancer.

82. The method of claim 71, wherein the cancer is prostate cancer.

83. The method of claim 82, wherein the prostate cancer is castration-resistant prostate cancer.

84. The method of claim 82, wherein the prostate cancer is locally advanced or metastatic castration-resistant prostate cancer.

85. A method for degrading a KAT6 protein, the method comprising contacting the KAT6 protein with a compound according to any one of claims 1 to 69 or a pharmaceutical composition according to claim 70.

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