WO2021155050A1 - Kinase modulators, pharmaceutical compositions, and therapeutic applications - Google Patents

Abstract

Provided herein are kinase modulators, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disease, disorder, or condition associated with a protein malfunction.

Description

KINASE MODULATORS, PHARMACEUTICAL COMPOSITIONS, AND THERAPEUTIC APPLICATIONS CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of the priority of U.S. Provisional Application No. 62/967,438, filed January 29, 2020; the disclosure of which is incorporated herein by reference in its entirety. FIELD [0002] Provided herein are kinase modulators and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disease, disorder, or condition associated with a protein malfunction. BACKGROUND [0003] Protein kinases are critical components of cell-signaling machinery. Kinases mediate cell-signaling by transferring a phosphoryl group from a nucleoside triphosphate (NTP) to a protein acceptor. These phosphorylation events function as molecular on/off switches that can regulate the biological function of a target protein. Phosphorylation can be triggered by a wide variety of extracellular and other stimuli, such as environmental and chemical stress signals, cytokines, and growth factors. Thus, kinases facilitate cellular responses to such stimuli, in, for example, cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, metabolism, control of protein synthesis, and cell cycle regulation. [0004] The initiation, progression through, and completion of the cell cycle are tightly regulated by various cyclin-dependent kinases (CDKs), which are critical for normal cell growth. CDKs act as a complex with a CDK subunit (the catalytic subunit) and a regulatory subunit (the cyclin). There are over ten known CDKs, many of which are involved in regulating cell cycle progression, as well as having other functions. Accordingly, modulating CDK activity may provide advantageous anti-proliferative activity. Indeed, inhibitors of CDK4/6 such as palbociclib and ribociclib are currently on the market for the treatment of breast cancer. [0005] Additional targets include several candidate genes involved in apoptosis and cell survival, including the translation termination factor GSPT1 (eRF3a), casein kinase 1α (CK1α), and the zinc-finger transcription factors aiolos, helios, and ikaros. Aiolos, helios, and ikaros are transcription factors, whose expression is restricted to lymphoid lineages. For example, aiolos binds to the Bcl-2 promoter and interacts with the Bcl-2 and Bcl-XL proteins to promote cell survival. Upregulation of aiolos expression, for example, can reduce apoptosis of HIV-1 infected cells. [0006] Likewise, expression of aiolos in lung and breast cancers predicts significantly reduced patient survival. Aiolos decreases expression of a large set of adhesion-related genes, disrupting cell-cell and cell-matrix interactions, and facilitating metastasis. Aiolos may also function as an epigenetic driver of lymphocyte mimicry in certain metastatic epithelial cancers. Similarly, aberrant ikaros and helios expression may promote By cl-XL expression, driving the development of hematopoietic malignancies. Thus, down-regulation of aiolos, ikaros, and/or helios may reduce or eliminate metastasis. [0007] GSPT1 mediates stop codon recognition and facilitates release of a nascent peptide from the ribosome and is also involved in several other critical cellular processes, such as cell cycle regulation, cytoskeleton organization and apoptosis. Accordingly, decreased levels of GSPT1 may impair control of cell proliferation and facilitate cell migration and scar formation. Indeed, GSPT1 has been implicated as an oncogenic driver of several different cancer types, including breast cancer, hepatocellular carcinoma, gastric cancer, and prostate cancer. See, e.g., Brito et al., Carcinogenesis 2005, 26, 2046-9; Wright and Lange, Rev. Urol. 2007, 9, 207-13; Chauvin et al., Mol. Cell. Biol. 2007, 27, 5619-29; Malta-Vacas et al., Cancer Genet. Cytogenet. 2009, 195, 132-42; Miri et al., Med. Oncol. 2012, 29, 1581-5; Hashimoto et al., Apoptosis 2012, 17, 1287-99; Li et. al., PLoS One 2014, 9, e86371. GSPT1 also contributes to glial scar formation and astrogliosis after a central nervous system (CNS) injury. See, e.g., Ishii et al., J. Biol. Chem. 2017, 292, 1240-50. [0008] Casein kinase 1α (CK1α) is a component of the β-catenin-degradation complex and a critical regulator of the Wnt signaling pathway, and its ablation induces both Wnt and p53 activation. Elyada et al., Nature 2011, 470, 409-13; Cheong and Virshup, Int. J. Biochem. Cell Biol. 2011, 43, 465-9; Schittek and Sinnberg, Mol. Cancer 2014, 13, 231. CK1α phosphorylates β- catenin, which is subsequently further phosphorylated by GSK-3β. This destabilizes β-catenin and marks the protein for ubiquitination and proteasomal degradation. Thus, CK1α functions as a molecular switch for the Wnt pathway. Amit et al., Genes Dev.2002, 16, 1066-76. CK1α is critical for embryogenesis and plays an important role in tissue development and response to DNA damage, at least partly coordinated with p53. Levine and Oren, Nat. Rev. Cancer 2009, 9, 749-58; Elyada et al., Nature 2011, 470, 409-13; Schneider et al., Cancer Cell 2014, 26, 509-20. [0009] Indeed, CK1α also phosphorylates p53, which inhibits binding to MDM2 (a p53 inhibitor) and stabilizes p53’s binding interactions with the transcriptional machinery. Huart et al., J. Biol. Chem. 2009, 284, 32384-94. Thus, inhibiting CK1α activity increases cellular levels of p53. This is of particular importance for skin cancer, which has killed more people since 1980 than all other types of cancer combined. Stern, Arch Dermatol. 2010, 146, 279-82. [0010] Most kinase inhibitors function by blocking the NTP binding site on the kinase. However, given the structural similarity of endogenous NTPs, kinase inhibitors may produce undesirable off-target effects by unintended, non-specific interactions, or via pathway cross-talk. One mechanism to disrupt protein drivers of a disease is to decrease the cellular concentration of these proteins. For example, proteolytic degradation of cellular proteins is essential to normal cell function. Hijacking this process by targeting a specific disease-related protein presents a novel mechanism for the treatment of a disease. The irreversible nature of proteolysis makes it well-suited to serve as a regulatory switch for controlling unidirectional processes. [0011] Ubiquitin-mediated proteolysis begins with ligation of one or more ubiquitin molecules to a particular protein substrate. Ubiquitination occurs through the activity of ubiquitin- activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3), acting sequentially to attach ubiquitin to lysine residues of a substrate protein. The E3 ligases confer specificity to ubiquitination reactions by binding directly to a particular substrate. SUMMARY [0012] Provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: ,

X is C1-C15 alkylene, 2 to 15 membered heteroalkylene, C2-C10 alkenylene, C2-C10 alkynylene, phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C₃-C₈ cycloalkylene, wherein each of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C3-C8 cycloalkylene is optionally substituted with one or more R⁷; or X is C1-C15 alkylene or 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units of X is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C3-C8 cycloalkylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷; each Y is independently CH2, O, S, or NH;

, , , , ,

,

L² is a bond, –(CH₂)_1-3–_, –(CH₂)_0-3C(=O)–, –(CH₂)_0-3S(=O)–, –(CH₂)_0-3S(=O)₂–, or –(CH2)0-3C(=O)NR^8a–; each of Q¹, Q², and Q³ is independently S or CH, provided that one of Q¹, Q², and Q³ is S; each Q is independently CH₂ or C(=O); each n is independently an integer of 0, 1, or 2; each R^A is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, optionally substituted amino, C1-C6 alkylamino, (amino)C1-C6 alkyl, –(C=O)NR^9aR^9b, (C1-C6 alkoxy)C1-C6 alkyl, –O-(C1-C6 alkoxy)C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl; each of R², R^2a and R^2b is independently H, deuterium, halogen, or C₁-C₆ alkyl; each R^2c is independently H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl, wherein C₃-C₈ cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, or C1-C6 haloalkyl; each R^2d is independently H, hydroxyl, halogen, –O–C1-C6 alkyl, –O–C1-C6 haloalkyl, or –O–C₃-C₈ cycloalkyl, wherein –O–C₃-C₈ cycloalkyl is optionally substituted with C₁-C₆ alkyl, halogen, or C1-C6 haloalkyl; each R^2e is independently –C(=O)–C1-C6 alkyl or –C(=O)–C3-C8 cycloalkyl, each optionally substituted with one or more substituents, each substituent independently selected from the group consisting of cyano, halogen, hydroxy, amino, and C1-C6 haloalkyl; each R³ is independently H, deuterium, or C1-C6 alkyl; each of R⁴ and R⁶ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl), or optionally substituted C₃- C7 cycloalkyl; each of R^5a, R^5b and R^5c is independently H or C1-C6 alkyl; each Ring A is independently phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C3-C8 cycloalkylene, each optionally substituted with one or more R⁷; Ring B is phenylene or 6 membered heteroarylene, each optionally substituted with one or more R⁷; each R⁷ is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1- C6 alkoxy)C1-C6 alkyl, –O–(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted amino, C1-C6 alkylamino, (amino)C₁-C₆ alkyl, halogen, nitro, or cyano; or two geminal R⁷ form oxo; each of R⁸, R^8a, and R^8b is independently H or C₁-C₆ alkyl; each of R^9a and R^9b is independently H or C1-C6 alkyl; or R^9a and R^9b together with the nitrogen atom to which they are attached form optionally substituted 5 or 6 membered heterocyclyl, optionally substituted with one or more R⁷; each Z¹ is independently a bond, –(CR^aR^b)q1–, –C(=O)–, –CH=CH–, or –C≡C–; each Z² is independently a bond or –(CR^cR^d)q2–; each of Z³ and Z⁴ is independently a bond, –NR^8b–, –O–, or –S–; each of R^a, R^b, R^c and R^d is independently H, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or optionally substituted C3-C6 cycloalkyl; q1 and q2 are each independently an integer of 1, 2, or 3; each of X¹ and X² is independently O or S; and each of m1, m2, m3, m4, m5, m6, m7, m8, m9, k1, k2, k3, k4, k5, k6, k7, k8 and k9 is independently an integer of 0, 1, 2, 3, 4, or 5. [0013] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0014] Additionally, provided herein is a method of decreasing the cellular level of a CDK in a cell, comprising contacting the cell with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. [0015] Furthermore, provided herein is a method of inhibiting the activity of a CDK in a biological sample, comprising contacting the biological sample with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the CDK is CDK9 or CDK16. [0016] Provided herein is a method of treating or ameliorating a disease, disorder, or condition associated with a CDK in a subject, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the CDK is CDK9 or CDK16. In certain embodiments, the disease, disorder, or condition is cancer. [0017] Provided herein is a method of treating or ameliorating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, gastric cancer, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, testicular cancer, liver cancer, esophageal cancer, kidney carcinoma, astrogliosis, leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, relapsed/refractory multiple myeloma, or neuroblastoma. DETAILED DESCRIPTION [0018] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as are commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. The use of “or” or “and” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting. [0019] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated. [0020] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. [0021] As used herein, any “R” group(s) represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together,” the R groups and the atoms they are attached to can form cycloalkyl, aryl, heteroaryl, or heterocyclyl. For example, without limitation, if R^a and R^b, and the atom to which they are attached, are indicated to be “taken together” or “joined together,” it means that they are covalently bonded to one another to form a ring. [0022] Whenever a group is described as being “optionally substituted,” that group may be unsubstituted or substituted with one or more of the substituents specified. Likewise, when a group is described as being “substituted,” the substituent may be selected from one or more of the substituents specified. If no substituents are specified, it is meant that the “optionally substituted” or “substituted” group may be substituted with one or more groups, each of which is individually and independently alkyl (e.g., C₁-C₆ alkyl); alkenyl (e.g., C₂-C₆ alkenyl); alkynyl (e.g., C₂-C₆ alkynyl); C3-C8 carbocyclyl (e.g., C3-C8 cycloalkyl, C3-C8 cycloalkenyl, or C3-C8 cycloalkynyl, each further optionally substituted, for example, with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or –O(C₁-C₆ alkoxy)C₁-C₆ alkyl); (C₃-C₇ carbocyclyl)C₁-C₆ alkyl (further optionally substituted , for example with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or O(C₁-C₆ alkoxy)C₁-C₆ alkyl); 5-10 membered heterocyclyl (further optionally substituted, for example, with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, or –O(C1-C6 alkoxy)C1-C6 alkyl); (5-10 membered heterocyclyl)C₁-C₆ alkyl (further optionally substituted, for example, with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, or –O(C1-C6 alkoxy)C1-C6 alkyl); aryl (further optionally substituted, for example, with halo, C1-C6 alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or –O(C₁-C₆ alkoxy)C1-C6 alkyl); (aryl)C1-C6 alkyl (further optionally substituted, for example, with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, or –O(C1-C6 alkoxy)C₁-C₆ alkyl); 5-10 membered heteroaryl (further optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or –O(C₁-C₆ alkoxy)C1-C6 alkyl); (5-10 membered heteroaryl)C1-C6 alkyl (further optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, or –O(C₁-C₆ alkoxy)C₁-C₆ alkyl); halo (e.g., fluoro, chloro, bromo, or iodo); cyano; hydroxyl; protected hydroxyl; alkoxy (e.g., C1-C6 alkoxy); haloalkyl (e.g., C1-C6 haloalkyl, such as –CF3); haloalkyl (e.g., C1-C6 haloalkoxy, such as –OCF3); (C1-C6 alkoxy)C1-C6 alkyl; –O(C1-C6 alkoxy)C1-C6 alkyl; (C₁-C₆ haloalkoxy)C₁-C₆ alkyl; –O(C₁-C₆ haloalkoxy)C₁-C₆ alkyl; aryloxy; sulfhydryl (mercapto); alkylthio (e.g., C1-C6 alkylthio); arylthio; azido; nitro; O-carbamyl; N-carbamyl; O-thiocarbamyl; N-thiocarbamyl; C-amido; N-amido; S-sulfonamido; N-sulfonamido; C-carboxy; protected C- carboxy; O-carboxy; acyl; cyanate; isocyanato; thiocyanato; isothiocyanato; silyl; sulfenyl; sulfinyl; sulfonyl; trihalomethanesulfonyl; trihalomethanesulfonamido; amino; mono-substituted amino (e.g., NH(C1-C6 alkyl); di-substituted amino (e.g., N(C1-C6 alkyl)2); oxo (=O); or thioxo (=S). [0023] As used herein, the term “Ca to Cb,” in which “a” and “b” are each an integer, refers to, for example, the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of ring atoms of a cycloalkyl, aryl, heteroaryl, or heterocyclyl group. That is, the alkyl, the ring of the cycloalkyl, or the ring of the aryl, contains from “a” to “b,” inclusive, carbon atoms. Likewise, the ring of the heteroaryl or the ring of the heterocyclyl contains from “a” to “b,” inclusive, total ring atoms. Thus, for example, a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, e.g., –CH3, –CH2CH3, –CH2CH2CH3, –CH(CH3)2, –CH2CH2CH2CH3, –CH(CH3)CH2CH3, and –C(CH₃)₃; a C₃ to C₄ cycloalkyl group refers to all cycloalkyl groups having from 3 to 4 carbon atoms, e.g., cyclopropyl and cyclobutyl. Similarly, a “4 to 6 membered heterocyclyl” group refers to all heterocyclyl groups with 4 to 6 total ring atoms, e.g., azetidinyl, oxetanyl, oxazolinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. If no a and b are designated with regard to an alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described in these definitions is to be assumed. As used herein, the term “C1-C6” includes C1, C2, C3, C4, C5, and C6, and a range defined by any of the two numbers. For example, C₁-C₆ alkyl includes C₁, C₂, C₃, C₄, C5, and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl, etc. Similarly, C3-C8 carbocyclyl or cycloalkyl each includes hydrocarbon ring containing 3, 4, 5, 6, 7, and 8 carbon atoms, or a range defined by any of the two numbers, such as C₃-C₇ cycloalkyl or C₅-C₆ cycloalkyl. [0024] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group can be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group can be a lower alkyl having 1 to 6 carbon atoms. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl (straight chain or branched), and hexyl (straight chain or branched). The alkyl group can be substituted or unsubstituted. [0025] As used herein, “alkenyl” refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group can have 2 to 20 carbon atoms. By way of example only, “C2-C6 alkenyl” indicates that there are two to six carbon atoms in the alkenyl chain, e.g., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen- 1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien- 4-yl. Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl. The alkenyl group can be substituted or unsubstituted. [0026] As used herein, “alkynyl” refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group can have 2 to 20 carbon atoms. By way of example only, “C_2-C₆ alkynyl” indicates that there are two to six carbon atoms in the alkynyl chain, e.g., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl. The alkynyl group can be substituted or unsubstituted. [0027] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term “fused” refers to two rings that have two atoms and one bond in common. As used herein, the term “bridged” refers to a cycloalkyl that contains a linkage of one or more atoms connecting non- adjacent atoms. As used herein, the term “spiro” refers to two rings that have one atom in common and the two rings are not linked by a bridge. A cycloalkyl group can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). A cycloalkyl group can be unsubstituted or substituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of bicyclic fused cycloalkyl groups include, but are not limited to, decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl. Examples of bicyclic bridged cycloalkyl groups include, but are not limited to, bicyclo[1.1.1]pentyl, adamantanyl, and norbornenyl. Examples of bicyclic spiro cycloalkyl groups include, but are not limited to, spiro[3.3]heptanyl and spiro[4.5]decanyl. [0028] As used herein, “carbocyclyl” refers to a non-aromatic mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. A carbocyclyl group can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). A carbocyclyl group can be unsubstituted or substituted. Examples of carbocyclyl groups include, but are not limited to, cycloalkyl groups, and the non-aromatic portions of 1,2,3,4- tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 5,6,7,8-tetrahydroquinolinyl, and 6,7-dihydro-5H- cyclopenta[b]pyridinyl. [0029] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond). For example, the aryl group can be a C₆ aryl group or a C₁₀ aryl group. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. An aryl group can be substituted or unsubstituted. [0030] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2, or 3 heteroatoms), that is, an element other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. For example, the heteroaryl group can contain 5 to 10 atoms in the ring(s), 6 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s); such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term “heteroaryl” includes fused ring systems, where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furanyl, furazanyl, thiophenyl, benzothiophenyl, phthalazinyl, pyrrolyl, oxazolyl, benzoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, indolyl, indazolyl, pyrazolyl, benzopyrazolyl, isoxazolyl, benzoisoxazolyl, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, pteridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, and triazinyl. A heteroaryl group can be substituted or unsubstituted. [0031] As used herein, “heterocyclyl” refers to a three-, four-, five-, six-, seven-, eight-, nine-, or ten-membered monocyclic, bicyclic, or tricyclic ring system, wherein carbon atoms together with from 1 to 5 heteroatoms constitute the ring system. A heterocyclyl group may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings (i.e., heterocyclyl groups are not aromatic). The heteroatom(s) is an element other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. A heterocyclyl group can further contain one or more carbonyl functionalities so as to make the definition to include oxo-systems such as lactams, lactones, and cyclic carbamates. When composed of two or more rings, the rings can be joined together in a fused, bridged, or spiro fashion. As used herein, the term “fused” refers to two rings that have two atoms and one bond in common As used herein the term “bridged heterocyclyl” refers to a heterocyclyl that contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings that have one atom in common and the two rings are not linked by a bridge. A heterocyclyl group can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), 3 to 6 atoms in the ring(s), or 5 to 6 atoms in the ring(s); for example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogen in a heterocyclyl group can be quaternized. A heterocyclyl group can be linked to the rest of a molecule via a carbon atom in the heterocyclyl group (C-linked) or via a heteroatom in the heterocyclyl group, such as a nitrogen atom (N-linked). Heterocyclyl groups can be unsubstituted or substituted. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyl, barbituryl, thiobarbituryl, dioxopiperazinyl, hydantoinyl, dihydrouracyl, trioxanyl, hexahydro-1,3,5-triazinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, N-oxypiperidinyl, piperidinyl, piperazinyl, pyrrolidinyl, azepanyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl, thiamorpholinyl, benzimidazolidinonyl, tetrahydroquinolinyl, and 3,4-methylenedioxyphenyl. Examples of spiro heterocyclyl groups include, but are not limited to, 2-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2-oxaspiro[3.4]octanyl, and 2- azaspiro[3.4]octanyl. [0032] As used herein, “alkylene” refers to a branched or straight chain fully saturated di- radical hydrocarbon group, which is attached to the rest of a molecule via two points of attachment. By way of example only, “C_1-C₁₀ alkylene” indicates that there are one to ten carbon atoms in the alkylene chain. Non-limiting examples include ethylene (–CH2CH2–), propylene (–CH2CH2CH2–), butylene (–CH2CH2CH2CH2–), and pentylene (–CH2CH2CH2CH2CH2–). [0033] As used herein, “alkenylene” refers to a straight or branched chain di-radical hydrocarbon group containing at least one carbon-carbon double bond, which is attached to the rest of a molecule via two points of attachment. By way of example only, C_2-C₁₀ alkenylene indicates that there are two to ten carbon atoms in the alkenylene chain. [0034] As used herein, “alkynylene” refers to a straight or branched chain di-radical hydrocarbon group containing at least one carbon-carbon triple bond, which is attached to the rest of a molecule via two points of attachment. By way of example only, “C2-C10 alkynylene” indicates that there are two to ten carbon atoms in the alkynylene chain. [0035] As used herein, “heteroalkylene” refers to an alkylene group as defined herein that contains one or more heteroatoms in the carbon backbone (i.e., an alkylene group in which one or more carbon atoms is replaced with a heteroatom, for example, a nitrogen atom, oxygen atom, or sulfur atom). Heteroalkylene groups include, but are not limited to, ether, thioether, amino-alkylene, and alkylene-amino-alkylene moieties. A 2 to 15 membered heteroalkylene group as described herein refers to heteroalkylene that contains a total of 2 to 15 carbon atom(s) and heteroatom(s) (such as nitrogen, oxygen, sulfur, etc.). [0036] As used herein, “aralkyl” and “(aryl)alkyl” refer to an aryl group as defined herein, connected, as a substituent, via an alkylene group as defined herein. The alkylene and aryl groups of an aralkyl can each be independently substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl. In certain embodiments, the alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s). [0037] As used herein, “heteroaralkyl” and “(heteroaryl)alkyl” refer to a heteroaryl group as defined herein, connected, as a substituent, via an alkylene group as defined herein. The alkylene and heteroaryl groups of heteroaralkyl can each be independently substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs. In certain embodiments, the alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s). [0038] As used herein, “(heterocyclyl)alkyl” refer to a heterocyclic or heterocyclyl group as defined herein, connected, as a substituent, via an alkylene group as defined herein. The alkylene and heterocyclyl groups of (heterocyclyl)alkyl can each be independently substituted or unsubstituted. Examples include, but are not limited to, (tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (1,3- thiazinan-4-yl)methyl. In certain embodiments, the alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s). [0039] As used herein, “cycloalkylalkyl” and “(cycloalkyl)alkyl” refer to a cycloalkyl group as defined herein, connected, as a substituent, via an alkylene group. The alkylene and cycloalkyl groups of (cycloalkyl)alkyl can each be independently substituted or unsubstituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, and cyclohexylpropyl. In certain embodiments, the alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s). [0040] As used herein, “alkoxy” refers to the formula –OR, wherein R is an alkyl group as defined herein. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, 1- methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. An alkoxy can be substituted or unsubstituted. [0041] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Examples include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. A haloalkyl can be substituted or unsubstituted. [0042] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri- haloalkoxy). Examples include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. A haloalkoxy can be substituted or unsubstituted. [0043] As used herein, “amino” refer to an –NH2 group. The term “mono-substituted amino group” as used herein refers to an amino (–NH₂) group, where one of the hydrogen atoms is replaced by a substituent. The term “di-substituted amino group” as used herein refers to an amino (–NH2) group, where each of the two hydrogen atoms is independently replaced by a substituent. The term “optionally substituted amino” as used herein refer to an –NR_AR_B group, where R_A and R_B are each independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. [0044] As used herein, “alkylamino” or “(alkyl)amino” refers to a –NRARB group, where RA and R_B are hydrogen or alkyl (e.g., C₁-C₆ alkyl). Examples of alkylamino groups include, but are not limited to, methylamino (–NHMe), ethylamino (–NHEt), dimethylamino (–N(Me)2), methylethylamino (–N(Me)(Et)), and isopropylamino (–NHiPr). [0045] As used herein, “aminoalkyl” or “(amino)alkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by an amino group or “–NRARB” group as defined herein. Examples of aminoalkyl groups include, but are not limited to, –(CH2)1-4NH2, –(CH2)1-4– NHCH₃, –(CH₂)_1-4–NHC₂H₅, –(CH₂)₁-₄–N(CH₃)₂, –(CH₂)₁-₄–N(C₂H₅)₂, –(CH₂)₁-₄–NH–CH(CH₃)₂, – (CH₂)₁-₄N(CH₃)C₂H₅, and –CH(NH₂)CH₃. [0046] The term “halogen atom” or “halogen” as used herein refers to fluorine, chlorine, bromine, or iodine. [0047] As used herein, “alkoxyalkyl” or “(alkoxy)alkyl” refers to an alkoxy group connected via an alkylene group, such as C2-C8 alkoxyalkyl or (C1-C6 alkoxy)C1-C6 alkyl, for example, –(CH2)1-3-OCH3. [0048] As used herein, “–O–alkoxyalkyl” or “–O–(alkoxy)alkyl” refers to an alkoxy group connected via an –O-(alkylene) group, such as –O–(C1-C6 alkoxy)C1-C6 alkyl, for example, –O–(CH2)1-3–OCH3. [0049] As used herein, “aryloxy” and “arylthio” refers to –OR and –SR, respectively, wherein R is aryl as defined herein, e.g., phenyl. An aryloxy and arylthio can each be independently substituted or unsubstituted. [0050] A “sulfenyl” group refers to an “–SR” group in which R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. A sulfenyl can be substituted or unsubstituted. [0051] A “sulfinyl” group refers to an “–S(=O)R” group in which R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. A sulfinyl can be substituted or unsubstituted. [0052] A sulfonyl group refers to an SO₂R group in which R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. A sulfonyl can be substituted or unsubstituted. [0053] An “O-carboxy” group refers to an “–OC(=O)R” group in which R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An O-carboxy can be substituted or unsubstituted. [0054] The terms “ester” and “C-carboxy” refer to a “–C(=O)OR” group in which R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An ester or C-carboxy can be substituted or unsubstituted. [0055] A “trihalomethanesulfonyl” group refers to an “–O₂SCX’₃ “group, wherein X’ is a halogen. [0056] A “trihalomethanesulfonamido” group refers to an “–N(R)S(O)2CX’3” group, wherein X’ is a halogen and R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. [0057] A “mercapto” group refers to an “–SH” group. [0058] An “S-sulfonamido” group refers to an “–SO₂N(R_AR_B)” group in which R_A and R_B can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An S-sulfonamido can be substituted or unsubstituted. [0059] An “N-sulfonamido” group refers to an “–N(R_A)SO₂R” group in which R and R_A can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An N-sulfonamido can be substituted or unsubstituted. [0060] An “O-carbamyl” group refers to an “–OC(=O)N(RARB)” group in which RA and RB can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An O-carbamyl can be substituted or unsubstituted. [0061] An “N-carbamyl” group refers to an “–N(RA)C(=O)OR” group in which R and RA can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An N-carbamyl can be substituted or unsubstituted. [0062] An “O-thiocarbamyl” group refers to an “–OC(=S)N(R_AR_B)” group in which R_A and RB can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An O-thiocarbamyl can be substituted or unsubstituted. [0063] An “N-thiocarbamyl” group refers to an “–N(R_A)C(=S)OR” group in which R and R_A can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An N-thiocarbamyl can be substituted or unsubstituted. [0064] A “C-amido” group refers to a “–C(=O)N(RARB)” group in which RA and RB can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. A C-amido can be substituted or unsubstituted. [0065] An “N-amido” group refers to an “–N(RA)C(=O)R” group in which R and RA can each be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein. An N-amido can be substituted or unsubstituted. [0066] Where the number of substituents is not specified (e.g., haloalkyl), there can be one or more substituents present. For example, “haloalkyl” can include one or more of the same or different halogens. [0067] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to water methanol ethanol n-propanol isopropanol and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate. [0068] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure or enantiomerically enriched, or can be stereoisomeric mixtures, and include all diastereomeric and enantiomeric forms. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond can independently be E or Z or a mixture thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. [0069] Wherever a substituent is depicted as a di-radical (i.e., has two points of attachment to the rest of a molecule), it is to be understood that the substituent can be attached in any directional configuration unless otherwise indicated. For example, unless a particular orientation is specified, the formula –AE– represents both –AE– and –EA–. In addition, if a group or substituent is depicted as

, and when L is defined as a bond or absent; such group or substituent is equivalent to

. In addition, when a group is depicted as a di-radical, such as X, Ring A, or Ring B in Formula (I), one of ordinary skill in the art understands that the definition of such a group should also be di-radical. For example, when X is defined as phenyl, 5 to 6 membered heteroaryl, 5 to 6 membered heterocyclyl, or C₃-C₈ cycloalkyl, one skilled in the art understands that X is a phenylene, 5 to 6 membered heteroarylene, 5 to 6 membered heterocyclylene, or C3-C8 cycloalkylene. [0070] It is to be understood that, where a compound disclosed herein has an unfilled valency, the valency is to be filled with hydrogen or deuterium. [0071] It is understood that the compounds described herein can be labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium can afford certain therapeutic advantages from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, a reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. [0072] It is understood that the methods and formulations described herein include the use of crystalline forms, amorphous phases, and/or pharmaceutically acceptable salts, solvates, hydrates, and conformers of the compounds provided herein, as well as metabolites and active metabolites of these compounds having the same type of activity. A conformer is a structure that is a conformational isomer. Conformational isomerism is the phenomenon of a molecule with the same structural formula but different conformations (conformers) of atoms about a rotating bond. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water or ethanol. In certain embodiments, the compounds provided herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Other forms in which the compounds provided herein can be provided include amorphous forms, milled forms, and nano-particulate forms. [0073] Likewise, it is understood that a compound described herein include the compound in any of the forms described herein (e.g., pharmaceutically acceptable salts, crystalline forms, amorphous form, solvated forms, enantiomeric forms, and tautomeric forms). [0074] As used herein, the abbreviations for any protective groups, amino acids, and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Eur. J. Biochem. 1992, 204, 1-3). [0075] The term “protecting group” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd. Ed. John Wiley & Sons, 1999; and in McOmie, Protective Groups in Organic Chemistry, Plenum Press, 1973; each of which is hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known in the art. [0076] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [0077] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human. [0078] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. [0079] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition. [0080] The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition. [0081] The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted. [0082] The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician. [0083] The term “IC₅₀” or “EC₅₀” refers to an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such a response. [0084] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human or an animal) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 22nd ed.; Allen Ed.; Pharmaceutical Press: London, 2012; Handbook of Pharmaceutical Excipients, 8th ed.; Sheskey et al., Eds.; Pharmaceutical Press: London, 2017; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; Drugs and the Pharmaceutical Sciences 199; Informa Healthcare: New York, NY, 2009. [0085] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. [0086] The term “CDK protein,” as used herein, refers to a protein in the cyclin-dependent kinase family, including, but not limited to, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, CDK14, CDK15, and CDK16. Compounds of Formula (I) [0087] In one embodiment, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R

, , ,

X is C1-C15 alkylene, 2 to 15 membered heteroalkylene, C2-C10 alkenylene, C2-C10 alkynylene, phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C₃-C₈ cycloalkylene, wherein each of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C3-C8 cycloalkylene is optionally substituted with one or more R⁷; or X is C1-C15 alkylene or 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units of X is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C3-C8 cycloalkylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷; each Y is independently CH₂, O, S, or NH; ,

, , , ,

L² is a bond, –(CH2)1-3–, –(CH2)0-3C(=O)–, –(CH2)0-3S(=O)–, –(CH2)0-3S(=O)2–, or –(CH₂)_0-3C(=O)NR^8a–; each Q¹, Q², and Q³ is independently S or CH, with the proviso that one of Q¹, Q², and Q³ is S; each Q is independently CH2 or C(=O); each n is independently an integer of 0, 1, or 2; each R^A is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, optionally substituted amino, C₁-C₆ alkylamino, (amino)C₁-C₆ alkyl, –(C=O)NR^9aR^9b, (C₁-C₆ alkoxy)C₁-C₆ alkyl, –O-(C₁-C₆ alkoxy)C₁-C₆ alkyl, or optionally substituted C₃-C₇ cycloalkyl; each of R², R^2a and R^2b is independently H, deuterium, halogen, or C1-C6 alkyl; each R^2c is independently H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl, wherein C₃-C₈ cycloalkyl is optionally substituted with C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; each R is independently H, hydroxyl, halogen, O C₁-C₆ alkyl, O C₁-C₆ haloalkyl, or –O–C3-C8 cycloalkyl, wherein –O–C3-C8 cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, or C1-C6 haloalkyl; each R^2e is independently –C(=O)–C₁-C₆ alkyl or –C(=O)–C₃-C₈ cycloalkyl, each optionally substituted with one or more substituents, each substituent independently selected from the group consisting of cyano, halogen, hydroxy, amino, and C1-C6 haloalkyl; each R³ is independently H, deuterium, or optionally substituted C₁-C₆ alkyl; each R⁴ and R⁶ is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, optionally substituted C3-C7 cycloalkyl(C1-C3 alkyl), or optionally substituted C3-C7 cycloalkyl; each R^5a, R^5b and R^5c is independently H or C₁-C₆ alkyl; each Ring A is independently phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C3-C8 cycloalkylene, each optionally substituted with one or more R⁷; Ring B is phenylene or 6 membered heteroarylene, each optionally substituted with one or more R⁷; each R⁷ is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1- C₆ alkoxy)C₁-C₆ alkyl, –O–(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted amino, C₁-C₆ alkylamino, (amino)C1-C6 alkyl, halogen, nitro, or cyano; or two geminal R⁷ form oxo; each R⁸, R^8a, and R^8b is independently H or C1-C6 alkyl; each R^9a and R^9b is independently H or C₁-C₆ alkyl; or R^9a and R^9b together with the nitrogen atom to which they are attached form optionally substituted 5 or 6 membered heterocyclyl, optionally substituted with one or more R⁷; each Z¹ is independently a bond, –(CR^aR^b)q1–, –C(=O)–, –CH=CH–, or –C≡C–; each Z² is independently a bond or –(CR^cR^d)_q2–; each Z³ and Z⁴ is independently a bond, –NR^8b–, –O–, or –S–; each R^a, R^b, R^c and R^d is independently H, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or optionally substituted C₃-C₆ cycloalkyl; each q1 and q2 is independently an integer of 1, 2, or 3; each X¹ and X² is independently O or S; and each m1, m2, m3, m4, m5, m6, m7, m8, m9, k1, k2, k3, k4, k5, k6, k7, k8 and k9 is independently an integer of 0, 1, 2, 3, 4, or 5. [0088] In certain embodiments, in Formula (I), when

,

Ring A is phenylene or five to six membered heteroarylene; L

,

, or

, wherein the asterisk * indicates the point of connection of L¹ to X; L² is a bond, –(CH2)0-3C(=O)– or –(CH2)0-3-C(=O)NR^8a–; X is C1-C15 alkylene or 2 to 15 membered heteroalkylene; Z³ is a bond, O, or NR^8b; Z⁴ is NR^8b, O, or S; m1, m2, m4, m5, m6, m7, k1, k2, k4, k5 and k6 are each independently an integer of 0, 1, 2, or 3; then Z¹ is –C(=O)–, –CH=CH–, or –C≡C–. In certain embodiments, in Formula (I), when

,

, x m

, wherein the asterisk * indicates the point of connection of L¹ to X; L² is a bond, –(CH₂)_0-3C(=O)–, or –(CH2)0-3-C(=O)NR^8a–; Z¹ is a bond or –(CR^aR^b)q1–; Z³ is a bond, O, or NR^8b; Z⁴ is NR^8b, O, or S; m1, m2, m4, m5, m6, m7, k1, k2, k4, k5 and k6 are each independently an integer of 0, 1, 2, or 3; then X is C₂-C₁₀ alkenylene, C₂-C₁₀ alkynylene, phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C3-C8 cycloalkylene; or X is C1-C15 alkylene or 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units of X is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C₃-C₈ cycloalkylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–. [0089] In certain embodiments, the compound of Formula (I) is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof; wherein Ring B, R¹, R⁴, R⁶, R^5a, R^5b, R^5c, L¹, L², and X are each as defined herein. [0090] In certain embodiments, in Formula (I) or (Ia), Ring B is phenylene. In certain embodiments, in Formula (I) or (Ia), Ring B is 6 membered heteroarylene containing 1 nitrogen atom. In certain embodiments, in Formula (I) or (Ia), Ring B is 6 membered heteroarylene containing 2 nitrogen atoms. In certain embodiments, in Formula (I) or (Ia), Ring B is 6 membered heteroarylene containing 3 nitrogen atoms. In certain embodiments, in Formula (I) or (Ia), Ring B is pyridinylene. In certain embodiments, in Formula (I) or (Ia), Ring B is pyrimidinylene. In certain embodiments, in Formula (I) or (Ia), Ring B is triazinylene. In certain embodiments, in Formula (I) or (Ia), Ring B is optionally substituted with one or more R⁷, where each R⁷ is as defined herein. In certain embodiments, in Formula (I) or (Ia), Ring B is

each optionally substi ^{7 7}

tuted with one R , where each R is as defined herein. In certain embodiments, in Formula (I) or (Ia), Ring B is

,

where each R⁷ is as defined herein. In certain embodiments, in * Formula (I) or (Ia), Ring B is _*

or , where ** indicates the point of attachment to

each R⁷ is as defined herein. In certain embodiments, in Formula (I) or (Ia), Ring B is unsubstituted. In certain embodiments, in Formula (I) or (Ia), each R⁷ is independently halogen, chloro, fluoro, C1-C6 alkyl (in one embodiment, methyl). [0091] In certain embodiments, in Formula (I) or (Ia), at least one of R⁴ and R⁶ is H. In certain embodiments, in Formula (I) or (Ia), one of R⁴ and R⁶ is H and the other of R⁴ and R⁶ is halogen, C1-C6 alkyl (in one embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t- butyl, pentyl (straight chain or branched), or hexyl (straight chain or branched)), C1-C6 haloalkyl (in one embodiment, –CH₂F, –CHF₂, –CF₃, –CH₂CF₃, or –CF₂Cl), C₁-C₆ alkoxy (in one embodiment, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy (straight chain or branched), or hexoxy (straight chain or branched)), optionally substituted C3-C7 cycloalkyl(C1-C3 alkyl) (in one embodiment, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, or cyclohexylethyl), halogen substituted C3-C7 cycloalkyl(C1-C3 alkyl) (in one embodiment, fluoro substituted cyclopropyl(C1-C3 alkyl), e.g., 1-fluorocyclopropylmethyl), or C1-C6 haloalkyl substituted C3-C7 cycloalkyl(C1-C3 alkyl) (in one embodiment, trifluoromethyl substituted cyclopropyl(C₁-C₃ alkyl), e.g., 1- trifluoromethylcyclopropylmethyl)), optionally substituted C3-C7 cycloalkyl (in embodiment, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogen substituted C3-C7 cycloalkyl (e.g., fluoro substituted cyclopropyl such as 1-fluorocyclpropyl), or C₁-C₆ haloalkyl substituted C₃-C₇ cycloalkyl (e.g., trifluoromethyl substituted cyclopropyl, such as 1-trifluoromethylcyclopropyl)), or C1-C6 haloalkoxy (in one embodiment, –OCH2F, –OCHF2, –OCF3, –OCH2CF3, or –OCF2Cl). In certain embodiments, in Formula (I) or (Ia), one of R⁴ and R⁶ is H and the other R⁴ and R⁶ is C₃-C₇ cycloalkyl(C_1-C₂ alkyl), in one embodiment, cyclopropyl(C_1-C₂ alkyl), cyclobutyl(C_1-C₂ alkyl), cyclopentyl(C1-C2 alkyl), or cyclohexyl(C1-C2 alkyl). In certain embodiments, in Formula (I) or (Ia), R⁴ is H and R⁶ is cyclopropyl(C1-C3 alkyl), in one embodiment, cyclopropylmethyl. In certain embodiments, in Formula (I) or (Ia), one of R⁴ and R⁶ is H and the other R⁴ and R⁶ is trifluoromethyl- or fluoro-substituted cyclopropyl or cyclopropyl(C1-C3 alkyl), in one embodiment, 1-fluorocyclopropyl, 1-trifluoromethylcyclopropyl, 1-fluorocyclopropylmethyl, or 1- trifluorocyclopropylmethyl. [0092] In certain embodiments, in Formula (I) or (Ia), R^5a is H. In certain embodiments, in Formula (I) or (Ia), R^5a is C1-C6 alkyl. In certain embodiments, in Formula (I) or (Ia), R^5a is methyl. [0093] In certain embodiments, in Formula (I) or (Ia), each of R^5b and R^5c is H. In certain embodiments, in Formula (I) or (Ia), at least one of R^5b and R^5c is C_1-C₆ alkyl. In certain embodiments, in Formula (I) or (Ia), one of R^5b and R^5c is methyl. In certain embodiments, in Formula (I) or (Ia), both R^5b and R^5c are methyl. [0094] In certain embodiments, the compound of Formula (I) is a compound of Formula (Ib) or (Ibʹ):

or a pharmaceutically acceptable salt thereof; wherein each R¹, L¹, L², and X is as defined herein in Formula (I); each R^5c is independently H or methyl; and each R⁷ is independently halogen (in one embodiment, F or Cl). [0095] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), n is an integer of 1. In certain embodiments, in Formula (

,

wherein each R², R³, R^A, and Q is as defined herein. In certain embodiments, in Formula (I

, wherein R², R³, and Q are each as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

, wherein R², R³, and Q are each as defined herein. In certain embodiments, in Formula (I

, , , , , wherein R², R³, and Q are each as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

, wherein R², R³, and Q are each as defined herein. In certain embodiments in Formula (I) (Ia) (Ib) or (Ibʹ) R¹ is

, wherein R², R³, and Q are each as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ib), R is

wherein R², R³, and Q are each as defined herein. In certain embodiments, in Formula (

wherein R², R³, R^A, and Q are each as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

, wherein R², R³, R^A, and Q are each as defined herein. In certain such embodiments, R² is H. [0096] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

, wherein each R³, R^2a, R^2b, and R^A is as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R

, wherein R³, R^2a, and R^2b are each as defined herein. In certain embodiments, in Formula (

, , , , , wherein R³, R^2a, R^2b, and R^A are each as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

wherein R³, R^2a, R^2b, and R^A are each as defined herein. In certain such embodiments, R^2a is H and R^2b is C1-C6 alkyl (in one embodiment, methyl). [0097] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), n is an integer of 0 or 2. In certain embodiments, R³ is H. In certain embodiments, R¹ is unsubstituted. In certain embodiments, R¹ is substituted with one R^A. In certain embodiments, R^A is halogen (such as –F) or optionally substituted C1-C6 alkyl. [0098] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

, or

In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

[0099] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

, ,

[0100] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is

, . [0101] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is a bond,

, , , , ,

wherein the asterisk * in L¹ indicates the point of connection to R¹; and wherein each Ring A, R⁸, X¹, X², Z¹, Z², Z³, Z⁴, k1, k2, k3, k4, k5, k6, k7, k8, k9, m1, m2, m3, m4, m5, m6, m7, m8, and m9 are as defined herein. [0102] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

, wherein each R⁸, X¹, Z¹, and m1 are as defined herein. In certain such embodiments, each of R⁸ is H; X¹ is O; Z¹ is a bond or –(CH₂)_1-3–; and m1 is an integer of 0 or 1. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is .

[0103] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

wherein Z³ is –O– or –NR^8b–; and R⁸, R^8b, X¹, Z¹, Z², and m3 are each as defined herein. In certain such embodiments, X¹ is O; Z¹ is a bond or –(CH₂)_1-3–; Z² is –(CH₂)_1-2–; and m3 is an integer of 0 or 1. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

[0104] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is –Z¹–Z³–(CH2)m6–, where Z¹, Z³, and m6 are each as defined herein. In certain such embodiments, Z¹ is –C(O)–; Z³ is a bond; and m6 is an integer of 0 or 1. In certain such embodiments, Z¹ is a bond or –(CH2)1-3–; Z³ is O or NH; and m6 is an integer of 0 or 1. [0105] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

, wherein Ring A, Z¹, Z³, Z⁴, k6, and m6 are each as defined herein. In certain such embodiments, Z³ is O or NR^8b, wherein R^8b is as defined herein. In certain such embodiments, Ring A is phenylene optionally substituted with R⁷; Z¹ is a bond or –(CH₂)_1-3–; Z⁴ is absent, –O–, or –NH–; and m6 and k6 is each independently an integer of 0 or 1; wherein R⁷ is as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

, , , . [0106] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

,

, ; wherein each Z¹ and m7 are as defined herein. In certain such embodiments Z¹ is a bond C≡C or (CH₂)_{1 -3}- ; and m7 is an integer of 0 or 1. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is .

[0107] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is ; whe ³

rein Z is a bond or NR^8b; and each R^8b, X¹, Z¹, Z², and m8 is as defined herein. In certain such embodiments, Z¹ is –C≡C–. In certain such embodiments, R^8b is H; X¹ is O; Z² is–CH₂–; and m8 is an integer of 0 or 1. [0108] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

; wherein each X¹, Z¹, Z², Z³, and m9 is as defined herein. In certain such embodiments, X¹ is O; Z¹ is a bond; Z³ is NR^8b; and m9 is an integer of 0 or 1; wherein R^8b is H or methyl. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

. [0109] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

, , , wherein each Z⁴ is independently a bond, O, or NR^8b; and wherein each R^8b, Ring A, Z¹, k7, and m7 is as defined herein. In certain such embodiments, R^8b is H or methyl; Ring A is phenylene, 6 membered heterocyclylene, or C₆-C₈ cycloalkylene; Z¹ is a bond; k7 is an integer of 0 or 1; and m7 is an integer of 0, 1, or 2. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is

, , ,

wherein R^8b is as defined herein. [0110] In certain embodiments, in any one of the embodiments of L¹ that contains Ring A, Ring A is phenylene; five or six membered heteroarylene containing one, two or three heteroatoms, each independently selected from the group consisting of N, O, and S; five or six membered heterocyclylene containing one or two heteroatoms, each independently selected from the group consisting of N, O, and S; or C3-C8 cycloalkylene, in one embodiment, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl. In certain such embodiments, Ring A is optionally substituted with one or more R⁷, wherein each R⁷ is as defined herein. [0111] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is –NH(CH₂)₂– N ,

^, [0112] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹– R¹ is:

, , , wherein ^A

each R is independently C1-C6 alkyl (in one embodiment, methyl) or halogen (in one embodiment, fluoro); and each Q is as defined herein. [0113] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L² is a bond. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L² is –(CH2)1-2–. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L² is –C(=O)–, –S(=O)–, or –S(=O)2–. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L² is –CH₂-C(=O)NR^8a–, wherein R^8a is H or methyl. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), one of L¹ and L² is not a bond. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹ is not a bond and L² is a bond. [0114] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is alkylene, in one embodiment, C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, or C₁₅ alkylene (including both straight-chained or branched). In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is C1-C8 alkylene, in one embodiment, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, or octylene. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is straight- chained alkylene, in one embodiment, straight-chained C1-C8 alkylene. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is unsubstituted. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is unsubstituted C₇ alkylene. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is 2 to 15 membered heteroalkylene (including both straight-chained or branched). In certain embodiments, the heteroatom in the heteroalkylene is oxygen (O), nitrogen (N), or sulfur (S). In certain such embodiments, X is 2 to 15 membered heteroalkylene containing carbon, hydrogen, and oxygen atoms, where at least one methylene unit is replaced by oxygen, in one embodiment, (–(CH2)2O–)1-5 or –((CH2)2O)1-4(CH2)2–. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is a 2 to 8 membered heteroalkylene containing carbon, hydrogen and nitrogen atoms, where at least one methylene unit is replaced by NR^8c; in one embodiment, –(CH₂)_1-5–NR^8c–(CH₂)_1-5–, wherein R^8c is H or C1-C6 alkyl (in one embodiment, methyl). In certain embodiments, R^8c is methyl. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is unsubstituted 2 to 15 membered heteroalkylene containing carbon, hydrogen, and one or both of oxygen and nitrogen atoms. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is straight-chained heteroalkylene. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ib), X is CH₂CH₂O , –(CH2CH2O)2-4–, –(CH2CH2O)1-4-(CH2)1-4– (in one embodiment, –(CH2CH2O)CH2CH2–, –(CH2CH2O)CH2CH2CH2–, –(CH2CH2O)2CH2CH2–, or –(CH2CH2O)3CH2CH2–), –(CH₂)_1-4O(CH₂)_1-4–, or –(CH₂)_1-4NR^8c(CH₂)_1-4– (in one embodiment, –CH₂NR^8cCH₂–, –CH2CH2NR^8cCH2CH2– or –(CH2)3NR^8c(CH2)2–); wherein each R^8c is as defined herein. In certain such embodiments, each R^8c is independently H or methyl. [0115] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is phenylene; five or six membered heteroarylene containing one, two, or three heteroatoms, each independently selected from the group consisting of N, O, and S; five or six membered heterocyclylene containing one or two heteroatoms, each independently selected from the group consisting of N, O, and S; or C₃-C₈ cycloalkylene (in one embodiment, cyclopropyl, cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene); each of which is optionally substituted with one or more R⁷; wherein each R⁷ is as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is C1-C15 alkylene or 2 to 15 membered heteroalkylene (in one embodiment, C₁-C₈ alkylene or 2 to 8 membered heteroalkylene, in another embodiment, straight chained), wherein one or more methylene units of X is each independently replaced by (i) a ring structure selected from 5 or 6 membered heteroarylene containing one, two, or three heteroatoms, each independently selected from the group consisting of N, O, and S; five or six membered heterocyclylene containing one or two heteroatoms, each independently selected from the group consisting of N, O, and S; and C3-C8 cycloalkylene (in one embodiment, cyclopropyl, cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene); or (ii) –C(=O)–; –CH=CH–; or –C≡C–; where each of the ring structure is optionally substituted with one or more R⁷ and where each R⁷ is as defined herein. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is straight chain C2-C8 alkylene or straight chain 2 to 8 membered heteroalkylene, wherein one methylene unit of X is replaced by a phenylene, pyrazolylene, imidazolylene, piperazinylene, or piperidinylene. In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), X is straight chain C2-C8 alkylene or straight chain 2 to 8 membered heteroalkylene, wherein one methylene unit of X is replaced by –C(=O)–; –CH=CH–; or –C≡C–. [0116] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), R¹ is as defined herein and –L¹-X-L²– is one listed in Table A. TABLE A

[0117] In certain embodiments, when R¹ is

,

; then -L²-X-L¹-* is not any one of the following structures (wherein * indicates the point of connection to R¹):

[0118] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), L¹-X-L² is: – ,

,

. [0119] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ibʹ), –L¹-X-L²– is: – ,

, . [0120] In certain embodiments, in Formula (I), (Ia), (Ib), or (Ib), L -X-L is: ,

[0121] In one embodiment, provided herein is: 4-((14-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin- 2-yl)amino)cyclohexyl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione 1; 3-(4-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-3-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 2; (S)-3-(4-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3; 3-(4-(1-(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)benzyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 4; (2S,4R)-1-((S)-2-(11-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 5; (S)-3-(1-((4-(((9-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)amino)methyl)phenoxy) methyl)-4-oxo-4H- thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 6; 3-(4-(1-(9-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 7; 3-(4-(1-(5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 8; (S)-3-(1-((4-(((5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)amino)methyl)phenoxy)methyl)-4-oxo-4H- thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 9; 3-(1-oxo-4-{2-[1-(5-{[(1r,4r)-4-({5-chloro-4-[5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl]pyrimidin-2-yl}amino)cyclohexyl]amino}pentanoyl)piperidin-4-yl]ethynyl}-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6-dione 10; (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)heptyl)(methyl)amino)methyl)- phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 11; 3-(5-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 12; 3-(4-((1-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)glycyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 13; 3-(4-(1-(3-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 14; 3-(4-(1-(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)phenethyl)piperidin-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione 15; 3-(4-(1-(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)benzyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 16; 3-(4-(1-(4-((2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)(methyl)amino)phenethyl)piperidin-4-yl)-6-fluoro- 1-oxoisoindolin-2-yl)piperidine-2,6-dione 17; (S)-3-(4-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 18; (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)(methyl)amino)methyl)-phenoxy)methyl)-4-oxo- 4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 19; (S)-3-(1-((4-(((2-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)piperidin-1-yl)ethyl)amino)methyl)- phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 20; (S)-3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 21; (S)-3-(1-((4-((((1r,4r)-4-((5-fluoro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 22; (S)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 23; (R)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 24; (S)-3-(1-((3-((((1r,4S)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 25; (S)-3-(4-((4-((4-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-2-fluorophenyl)piperazin-1- yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 26; 3-(4-(1-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 27; 3-(5-(1-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 28; 3-(4-(1-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 29; 3-(5-(1-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 30; 3-(1-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 31; 3-(1-((4-((((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)piperidine-2,6-dione 32; 3-(1-((4-((((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)piperidine-2,6-dione 33; (S)-3-(4-((4-((4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperazin-1-yl)methyl)benzyl)oxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 34; 3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(2-hydroxyethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)piperidine-2,6-dione 35; (S)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane-2,7- dione 36; (S)-3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)azepane-2,7-dione 37; 2-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)propyl)-4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazin-1-yl)benzonitrile 38; 3-(5-(1-(4-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)butyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 39; 3-(5-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6- dione 40; 3-(5-(1-(5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 41; 3-(5-((2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)amino)-6-fluoro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 42; or 3-(5-(1-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)propyl)piperidin-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione 43; or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. [0122] In another embodiment, provided herein is: N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)-7-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol- 1-yl)methyl)ureido)heptanamide (A1); N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)-7-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol- 2-yl)methyl)ureido)heptanamide (A2); N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)-7-((2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)amino)-2-oxoethyl)amino)heptanamide (A3); N-((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)-7-((2-((2-((S)-2,7-dioxoazepan-3-yl)-1-oxoisoindolin-4-yl)amino)-2- oxoethyl)amino)heptanamide (A4); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(5-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)acetamide (A5); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(5-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)ureido)pentyl)acetamide (A6); 1-(6-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)hexyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)urea (A7); 1-(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)urea (A8); 1-(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)urea (A9); 1-(6-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)hexyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)urea (A10); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide (A11); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-(2-(2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)amino)-2-oxoethoxy)ethoxy)ethyl)acetamide (A12); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-(2-(2-((4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)amino)-2-oxoethoxy)ethoxy)ethyl)acetamide (A13); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide (A14); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H- thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide (A15); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(5-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H- thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)pentyl)acetamide (A16); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide (A17); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide (A18); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide (A19); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H- thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide (A20); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H- thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide (A21); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)ethyl)acetamide (A22); 14-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)acetamido)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)-6,9,12-trioxa-3-azatetradecanamide (A23); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)ureido)ethyl)acetamide (A24); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3- c]pyrrol-2-yl)-3-oxo-7,10,13-trioxa-2,4-diazapentadecan-15-yl)acetamide (A25); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H- thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide (A26); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide (A27); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide (A28); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(4-((2-(((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H- thieno[3,4-c]pyrrol-1-yl)methyl)amino)-2-oxoethyl)amino)butyl)acetamide (A29); 2-((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)heptyl)amino)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)acetamide (A30); 2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide (A31); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)acetamide (A32); 1-(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2- yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)urea (A33); 2-((5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)pentyl)amino)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)acetamide (A34); 1-(8-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)octyl)-3-((3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4- dihydrothieno[3,4-d]pyrimidin-7-yl)methyl)urea (A35); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2- yl)amino)cyclohexyl)amino)-N-(1-(5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3- c]pyrrol-2-yl)-5,8,11-trioxa-2-azatridecan-13-yl)acetamide (A36); 2-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyridin-2- yl)amino)cyclohexyl)amino)-N-(2-((2-(((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)amino)-2-oxoethyl)amino)ethyl)acetamide (A37); 4-((14-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (A38); 1-(8-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-1,3,5-triazin-2- yl)amino)cyclohexyl)amino)octyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)methyl)urea (A39); 3-(2-(13-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-5,8,11-trioxa-2-azatridecyl)-6-oxo-4,6-dihydro-5H- thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione (A40); (S)-3-(1-((4-(((2-(2-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)ethoxy)ethyl)amino)methyl)phenoxy)methyl)- 4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione (A41); (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)methyl)phenoxy)methyl)-4-oxo-4H- thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione (A42); (S)-3-(1-((4-(13-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-5,8,11-trioxa-2-azatridecyl)phenoxy)methyl)-4-oxo- 4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione (A43); 3-(4-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione (A44); 4-((14-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (A45); or (S)-3-(4-((4-(13-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-5,8,11-trioxa-2-azatridecyl)benzyl)oxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (A46); or a pharmaceutically acceptable salt thereof. [0123] In certain embodiments, a compound of Formula (I) is not any one of compounds A1 to A46, or a pharmaceutically acceptable salt thereof. [0124] In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight. [0125] The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cis/trans (or Z/E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. [0126] A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation. [0127] When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate. [0128] Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)- (1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid. [0129] Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2- amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine. [0130] A compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Uses or Methods of Treatment [0131] In one embodiment, provided herein is a method of inhibiting the activity of a protein in a biological sample, comprising contacting a compound provided herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof) with one or more cells in the biological sample. In certain embodiments, the protein is CDK, GSPT1, CK1α, aiolos, helios, or ikaros. In certain embodiments, the protein is CDK. In certain embodiments, the protein is GSPT1. In certain embodiments, the protein is CK1α. In certain embodiments, the protein is aiolos. In certain embodiments, the protein is helios. In certain embodiments, the protein is ikaros. In certain embodiments, the protein is a CDK protein. In certain embodiments, the protein is a CDK9 protein. In certain embodiments, the protein is a CDK16 protein. [0132] In another embodiment, provided herein is a method of decreasing the cellular level of a protein, comprising contacting a compound provided herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof) with one or more cells in the biological sample. In certain embodiments, the protein is CDK, GSPT1, CK1α, aiolos, helios, or ikaros. In certain embodiments, the protein is CDK. In certain embodiments, the protein is GSPT1. In certain embodiments, the protein is CK1α. In certain embodiments, the protein is aiolos. In certain embodiments, the protein is helios. In certain embodiments, the protein is ikaros. In certain embodiments, the protein is a CDK protein. In certain embodiments, the protein is a CDK9 protein. In certain embodiments, the protein is a CDK16 protein. [0133] In yet another embodiment, provided herein is method of inducing the activity of IL- 2, comprising contacting one or more cells with an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof). In yet another embodiment, provided herein is a method of increasing the cellular level of IL-2, comprising contacting one or more cells with an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof). [0134] In certain embodiments, the cell is a cancer cell. In certain embodiments, the cancer cell is small cell lung cancer cell, non-small cell lung cancer cell, breast cancer cell, prostate cancer cell, head and neck cancer cell, pancreatic cancer cell, colon cancer cell, rectal cancer cell, teratoma cell, gastric cancer cell, ovarian cancer cell, endometrial cancer cell, brain cancer cell, retinoblastoma cell, leukemia cell, skin cancer cell, melanoma cell, squamous cell carcinoma cell, liposarcoma cell, lymphoma cell, multiple myeloma cell, myelodysplastic syndrome cell, testicular cancer cell, liver cancer cell, esophageal cancer cell, kidney carcinoma cell, astrogliosis cell, relapsed/refractory multiple myeloma cell, or neuroblastoma cell. In certain embodiments, the cancer cell is leukemia cell, lymphoma cell, multiple myeloma cell, or relapsed/refractory multiple myeloma cell. [0135] In yet another embodiment, provided herein is a method of treating or ameliorating a disease, disorder, or condition associated with a protein malfunction in a subject; the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof). In certain embodiments, the disease, disorder, or condition is cancer. In certain embodiments, the protein is CDK, GSPT1, CK1α, aiolos, helios, or ikaros. In certain embodiments, the protein is CDK. In certain embodiments, the protein is GSPT1. In certain embodiments, the protein is CK1α. In certain embodiments, the protein is aiolos. In certain embodiments, the protein is helios. In certain embodiments, the protein is ikaros. In certain embodiments, the protein is a CDK protein. In certain embodiments, the protein is a CDK9 protein. In certain embodiments, the protein is a CDK16 protein. [0136] In yet another embodiment, provided herein is a method of treating or ameliorating cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof). [0137] In certain embodiments, the cancer is small cell lung cancer, non-small cell lung cancer, breast cancer, prostate cancer, head and neck cancer, pancreatic cancer, colon cancer, rectal cancer, teratoma, gastric cancer, ovarian cancer, endometrial cancer, brain cancer, retinoblastoma, skin cancer, melanoma, squamous cell carcinoma, liposarcoma, testicular cancer, liver cancer, esophageal cancer, kidney carcinoma, astrogliosis, leukemia, lymphoma, multiple myeloma, myelodysplastic syndrome, relapsed/refractory multiple myeloma, or neuroblastoma. In certain embodiments, the cancer is leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, or relapsed/refractory multiple myeloma. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute lymphocytic/lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic/lyphoblastic leukemia (CLL), or chronic myeloid leukemia (CML). In certain embodiments, the cancer is T-cell acute lymphocytic leukemia (T-ALL) or B-cell acute lymphoblastic leukemia. [0138] In certain embodiments, the CDK protein is CDK1. In certain embodiments, the CDK protein is CDK2. In certain embodiments, the CDK protein is CDK4. In certain embodiments, the CDK protein is CDK5. In certain embodiments, the CDK protein is CDK6. In certain embodiments, the CDK protein is CDK9. In certain embodiments, the CDK protein is CDK16. In certain embodiments, the CDK protein is wild-type. In certain embodiments, the CDK protein is a mutant form of a CDK protein. In certain embodiments, the CDK protein is overexpressed. [0139] In still another embodiment, provided herein is a method of treating or ameliorating an inflammatory disease, disorder, or condition in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof). [0140] In certain embodiments, the inflammatory disease, disorder, or condition is a neurodegenerative disease (such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease), fibrosis (such as pulmonary fibrosis), lupus, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, uveitis, or chronic obstructive pulmonary disease. In certain embodiments, the inflammatory disease, disorder, or condition is associated with a protein, wherein the protein is CK1α, GSPT1, aiolos, helios, or ikaros. In certain embodiments, the protein is wild- type. In certain embodiments, the protein is a mutant form of the protein. In certain embodiments, the protein is overexpressed. Dosing Regimes [0141] In certain embodiments, a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof is ranging from about 1 mg to about 5 g per day, per week, or per cycle of treatment. [0142] In certain embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is administered once per day, twice per day, three times per day, four times per day, or more than four times per day. In certain embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is administered once per day, twice per day, three times per day, four times per day, or more than four times per cycle of treatment. [0143] In certain embodiments, each cycle of treatment lasts from 1 day to 14 days. In some embodiments, each cycle of treatment has from at least one day up to fourteen days between administration. In certain embodiments, a compound provided herein or a pharmaceutically acceptable salt thereof is administered intravenously over about 10 minutes to over about 4 h. Pharmaceutical Compositions [0144] In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, e.g., a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [0145] In certain embodiments, a pharmaceutical composition provided herein is formulated for intravenous injection, subcutaneous injection, oral administration, buccal administration, inhalation, nasal administration, topical administration, transdermal administration, ophthalmic administration, or otic administration. In certain embodiments, a pharmaceutical composition provided herein is in the form of a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. [0146] Multiple techniques of administering a compound, salt and/or composition exist in the art, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. [0147] In certain embodiments, a compound of Formula (I), (Ia), (Ib), and (Ib), or a pharmaceutically acceptable salt thereof is administered orally. In certain embodiments, a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof is administered locally rather than systematically, for example, via injection or implantation of the compound directly into the affected area, e.g., in a depot or sustained release formulation. In certain embodiments, a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof is administered in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. In certain embodiments, a compound of Formula (I), (Ia), (Ib), and (Ibʹ), or a pharmaceutically acceptable salt thereof is administered intranasally or via pulmonary delivery. [0148] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical excipient may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0149] The disclosure will be further understood by the following non-limiting examples. EXAMPLES [0150] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); µL (microliters); mM (millimolar); µM (micromolar); mmol (millimoles); h (hour or hours); min (minute or minutes); amphos (di-tert-butyl(4-dimethylaminophenyl)phosphine); Boc (tert-butoxycarbonyl); dppf (1,1’- bis(diphenylphosphino)ferrocene); Et (ethyl); EtO (ethoxy); Me (methyl); MeO (methoxy); ACN (acetonitrile); AcOH (acetic acid); DCM (dichloromethane); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); EtOH (ethanol); EtOAc (ethyl acetate); MeOH (methanol); PE (petroleum ether); THF (tetrahydrofuran); CDI (1,1’-carbonyldiimidazole); DIPEA (N,N-diisopropylethyl- amine); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); HOBt (1-hydroxybenzotriazole); NBS (N-bromosuccinimide); TEA (triethylamine); TFA (trifluoroacetic acid); HPLC (high- performance liquid chromatography); MS (mass spectrometry); NMR (nuclear magnetic resonance); and TLC (thin-layer chromatography). [0151] For all the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ºC (degrees Centigrade). All reactions are conducted at room temperature unless otherwise specified. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure. Example 1 Synthesis of 4-((14-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5- fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione 1

[0152] To a solution of tert-butyl 14-hydroxy-3,6,9,12-tetraoxatetradecan-1-oate (1.9 g, 6.17 mmol) in DCM (40 mL) at 0 °C were added carbon tetrabromide (2.05 g, 6.17 mmol) and triphenylphosphine (1.62 g, 6.17 mmol). After stirred at room temperature for 16 h, the mixture was concentrated. The residue was purified using silica gel eluting with EtOAc in PE from 0% to 30% to give tert-butyl 14-bromo-3,6,9,12-tetraoxatetradecan-1-oate (1.62 g) in 71% yield. MS (ESI) m/z: 388.1 [M+18]⁺, 390.1 [M+2+18]⁺. [0153] To a solution of tert-butyl 14-bromo-3,6,9,12-tetraoxatetradecan-1-oate (1.62 g, 4.38 mmol) in DCM (24 mL) at 0 °C was added TFA (6 mL). After stirred at room temperature for 16 h, the mixture was concentrated to give 14-bromo-3,6,9,12-tetraoxatetradecan-1-oic acid (1.50 g). [0154] To a solution of 14-bromo-3,6,9,12-tetraoxatetradecan-1-oic acid (1.50 g, crude) in DCM (20 mL) were added EDCI (1.26 g, 6.57 mmol) and TEA (885 mg, 8.76 mmol). N,O- Dimethylhydroxylamine HCl (555 mg, 5.69 mmol) and N,N-dimethylpyridin-4-amine (54 mg, 0.438 mmol) were added. After stirred overnight, the mixture was diluted with H₂O and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified using silica gel eluting with MeOH in DCM from 0% to 5% to give 14-bromo-N-methoxy- N-methyl-3,6,9,12-tetraoxatetradecan-1-amide (1.34 g) in 81% yield. MS (ESI) m/z: 378.1 [M+18]⁺, 380.1 [M+2+18]⁺. [0155] To a solution of 4-hydroxyisobenzofuran-1, 3-dione (600 mg, 3.66 mmol) in benzyl alcohol (5 mL) at 0 °C was added SOCl2 (2.18 g, 18.3 mmol) dropwise. After heated at 80 °C for 16 h, the mixture was diluted with H₂O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified using silica gel eluting with EtOAc in PE from 0% to 8% to give dibenzyl 3-hydroxyphthalate (165 mg) in 13% yield. MS (ESI) m/z: 380.1 [M+18]⁺, 385.1 [M+Na]⁺. [0156] To a solution of dibenzyl 3-hydroxyphthalate (165 mg, 0.456 mmol) in DMF (10 mL) were added 14-bromo-N-methoxy-N-methyl-3,6,9,12-tetraoxatetradecan-1-amide (162 mg, 0.456 mmol) and K₂CO₃ (126 mg, 0.912 mmol). The mixture was heated at 50 °C for 16 h and then concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 8% to give dibenzyl 3-((3-methyl-4-oxo-2,6,9,12,15-pentaoxa-3-azaheptadecan-17-yl)oxy)phthalate (269 mg) in 92% yield. MS (ESI) m/z: 640.2 [M+H]⁺. [0157] To a solution of dibenzyl 3-((3-methyl-4-oxo-2,6,9,12,15-pentaoxa-3-azaheptadecan- 17-yl)oxy)phthalate (269 mg, 0.421 mmol) in MeOH (8 mL) at room temperature was added Pd/C (100 mg). The mixture was stirred for 1 h under H2 and then filtered. The filtrate was concentrated to give 3-((3-methyl-4-oxo-2,6,9,12,15-pentaoxa-3-azaheptadecan-17-yl)oxy)phthalic acid (190 mg) in 98% yield. [0158] To a solution of 3-((3-methyl-4-oxo-2,6,9,12,15-pentaoxa-3-azaheptadecan-17- yl)oxy)phthalic acid (168 mg, 0.366 mmol) in pyridine (5 mL) was added 3-aminopiperidine-2,6- dione (71 mg, 0.439 mmol). The mixture was heated at 120 C for 10 h and then concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 8%, and then prep- TLC (DCM/MeOH: 10:1) to give 14-((2-(2, 6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- methoxy-N-methyl-3,6,9,12-tetraoxatetradecan-1-amide (80 mg) in 38% yield. MS (ESI) m/z: 569.2 [M+18]⁺. [0159] To a solution of 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- methoxy-N-methyl-3,6,9,12-tetraoxatetradecan-1-amide (80 mg, 0.145 mmol) in THF (5 mL) at -70 °C was added LiAlH4 (0.22 mL, 1 M in THF) dropwise over 10 min. After stirred at 0 °C for 30 min, the mixture was quenched with saturated NH4Cl (5 mL) slowly. The mixture was then diluted with EtOAc (15 mL) and washed with H₂O (10 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give 14-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)-3,6,9,12-tetraoxatetradecan-1-al (68 mg, crude). [0160] To a solution of (1r,4r)-N¹-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5- fluoropyrimidin-2-yl)cyclohexane-1,4-diamine (50 mg, 0.146 mmol) in MeOH/DCM (1mL:3 mL) were added 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-3,6,9,12-tetraoxa- tetradecan-1-al (68 mg, crude), NaBH3CN (37 mg, 0.584 mmol), and acetic acid (1 drop). After stirred for 16 h, the mixture was concentrated and purified by prep-TLC (DCM/MeOH: 10:1), followed by prep-HPLC eluting with ACN/H2O to afford 4-((14-(((1r,4r)-4-((4-(5-(cyclopropyl- methyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin-2-yl)amino)cyclohexyl)amino)-3,6,9,12- tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 1 (9.2 mg) in 13% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d, J = 4.0 Hz, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.80 (dd, J = 7.6, 8.8 Hz, 1H ), 7.52 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 6.86 (s, 1H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 4.34 (t, J = 4.4 Hz,, 2H), 3.85 (s, 3H), 3.83-3.79 (m, 2H), 3.66-3.63 (m, 3H), 3.55-3.52 (m, 3H), 3.51-3.43 (m, 11H), 3.20 (d, J = 6.8 Hz, 2H), 2.92-2.83 (m, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.61-2.51 (m, 2H), 2.43-2.36 (m, 1H), 2.04-1.99 (m, 1H), 1.91-1.89 (m, 2H), 1.32-1.26 (m, 2H), 1.13-1.04 (m, 3H), 0.42-0.37 (m, 2H), 0.24-0.20 (m, 2H); MS (ESI) m/z: 821.3 [M+H]⁺. Example 2 Synthesis of 3-(4-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-3-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 2

[0161] To a solution of 3-(4-bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (500 mg, 1.475 mmol) in DMF (18 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.367 g, 4.425 mmol) and K2CO3 (610 mg, 4.43 mmol). The mixture was purged with N2 and Pd(dppf)2Cl2 (324 mg, 0.443 mmol) was added. After stirred at 100 °C for 16 h, the mixture was filtered, concentrated, and purified using silica gel eluting with EtOAc/PE from 0% to 60% to give tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1- oxoisoindolin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (420 mg) in 71% yield. MS (ESI) m/z: 388 [M-55]⁺. [0162] To a solution of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4- yl)-5,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.346 mmol) in THF (10 mL) was added Pd/C (200 mg). After stirred under H₂ for 18 h, the mixture was filtered and concentrated to give tert- butyl 3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidine-1-carboxylate (105 mg, crude). [0163] To a solution of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4- yl)piperidine-1-carboxylate (50 mg, 0.112 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred for 1 h and then concentrated to give 3-(6-fluoro-1-oxo-4-(piperidin-3- yl)isoindolin-2-yl)piperidine-2,6-dione as a TFA salt (crude). MS (ESI) m/z: 346 [M+H] ⁺. [0164] To a solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-(methoxy(methyl)amino)-7-oxoheptyl)carbamate (75 mg, 0.113 mmol) in THF (3 mL) under N2 at -78 °C was added LiAlH4 (0.17 mL, 0.17 mmol, 1M in THF) dropwise. After stirred at -78 °C for 30 min, the mixture was quenched with saturated NH₄Cl (5 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-oxoheptyl)carbamate (68.0 mg, crude). [0165] To a solution of 3-(6-fluoro-1-oxo-4-(piperidin-3-yl)isoindolin-2-yl)piperidine-2,6- dione (68.0 mg, 0.112 mmol) in DCM/MeOH (8mL:1mL) was added DIPEA (14.0 mg, 0.112 mmol). The mixture was stirred for 3 min and benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropyl- methyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-oxoheptyl)carbamate (68.0 mg, crude) and NaBH3CN (28 mg, 0.448 mmol) were added. After stirred for 3 h, the mixture was concentrated and purified by prep-TLC (DCM/MeOH: 10:1) to give benzyl ((1r,4r)-4-((5-chloro-4- (5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-(3-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)carbamate (55 mg) in 53% yield. [0166] To a solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(7-(3-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1- oxoisoindolin-4-yl)piperidin-1-yl)heptyl)carbamate (55 mg, 0.059 mmol) in AcOH (2 mL) was added HBr (33% in AcOH, 2 mL). The mixture was stirred for 1 h and then concentrated. The residue was dissolved in DMF (2 mL), neutralized to pH 7 with TEA, and then concentrated. The residue was purified by prep-HPLC eluting with ACN/H2O to afford 3-(4-(1-(7-(((1r,4r)-4-((5- chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)- amino)heptyl)piperidin-3-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2 (8.1 mg) in 17% yield. ¹ (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.329 (s, 2H), 8.289 (s, 1H), 7.48-7.31 (m, 1H), 5.14-5.17 (m, 1H), 4.45 (s, 1H), 3.86 (s, 3H), 3.67 (s, 1H), 3.53-3.56 (m, 2H), 3.13-3.14 (m, 1H), 2.90-2.91 (m, 12H), 2.66-2.67 (m, 1H), 2.33-2.35 (m, 1H), 1.99-2.08 (m, 9H), 1.57-1.66 (m, 4H), 1.30-1.38 (m, 10H), 0.98-0.95 (m, 1H), 0.41-0.37 (m, 2H), 0.14-0.11 (m, 2H); MS (ESI) m/z: 802.3 [M+H]⁺, 401.7 [1/2M+H]⁺. Example 3 Synthesis of 3-(4-(1-(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)benzyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 4

[0167] To a stirred solution of 4-(2-bromoethyl)benzoic acid (5.20 g, 22.7 mmol) in THF (100 mL) at -10 °C was dropwise added borane (45.4 mL, 1M solution in THF). After stirred at room temperature for 2 h, the mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated to give (4-(2-bromoethyl)phenyl)methanol (4.7 g) in 96% yield. [0168] To a stirred solution of (4-(2-bromoethyl)phenyl)methanol (4.70 g, 21.9 mmol) in chloroform (100 mL) was added manganese dioxide (8.7 g, 0.1 mol). The mixture was stirred at 70 °C overnight, filtered, and concentrated to give 4-(2-bromoethyl)benzaldehyde (4.0 g) in 86% yield. ¹H NMR (400 MHz, CDCl₃) δ 10.00 (s, 1H), 8.85 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 3.60 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.2 Hz, 2H). [0169] To a stirred solution of 4-(2-bromoethyl)benzaldehyde (1 g, 4.69 mmol) in toluene (20 mL) were added ethylene glycol (1 g, 16.1 mmol) and p-toluenesulfonic acid (90 mg, 0.47 mmol). After refluxed overnight, the mixture was concentrated, and diluted with EtOAc. The organic layer was washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give 2-(4-(2-bromoethyl)phenyl)-1,3-dioxolane (1.3 g, crude). ¹H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 5.79 (s, 1H), 4.14-4.11 (m, 2H), 4.04-4.01(m, 2H), 3.54 (t, J = 7.6 Hz, 2H), 3.17 (t, J = 7.6 Hz, 2H). [0170] To a stirred solution of (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (600 mg, 1.38 mmol) and 2-(4-(2- bromoethyl)phenyl)-1,3-dioxolane (430 mg, 1.66 mmol) in DMF (10 mL) was added K2CO3 (572 mg, 4.14 mmol). After stirred at 80 °C overnight, the mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated, and purified using silica gel (DCM/MeOH: 10:1) to give (1r,4r)-N¹-(4-(1,3- dioxolan-2-yl)phenethyl)-N -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (350 mg) in 47% yield. MS (ESI) m/z: 537.3 [M+H]⁺. [0171] To a solution of (1r,4r)-N¹-(4-(1,3-dioxolan-2-yl)phenethyl)-N⁴-(5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (300 mg, 0.56 mmol) in THF (8 mL) and water (2 mL) were added sodium carbonate (180 mg, 1.68 mmol) and benzyl chloroformate (145 mg, 0.84 mmol). The mixture was stirred for 1 h and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give benzyl 4-(1,3-dioxolan-2- yl)phenethyl((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)carbamate (crude). MS (ESI) m/z: 671.3 [M+H]⁺. [0172] To a stirred solution of benzyl 4-(1,3-dioxolan-2-yl)phenethyl((1r,4r)-4-((5-chloro-4- (5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate (0.56 mmol) in acetone (10 mL) and water (1 mL) was added pyridinium p-toluenesulfonate (30 mg, 0.12 mmol). After heated at 70 °C overnight, the mixture was concentrated and purified using silica gel eluting with EtOAc/PE (1:1) to give benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(4-formylphenethyl)carbamate (300 mg) in 86% yield. MS (ESI) m/z: 627.3 [M+H]⁺. [0173] To a stirred solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(4-formylphenethyl)carbamate (100 mg, 0.16 mmol) and 3-(6-fluoro-1-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (0.22 mmol) in DCM (8 mL) were added 4 drops of DIPEA, sodium cyanoborohydride (40 mg, 0.64 mmol), AcOH (5 drops), and MeOH (0.4 mL). After stirred overnight, the mixture was concentrated and purified using prep-TLC eluting with EtOAc to give benzyl ((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(4-((4-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)methyl)phenethyl)carbamate (100 mg) in 66% yield. MS (ESI) m/z: 478.8 [1/2M+H]⁺. [0174] A solution of ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4- yl)piperidin-1-yl)methyl)phenethyl)carbamate (100 mg, 0.1 mmol) in TFA (2 mL) was stirred at 80 °C for 1 h. The mixture was concentrated and purified using prep-HPLC eluting with ACN/H₂O to afford 3- (4- (1-(4- (2- (((1r,4r) -4- ((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)benzyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 4 (30.2 mg) in 35% yield. ¹ (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.25 (s, 1H), 7.98 (brs, 1H), 7.42-7.39 (m, 1H), 7.35-7.33 (m, 1H), 7.24-7.17 (m, 5H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.51-4.30 (m, 2H), 3.85 (s, 3H), 3.63 (brs, 1H), 3.47 (s, 2H), 3.08-3.06 (m, 2H), 2.94-2.87 (m, 3H), 2.82-2.79 (m, 2H), 2.71-2.66 (m, 2H), 2.61-2.57 (m, 2H), 2.44-2.40 (m, 2H), 2.02-1.99 (m, 3H), 1.93-1.87 (m, 5H), 1.75-1.70 (m, 4H), 1.31-1.23 (m, 2H), 1.12-1.03 (m, 2H), 0.97-0.96 (m, 1H), 0.39-0.38 (m, 2H), 0.14-0.12 (m, 2H); MS (ESI) m/z: 822.4 [M+H]⁺. Example 4 Synthesis of (2S,4R)-1-((S)-2-(11-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)undecanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 5

[0175] To a solution of (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (100 mg, 0.28 mmol) in DMF (5 mL) were added tert- butyl 11-bromoundecanoate (85 mg, 0.28 mmol) and K2CO3 (76 mg, 0.56 mmol). After stirred at 80 °C overnight, the mixture was concentrated and purified using silica gel eluting with DCM/MeOH (50:1 to 20:1) to give tert-butyl 11-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)undecanoate (51 mg) in 31% yield. MS (ESI) m/z: 601.0 [M+H]⁺. [0176] To a solution of tert-butyl 11-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)undecanoate (51 mg, 0.08 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 2 h and then concentrated. The residue was dissolved in DMF (10 mL). (2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (40 mg, 0.08 mmol), HOBt (17 mg, 0.13 mmol), EDCI∙HCl (24 mg, 0.13 mmol), and DIPEA (44 mg, 0.32 mmol) were added. After stirred overnight, the mixture was concentrated and purified by prep-HPLC eluting with ACN/H₂O to afford (2S,4R)-1-((S)-2-(11-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl- 1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-undecanamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 5. ¹H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.54 (t, J = 5.6 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.42-7.34 (m, 5H), 7.15 (s, 1H), 5.10 (s, 1H), 4.55-4.52 (m, 1H), 4.45-4.40 (m, 2H), 4.36-4.32 (m, 1H), 4.27-4.18 (m, 1H), 3.83 (s, 3H), 3.69-3.59 (m, 2H), 3.14-3.06 (m, 2H), 2.56-2.52 (m, 1H), 2.44 (s, 3H), 2.33-2.22 (m, 2H), 2.13-2.02 (m, 2H), 1.93-1.87 (m, 8H), 1.54-1.33 (m, 6H), 1.24 (s, 12H), 1.10-1.02 (m, 2 H), 0.93 (s, 9H) , 0.42-0.35 (m, 2 H), 0.14-0.12 (m, 2 H); MS (ESI) m/z: 957.5 [M+H]⁺. Example 5 Synthesis of (S)-3-(1-((4-(((9-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)amino)methyl)phenoxy) methyl)-4-oxo-4H- thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 6

[0177] To a solution of 9-((tert-butoxycarbonyl)amino)nonanoic acid (1.0 g, 3.66 mmol) in DCM (18 mL) were added EDCI (1.055 g, 5.49 mmol) and TEA (740 mg, 7.32 mmol). N,O- Dimethylhydroxylamine (393 mg, 4.03 mmol) and N,N-dimethylpyridin-4-amine (45 mg, 0.366 mmol) were added. After stirred overnight, the mixture was diluted with H₂O and extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated, and purified using silica gel eluting with MeOH in DCM from 0% to 5% to give tert-butyl (9- (methoxy(methyl)amino)-9-oxononyl)carbamate (895 mg) in 77% yield. MS (ESI) m/z: 317.2 [M+H]⁺, 261.2 [M-Boc]⁺. [0178] To a solution of tert-butyl (9-(methoxy(methyl)amino)-9-oxononyl)carbamate (447 mg, 1.41 mmol) in THF (8 mL) at -78 °C was added LiAlH4 (2.2 mL, 1 M in THF) dropwise over 10 min. The mixture was stirred at -78 °C for 30 min and then quenched with saturated NH₄Cl (5 mL) slowly. The mixture was extracted with EtOAc and washed with H₂O. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give tert-butyl (9-oxononyl)carbamate (362 mg, crude). MS (ESI) m/z: 202.2 [M-Boc]⁺. [0179] To a solution of (1r,4r)-N -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine HCl (610 mg, 1.41 mmol) in DCM/MeOH (10 mL:2 mL) was added DIPEA (80 mg, 0.62 mmol). The solution was stirred for 10 min, and then tert-butyl (9-oxononyl)carbamate (362 mg, 1.41 mmol), NaBH₃CN (444 mg, 7.05 mmol), and AcOH (2 drops) were added. After stirred overnight, the mixture was concentrated and purified using silica gel eluting with MeOH in DCM from 0% to 6% to give tert-butyl (9-(((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)-amino)nonyl) carbamate (470 mg) in 53% yield. MS (ESI) m/z 602.3 [M+H]⁺. [0180] To a solution of tert-butyl (9-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)carbamate (100 mg, 0.166 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred for 1 h and then concentrated. The resulting amine salt was dissolved in MeOH/DCM (2 mL:8 mL) and cooled to 0°C, and then DIPEA (89 mg, 0.693 mmol) was added. After the mixture was stirred for 5 min, (S)- 4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)- benzaldehyde (60 mg, 0.156 mmol), NaBH3CN (49 mg, 0.78 mmol), and AcOH (2 drops) were added. After stirred overnight, the mixture was concentrated and purified by prep-TLC (DCM/MeOH: 10:1) to afford (S)-3-(1-((4-(((9-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)-amino)methyl)phenoxy) methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 6 (11.1 mg) in 8% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.02 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.25-7.20 (m, 1H), 7.08 (d, J = 8.4 Hz, 2H), 5.33-5.30 (m, 3H), 5.04-5.01 (m, 1H), 4.34 (q, J = 15.6 Hz, 2H), 3.99- 3.95 (m, 2H), 3.85 (s, 3H), 3.67-3.61 (m, 1 H), 3.06-3.04 (m, 2H), 2.95-2.76 (m, 5H), 2.60-2.56 (m, 1H), 2.35-2.32 (m, 1H), 2.12-2.09 (m, 2H), 2.00-1.96 (m, 5H), 1.60-1.55 (m, 4H), 1.49-1.23 (m, 3H), 1.40-1.23 (m, 12H), 0.98 (s, 1H), 0.86-0.83 (m, 1H), 0.42-0.40 (m, 2H), 0.13-0.10 (m, 2H); MS (ESI) m/z: 435.71/2 [M+H]⁺, 870.3 [M+H]⁺. Example 6 Synthesis of 3-(1-oxo-4-{2-[1-(5-{[(1r,4r)-4-({5-chloro-4-[5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]amino}pentanoyl)piperidin-4-yl]ethynyl}-2,3- dihydro-1H-isoindol-2-yl)piperidine-2,6-dione 10

[0181] To a stirred solution of methyl 3-iodo-2-methylbenzoate (4.06 g, 14.6 mmol) in carbon tetrachloride (25 mL) were added NBS (3.10 g, 17.5 mmol) and 2,2’-azobis(2- methylpropionitrile) (240 mg, 1.46 mmol). After stirred at 85 °C overnight, the mixture was filtered and the filtrate was concentrated. The residue was purified using silica gel eluting with PE/EtOAc (20:1) to give methyl-2-(bromomethyl)-3-iodobenzoate (4.66 g) in 91% yield. MS (ESI) m/z: 355.1 [M+1]⁺, 357.1 [M+3]⁺. [0182] To a stirred solution of methyl-2-(bromomethyl)-3-iodobenzoate (4.66 g, 13.2 mmol) and 3-aminopiperidine-2,6-dione (2.59 g, 15.7 mmol) in ACN (20 mL) was added DIPEA (8.39 g, 65.5 mmol). After stirred at 90 °C overnight, the mixture was poured into water and filtered to give 3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.9 g) in 80% yield. MS (ESI) m/z: 370.1 [M+H]⁺. [0183] To a solution of 3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 2.7 mmol) in THF (20 mL) were added tert-butyl 4-ethynylpiperidine-1-carboxylate (520 mg, 2.46 mmol), CuI (50 mg, 0.25 mmol), and TEA (2.48 g, 24.6 mmol), followed by addition of Pd(PPh3)2Cl2 (180 mg, 0.25 mmol) under N2. After stirred at 65 °C for 6 h, the mixture was filtered, concentrated, and purified using silica gel eluting with DCM in EtOAc from 10% to 50% to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carboxylate (1.01 g) in 75% yield. MS (ESI) m/z: 452.2 [M+1]⁺. [0184] To a solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(5-(methoxy(methyl)amino)-5-oxopentyl)carbamate (110 mg, 0.173 mmol) in MeOH (8 mL) was added NaOH (15 mg, 0.345 mmol). After stirred at 80 °C for 4 h, the mixture was treated with 1N HCl and extracted with DCM. The combined organic layers were concentrated to give 5-(((benzyloxy)carbonyl)((1r,4r)-4-((5-chloro-4-(5-(cyclopropyl- methyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-pentanoic acid (100 mg, crude). MS (ESI) m/z: 595.1 [M+1]⁺. [0185] To a solution of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)ethynyl)piperidine-1-carboxylate (77 mg, 0.172 mmol) in DCM (2 mL) was added HCl/EtOAc (0.5 mL). The mixture was stirred for 1 h and then concentrated to give 3-(1-oxo-4-(piperidin-4- ylethynyl)isoindolin-2-yl)piperidine-2,6-dione as a HCl salt (70 mg, crude). MS (ESI) m/z: 352.1 [M+1]⁺. [0186] To a solution of 3-(1-oxo-4-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6- dione HCl (crude) in DMF (10 mL) were added 5-(((benzyloxy)carbonyl)((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentanoic acid (100 mg, crude), HOBt (35 mg, 0.258 mmol), EDCI∙HCl (50 mg, 0.258 mmol), and DIPEA (67 mg, 0.516 mmol). After stirred overnight, the mixture was diluted with H₂O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by prep-TLC eluting with DCM and MeOH (10:1) and prep-HPLC eluting with water (0.1% TFA) in ACN (0.1% TFA) with a gradient of 95 to 5% to give benzyl ((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(5-(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)carbamate (132 mg) in 82% yield. [0187] To a solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)carbamate (132 mg, 0.142mmol) in acetic acid (2 mL) was added HBr (2 mL, 33% in acetic acid). The mixture was stirred for 1 h and then concentrated to give 3-(1-oxo-4-{2-[1-(5-{[(1r,4r)-4-({5-chloro-4-[5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl]pyrimidin-2-yl}amino)cyclohexyl]amino}pentanoyl)piperidin-4-yl]ethynyl}-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6-dione 10 (36.1 mg) as a trifluoroacetic acid salt in 32% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (s, 1H), 8.01 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.16 (s, 1H), 5.13 (dd, J = 13.2, 8.4 Hz, 1H), 4.47-4.30 (m, 2H), 3.92-3.87 (m, 1H), 3.85 (s, 3H), 3.73-3.65 (m, 3H), 3.22-3.17 (m, 3H), 3.08 (d, J = 6.0 Hz, 2H), 2.61-2.54 (m, 2H), 2.31 (t, J = 1.8 Hz, 2H), 2.03-1.99 (m, 1H), 1.94-1.90 (m, 7H), 1.63-1.60 (m, 1H), 1.56-1.48 (m, 3H), 1.44-1.39 (m, 2H), 1.30-1.27 (m, 2H), 1.10-1.04 (m, 2H), 1.01-0.97 (m, 1H), 0.39-0.38 (m, 2H), 0.14-0.12 (m, 2H); MS (ESI) m/z: 794.3 [M+H]⁺. Example 7 Synthesis of (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)heptyl)(methyl)amino)methyl)- phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 11

[0188] To a solution of 7-((tert-butoxycarbonyl)amino)heptanoic acid (3.00 g, 12.2 mmol) in DCM (40 mL) were added EDCI∙HCl (3.526 g, 18.36 mmol) and TEA (2.473 g, 24.48 mmol). N,O- Dimethylhydroxylamine (1.313 g, 13.47 mmol) and N,N-dimethylpyridin-4-amine (149 mg, 1.224 mmol) were the added. After stirred overnight, the mixture was diluted with H₂O and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified using silica gel eluting with MeOH in DCM from 0% to 2% to give tert-butyl (7- (methoxy(methyl)amino)-7-oxoheptyl)carbamate (1.024 g) in 29% yield. MS (ESI) m/z: 233.2 [M- 56+H]⁺. [0189] To a solution of tert-butyl (7-(methoxy(methyl)amino)-7-oxoheptyl)carbamate (397 mg, 1.37 mmol) in THF (10 mL) at 0 °C was added NaH (99 mg, 4.13 mmol) portion wise. After the mixture was stirred at 0 °C for 45 min, iodomethane (389 mg, 2.74 mmol) was added. After stirred at room temperature overnight, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified using silica gel eluting with MeOH in DCM from 0% to 5% to give tert-butyl (7-(methoxy(methyl)- amino)-7-oxoheptyl)(methyl)carbamate (354 mg) in 85% yield. MS (ESI) m/z: 203.2[M-56+H]⁺. [0190] To a solution of tert-butyl (7-(methoxy(methyl)amino)-7-oxoheptyl)(methyl)- carbamate (354 mg, 1.17 mmol) in THF (8 mL) at -78 °C was added LiAlH₄ (1.8 mL, 1 M in THF) dropwise. After stirred at -78 °C for 30 min, the mixture was quenched with saturated ammonium chloride (10 mL) slowly. The mixture was then extracted with EtOAc and washed with H2O. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give tert- butyl methyl(7-oxoheptyl)carbamate (251 mg, crude). MS (ESI) m/z: 188.2 [M-56+H]⁺. [0191] To a solution of (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine HCl (400 mg, 0.923 mmol) in DCM/EtOH (10 mL/2 mL) was added DIPEA (238 mg 185 mmol) After the solution was stirred for 10 min, tert-butyl methyl(7-oxoheptyl)carbamate (251 mg, crude), NaBH₃CN (291 mg, 4.62 mmol), and acetic acid (2 drops) were added. After stirred overnight, the mixture was concentrated and purified using silica gel eluting with MeOH in DCM from 0% to 6% to give tert-butyl (7-(((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)- (methyl)carbamate (423 mg) in 78 % yield. MS (ESI) m/z: 588.3 [M+H]⁺. [0192] To a solution of tert-butyl (7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)(methyl)carbamate (206 mg, 0.35 mmol) in MeOH (10 mL) were added formaldehyde solution (105 mg, 3.5 mmol) and NaBH3CN (110.5 mg, 1.75 mmol). After stirred overnight, the mixture was concentrated and purified using silica gel eluting with MeOH in DCM from 0% to 10% to give tert-butyl (7-(((1r,4r)- 4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)(methyl)amino)heptyl-)(methyl)carbamate (113 mg) in 58% yield. MS (ESI) m/z: 602.4 [M+H]⁺. [0193] To a solution of tert-butyl (7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)heptyl)(methyl)carbamate (56 mg, 0.093 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred for 1 h and then concentrated. The resulting amine TFA salt was dissolved in MeOH/DCM (1 mL/4 mL) and cooled to 0 °C. DIPEA (24 mg, 0.186 mmol) was then added and the mixture was stirred for 5 min. (S)-4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)- benzaldehyde (36 mg, 0.093 mmol), NaBH₃CN (29.3 mg, 0.465 mmol), and acetic acid (2 drops) were added. The mixture was stirred overnight and then concentrated. The residue was purified by prep-TLC to give (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)-heptyl)(methyl)amino)- methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 11 (17.9 mg) in 22% yield. ¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.97 (s, 1H), 8.28 (s, 1H), 8.06-7.97 (m, 2H), 7.44 (s, 1H), 7.16 (s, 1H), 7.09 (d, J = 6.8 Hz, 2H), 5.33 (s, 2H), 5.03 (dd, J = 4.8, 13.2 Hz, 1H), 4.38-4.20 (m, 2H), 3.85 (s, 3H), 3.69-3.67 (m, 1H), 3.52-3.50 (m, 1H), 3.11-2.84 (m, 7H), 2.66 (s, 3H), 2.60-2.56 (m, 2H), 2.34-2.25 (m, 2H), 2.03-2.00 (m, 6H), 1.65-1.54 (m, 6H), 1.4-1.34 (m, 6H), 1.29-1.23 (m, 4H), 1.04-0.80 (m, 1H), 0.38-0.37 (m, 2H), 0.11-0.10 (m, 2H); MS (ESI) m/z: 870.4 [M+H]⁺. Example 8 Synthesis of 3-(4-(1-(3-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 14

[0194] To a stirred solution of 3-bromopropanoic acid (1.00 g, 6.53 mmol) and 1H-pyrazole- 4-carbaldehyde (0.94 g, 9.8 mmol) in DMC (10 mL) were added potassium carbonate (1.80 g, 13.1 mmol) and potassium iodide (543 mg, 3.27 mmol). After stirred at 80 °C overnight, the mixture was treated with water (10 mL) and neutralized to pH 6 with 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 5% to give 3-(4- formyl-1H-pyrazol-1-yl)propanoic acid (550 mg) in 50% yield. [0195] To a stirred solution of 3-(4-formyl-1H-pyrazol-1-yl) propanoic acid (550 mg, 3.27 mmol) in DCM (15 mL) were added N,O-dimethylhydroxylamine hydrochloride (385 mg, 3.92 mmol), TEA (660 mg, 6.54 mmol), EDCI (942 mg, 4.00 mmol), and 4-dimethylaminopyridine (40 mg, 0.33 mmol). After stirred overnight, the mixture was treated with water (10 mL) and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using silica gel eluting with EtOAc in PE from 10% to 25% to give 3-(4-formyl-1H-pyrazol-1-yl)-N- methoxy-N-methylpropanamide (340 mg) in 50% yield. [0196] To a stirred solution of (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (250 mg, 0.58 mmol) in THF (4 mL) were added 3-(4-formyl-1H-pyrazol-1-yl)-N- methoxy-N-methylpropanamide (243 mg, 1.16 mmol) and Ti(OEt)4 (525 mg, 2.32 mmol). The mixture was stirred at 90 °C for 2 h. NaBH3CN (140 mg, 2.32 mmol) was added. After stirred at room temperature for 4 h, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by prep-TLC eluting with DCM/MeOH (10:1) to give 3- (4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)methyl)-1H-pyrazol-1-yl)-N-methoxy-N-methylpropanamide (160 mg) in 50% yield. MS (ESI) m/z : 556.3 [M+H] ⁺. [0197] To a stirred solution of 3-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-1H-pyrazol-1-yl)-N- methoxy-N-methylpropanamide (160 mg, 0.29 mmol) in THF/H2O (4 mL/1 mL) were added benzyl chloroformate (74 mg, 0.43 mmol) and Na₂CO₃ (62 mg, 0.58 mmol). The mixture was stirred for 2 h and then concentrated. The residue was purified by prep-TLC eluting with MeOH/DCM (1 :20) to give benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)((1-(3-(methoxy(methyl)amino)-3-oxopropyl)-1H-pyrazol-4- yl)methyl)carbamate (120 mg) in 61% yield. MS (ESI) m/z : 690.3 [M+H] ⁺. [0198] To a stirred solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)((1-(3-(methoxy(methyl)amino)-3- oxopropyl)-1H-pyrazol-4-yl)methyl)carbamate (120 mg, 0.174 mmol) in THF (5 mL) was added LiAlH4 (0.26 mL, 1 M in THF) at -70 °C under N2. After stirred at -70 °C for 1 h, the mixture was treated with saturated NH4Cl (5 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give benzyl ((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)((1-(3- oxopropyl)-1H-pyrazol-4-yl)methyl)carbamate (80 mg) in 73% yield. MS (ESI) m/z : 631.2 [M+H]⁺. [0199] To a stirred solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)((1-(3-oxopropyl)-1H-pyrazol-4- yl)methyl)carbamate (80.0 mg, 0.126 mmol) in DCM (5 mL) was added 3-(6-fluoro-1-oxo-4- (piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (44.0 mg, 0.126 mmol). The mixture was stirred for 30 min. NaBH3CN (31 mg, 0.504 mmol) was added. After stirred overnight, the mixture was concentration and purified using prep-TLC eluting with DCM/MeOH (10:1) to give benzyl ((1r,4r)- 4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)- cyclohexyl)((1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1- yl)propyl)-1H-pyrazol-4-yl)methyl)carbamate (60 mg) in 50% yield. [0200] To a stirred solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)((1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propyl)-1H-pyrazol-4-yl)methyl)carbamate (60 mg, 0.0625 mmol) in acetic acid (2 mL) was added HBr (0.5 mL, 33% in acetic acid). The mixture was stirred for 30 min. The solvent was removed, and the residue was disolved with DCM (2 mL) and neutralized to pH 8 with TEA. The mixture was concentrated. The residue was purified by prep- HPLC to give 3-(4-(1-(3-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-methyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (6.0 mg) in 12% yield. ¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 8.00 (s, 1H), 7.60 (s, 1H), 7.41 (dd, J = 2.4, 10.8 Hz, 1H), 7.36-7.34 (m, 1H), 7.16 (s, 1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.52-4.31 (m, 2H), 4.09 (t, J = 6.8 Hz, 2H), 4.50 (d, J = 7.2 Hz, 1H), 4.33 (d, J = 7.2 Hz, 1H), 4.09 (t, J = 6.8Hz, 2H), 3.85 (s, 3H), 3.67-3.63 (m, 1H), 3.60 (s, 2H), 3.22-3.17 (m, 2H), 3.08-3.06 (m, 2H), 2.95-2.87 (m, 4H), 2.67-2.57 (m, 2H), 2.45-2.37 (m, 2H), 2.26-2.23 (m, 2H), 2.02-1.91 (m, 7H), 1.75-1.73 (m, 4H), 1.31-1.24 (m, 2H), 1.13-1.05 (m, 2H), 0.99-0.95 (m, 1H), 0.39-0.38 (m, 2H), 0.14-0.12 (m, 2H); MS (ESI) m/z : 826.4 [M+H]⁺. Example 9 Synthesis of (S)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 23

[0201] To a solution of (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (100 mg, 0.23 mmol) in DCM/MeOH (4 mL/2 mL) at 0 °C was added DIPEA (59 mg, 0.46 mmol). 4-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzaldehyde (87 mg, 0.23 mmol), NaBH₃CN (58 mg, 0.92 mmol), and acetic acid (1 drop) were then added. After stirred at room temperature overnight, the mixture was concentrated and purified by prep-HPLC to give 3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-benzyl)oxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (50 mg) in 30% yield. MS (ESI) m/z: 723.3 [M+H]⁺. [0202] 3-(4-((4-((((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (50 mg, 0.069 mmol) was resolved by chiral separation to give (S)-3-(4-((4-((((1r,4r)-4- ((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)-methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 23 (12.2 mg) and (R)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)-methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (14.0 mg). [0203] Compound 23: ¹

NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.54-7.17 (m, 5H), 7.36-7.33 (m, 2H), 7.21 (s, 1H), 5.27 (s, 2H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.45-4.25 (m, 2H), 4.00 (s, 2H), 3.86 (s, 3H), 3.69-3.67 (m, 1H), 3.07 -3.06 (m, 2H), 2.98-2.87 (m, 1H), 2.75-2.71 (m, 1H), 2.61-2.56 (m, 1H), 2.46-2.42 (m, 1H), 2.08-2.07 (m, 2H), 1.96-1.92 (m, 4H), 1.31-1.25 (m, 2H), 1.19-1.09 (m, 1H), 1.07-0.98 (m, 2H), 0.42-0.39 (m, 2H), 0.17-0.14 (m, 2H); MS (ESI) m/z: 723.3 [M+H]⁺. Example 10 Synthesis of (S)-3-(4-((4-((4-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-2-fluorophenyl)piperazin-1- yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 26

[0204] To a solution of (S)-tert-butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5- oxopentanoate (668 mg, 2.00 mmol) in ACN (10 mL) were added potassium carbonate (828 mg, 6.00 mmol) and 4-(bromomethyl)benzaldehyde (396 mg, 2.00 mmol). After stirred at 90 °C for 3 h, the mixture was concentrated and purified using silica gel eluting with MeOH in DCM from 0% to 10% to give (S)-tert-butyl 5-amino-4-(4-((4-formylbenzyl)oxy)-1-oxoisoindolin-2-yl)-5- oxopentanoate (793 mg) in 88% yield. MS (ESI) m/z: 453.2 [M+H]⁺. [0205] To a solution of (S)-tert-butyl 5-amino-4-(4-((4-formylbenzyl)oxy)-1-oxoisoindolin- 2-yl)-5-oxopentanoate (200 mg, 0.442 mmol) in DCM/MeOH (4 mL/0.4 mL) were added 3-fluoro- 4-(piperazin-1-yl)benzonitrile (91 mg, 0.442 mmol), NaBH3CN (56 mg, 0.884 mmol), and acetic acid (1 drop). The mixture was stirred overnight and then concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 10% to give (S)-tert-butyl 5-amino-4-(4-((4- ((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5- oxopentanoate (180 mg) in 64% yield. MS (ESI) m/z: 642.3 [M+H]⁺. [0206] To a mixture of (S)-tert-butyl 5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)- piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (180 mg, 0.280 mmol) in water/pyridine/acetic acid (1 mL/2 mL/1 mL) were added sodium hypophosphite (123 mg, 1.405 mmol) and Raney-Ni (50 mg). The mixture was stirred at 0 °C for 3 h and then filtered. The filtrate was concentrated to give (S)-tert-butyl 5-amino-4-(4-((4-((4-(2-fluoro-4-formylphenyl)-piperazin-1- yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (89.0 mg) in 44% yield. MS (ESI) m/z: 645.3 [M+H]⁺. [0207] To a solution of (S)-tert-butyl 5-amino-4-(4-((4-((4-(2-fluoro-4-formylphenyl)- piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (89 mg, 0.138 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred overnight and then concentrated to give (S)-5-amino-4-(4-((4-((4-(2-fluoro-4-formylphenyl)piperazin-1-yl)methyl)benzyl)oxy)-1- oxoisoindolin-2-yl)-5-oxopentanoic acid (81 mg, crude). [0208] To a solution of (S)-5-amino-4-(4-((4-((4-(2-fluoro-4-formylphenyl)piperazin-1- yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoic acid (81 mg, crude) in ACN (4 mL) was added CDI (45 mg, 0.276 mmol). After stirred at 90 °C overnight, the mixture was filtered. The filtrate was concentrated and purified by prep-TLC eluting with DCM/MeOH (10:1) to give (S)- 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3- fluorobenzaldehyde (26 mg) in 30% yield. MS (ESI) m/z: 571.2[M+H]⁺. [0209] To a solution of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzaldehyde (26 mg, 0.045 mmol) in DCM/MeOH (3 mL/0.3 mL) were added (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (20 mg, 0.045 mmol), acetic acid (1 drop), and NaBH₃CN (6 mg, 0.091 mmol). The mixture was stirred overnight and then concentrated. The residue was purified by prep-TLC eluting with DCM/MeOH (10:1) and further purified by prep- HPLC to give (S)-3-(4-((4-((4-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-2-fluorophenyl)piperazin-1- yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 26 (15.6 mg) in 38% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.54-7.45 (m, 3H), 7.33-7.30 (m, 4H), 7.18-7.07 (m, 3H), 6.99-6.95 (m, 1H), 5.23 (s, 2H), 5.11 (dd, J = 5.6, 13.2 Hz, 1H), 4.44- 4.42 (m, 2H), 3.85 (s, 3H), 3.75-3.61 (m, 3H), 3.54 (s, 2H), 3.07-3.03 (m, 2H), 2.99-2.95 (m, 4H), 2.91-2.87 (m, 1H), 2.79-2.50 (m, 5H), 2.43-2.40 (m, 1H), 2.00-1.96 (m, 3H), 1.93-1.85 (m, 4H), 1.27-1.23 (m, 4H), 1.01-0.97 (m, 1H), 0.39-0.31 (m, 2H), 0.14-0.13 (m, 2H); MS (ESI) m/z: 915.4 [M+H]⁺. Example 11 Synthesis of 3-(5-(1-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 28

[0210] To a solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (272 mg, 0.457 mmol) in THF (5 mL) at -78 °C under N₂ was added LiAlH₄ (0.9 mL, 1 M in THF) dropwise. After stirred at -78 °C for 1 h, the mixture was quenched with sat. NH4Cl (5 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-oxoethyl)carbamate (220 mg, crude). MS (ESI) m/z: 537.2 [M+H]⁺. [0211] To a solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-oxoethyl)carbamate (110 mg, 0.205 mmol) in DCM/MeOH (4 mL/0.4 mL) were added 3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2- yl)piperidine-2,6-dione (78 mg, 0.225 mmol), acetic acid (1 drop), and NaBH₃CN (26 mg, 0.410 mmol). The mixture was stirred overnight and then concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 10% to give benzyl ((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-(4-(2-(2,6- dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)ethyl)carbamate (140 mg) in 79% yield. MS (ESI) m/z: 866.4 [M+H]⁺. [0212] A solution of benzyl ((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)(2-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1- oxoisoindolin-5-yl)piperidin-1-yl)ethyl)carbamate (140 mg, 0.161 mmol) in TFA (4 mL) was stirred at 80 °C for 4 h. The solution was then concentrated and the residue was purified by prep-HPLC to give 3-(5-(1-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)-piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 28 (38.0 mg) in 32% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.06 (s, 1H), 8.96 (s, 2H), 8.30 (s, 1H), 8.02 (s, 1H), 7.57-7.54 (m, 2H), 7.34 (s, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.37-4.30 (m, 2H), 3.86 (s, 3H), 3.85-3.82 (m, 2H), 3.43 (s, 4H), 3.25-3.11 (m, 4H), 3.05 (d, J = 6.4 Hz, 2H), 2.96-2.87 (m, 1H), 2.62-2.50 (m, 1H), 2.42-2.38 (m, 1H), 2.13-1.99 (m, 10H), 1.47-1.23 (m, 4H), 0.98-0.95 (m, 1H), 0.41-0.37 (m, 2H), 0.15-0.14 (m, 1H); MS (ESI) m/z: 732.4 [M+H]⁺. Example 12 Synthesis of 3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(2-hydroxyethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 35

[0213] To a solution of 1-methyl-1H-pyrazole (4.0 g, 48.78 mmol) in THF (80 mL) at -65 °C under N₂ was added n-BuLi in hexane (2.5 M, 21.5 mL). After the mixture was stirred at -65 °C for 1 h, (2-bromoethoxy)(tert-butyl)dimethylsilane (11.66 g, 48.78 mmol) was added slowly. After 2 h, the mixture was warmed to room temperature and stirred overnight. Saturated ammonium chloride aqueous (30 mL) was added and the mixture was concentrated. The aqueous layer was neutralized with 1N HCl and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ filtered, and concentrated. The residue was purified using silica gel eluting with EtOAc in PE from 0% to 15% to give 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-pyrazole (2.21 g) in 19% yield. MS (ESI) m/z: 241.2 [M+H]⁺. [0214] To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-pyrazole (1.13 g, 4.72 mmol) in DCM (12 mL) at 0 °C was added NBS (857 mg , 4.82 mmol). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified using silica gel eluting with EtOAc in PE from 0% to 15% to give 4-bromo-5-(2-((tert-butyldimethylsilyl)- oxy)ethyl)-1-methyl-1H-pyrazole (2.9 g) in 73% yield. MS (ESI) m/z: 319.1 [M+1]⁺, 321.1 [M+3]⁺. [0215] To a solution of 4-bromo-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H- pyrazole (501 mg, 1.575 mmol) in THF (10 mL) at -78 °C was added n-BuLi (0.9 mL , 2.363 mmol) dropwise. After 30 min at -78 °C, a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (586 mg, 3.15 mmol) in THF (6 mL) was added. The resulting mixture was warmed to room temperature and stirred for 30 min, and then quenched with saturated ammonium chloride aqueous (20 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified using silica gel eluting with EtOAc in PE from 0% to 20% to give 5-(2-((tert-butyldimethyl-silyl)oxy)ethyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (343 mg) in 60% yield. MS (ESI) m/z: 367.3 [M+H]⁺. [0216] To a solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (343 mg, 0.937 mmol) in 1,2-dimethoxyethane (8 mL) were added 2,4,5-trichloropyrimidine (205 mg, 1.125 mmol), sodium carbonate (1.03 ml, 2M), and PdCl₂(amphos)₂ (66 mg, 0.0937 mmol). The mixture was stirred at 85 °C for 2 h under N₂. The mixture was treated with saturated ammonium chloride aqueous (20 mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using silica gel eluting with EtOAc in PE from 0% to 20% to give 4-(5-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-pyrazol-4-yl)-2,5-dichloropyrimidine (166 mg) in 45.9% yield. MS (ESI) m/z: 387.1 [M+H]⁺. [0217] To a solution of 4-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-pyrazol-4- yl)-2,5-dichloropyrimidine (83 mg, 0.215 mmol) in 1,4-dioxane (6 mL) were added (1r,4r)- cyclohexane-1,4-diamine (74 mg, 0.645 mmol), t-BuONa (62 mg, 0.645 mmol), and PdCl₂(Amphos)₂ (30 mg, 0.043 mmol). After stirred at 90 °C for 3 h under N₂, the mixture was concentrated and purified using silica gel eluting with MeOH in DCM from 0% to 20% to give (1r,4r)-N -(5-chloro-4-(5-ethyl-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (98 mg) in 49% yield. MS (ESI) m/z: 465.3 [M+H]⁺. [0218] To a solution of (1r,4r)-N¹-(5-chloro-4-(5-ethyl-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)cyclohexane-1,4-diamine (120 mg, 0.258 mmol) in DMF (8 mL) were added potassium fluoride (45 mg, 0.78 mmol) and 40% HBr (157 mg, 0.776 mmol). The mixture was stirred overnight and then concentrated. The residue was purified by prep-HPLC to give 2-(4-(2-(((1r,4r)-4-amino- cyclohexyl)amino)-5-chloropyrimidin-4-yl)-1-methyl-1H-pyrazol-5-yl)ethanol (104 mg) in 65% yield. MS (ESI) m/z: 351.2 [M+H]⁺. [0219] To a solution of 2-(4-(2-(((1r,4r)-4-aminocyclohexyl)amino)-5-chloropyrimidin-4- yl)-1-methyl-1H-pyrazol-5-yl)ethanol (53 mg, 0.151 mmol) in DCM/MeOH (8 mL/2 mL) were added DIPEA (1 drop), 4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1- yl)methoxy)benzaldehyde (58 mg, 0.151 mmol), NaBH3CN (48 mg, 0.757 mmol), and acetic acid (1 drop). The mixture was stirred overnight and then concentrated. The residue was purified by prep- HPLC to give 3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(2-hydroxyethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-phenoxy)methyl)-4-oxo-4H-thieno[3,4- c]pyrrol-5(6H)-yl)piperidine-2,6-dione 35 (22.6 mg) in 21% yield. ¹H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.04-8.01 (m, 2H), 7.27-7.25 (m, 2H), 7.11 (s, 1H), 6.97-6.95 (m, 2H), 5.28 (s, 2H), 5.02 (dd, J = 4.8 Hz, 12.8 Hz, 1H), 4.80 (s, 1H), 4.37-4.20 (m, 2H), 3.86 (s, 3H), 3.66-3.58 (m, 5H), 3.21-3.18 (m, 3H), 2.91-2.84 (m, 1H), 2.60-2.56 (m, 1H), 2.35-2.29 (m, 2H), 2.07-1.86 (m, 3H), 1.23-1.11 (m, 6H); MS (ESI) m/z: 719.3 [M+H]⁺. Example 13 Synthesis of (S)-3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)azepane-2,7-dione 37

[0220] To a solution of (S)-4-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4- c]pyrrole 1 carbonitrile (500 mg 181 mmol) in pyridine/AcOH/H₂O (10 mL/5mL/5mL) was added sodium hypophosphite (637 mg, 7.24 mmol). After stirred for 6 h, the mixture was filtered and the filtrate was concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 5% to give (S)-4-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-1- carbaldehyde (200 mg) in 40% yield. MS (ESI) m/z: 279.1 [M+H]⁺. [0221] To a solution of (S)-4-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4- c]pyrrole-1-carbaldehyde (200 mg, 0.72 mmol) in MeOH (5 mL) was added sodium borohydride (11 mg, 0.29 mmol). After stirred for 30 min, the mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 6% to give (S)-1-(hydroxymethyl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4- c]pyrrol-4-one (145 mg) in 70% yield. MS (ESI) m/z: 281.1[M+H]⁺. [0222] To a solution of (S)-1-(hydroxymethyl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H- thieno[3,4-c]pyrrol-4-one (145 mg, 0.517 mmol) in DCM (6 mL) at 0 °C were added TEA (131 mg, 1.29 mmol), 4-dimethylaminopyridine (6.3 mg, 0.05 mmol), and methanesulfonyl chloride (89 mg, 0.78 mmol). The mixture was stirred at 0 °C for 1 h. Water (10 mL) was then added and the mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give (S)-1-(chloromethyl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H- thieno[3,4-c]pyrrol-4-one (120 mg, crude). MS (ESI) m/z: 299.1 [M+H]⁺. [0223] To a solution of (S)-1-(chloromethyl)-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H- thieno[3,4-c]pyrrol-4-one (154 mg, 0.517 mmol) in DMF (5 mL) were added potassium carbonate (143 mg, 1.034 mmol) and 4-hydroxybenzaldehyde (95 mg, 0.776 mmol). The mixture was stirred at 80 °C overnight and then concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 3% to give (S)-4-((4-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H- thieno[3,4-c]pyrrol-1-yl)methoxy)benzaldehyde (117 mg) in 59% yield. MS (ESI) m/z: 385.1 [M+H]⁺. [0224] To a solution of (S)-4-((4-oxo-5-(2-oxoazepan-3-yl)-5,6-dihydro-4H-thieno[3,4- c]pyrrol-1-yl)methoxy)benzaldehyde (5) (117 mg, 0.30 mmol) in fluorobenzene/DMSO (18 mL/3 mL, 1 drop H2O in DMSO) was added Dess-Martin reagent (323 mg, 0.76 mmol). After heated at 80 °C for 18 h, the mixture was filtered. The filtrate was added to saturated sodium thiosulfate aqueous (30 mL). The mixture was stirred at 0 °C for 5 min and then extracted with DCM. The combined organic layers were washed with 10% Na₂S₂O₃/sat. NaHCO₃ (1:1), brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by prep-TLC eluting with EtOAc to give (S)-4-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1- yl)methoxy)-benzaldehyde (33 mg) in 27% yield. MS (ESI) m/z: 399.1 [M+H]⁺. [0225] To a solution of (S)-4-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4- c]pyrrol-1-yl)methoxy)benzaldehyde (33 mg, 0.083 mmol) in DCM (6 mL) were added (1r,4r)-N¹- (5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4- diamine (36 mg, 0.083 mmol) and NaBH₃CN (53 mg, 0.249 mmol). The mixture was stirred overnight and then concentrated. The residue was purified by prep-HPLC to give (S)-3-(1-((4- ((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)azepane-2,7-dione 37 (3 mg) in 5% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.88 (s, 1H), 7.15 (d, J = 6.8 Hz, 2H), 7.12-6.98 (m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.16-5.15 (m, 2H), 5.02 (dd, J = 4.0, 12.0 Hz, 1H), 4.28 (s, 2H), 3.72 (s, 3H), 3.55-3.53 (m, 3H), 2.94-2.92 (m, 4H), 2.53- 2.50 (m, 1H), 2.21-2.19 (m, 2H), 1.91-1.80 (m, 5H), 1.32-1.31 (m, 2H), 0.98-0.94 (m, 2H), 0.93-0.86 (m, 2H), 0.85-0.83 (m, 1H), 0.27-0.25 (m, 2H), 0.18-0.11(m, 2H); MS (ESI) m/z: 743.3 [M+H]⁺. Example 14 Synthesis of 2-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)-4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)benzonitrile 38

[0226] To a solution of tert-butyl 4-(3-bromo-4-cyanophenyl)piperazine-1-carboxylate (200 mg, 0.546 mmol) and ethyl acrylate (5456 mg, 54.6 mmol) in DMF (4 mL) were added P(p-Tol) 3 (299 mg, 0.98 mmol), Pd(OAc)2 (37 mg, 0.164 mmol), and TEA (165 mg, 1.64 mmol). After stirred at 100 °C overnight under N₂, the mixture was concentrated. The residue was purified using silica gel eluting with EtOAc in PE from 0% to 17% to give (E)-tert-butyl 4-(4-cyano-3-(3-ethoxy-3- oxoprop-1-en-1-yl)phenyl)piperazine-1-carboxylate (137 mg) in 65% yield. MS (ESI) m/z: 330.2 [M-56+H]⁺ [0227] To a solution of (E)-tert-butyl 4-(4-cyano-3-(3-ethoxy-3-oxoprop-1-en-1- yl)phenyl)piperazine-1-carboxylate (260 mg, 0.675 mmol) in THF (8 mL) was added Pd/C (120 mg). The mixture was stirred overnight under H2 and then filtered. The filtrate was concentrated and the residue was purified by prep-TLC (PE/EtOAc (4:1)) to give tert-butyl 4-(4-cyano-3-(3- ethoxy-3-oxopropyl)phenyl)piperazine-1-carboxylate (208 mg) in 80% yield. MS (ESI) m/z: 332.2 [M-56+H]⁺. [0228] To a solution of tert-butyl 4-(4-cyano-3-(3-ethoxy-3-oxopropyl)phenyl)piperazine-1- carboxylate (208 mg, 0.54 mmol) in THF/MeOH/H2O (4mL/1 mL/1 mL) at 0 °C was added LiOH (45 mg, 1.07 mmol). After stirred at room temperature overnight, the mixture was diluted with water (10 mL) and neutralized to pH 6 with 1N HCl and extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give 3-(5-(4-(tert- butoxycarbonyl)piperazin-1-yl)-2-cyanophenyl)propanoic acid (192 mg) in a quantitative yield. MS (ESI) m/z: 358.2[M-H]⁺. [0229] To a solution of 3-(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-cyanophenyl)- propanoic acid (100 mg, 0.166 mmol) in DCM (10 mL) were added EDCI∙HCl (154 mg, 0.80 mmol), TEA (108 mg, 1.07 mmol), 4-dimethylaminopyridine (7 mg, 0.053 mmol), and N,O- dimethylhydroxylamine HCl (57 mg, 0.588 mmol). After stirred overnight, the mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified using silica gel eluting with MeOH in DCM from 0% to 10% to give tert-butyl 4-(4-cyano-3-(3-(methoxy(methyl)amino)-3-oxopropyl)phenyl)piperazine-1- carboxylate (200 mg) in 93% yield. MS (ESI) m/z: 347.2 [M-56+H]⁺. [0230] To a solution of tert-butyl 4-(4-cyano-3-(3-(methoxy(methyl)amino)-3- oxopropyl)phenyl)piperazine-1-carboxylate (100 mg, 0.249 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred for 1 h and then concentrated. The resulting amine salt was dissolved in MeOH/DCM (2 mL/8 mL) and cooled to 0 °C. DIPEA (48.0 mg, 0.372 mmol) was then added and the mixture was stirred for 5 min. (S)-4-(((2-(2,6-Dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzaldehyde (94 mg, 0.248 mmol), NaBH₃CN (78 mg, 1.242 mmol), and acetic acid (2 drops) were added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by prep-TLC to give (S)-3-(2-cyano-5-(4- (4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)phenyl)-N- methoxy-N-methylpropanamide (100 mg) in 61% yield. MS (ESI) m/z: 665.3[M+H]⁺. [0231] To a solution of (S)-3-(2-cyano-5-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)phenyl)-N-methoxy-N-methylpropanamide (100 mg, 0.15 mmol) in THF (10 mL) at -78 °C was added LiAlH4 (0.38 mL, 1M in THF) dropwise. The mixture was stirred at -78 °C for 30 min and then quenched with aqueous saturated ammonium chloride (5 mL) slowly. The mixture was extracted with EtOAc and washed with H2O. The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give (S)-4-(4-(4-(((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-2-(3-oxopropyl)- benzonitrile (91 mg, crude). MS (ESI) m/z: 606.3[M+H]⁺. [0232] To a mixture of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazin-1-yl)-2-(3-oxopropyl)benzonitrile (91 mg, 0.15 mmol) and (1r,4r)- N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4- diamine (65 mg, 0.15 mmol) in DCM (8 mL) was added NaBH(OAc)3 (96 mg, 0.45 mmol). The mixture was stirred overnight and then concentrated. The residue was purified by prep-HPLC to give 2-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)propyl)-4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazin-1-yl)benzonitrile 38 (5.8 mg) in 4% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (s, 1H), 8.01 (s, 1H), 7.50-7.43 (m, 4H), 7.35-7.31 (m, 4H), 7.18 (s, 1H), 6.90 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.22 (s, 2H), 5.11 (dd, J = 5.2 Hz, 13.2 Hz, 1H), 4.43-4.23 (m, 2H), 3.84 (s, 3H), 3.69-3.63 (m, 2H), 3.43-3.39 (m, 4H), 3.08-3.06 (m, 3H), 2.94-2.85 (m, 1H), 2.71-2.67 (m, 2H), 2.59-2.55 (m, 3H), 2.46-2.32 (m, 6H), 2.00-1.96 (m, 2H), 1.74-1.69 (m, 2H), 1.44-1.40 (m, 1H), 1.32-1.29 (m, 4H), 1.10-1.04 (m, 3H), 0.86-0.83 (m, 1H), 0.39-0.37 (m, 2H), 0.13-0.11 (m, 2H); MS (ESI) m/z: 950.5 [M+H]⁺. Example 15 Synthesis of 3-(5-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6- dione 40

[0233] To a solution of (1r,4r)-N -(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine (130 mg, 0.36 mmol) in DMF (3 mL) were added 3- bromoprop-1-yne (42 mg, 0.36 mmol) and potassium carbonate (100 mg, 0.72 mmol). The mixture was stirred overnight and then concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 6% to give (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)-N-(prop-2-yn-1-yl)cyclohexane-1,4-diamine (115 mg) in 80% yield. MS (ESI) m/z: 399.2[M+H]⁺. [0234] To a solution of (1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)-N-(prop-2-yn-1-yl)-cyclohexane-1,4-diamine (115 mg,0.29 mmol) in DMF (5 mL) were added 3-(5-bromo-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (197 mg, 0.58 mmol), cuprous iodide (11 mg, 0.058 mmol), and TEA (88 mg, 0.87 mmol). Pd(PPh₃)₂Cl₂ (41 mg, 0.058 mmol) was then added un N2. After stirred at 50 °C overnight, the mixture was concentrated. The residue was purified using silica gel eluting with MeOH in DCM from 0% to 10% and further purified by prep-TLC (DCM/MeOH: 12/1) to give 3-(5-(3-(((1r,4r)-4-((5-chloro-4-(5- (cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)prop-1-yn- 1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (60 mg) in 31% yield. MS (ESI) m/z: 659.2 [M+H]⁺. [0235] To a solution of 3-(5-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl- 1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)prop-1-yn-1-yl)-6-fluoro-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (60 mg, 0.09 mmol) in THF (4 mL) was added Pt/C (20 mg). After stirred under H₂ overnight, the mixture was filtered and the filtrate was concentrated. The residue was purified using prep-HPLC to give 3-(5-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropyl-methyl)-1- methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)-6-fluoro-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 40 (18.8 mg) in 37% yield.

NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.55 (d, J = 6.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 5.10 (dd, J = 5.2, 13.6 Hz, 1H), 4.44-4.27 (m, 2H), 3.86 (s, 3H), 3.67-3.63 (m, 1H), 3.13-3.08 (m, 2H), 2.94-2.87 (m, 1H), 2.74 (t, J = 7.2Hz, 2H), 2.67-2.61(m, 1H), 2.58-2.54 (m, 2H), 2.44-2.29 (m, 3H), 2.01-1.97 (m, 1H), 1.85-1.83 (m, 4H), 1.76- 1.67 (m, 2H), 1.33-1.274 (m, 2H), 1.09-0.96 (m, 3H), 0.39-0.38 (m, 2H), 0.14-0.11 (m, 2H); MS (ESI) m/z: 663.3 [M+H]⁺. [0236] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein. [0237] (S)-3-(4-(1-(7-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3. MS (ESI) m/z: 804.3 [M+H]⁺.

[0238] 3-(4-(1-(9-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 7. MS (ESI) m/z: 830.4 [M+H]⁺.

[0239] 3-(4-(1-(5-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 8. MS (ESI) m/z: 774.4 [M+H]⁺.

[0240] (S)-3-(1-((4-(((5-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)amino)methyl)phenoxy)methyl)-4- oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 9. MS (ESI) m/z: 814.4 [M+H]⁺.

[0241] 3-(5-(1-(7-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 12. MS (ESI) m/z: 784.4 [M+H]⁺.

[0242] 3-(4-((1-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)glycyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 13. MS (ESI) m/z: 752.3 [M+H]⁺.

[0243] 3-(4-(1-(4-(2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)phenethyl)piperidin-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione 15. MS (ESI) m/z: 852.0 [M+H]⁺.

[0244] 3-(4-(1-(4-(2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)benzyl)piperidin-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione 16. MS (ESI) m/z: 838.0 [M+H]⁺.

[0245] 3-(4-(1-(4-((2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)(methyl)amino)phenethyl)piperidin-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 17. MS (ESI) m/z: 865.4 [M+H]⁺.

[0246] (S)-3-(4-((4-(((7-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)methyl)benzyl)oxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 18. MS (ESI) m/z: 836.4 [M+H]⁺.

[0247] (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)(methyl)amino)methyl)- phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 19. MS (ESI) m/z: 856.0 [M+H]⁺.

[0248] (S)-3-(1-((4-(((2-(4-((((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)piperidin-1-yl)ethyl)amino)methyl)- phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 20. MS (ESI) m/z: 869.0 [M+H]⁺.

[0249] (S)-3-(1-((4-((((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4- c]pyrrol-5(6H)-yl)piperidine-2,6-dione 21. MS (ESI) m/z: 730.3 [M+H]⁺.

[0250] (S)-3-(1-((4-((((1r,4r)-4-((5-Fluoro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4- c]pyrrol-5(6H)-yl)piperidine-2,6-dione 22. MS (ESI) m/z: 713.8 [M+H]⁺.

[0251] (R)-3-(4-((4-((((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 24. MS (ESI) m/z: 724.2 [M+H]⁺.

[0252] (S)-3-(1-((3-((((1r,4S)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4- c]pyrrol-5(6H)-yl)piperidine-2,6-dione 25. MS (ESI) m/z: 730.3 [M+H]⁺.

[0253] 3-(4-(1-(2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 27. MS (ESI) m/z: 733.0 [M+H]⁺.

[0254] 3-(4-(1-(3-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 29. MS (ESI) m/z: 747.3 [M+H]⁺.

[0255] 3-(5-(1-(3-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 30. MS (ESI) m/z: 747.3 [M+H]⁺.

[0256] 3-(1-((((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)piperidine-2,6-dione 31. MS (ESI) m/z: 624.2 [M+H]⁺.

[0257] 3-(1-((4-((((1r,4r)-4-((4-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 32. MS (ESI) m/z: 695.8 [M+H]⁺.

[0258] 3-(1-((4-((((1r,4r)-4-((4-(5-(Cyclopropylmethyl)-1-isopropyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 33. MS (ESI) m/z: 723.9 [M+H]⁺.

[0259] (S)-3-(4-((4-((4-(2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H- pyrazol-4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperazin-1-yl)methyl)benzyl)oxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 34. MS (ESI) m/z: 836.3 [M+H]⁺.

[0260] 3-(1-((4-((((1r,4r)-4-((5-Chloro-4-(5-(2-hydroxyethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 35. MS (ESI) m/z: 720.3 [M+H]⁺.

[0261] (S)-3-(4-((4-((((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane- 2,7-dione 36. MS (ESI) m/z: 738.3 [M+H]⁺.

[0262] 3-(5-(1-(4-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)butyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 39. MS (ESI) m/z: 761.3 [M+H]⁺.

[0263] 3-(5-(1-(5-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 41. MS (ESI) m/z: 775.4 [M+H]⁺.

[0264] 3-(5-((2-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)amino)-6-fluoro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 42. MS (ESI) m/z: 665.3 [M+H]⁺.

[0265] 3-(5-(1-(3-(((1r,4r)-4-((5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)propyl)piperidin-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione 43. MS (ESI) m/z: 761.4 [M+H]⁺.

Example B1. Cell Viability Assays [0266] MOLM-13 and MV-4-11 cells were independently cultured in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. The cells were plated in walled 96-well plates at 4,000 cells/well. The cells were incubated in DMSO (control) or a compound for 3 days at 37 °C under 5% CO2. A CELLTITER-GLO® reagent (100 µL) was then added to each well. After a 10 min incubation with shaking, luminescence was measured using an ENVISION® multimode plate reader. [0267] The results are summarized in Table 1. The cell viability values as % DMSO are reported as “A,” “B,” “C,” or “D;” where “A” represents a % viability value of less than 10%; “B” represents a % viability value of no less than 10% and less than 25%; “C” represents a % viability value of no less than 25% and less than 50%; and “D” represents a % viability value of no less than 50%. “A’” represents an IC₅₀ value of no greater than 100 nM, “B’” represents an IC₅₀ value of greater than 100 nM and no greater than 200 nM, “C’” represents an IC₅₀ value of greater than 200 nM and no greater than 500 nM, and “D’” represents an IC50 value of greater than 1 µM. TABLE 1. Effect on MOLM-13 and MV-4-11 Cell Viability

Example B1. Western Blot Analysis [0268] MV-4-11 cells were grown in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. The cells were plated in 24-well plates in the growth media. The cells were then treated with a compound or DMSO (control) for 6 h at predetermined concentrations. Whole cell extracts were prepared using an immunoprecipitation (IP) lysis buffer. Briefly, the cells were washed once in PBS, and the cell pellets were resuspended in the IP lysis buffer and incubated for 15 min on ice. Cells debris was removed by centrifugation and the cleared whole cell lysates were transferred to new tubes for further analysis. [0269] For a western blot analysis, the whole cell protein extracts were separated on 4-12% SDS-polyacrylamide gels, transferred to nitrocellulose, and probed with primary antibodies. Membranes were subsequently washed and probed with IRDYE^® secondary antibodies. The signals were detected using an ODYSSEY^® Imaging System. The antibodies used in the assay included anti-CK1α rabbit monoclonal antibody; β-actin mouse monoclonal antibody; IRDYE^® 680RD goat anti-rabbit antibody; and IRDYE^® 800CW goat anti-mouse antibody. [0270] The results are summarized in Table 2. The % degradation values relative to the DMSO control are reported as “A,” “B,” “C,” or “D;” where “A” represents a % degradation value of no less than 50%; “B” represents a % degradation value of less than 50% and no less than 25%; “C” represents a % degradation value of less than 25% and no less than 10%; and “D” represents a % degradation value of less than 10%. TABEL 2. Effect on CK1α Protein Degradation

* * * * * [0271] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is: 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: ,

X is C₁-C₁₅ alkylene, 2 to 15 membered heteroalkylene, C₂-C₁₀ alkenylene, C₂-C₁₀ alkynylene, phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C3-C8 cycloalkylene, wherein each of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C3-C8 cycloalkylene is optionally substituted with one or more R⁷; or X is C₁-C₁₅ alkylene or 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units of X is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C3-C8 cycloalkylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷; each Y is independently CH₂, O, S, or NH; L¹ is a bond,

,

, L is a bond, (CH₂)_{1-3 ,} (CH₂)_0-3C( O) , (CH₂)_0-3S( O) , (CH₂)_0-3S( O)₂ , or –(CH2)0-3C(=O)NR^8a–; each of Q¹, Q², and Q³ is independently S or CH, provided that one of Q¹, Q², and Q³ is S; each Q is independently CH₂ or C(=O); each n is independently an integer of 0, 1, or 2; each R^A is independently deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, optionally substituted amino, C1-C6 alkylamino, (amino)C1-C6 alkyl, –(C=O)NR^9aR^9b, (C1-C6 alkoxy)C1-C6 alkyl, –O-(C1-C6 alkoxy)C1-C6 alkyl, or optionally substituted C3-C7 cycloalkyl; each of R², R^2a and R^2b is independently H, deuterium, halogen, or C₁-C₆ alkyl; each R^2c is independently H, C₁-C₆ alkyl, or C₃-C₈ cycloalkyl, wherein C₃-C₈ cycloalkyl is optionally substituted with C1-C6 alkyl, halogen, or C1-C6 haloalkyl; each R^2d is independently H, hydroxyl, halogen, –O–C1-C6 alkyl, –O–C1-C6 haloalkyl, or –O–C₃-C₈ cycloalkyl, wherein –O–C₃-C₈ cycloalkyl is optionally substituted with C₁-C₆ alkyl, halogen, or C1-C6 haloalkyl; each R^2e is independently –C(=O)–C1-C6 alkyl or –C(=O)–C3-C8 cycloalkyl, each optionally substituted with one or more substituents, each substituent independently selected from the group consisting of cyano, halogen, hydroxy, amino, and C1-C6 haloalkyl; each R³ is independently H, deuterium, or C1-C6 alkyl; each of R⁴ and R⁶ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl), or optionally substituted C₃- C7 cycloalkyl; each of R^5a, R^5b and R^5c is independently H or C1-C6 alkyl; each Ring A is independently phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C3-C8 cycloalkylene, each optionally substituted with one or more R⁷; Ring B is phenylene or 6 membered heteroarylene, each optionally substituted with one or more R⁷; each R⁷ is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, (C1- C6 alkoxy)C1-C6 alkyl, –O–(C1-C6 alkoxy)C1-C6 alkyl, optionally substituted amino, C1-C6 alkylamino, (amino)C₁-C₆ alkyl, halogen, nitro, or cyano; or two geminal R⁷ form oxo; each of R⁸, R^8a, and R^8b is independently H or C₁-C₆ alkyl; each of R^9a andR^9b is independently H or C₁-C₆ alkyl; orR^9a and R^9b together with the nitrogen atom to which they are attached form optionally substituted 5 or 6 membered heterocyclyl, optionally substituted with one or more R⁷; each Z¹ is independently a bond, –(CR^aR^b)_q1–, –C(=O)–, –CH=CH–, or –C≡C–; each Z² is independently a bond or –(CR^cR^d)q2–; each of Z³ and Z⁴ is independently a bond, –NR^8b–, –O–, or –S–; each of R^a, R^b, R^c and R^d is independently H, halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or optionally substituted C3-C6 cycloalkyl; q1 and q2 are each independently an integer of 1, 2, or 3; each of X¹ and X² is independently O or S; and each of m1, m2, m3, m4, m5, m6, m7, m8, m9, k1, k2, k3, k4, k5, k6, k7, k8 and k9 is independently an integer of 0, 1, 2, 3, 4, or 5; with the provisions that, when

r

Ring A is phenylene or five to six membered heteroarylene; L¹ is ,

, , , wherein the asterisk * indicates the point of connection of L¹ to X; L² is a bond, –(CH₂)_0-3C(=O)– or –(CH₂)_0-3-C(=O)NR^8a–; X is C₁-C₁₅ alkylene or 2 to 15 membered heteroalkylene; Z³ is a bond, O, or NR^8b; Z⁴ is NR^8b, O, or S; m1, m2, m4, m5, m6, m7, k1, k2, k4, k5 and k6 are each independently an integer of 0, 1, 2, or 3; then Z¹ is –C(=O)–, –CH=CH–, or – b

, or

, wherein the asterisk * indicates the point of connection of L¹ to X; L² is a bond, –(CH2)0-3C(=O)–, or –(CH2)0-3-C(=O)NR^8a–; Z¹ is a bond or –(CR^aR^b)q1–; Z³ is a bond, O, or NR^8b; Z⁴ is NR^8b, O, or S; m1, m2, m4, m5, m6, m7, k1, k2, k4, k5 and k6 are each independently an integer of 0, 1, 2, or 3; then X is C₂-C₁₀ alkenylene, C₂-C₁₀ alkynylene, phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, or C3-C8 cycloalkylene; or X is C1- C15 alkylene or 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units of X is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C₃-C₈ cycloalkylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–.

2. The compound of Claim 1, wherein L¹-X-L² is .

3. The compound of claim 1 or 2, wherein Ring B is 6 membered heteroarylene, optionally substituted with one or more R⁷.

4. The compound of any one of claims 1 to 3, wherein Ring B is 6 membered heteroaryl containing one, two, or three nitrogen atoms, optionally substituted with one or more R⁷.

5. The compound of any one of claims 1 to 4, wherein Ring B is ,

6. The compound of any one of claims 1 to 5, wherein Ring B is

.

7. The compound of any one of claims 1 to 6, wherein R⁴ is H.

8. The compound of any one of claims 1 to 7, wherein R^5a is C1-C6 alkyl.

9. The compound of any one of claims 1 to 8, wherein R^5a is methyl.

10. The compound of any one of claims 1 to 9, wherein R^5b is H.

11. The compound of any one of claims 1 to 10, wherein R⁶ is C1-C6 alkyl, C1-C6 haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₃-C₇ cycloalkyl(C₁-C₃ alkyl), or optionally substituted C₃-C₇ cycloalkyl.

12. The compound of any one of claims 1 to 11, wherein R⁶ is optionally substituted C3- C7 cycloalkyl(C1-C3 alkyl).

13. The compound of any one of claims 1 to 12, wherein R⁶ is cyclopropyl(C₁-C₃ alkyl).

14. The compound of any one of claims 1 to 13, wherein R⁶ is cyclopropylmethyl.

15. The compound of any one of claims 1 to 14, wherein the compound is a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1 to 15, wherein the compound is a compound of Formula (Ibʹ):

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 15 or 16, wherein R⁷ is halogen.

18. The compound of any one of claims 15 to 17, wherein R⁷ is fluoro or chloro.

19. The compound of any one of claims 1 to 18, wherein R^5c is H.

20. The compound of any one of claims 1 to 19, wherein R¹ is

.

21. The compound of any one of claims 1 to 19, wherein R¹ is

,

22. The compound of any one of claims 1 to 20, wherein R¹ is

23. The compound of any one of claims 1 to 20, wherein R¹ is

24. The compound of any one of claims 1 to 19, wherein R¹ is

25. The compound of any one of claims 1 to 19 and 24, wherein R¹ is

26. The compound of any one of claims 1 to 19 and 24, wherein R¹ is

27. The compound of any one of claims 1 to 26, wherein R² is H.

28. The compound of any one of claims 1 to 27, wherein R³ is H.

29. The compound of any one of claims 1 to 27, wherein R³ is C1-C6 alkyl.

30. The compound of any one of claims 1 to 19 and 24 to 29, wherein Q is C( O).

31. The compound of any one of claims 1 to 19 and 24 to 29, wherein Q is CH2.

32. The compound of claim 31, wherein R¹ is

or

33. The compound of claim 31, wherein R¹ is ,

.

34. The compound of any one of claims 1 to 19, wherein R¹ is

.

35. The compound of any one of claims 1 to 34, wherein L¹ is a bond.

36. The compound of any one of claims 1 to 35, wherein L² is a bond.

37. The compound of any one of claims 1 to 36, wherein X is C1-C15 alkylene, or 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C3-C8 cycloalkylene; or (ii) –C(=O)–, –CH=CH– or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷.

38. The compound of any one of claims 1 to 37, wherein X is C₁-C₁₅ alkylene, wherein one or more methylene repeating units is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, or five to six membered heterocyclylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷.

39. The compound of any one of claims 1 to 38, wherein X is C1-C15 alkylene, wherein one or more methylene repeating units is independently replaced by (i) a ring structure selected from the group consisting of phenylene, pyrazolylene, imidazolylene, piperazinylene, or piperidinylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷.

40. The compound of any one of claims 1 to 36, wherein X is 2 to 15 membered heteroalkylene, or 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, five to six membered heterocyclylene, and C₃-C₈ cycloalkylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷.

41. The compound of any one of claims 1 to 36 and 40, wherein X is 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units is independently replaced by (i) a ring structure selected from the group consisting of phenylene, five to six membered heteroarylene, or five to six membered heterocyclylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷.

42. The compound of any one of claims 1 to 36, 40, and 41, wherein X is 2 to 15 membered heteroalkylene, wherein one or more methylene repeating units is independently replaced by (i) a ring structure selected from the group consisting of phenylene, pyrazolylene, imidazolylene, piperazinylene, or piperidinylene; or (ii) –C(=O)–, –CH=CH–, or –C≡C–; and wherein each ring structure is optionally substituted with one or more R⁷.

43. The compound of any one of claims 1 to 42, wherein L¹-X-L² is:

,

44. The compound of any one of claims 1 to 43, wherein L¹-X-L² is

, , or

.

45. A compound of: 4-((14-(((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropyrimidin- 2-yl)amino)cyclohexyl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione 1; 3-(4-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-3-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 2; (S)-3-(4-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 3; 3-(4-(1-(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)benzyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 4; (2S,4R)-1-((S)-2-(11-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl)pyrimidin-2-yl)amino)cyclohexyl)amino)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N- (4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide 5; (S)-3-(1-((4-(((9-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)amino)methyl)phenoxy) methyl)-4-oxo-4H- thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 6; 3-(4-(1-(9-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)nonyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 7; 3-(4-(1-(5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 8; (S)-3-(1-((4-(((5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)amino)methyl)phenoxy)methyl)-4-oxo-4H- thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 9; 3-(1-oxo-4-{2-[1-(5-{[(1r,4r)-4-({5-chloro-4-[5-(cyclopropylmethyl)-1-methyl-1H-pyrazol- 4-yl]pyrimidin-2-yl}amino)cyclohexyl]amino}pentanoyl)piperidin-4-yl]ethynyl}-2,3-dihydro-1H- isoindol-2-yl)piperidine-2,6-dione 10; (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)heptyl)(methyl)amino)methyl)- phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 11; 3-(5-(1-(7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 12; 3-(4-((1-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)glycyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 13; 3-(4-(1-(3-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-1H-pyrazol-1-yl)propyl)piperidin-4-yl)-6- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 14; 3-(4-(1-(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)phenethyl)piperidin-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione 15; 3-(4-(1-(4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethoxy)benzyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin- 2-yl)piperidine-2,6-dione 16; 3-(4-(1-(4-((2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)(methyl)amino)phenethyl)piperidin-4-yl)-6-fluoro- 1-oxoisoindolin-2-yl)piperidine-2,6-dione 17; (S)-3-(4-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2- yl)piperidine-2,6-dione 18; (S)-3-(1-((4-(((7-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)heptyl)(methyl)amino)methyl)-phenoxy)methyl)-4-oxo- 4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 19; (S)-3-(1-((4-(((2-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)piperidin-1-yl)ethyl)amino)methyl)- phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 20; (S)-3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 21; (S)-3-(1-((4-((((1r,4r)-4-((5-fluoro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 22; (S)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 23; (R)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 24; (S)-3-(1-((3-((((1r,4S)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)piperidine-2,6-dione 25; (S)-3-(4-((4-((4-(4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)-2-fluorophenyl)piperazin-1- yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 26; 3-(4-(1-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 27; 3-(5-(1-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 28; 3-(4-(1-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 29; 3-(5-(1-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 30; 3-(1-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 31; 3-(1-((4-((((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)piperidine-2,6-dione 32; 3-(1-((4-((((1r,4r)-4-((4-(5-(cyclopropylmethyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)piperidine-2,6-dione 33; (S)-3-(4-((4-((4-(2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)piperazin-1-yl)methyl)benzyl)oxy)-1- oxoisoindolin-2-yl)piperidine-2,6-dione 34; 3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(2-hydroxyethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin- 2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)- yl)piperidine-2,6-dione 35; (S)-3-(4-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)azepane-2,7- dione 36; (S)-3-(1-((4-((((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol- 5(6H)-yl)azepane-2,7-dione 37; 2-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- yl)amino)cyclohexyl)amino)propyl)-4-(4-(4-(((2-((S)-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)methyl)benzyl)piperazin-1-yl)benzonitrile 38; 3-(5-(1-(4-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)butyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 39; 3-(5-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)propyl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6- dione 40; 3-(5-(1-(5-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)pentyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione 41; 3-(5-((2-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)amino)ethyl)amino)-6-fluoro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione 42; or 3-(5-(1-(3-(((1r,4r)-4-((5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl)amino)cyclohexyl)(methyl)amino)propyl)piperidin-4-yl)-6-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione 43; or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

47. The pharmaceutical composition of claim 46, wherein the composition is in single dosage form.

48. The pharmaceutical composition of claim 46 or 47, wherein the composition is in an oral, parenteral, or intravenous dosage form.

49. The pharmaceutical composition of claim 48, wherein the composition is formulated in an oral dosage form.

50. The pharmaceutical composition of claim 49, wherein the oral dosage form is a tablet or capsule.

51. A method of treating or ameliorating cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof.