Cyclin-dependent kinase 2 degraders

Abstract

The present disclosure provides a compound represented by structural Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof. Compounds of the disclosure are useful for degrading cyclin-dependent kinases (CDKs) and for treating diseases and disorders mediated by CDKs.

Description

[0001] CYCLIN-DEPENDENT KINASE 2 DEGRADERS RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial Number 63 / 605,062, filed on December 1, 2023, the entire contents of which are hereby incorporated by reference herein. FIELD The disclosure relates to novel compounds and their use as degraders of cyclin- dependent kinase (CDK) 2, which have a central role in cell cycle progression. BACKGROUND CDKs are serine / threonine protein kinases that have a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and it is the selective activation of specific CDKs allows tor the proper ordering of the steps in cell cycle progression. Cyclins and their binding partner CDKs are key regulatory enzymes driving the cell cycle and cell proliferation. The catalytic activities of CDKs are regulated by their interactions with cyclins (including cyclin A, cyclin B, D-type cyclins, and cyclins E), and with CDK inhibitors (Ding, L. et al., Int. J. Mol. Sci. (2020) 21(6): 1960). In mammals there is one mitotic CDK (CDK1) and multiple interphase CDKs, including CDK2, CDK4, and CDK6. Cyclin E is part of the core cell cycle machinery as it complexes with CDK2 to move cells through the first gap phase (G1) / synthetic (S) boundary via inactivation of the retinoblastoma tumor suppressor protein (Rb) and release of the transcription factor E2F1. Cyclin E protein levels peak at the G1 / S progression, followed by an increase in cyclin A levels in the S phase. Both cyclin E and A interact with and activate CDK2, whereas cyclin A can also bind CDK1. At the G2 / M boundary, cyclin B levels increase, resulting in activation of CDK1. Cyclin D1 is an important cell cycle regulator that activates CDK4 / 6. Upon activation, CDK4 / 6 phosphorylate the Rb protein, leading to the release of its repression on the transcription factor E2F1, which is then free to induce the expression of proteins involved in G1 to S phase transition. This fluctuation in cyclin expression results in the oscillation in CDK activity and the tightly regulated cell cycle. In cancer cells, the cell cycle is often dysregulated, and such cells then develop dependencies on individual cyclins or CDKs, such as CDK2, providing opportunities for therapeutic targeting (Suski, J.M. et al., Cancer Cell (2021) 39(6): 759-778). Given their key roles in the cell cycle, CDK2, CDK4, and CDK6 inhibitors have been developed for therapeutic cancer targeting. Several CDK4 / 6 inhibitors have been approved for the treatment of stage IV or recurrent hormone receptor positive (HR+) / human epidermal growth factor receptor-2 negative (HER2-) breast cancers (Goel, S. et al., Nat. Rev. Cancer (2022) 22(6): 356-372; Sherr, C.J. et al., Cancer Discov. (2016) Cancer Disc.6(4): 353-367). However, their effects are limited by intrinsic or acquired resistance to CDK4 / 6 inhibitors, and almost all patients progress after treatment (Yuan, K. et al., Acta Pharm. Sin. B (2021) 11(1): 30-54, Epub 2000). Multiple mechanisms of resistance to CDK4 / 6 inhibitors have been previously identified, including loss of Rb and amplification and / or overexpression of p16, CDK6, cyclin D1, and cyclin E, where activation of the cyclin E-CDK2 pathway compensates for CDK4 / 6 inhibition via a bypass mechanism. Recent research has identified the aberrant activation of cyclin E / CDK2 as key mechanism by which tumors can evade CDK4 / 6 blockade (Freeman-Cook, K. et al., Cancer Cell (2021) 39: 1404-1421; Wang, B. et al., Front. Oncol. (2021) 11: 405), indicating that CDK4 / 6 inhibitor resistance might be overcome by CDK2 inhibitor treatment. Independent of prior exposure to CDK4 / 6 inhibitors, a variety of tumor types have also been demonstrated to have dysregulation and dependence of cell proliferation on the cyclin E / CDK2 axis, by harboring amplification or overexpression of the cyclin E1 gene CCNE1 (Ooi, A. et al., Hum. Pathol. (2017) 61: 58-67, Epub 2016; Nakayama, K. et al., Int. J. Oncol. (2016) 48(2): 506-516). Thus, anti-CDK2 therapies may impact a broad number of cancers that have acquired dependency on CDK2 or harbor gene alterations that require intact CDK2 function for oncogenesis. Targeted protein degradation (TPD) has emerged recently as an attractive novel therapeutic approach, due to the potential benefits including improved selectivity and catalytic nature hence less stringent requirement on exposure compared to traditional small- molecule inhibitors (Békés, M. et al., Nat. Rev. Drug Discov. (2022) 21(3): 181-200). Heterobifunctional degraders, or proteolysis-targeting chimeras (PROTAC), are a commonly used therapeutic modality to achieve targeted protein degradation (Lai, A.C. and Crews, C.M., Nat. Rev. Drug Discov. (2017) 16(2): 101-114). PROTACs are bifunctional degraders that include 2 binding moieties, i.e. the warheads and the E3 ubiquitin ligase-binding moieties. The warheads bind to the target protein of interest with high affinity. The E3 ubiquitin ligase-binding moieties recruit E3 ligases that ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The two ligands are connected by linkers of various flavors. No CDK2degrader has been approved by FDA so far. A few CDK2 degraders have been reported. For example, Teng and Gray et. al. have reported a CDK2 / 5 dual degrader TMX-2172 (Teng, M. et al., Angew. Chem. In. Ed. (2020) 59(33): 13865-13870), Wang and Rao have reported a selective CDK2 degrader (Wang, L. et al., Nat. Chem. Biol. (2021) 17(5): 567-575). But they either lack the necessary selectivity or drug-like properties to become anit-CDK2 therapies for human patients. There remains a need for the development of potent and targeted CDK2 degraders which can be used to treat CDK2 dependent cancers. SUMMARY Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions that are useful for degrading CDK2, and for treating various cancers. The compounds of the disclosure are potent degraders of CDK2 (see Biological Example 1). Some of the compounds of the disclosure are orally bioavailable and selectively and catalytically degrade their target protein (e.g., CDK2) over other CDKs and other proteins. In one aspect, provided herein is a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below. In another aspect, provided herein is a compound represented by Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below. In another aspect, provided herein is a compound represented by Formula (II): or a pharmaceutically acceptable salt thereof, wherein the definition of each variable is provided below. In another aspect, provided herein is a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In another aspect, provided herein is a method of degrading CDK2, comprising contacting CDK2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure. In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers. In another aspect, provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the treatment of cancers. DETAILED DESCRIPTION Compounds of the Disclosure Provided herein, among other things, are compounds and compositions that modulate (e.g., by protein degradation) the activity of CDK2. In one aspect, provided herein is a compound of Formula (I):

[0002] or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6is H or D; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2; Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1and Rb2is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rbattached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; L is a linker moiety; and Z is an E3 ubiquitin ligase-binding moiety. In some embodiments, provided herein is a compound of Formula (Ia): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, and Ring A are defined as defined herein; L is a linker moiety; and Z’ is a means for binding an E3 ubiquitin ligase. In another aspect, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2; L is a linker moiety; Ring B is: Each Y1is independently selected from C(Rd5)2and NRc12; Y2is C(Re3)2 or C(=O); W is CH or N; Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1or Rb2attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc12, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd5is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re3is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; and t is an integer from 0 to 4. In some embodiments, provided herein is a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2; L1is selected from a covalent bond, -S(=O)2-, -*NRc3-S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3-S(=O)2-(C(Rd1)2)n-O- (C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb3, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 4 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 4 Rb4; or X1– L2– X2form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb5, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 4 Rb5; L3is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; Each X3is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12- membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb6, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc9and then are optionally substituted on a ring carbon with 1 to 4 Rb6; or X2– L3– X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7; or Two X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7; L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, - *(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, - *NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n- NRc11-C(=O)- wherein * denotes the point of attachment of L4to Ring B; wherein no more than three of L1, X1, L2, X2, and L4can simultaneously be a covalent bond; Ring B is 10 Each Y1is independently selected from C(Rd5)2 and NRc12; Y2is C(Re3)2or C(=O); W is CH or N; Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, and wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2Rb3, Rb4, Rb5, Rb6, or Rb7attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd1, Rd2, Rd3, Rd4, and Rd5is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; n is an integer from 0 to 8; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 4. In some embodiments, provided herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 3 Rb1, and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1and then is optionally substituted on a ring carbon with 1 to 3 Rb1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, C5- C10spirocycloalkyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C5-C10spirocycloalkyl, and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from a covalent bond, -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, - *S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a C5-C10spirocycloalkyl or 5 to 10-membered spiroheterocyclyl, wherein the C5-C10spirocycloalkyl is optionally substituted with 1 to 3 Rb5, and wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; Each X3is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10- membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3form a C5-C10spirocycloalkyl or 5 to 10-membered spiroheterocyclyl, wherein the C5-C10spirocycloalkyl is optionally substituted with 1 to 3 Rb7, and wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or Two X3form a C5-C10spirocycloalkyl or 5 to 10-membered spiroheterocyclyl, wherein the C5-C10spirocycloalkyl is optionally substituted with 1 to 3 Rb7, wherein the 5 to 10- membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7; L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, - *(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6 alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, - *NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11- (C(Rd4)2)n-NRc11-C(=O)- wherein * denotes the point of attachment of L4to Ring B; wherein no more than two of L1, X1, L2, X2, and L4can simultaneously be a covalent bond; Ring B is Each Y1is independently selected from C(Rd5)2 and NRc12; Y2is C(Re3)2 or C(=O); W is CH or N; Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2Rb3, Rb4, Rb5, Rb6, or Rb7attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D and OH; Each Rd1, Rd2, Rd3, Rd4, and Rd5is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3is independently selected from H, D, and C1-C4alkyl; m is 0 or 1; n is an integer from 0 to 6; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3. In some embodiments, the compound described herein is represented by Formula (IV): or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 4, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, W, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (IVa): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (IVb): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula ( or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (IVd): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (V):

[0003] or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 3, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, Y2, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (Va): (Va), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vb): (Vb), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vc):

[0004] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vd): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (Ve): (Ve), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (Vf):

[0005] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L3, X3, L4, t, and Rb8are as defined herein. In some embodiments, described herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; X3is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, and -*NRc11-(C(Rd4)2)n-C(=O)- wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2or C(=O); Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2Rb3, Rb4, Rb5, Rb6, or Rb7attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Each Rd1, Rd2, Rd3, and Rd4is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3is independently selected from H, D, and C1-C4alkyl; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3. In some embodiments, described herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, and C1-C4alkyl; R4is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6is H or D; R7is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(R2d)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; X3is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2or C(=O); Each Ra1and Ra2is independently selected from H, D, OH, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2Rb3, Rb4, Rb5, Rb6, or Rb7attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, and Rc11is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4is independently selected from H, D, and C1-C4alkyl; Each Re1, Re2, and Re3is independently H or D; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3. In some embodiments, described herein is a compound of a formula described herein, or a pharmaceutically acceptable salt thereof, wherein: R1is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2is selected from H, D, and C1-C4alkyl; R3is selected from H, D, and C1-C4alkyl; R4is selected from H, D, halo, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5is selected from H, D, and C1-C4alkyl; R6is H or D; R7is selected from H, D, and C1-C4alkyl; Ring A is selected from 6-membered heterocyclyl, 6-membered aryl, and 6-membered heteroaryl, wherein the 6-membered aryl is optionally substituted with 1 or 2 Rb2, and wherein the 6-membered heterocyclyl and 6-membered heteroaryl have 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 or 2 Rb2; L1is -S(=O)2- or -*S(=O)2-NRc3-wherein * denotes the point of attachment of L1to Ring A; X1is C6cycloalkyl or 6-membered heterocyclyl, wherein the C6cycloalkyl is optionally substituted with 1 or 2 Rb3, and wherein the 6-membered heterocyclyl has 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc4and then is optionally substituted on a ring carbon with 1 or 2 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-, and -C(=O)-, wherein * denotes the point of attachment of L2to X1; X2is a covalent bond or 3 to 6-membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc6and then is optionally substituted on a ring carbon with 1 or 2 Rb4; or X1– L2– X2form a 7 to 10-membered spiroheterocyclyl, wherein the 7 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 or 2 Rb5; L3is -O- or -(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; X3is 6-membered heterocyclyl, wherein the 6-membered heterocyclyl has 1 or 2 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with 1 or 2 Rb6; or X2– L3– X3form a 7 to 10-membered spiroheterocyclyl, wherein the 7 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 or 2 Rb7; or L4is selected from a covalent bond, -O-, -*C2-C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4to Ring B; wherein no more than two of L1, X1, L2, X2, and L4can simultaneously be a covalent bond; Ring B is Y2is C(Re3)2 or C(=O); W is CH or N; Ra1is independently selected from H, D, OH, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, Rb6, and Rb7is independently selected from D, halo, OH, and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc9, Rc10, and Rc11is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4is independently selected from H, D, and C1-C4alkyl; Re3is independently H or D; m is 0; n is 1; p is 0 or 1; q is 0, 1, or 2; fs is 1; and t is an integer from 0 to 2. In some embodiments, the compound described herein is represented by Formula (VI): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, ring B, Y1, and m are as defined herein. In some embodiments, the compound described herein is represented by Formula (VII):

[0006] or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 4, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, and Rb8are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIa): (VIIa), or a pharmaceutically acceptable salt thereof, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIb): or a pharmac L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIII):

[0007] or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 3, and wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Y2, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIa): (VIIIa), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIb): (VIIIb), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIc):

[0008] or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIId): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIe): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (VIIIf): (VIIIf), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compound described herein is represented by Formula (IX): or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, ring A, L1, X1, L2, X2, L4, Rb8, and t are as defined herein. In some embodiments, the compounds described herein of a formula described herein, or a pharmaceutically acceptable thereof, wherein: R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2or C(=O); Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb2, Rb3, Rb4, Rb5, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb2Rb3, Rb4, or Rb5attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)C1-4alkyl; Each Rd1, Rd2, and Rd4is independently selected from H, D, halo, OH, C1-C4alkyl, and C3- C6cycloalkyl; Each Re1and Re3is independently selected from H, D, and C1-C4 alkyl; n is an integer from 0 to 4; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3. In some embodiments, the compounds described herein of a formula described herein, or a pharmaceutically acceptable thereof, wherein: R1is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, and C1-C4alkyl; R4is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6is H or D; R7is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, wherein the 3 to 6-membered heterocyclyl and 5 or or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-,-*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2 or C(=O); Each Ra1and Ra2is independently selected from H, D, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, and Rb8is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2, Rb3, Rb4, or Rb5attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4is independently selected from H, D, and C1-C4alkyl; Each Re1and Re3is independently H or D; n is an integer from 0 to 4; r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3. In some embodiments, R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1. In some embodiments, R1is C1-C6alkyl optionally substituted with 1 to 3 Ra1. In some embodiments, R1is C1-C6alkyl optionally substituted with 1 or 2 Ra1. In some embodiments, R1is C1-C6alkyl optionally substituted with OH. In some embodiments, R1is C1-C6alkyl. In some embodiments, R1is CH3 or CH2C(CH3)2OH. In some embodiments, R1is CH3. In some embodiments, R1is CH2C(CH3)2OH. In some embodiments, R2is selected from H, D, and C1-C4alkyl, wherein the C1- C4alkyl is optionally substituted with 1 to 3 Ra2. In some embodiments, R2is H or C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2. In some embodiments, R2is H, D, or C1-C4alkyl. In some embodiments, R2is H or D. In some embodiments, R2is H. In some embodiments, R3is selected from H, D, halo, CN, and C1-C4alkyl. In some embodiments, R3is H. In some embodiments, R3is H or D. In some embodiments, R4is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1- C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN. In some embodiments, R4is C1-C4alkyl, CN, or halo, wherein said C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from halo. In some embodiments, R4is CH3, CHF2, CF3, CN, or Cl. In some embodiments, R4is CH3. In some embodiments, R4is CHF2. In some embodiments, R4is CF3. In some embodiments, R4is CN. In some embodiments, R4is Cl. In some embodiments, R4is H, D, CH3, CHF2, CF3, CN, or Cl. In some embodiments, R4is H, CH3, CHF2, CF3, CN, or Cl. In some embodiments, R4is H or D. In some embodiments, R4is H. In some embodiments, R5is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1- C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN. In some embodiments, R5is selected from H, D, halo, OH, and CN. In some embodiments, R5is H or D. In some embodiments, R5is H. In some embodiments, R6is H. In some embodiments, R6is D. In some embodiments, R7is selected from H, D, and C1-C4alkyl. In some embodiments, R7is H or C1-C4alkyl. In some embodiments, R7is methyl. In some embodiments, R7is H. In some embodiments, R7is H, D, or C1-C4alkyl. In some embodiments, R7is H, D, or methyl. In some embodiments, R7is H or methyl. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 or 2 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 or 2 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C9-C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6- membered heteroaryl, wherein the C3-C6cycloalkyl, C9-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 9 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C9-C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C9- C12spirocycloalkyl, and phenyl are each optionally substituted with 1 or 2 Rb2, and wherein the 3 to 6-membered heterocyclyl, 9 to 12-membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C9- C12spirocycloalkyl, 9 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C9-C12spirocycloalkyl, and phenyl are each optionally substituted with Rb2, and wherein the 3 to 6-membered heterocyclyl, 9 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from C3-C6cycloalkyl optionally substituted with Rb2. In some embodiments, Ring A is C3-C6cycloalkyl. In some embodiments, Ring A is cyclohexyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is cyclohexyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is cyclohexyl optionally substituted with Rb2. In some embodiments, Ring A is cyclohexyl. In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 6 to 12-membered aryl optionally substituted with Rb2. In some embodiments, Ring A is 6 to 12-membered aryl. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is phenyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is phenyl optionally substituted with Rb2. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 3 to 12- membered heterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is selected from 3 to 12-membered heterocyclyl. In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 3 to 6- membered heterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is selected from 3 to 6-membered heterocyclyl. In some embodiments, Ring A is piperidinyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is piperidinyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is piperidinyl optionally substituted with Rb2. In some embodiments, Ring A is piperidinyl. In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 5 to 12- membered spiroheterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is selected from 5 to 12-membered spiroheterocyclyl. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is 9 to 12-membered spiroheterocyclyl. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with Rb2. In some embodiments, Ring A is 6 to 11-membered spiroheterocyclyl. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with Rb2. In some embodiments, Ring A is 2-azaspiro[3.3]heptanyl. In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 5 to 12- membered heteroaryl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl optionally substituted with Rb2. In some embodiments, Ring A is selected from 5 to 12-membered heteroaryl. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with Rb2. In some embodiments, Ring A is selected from 5 or 6-membered heteroaryl. In some embodiments, Ring A is pyridinyl optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is pyridinyl optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is pyridinyl optionally substituted with Rb2. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2- azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 to 4 Rb2. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 or 2 Rb2. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with Rb2. In some embodiments, Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl. In some embodiments, Rb2is selected from C1-C4alkyl and halo. In some embodiments, Rb2is C1-C4alkyl. In some embodiments, Rb2is halo. In some embodiments, Rb2is selected from F and methyl. In some embodiments, Rb2is F. In some embodiments, Rb2is methyl. In some embodiments, L1is selected from covalent bond, -S(=O)2-, -*NRc3-S(=O)2-, - *S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3- S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1is selected from -S(=O)2-, -*NRc3-S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3-S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n- , and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1is selected from covalent bond, -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2- NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1is selected from -S(=O)2-, - *S(=O)2-NRc3-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O- (C(Rd1)2)n-. In some embodiments, L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1is selected from -S(=O)2- and -*S(=O)2-NRc3-. In some embodiments, L1is -S(=O)2-. In some embodiments, L1is -*S(=O)2-NRc3-. In some embodiments, L1is -*S(=O)2-(C(Rd1)2)n- O-(C(Rd1)2)n-. In some embodiments, L1is -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1is covalent bond. In some embodiments, L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-. In some embodiments, L1is selected from -S(=O)2- and -*S(=O)2-NH-. In some embodiments, L1is -*S(=O)2- (CH2)3-O-CH2-. In some embodiments, L1is -*S(=O)2-N(CH2CH2OH)-CH2-. In some embodiments, L1is -*S(=O)2-NH-(CH2)2-O-CH2-. In some embodiments, X1is a covalent bond. In some embodiments, X1is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12- membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb3, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 4 Rb3. In some embodiments, X1is selected from covalent bond, C3-C6cycloalkyl, 3 to 6- membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3- C6cycloalkyl and phenyl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3. In some embodiments, X1is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and phenyl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3. In some embodiments, X1is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 3 Rb3, wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3. In some embodiments, X1is selected from C3-C10cycloalkyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1is selected from C3-C10cycloalkyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1is selected from C3-C10cycloalkyl optionally substituted with Rb3. In some embodiments, X1is selected from C3-C10cycloalkyl. In some embodiments, X1is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1is selected from C3-C6cycloalkyl optionally substituted with Rb3. In some embodiments, X1is selected from C3-C6cycloalkyl. In some embodiments, X1is cyclobutyl or cyclohexyl, each optionally substituted with 1 to 3 Rb3. In some embodiments, X1is cyclobutyl or cyclohexyl, each optionally substituted with 1 or 2 Rb3. In some embodiments, X1is cyclobutyl or cyclohexyl, each optionally substituted with Rb3. In some embodiments, X1is cyclobutyl or cyclohexyl. In some embodiments, X1is cyclobutyl. In some embodiments, X1is cyclohexyl. In some embodiments, X1is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1is selected from 3 to 12-membered heterocyclyl optionally substituted with Rb3. In some embodiments, X1is selected from 3 to 12-membered heterocyclyl. In some embodiments, X1is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb3. In some embodiments, X1is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1is selected from 3 to 6-membered heterocyclyl optionally substituted with Rb3. In some embodiments, X1is selected from 3 to 6-membered heterocyclyl. In some embodiments, X1is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 to 3 Rb3. In some embodiments, X1is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 or 2 Rb3. In some embodiments, X1is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with Rb3. In some embodiments, X1is pyrrolidinyl, piperidinyl, or piperazinyl. In some embodiments, X1is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 3 Rb3. In some embodiments, X1is selected from 5 to 12-membered heteroaryl optionally substituted with 1 or 2 Rb3. In some embodiments, X1is selected from 5 to 12-membered heteroaryl optionally substituted with Rb3. In some embodiments, X1is selected from 5 to 12-membered heteroaryl. In some embodiments, X1is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb3. In some embodiments, X1is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 Rb3. In some embodiments, X1is selected from 5 or 6-membered heteroaryl optionally substituted with Rb3. In some embodiments, X1is selected from 5 or 6-membered heteroaryl. In some embodiments, X1is 1,2,3-triazolyl optionally substituted with 1 or 2 Rb3. In some embodiments, X1is 1,2,3-triazolyl optionally substituted with Rb3. In some embodiments, X1is 1,2,3-triazolyl. In some embodiments, L2is selected from covalent bond, -*(C(Re1)2C(Re1)2O)r- (C(Rd2)2)n-, -(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, -*NRc5-(C(Rd2)2)n-, and -*(C(Rd2)2)n-O- (C(Rd2)2)n-. In some embodiments, L2is selected from -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, - (C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, -*NRc5-(C(Rd2)2)n-, and -*(C(Rd2)2)n-O-(C(Rd2)2)n-. In some embodiments, L2is -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-. In some embodiments, L2is - (C(Rd2)2)n-. In some embodiments, L2is -*(C(Rd2)2)n-C(=O)-. In some embodiments, L2is - *NRc5-(C(Rd2)2)n-. In some embodiments, L2is -*(C(Rd2)2)n-O-(C(Rd2)2)n-. In some embodiments, L2is covalent bond. In some embodiments, L2is selected from -*(CH2CH2O)r-(CH2)n-, -(CH2)n-, - *(CH2)n-C(=O)-, -*NRc5-(CH2)n-, and -*(CH2)n-O-(CH2)n-. In some embodiments, L2is - *(CH2CH2O)r-(CH2)n-. In some embodiments, L2is -(CH2)n-. In some embodiments, L2is - CH2-. In some embodiments, L2is -CH2CH2-. In some embodiments, L2is -*(CH2)n-O- (CH2)n-. In some embodiments, X2is a covalent bond. In some embodiments, X2is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12- membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 4 Rb4. In some embodiments, X2is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 4 Rb4. In some embodiments, X2is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with 1 or 2 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 or 2 Rb4. In some embodiments, X2is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl is optionally substituted with Rb4, and wherein the 3 to 12- membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with Rb4. In some embodiments, X2is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6- membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 4 Rb4. In some embodiments, X2is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6- membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 or 2 Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 or 2 Rb4. In some embodiments, X2is selected from C3- C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with Rb4. In some embodiments, X2is selected from C3-C6cycloalkyl, 3 to 6- membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6. In some embodiments, X2is selected from C3-C10cycloalkyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2is selected from C3-C10cycloalkyl optionally substituted with 1 or 2 Rb4. In some embodiments, X2is selected from C3-C10cycloalkyl optionally substituted with Rb4. In some embodiments, X2is selected from C3-C10cycloalkyl. In some embodiments, X2is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2is selected from C3-C6cycloalkyl optionally substituted with 1 or 2 Rb4. In some embodiments, X2is selected from C3-C6cycloalkyl optionally substituted with Rb4. In some embodiments, X2is selected from C3-C6cycloalkyl. In some embodiments, X2is cyclohexyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2is cyclohexyl optionally substituted with Rb4. In some embodiments, X2is cyclohexyl. In some embodiments, X2is selected from 3 to 12-membered heterocyclyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2is selected from 3 to 12-membered heterocyclyl optionally substituted with Rb4. In some embodiments, X2is selected from 3 to 12-membered heterocyclyl. In some embodiments, X2is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb4. In some embodiments, X2is selected from 3 to 6-membered heterocyclyl optionally substituted with Rb4. In some embodiments, X2is selected from 3 to 6-membered heterocyclyl. In some embodiments, X2is azetidinyl, piperidinyl, or piperazinyl, each optionally substituted with 1 to 3 Rb4. In some embodiments, X2is azetidinyl, piperidinyl, or piperazinyl, each optionally substituted with Rb4. In some embodiments, X2is azetidinyl, piperidinyl, or piperazinyl. In some embodiments, X2is azetidinyl. In some embodiments, X2is piperidinyl. In some embodiments, X2is piperazinyl. In some embodiments, X2is selected from 5 to 12-membered heteroaryl optionally substituted with 1 to 3 Rb4. In some embodiments, X2is selected from 5 to 12-membered heteroaryl optionally substituted with 1 or 2 Rb4. In some embodiments, X2is selected from 5 to 12-membered heteroaryl optionally substituted with Rb4. In some embodiments, X2is selected from 5 to 12-membered heteroaryl. In some embodiments, X2is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb4. In some embodiments, X2is selected from 5 or 6-membered heteroaryl optionally substituted with 1 or 2 Rb4. In some embodiments, X2is selected from 5 or 6-membered heteroaryl optionally substituted with Rb4. In some embodiments, X2is selected from 5 or 6-membered heteroaryl. In some embodiments, X2is 1,2,3-triazolyl optionally substituted with 1 or 2 Rb4. In some embodiments, X2is 1,2,3-triazolyl optionally substituted with Rb4. In some embodiments, X2is 1,2,3-triazolyl. In some embodiments, L3is selected from -O-, -*C(=O)-(C(Rd3)2)n-, -(C(Rd3)2)n-, and -*(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-. In some embodiments, L3is -O-. In some embodiments, L3is -*C(=O)-(C(Rd3)2)n-. In some embodiments, L3is -(C(Rd3)2)n-. In some embodiments, L3is -*(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-. In some embodiments, L3is selected from -O-, -*C(=O)-(CH2)n-, -(CH2)n-, and - *(CH2CH2O)r-(CH2)n-. In some embodiments, L3is -*C(=O)-(CH2)n-. In some embodiments, L3is -(CH2)n-. In some embodiments, L3is -*(CH2CH2O)r-(CH2)n-. In some embodiments, X3is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with 1 to 3 Rb6. In some embodiments, X3is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with 1 or 2 Rb6. In some embodiments, X3is selected from 3 to 12-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with Rb6. In some embodiments, X3is selected from 3 to 12- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9. In some embodiments, X3is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with 1 to 3 Rb6. In some embodiments, X3is selected from 3 to 6- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with 1 or 2 Rb6. In some embodiments, X3is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with Rb6. In some embodiments, X3is selected from 3 to 6- membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9. In some embodiments, X3is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 to 3 Rb6. In some embodiments, X3is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 or 2 Rb6. In some embodiments, X3is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with Rb6. In some embodiments, X3is selected from piperazinyl and piperidinyl. In some embodiments, X3is piperazinyl. In some embodiments, X3is piperidinyl. In some embodiments, X2– L3– X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, X2– L3– X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 or 2 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, X2– L3– X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5- C12spirocycloalkyl is optionally substituted with Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with Rb7. In some embodiments, X2– L3– X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, X2– L3– X3form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, X2– L3– X3form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, X2– L3– X3form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with Rb7. In some embodiments, X2– L3– X3form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, X2– L3– X3form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, X2– L3– X3form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, X2– L3– X3form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with Rb7. In some embodiments, X2– L3– X3form a 10 or 11-membered spiroheterocyclyl, wherein the 10 or 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, two X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, two X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 or 2 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, two X3form a C5- C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5- C12spirocycloalkyl is optionally substituted with Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with Rb7. In some embodiments, two X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10. In some embodiments, two X3form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, two X3form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 to 4 Rb7. In some embodiments, two X3form 3,9- diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 or 2 Rb7. In some embodiments, two X3form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with Rb7. In some embodiments, two X3form 3,9-diazaspiro[5.5]undecane. In some embodiments, L4is a covalent bond. In some embodiments, L4is selected from -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, - *NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)- (C(Rd4)2)n-, -*(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n-NRc11-C(=O)-. In some embodiments, L4is selected from covalent bond, -O-, -NRc11-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*NRc11- (C(Rd4)2)n-, -*O-(C(Rd4)2)n-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)- NRc11-. In some embodiments, L4is selected from -O-, -NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)- NRc11-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*NRc11-(C(Rd4)2)n-, -*O- (C(Rd4)2)n-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)-NRc11-. In some embodiments, L4is selected from covalent bond, -O-, -NH-, -*NH-(CH2)n- C(=O)-NH-, -*C2-C6alkynylene-(O)s-, -*NH-(CH2)n-, -*O-(CH2)n-C(=O)-, -*NH-(CH2)n- C(=O)-, and -*O-(CH2)n-C(=O)-NH-. In some embodiments, L4is selected from -O-, -NH-, - *NH-(CH2)n-C(=O)-NH-, -*C2-C6alkynylene-(O)s-, -*NH-(CH2)n-, -*O-(CH2)n-C(=O)-, - *NH-(CH2)n-C(=O)-, and -*O-(CH2)n-C(=O)-NH-. In some embodiments, L4is selected from -O- and -NRc11-. In some embodiments, L4is -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-. In some embodiments, L4is -*O-(C(Rd4)2)n-C(=O)-NRc11-. In some embodiments, L4is -*C2- C6alkynylene-O-. In some embodiments, L4is -*C2-C6alkynylene-. In some embodiments, L4is -*C3alkynylene-. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 Rb2and L1is -*S(=O)2-NRc3-. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 Rb2, L1is - *S(=O)2-NRc3-, and X1is C3-C8cycloalkyl. In some embodiments, Ring A is piperidinyl optionally substituted with 1 to 4 Rb2and L1is -S(=O)2-. In some embodiments, Ring A is piperidinyl optionally substituted with 1 to 4 Rb2, L1is -S(=O)2-, and X1is 3 to 10-membered heterocyclyl. In some embodiments, Ring B is . In some embodiments, Ring In some embodiments, Rb8is halo or C1-C4alkyl. In some embodiments, Rb8is F or methyl. In some embodiments, Rb8is methyl. In some embodiments, W is CH. In some embodiments, W is N. In some embodiments, Y1is C(Rd5)2. In some embodiments, Y1is CH2. In some embodiments, Y1is NRc12. In some embodiments, Y1is NH. In some embodiments, Y2is C(Re3)2. In some embodiments, Y2is CH2. In some embodiments, Y2is C(=O). In some embodiments, m is 0. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 0. In some embodiments, n is an integer from 1 to 8. In some embodiments, n is an integer from 0 to 4. In some embodiments, n is an integer from 0 to 3. In some embodiments, n is an integer from 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is an integer from 1 to 4. In some embodiments, n is an integer from 1 to 3. In some embodiments, n is 1 or 2. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is an integer from 2 to 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, q is 0. In some embodiments, q is 1 or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, r is an integer from 1 to 5. In some embodiments, r is an integer from 1 to 4. In some embodiments, r is an integer from 1 to 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1. In some embodiments, r is an integer from 2 to 6. In some embodiments, r is an integer from 2 to 4. In some embodiments, r is 2 or 3. In some embodiments, r is an integer from 3 to 6. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, t is 0. In some embodiments, t is an integer from 0 to 3. In some embodiments, t is 0 or 2. In some embodiments, t is an integer from 1 to 4. In some embodiments, t is an integer from 1 to 3. In some embodiments, t is an integer from 2 to 3. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, the compound is selected from Table 1. Table 1. Selected bifunctional degrader compounds.

[0009] The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 8 carbon atoms (C1-C8alkyl) (i.e., 1, 2, 3, 4, 5, 6, 7, or 8), alternatively, 1 to 6 carbon atoms (C1-C6alkyl) (i.e., 1, 2, 3, 4, 5, or 6), alternatively, 1 to 4 carbon atoms (C1-C4alkyl) (i.e., 1, 2, 3, or 4). As used herein, a “(C1-C4)alkyl” group means a radical having from 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, butyl, tert-butyl, and the like. The term “alkenylene”, used alone or as part of a larger moiety, means an alkyl group that is a bivalent hydrocarbon radical in which one or more carbon-carbon single bonds is replaced by a double bond. The term “alkynylene”, used alone or as part of a larger moiety, means an alkyl group that is a bivalent hydrocarbon radical in which one or more carbon-carbon single bonds is replaced by a triple bond. The term “alkoxy” means a monovalent radical composed of an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. Examples include methoxy, ethoxy, propoxy, butoxy, and the like. The term “aryl” refers to a radical of a 6 to 12-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms provided in an aromatic ring system. Examples of aryl groups include phenyl, naphthyl, and the like. The number of ring members designates the number of ring members in the fused ring system. An aryl group may be described as, e.g., a 6 to 12- membered aryl, alternatively, a 6 to 10-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. The term “cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Unless otherwise specified, a cycloalkyl has 3 to 10 carbon atoms (C3-C10cycloalkyl), alternatively, 3 to 8 carbon atoms (C3- C8cycloalkyl), alternatively, 3 to 6 carbon atoms (C3-C6cycloalkyl). “Cycloalkyl” also includes ring systems comprising two cycloalkyl groups, as defined above, sharing 2, 3, or 4 adjacent ring atoms to form a fused or bridged bicycloalkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[4.2.0]octanyl, octahydro-1H-indenyl, decahydronaphthalenyl, bicyclo[2.2.1]hepantyl, bicyclo[2.2.2]octantyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.2]nonanyl, and the like. The term “spirocycloalkyl” refers to a group comprising two cycloalkyls which share one common ring atom. Unless otherwise specified, a spirocycloalkyl has 5 to 12 carbon atoms (C5-C12spirocycloalkyl), alternatively, 5 to 10 carbon atoms (C5-C10cycloalkyl). Examples include spiro[2.2]pentanyl, spiro[3.3]heptanyl, spiro[3.5]nonanyl, spiro[5.5]undecanyl, and the like. The term “E3 ubiquitin ligase-binding moiety” refers to a chemical group that binds to an E3 ubiquiting ligase. E3 ubiquitin ligase binding moieties are known and well-described in the art, for example: Bondeson, D. P., et al. Nat Chem Biol.201511(8):611-617; An S, et al. EBioMedicine 201836:553-562; Paiva S-L. et al, Curr. Op. in Chem. Bio.2010, 50:111- 119, each of which is incorporated by reference in its entirety. The term “halo” means halogen and includes chloro (Cl), fluoro (F), bromo (Br), and iodo (I). The term “heterocyclyl” or “heterocycle” refers to a monocyclic or bicyclic non- aromatic ring radical. Unless otherwise specified, a heterocyclyl has 3 to 12 ring atoms (i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered), alternatively, 3 to 10 ring atoms (i.e., 3, 4, 5, 6, 7, 8, 9, or 10-membered), alternatively, 3 to 6 ring atoms (i.e., 3, 4, 5, or 6-membered), selected from carbon atoms and and 1 to 4 heteroatoms, wherein each heteroatom is independently selected from oxygen (O), sulfur (S), including sulfoxide and sulfone, and nitrogen (N or NRc1, including quaternary nitrogen, oxidized nitrogen (e.g., NO)). “Heterocyclyl” also includes ring systems comprising a heterocycle which shares 2, 3, or 4 adjacent ring atoms with a cycloalkyl or a second heterocycle, as defined herein. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Examples of heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, 1,2-thiazinanyl-1,1-dioxide, 3-azabicyclo[4.2.0]-octanyl, octahydro-1H-indolyl, decahydroquinolinyl, decahydro-1,5- naphthyridinyl, 5-oxabicyclo[2.1.1]-hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 6- oxabicyclo[3.1.1]heptanyl, 2-oxabicyclo[2.2.2]octanyl, 7-oxabicyclo[4.1.1]octanyl, 8- oxabicyclo[3.2.1]octanyl, and the like. The term “spiroheterocyclyl” refers to bicyclic non-aromatic ring radical comprising a heterocycle which shares one common ring atom with a cycloalkyl or a second heterocycle. Unless otherwise specified, a spiroheterocyclyl has 5 to 12 ring atoms (i.e., 5, 6, 7, 8, 9, 10, 11, or 12-membered), alternatively, 5 to 10 ring atoms (i.e., 5, 6, 7, 8, 9, or 10-membered), selected from carbon atoms and 1 to 4 heteroatoms, wherein each heteroatom is independently selected from oxygen (O), sulfur (S), including sulfoxide and sulfone, and nitrogen (N or NRc1, including quaternary nitrogen, oxidized nitrogen (e.g., NO)). Examples include 2-azaspiro[3.3]heptanyl, 2,5-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 3- azaspiro[5.5]undecanyl, diazaspiro[5.5]undecanyl, and the like. The term “heteroaryl” refers to a radical of a 5-12 membered monocyclic or bicyclic aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–12 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). A heteroaryl group may be described as, e.g., a 6- 10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. The terms “linker moiety” and “linker” refer to a bivalent chemical moiety that binds (e.g., bridges) two separate entities to one another. As used herein, the terms “linker moiety” and “linker” can refer to a bivalent chemical moiety that is covalently bonded to both ring A of the compounds of the disclosure and group Z or Z’ of the compounds of the disclosure. The terms “linker moiety” and “linker” can further refer to a bivalent chemical moiety that is covalently bonded to both ring A of the compounds of the disclosure and ring B of the compounds of the disclosure. The term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1–19. Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other. When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate” accompanies the structure or name, as explained in the following two paragraphs). “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture. When the stereochemical configuration at a chiral center in a compound is depicted by chemical name (e.g., where the configuration is indicated in the name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds) and the designation “rac” or “racemate” accompanies the structure or is designated in the chemical name, a racemic mixture is intended. When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two stereoisomers is intended, but not both. When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center. A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds disclosed herein. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods. “Peak 1” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation / purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2”. When a disclosed compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers. When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. In the compounds of the disclosure, any position specifically designated as “D” or “deuterium” is understood to have deuterium enrichment at 50, 80, 90, 95, 98 or 99%. “Deuterium enrichment” is a mole percent and is determined by dividing the number of compounds with deuterium at the indicated position by the total number of all of the compounds. When a position is designated as “H” or “hydrogen”, the position has hydrogen at its natural abundance. When a position is silent as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance. One specific alternative embodiment is directed to a compound of the disclosure having deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions not specifically designated as “D” or “deuterium”. As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl or heterocyclyl) are referred to as being either “substituted” or “optionally substituted”. When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and / or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety. Pharmaceutical Compositions In another aspect, provided herein is a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient and (a “pharmaceutical composition of the disclosure”). “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject. Non- limiting examples of pharmaceutically acceptable carriers / excipients include: (1) sugars, such as, e.g., lactose, glucose, and sucrose; (2) starches, such as, e.g., corn starch and potato starch; (3) cellulose and its derivatives, such as, e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, e.g., cocoa butter and suppository waxes; (9) oils, such as, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as, e.g., propylene glycol; (11) polyols, such as, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, e.g., ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as, e.g., magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) lactate buffer solutions; (21) cyclodextrins, such as, e.g., CAPTISOL®; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. Methods of Treatment In one aspect, the disclosure provides methods of modulating (e.g., degrading) CDK2 activity and therefore are useful for treating diseases for which CDK2 are dysregulated, such as cancer. In some embodiments, the method of modulating is a method of degrading CDK2 comprising contacting CDK2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of modulating is a method of degrading CDK2 in a subject in need thereof, comprising contacting CDK2 with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure. Compounds of the disclosure are CDK2 degraders. The use of the word “degrader” means that a compound, or a pharmaceutically acceptable salt thereof, degrades CDK2 protein. The terms “degrade”, “degrading”, or “degradation” mean the partial or full breakdown of CDK2 proteins, which reduces or eliminates the biological activity of CDK2, as compared to the amount of those proteins in the absence of the degrader (e.g., before administration of the degrader). In some alternatives, the term “degrade” means a decrease in the levels of CDK2 protein of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90% or at least 95% (e.g., before administration of the degrader or at two different timepoints during treatment with the degrader). In other alternatives, inhibit means a decrease in the levels of CDK2 of 5% to 25%, 25% to 50%, 50 to 70%, 75 to 100%. In some embodiments, degrade means a decrease in the levels of CDK2 of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro degradation assays. In another aspect, provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the treatment of cancers. In another aspect, provided herein is a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the prevention of cancers. As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease in an individual who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and / or symptomatology). As used herein the term “preventing” or “prevention” refers to preventing the disease in an individual who may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease. In some embodiments, the disclosure is directed to a method of preventing a disease in a patient, by administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” CDK2, or “contacting” a cell with a compound of the disclosure, includes the administration of a compound of the present disclosure to a subject or patient, such as a human, having CDK2, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing CDK2. As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal. Compounds of the disclosure, or pharmaceutically acceptable salts thereof, are CDK2 degraders with warheads that target CDK2 with high affinity and selectivity compared to traditional small-molecule inhibitors. As used herein, the term “CDK2 degrader” means a compound which selectively and catalytically degrades CDK2 over other CDKs and other proteins. Said another way, a CDK2 degrader shows no or low degradation of other CDKs and other proteins. A CDK2 degrader degrades CDK2 to a greater extent in terms of DC50value (i.e., the DC50 value is nanomolar) when compared with the degradation of other CDKs and other proteins. Degradation can be measured using known biochemical assays. The DC50value refers to the concentration at which 50% maximal degradation was observed. The ability to selectively target CDK2 with a compound of the disclosure provides advantages in terms of targeted degradation of CDK2, little to no off-target activity, and an increased probability of clinical success in comparison with traditional small-molecule inhibitors. A CDK2 degrader may show degradation that is at least 2-fold relative to another target protein (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200- fold. In some alternatives, a CDK2 degrader exhibits at least 15-fold selectivity over another CDK, e.g., CDK1, CDK4, and CDK6. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK1. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK1. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK4 and / or CDK6. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK4 and / or CDK6. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK4 and / or CDK6. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK4 and / or CDK6. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK4 and / or CDK6. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK4 and / or CDK6. For example, compounds show at least 100-fold selectivity for CDK2 versus CDK4 and / or CDK6. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK1. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK1. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK1. In some embodiments, the compounds of the disclosure are selective against CDK2 versus CDK6. In some embodiments, compounds show at least 10-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 20-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 30-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 40-fold selectivity for CDK2 versus CDK6. In some embodiments, compounds show at least 50-fold selectivity for CDK2 versus CDK6. Some compounds of the disclosure have the advantage of oral bioavailability. In some embodiments, a compound of the disclosure selectively degrades its target protein compared to other CDKs and other proteins. In some embodiments, a compound of the disclosure catalytically degrades its target protein, which may require a lower dose compared to traditional small molecule inhibitor. For example, many CDK4 / 6 inhibitors, including ribociclib, palbociclib, and abemaciclib, bind the adenosine triphosphate (ATP) cleft, which contains the catalytic residues, and compete with ATP to inhibit activity. In some embodiments, a compound of the disclosure is a bifunctional degrader with a warhead that binds to the target protein (e.g., CDK2) linked to an E3 ubiquitin ligase-binding moiety that recruit E3 ligases to ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The compounds of the disclosure can be used repeatedly to trigger this targeted protein degradation. In some embodiments, a compound of the disclosure may eliminate certain side effects, for example, drug-drug interactions and off-target effects, such as CDK6 mediated heme toxicity. In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to a patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure. In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers. In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the preparation of a medicament for the treatment of cancers. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as first line therapy. In other embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy. As used herein “cancer” refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. Cancer encompasses all forms of cancer including, but not limited to, all forms of solid tumors, carcinomas, melanomas, blastomas, sarcomas, lymphomas, and leukemias. Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one. In embodiments of the cancers and the methods provided herein, the cancer is a solid tumor cancer. In embodiments, the solid tumor cancer is a carcinoma or a sarcoma (e.g., CIC- DUX4 sarcoma). In embodiments, the solid tumor cancer is an adenocarcinoma, a carcinoma, or a cystadenocarcinoma. In some embodiments, the subject has an advanced and / or relapsed solid tumor. In some embodiments, cancers that are treatable using compounds of the disclosure, or pharmaceutically acceptable salts thereof, include, but are not limited to, bone cancers, breast cancers. gastrointestinal cancers, genitourinary tract cancers, gynecological cancers, head and neck cancers, hematological cancers, liver cancers, nervous system cancers, respiratory tract cancers, sarcomas, and skin cancers. Exemplary bone cancers include, but are not limited to, benign chondroma, chondroblastoma, chondromyxofibroma, chondrosarcoma, Ewing’s sarcoma, fibrosarcoma, giant cell tumors, malignant fibrous histiocytoma, malignant lymphoma (e.g., reticulum cell sarcoma), malignant giant cell tumor chordoma, multiple myeloma, osteochronfroma (e.g., osteocartilaginous exostoses), osteogenic sarcoma (e.g., osteosarcoma, e.g.,), and osteoid osteoma. Exemplary breast cancers include, but are not limited to, ductal carcinoma in situ, ER+ breast cancer (estrogen receptor positive breast cancer); ER+ / HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer); HR+ breast cancer (hormone receptor positive breast cancer); HR+ / HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer); HER2- breast cancer (human epidermal growth factor 2 negative breast cancer); HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer); HER2-low breast cancer (human epidermal growth factor 2 low breast cancer); invasive ductal carcinoma (IDC); invasive lobular carcinoma, lobular carcinoma in situ, PR+ / HER2- breast cancer (progesterone receptor positive, human epidermal growth factor 2 negative breast cancer); triple negative breast cancer (TNBC); and tubular breast carcinoma. Exemplary gastrointestinal cancers include, but are not limited to, cancers of the anus (e.g., anal cancer, e.g., anal neuroendocrine carcinoma), colon (e.g., colon adenocarcinoma (COAD)); colorectal cancer (e.g., hereditary non-polyposis colorectal cancer); esophagus (e.g., adenocarcinoma, leiomyosarcoma, lymphoma, and squamous cell carcinoma); familiar adenomatous polyposis carcinoma; gall bladder (e.g., adenocarcinoma and cholangiocarcinoma); intestinal type and diffuse type gastric adenocarcinoma (e.g., gastrointestinal stromal tumor); large bowel (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); large intestine (e.g., adenocarcinoma, hamartoma, leiomyoma, tubular adenoma, and villous adenoma,); pancreas (e.g., adenocarcinoma (PAAD), carcinoid tumors, ductal adenocarcinoma, glucagonoma, gastrinoma, insulinoma, islet cell cancer, and vipoma); small intestine (e.g., adenocarcinoma (PDAC), carcinoid tumors, fibroma, hemangioma, leiomyoma, lipoma, lymphoma, Kaposi’s sarcoma, and neurofibroma); stomach (or gastric cancer, e.g., adenocarcinoma, carcinoma, leiomyosarcoma, and lymphoma); and rectum carcinoma (e.g., rectum adenocarcinoma (READ)). Exemplary genitourinary tract cancers include, but are not limited to, cancers of the adrenal gland (e.g., adrenocortical carcinoma); bladder (e.g., adenocarcinoma, sarcoma, small cell carcinoma, squamous cell carcinoma, and transitional cell carcinoma); kidney (e.g., adenocarcinoma, renal cell carcinoma (RCC), urothelial carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, Bellinio duct carcinoma, clear-cell sarcoma of the kidney, and mesoblastic nephroma, renal oncocytoma, and Wilm’s tumor [nephroblastoma]); renal pelvis; pancreas; penis; prostate (e.g., adenocarcinoma (PRAD), androgen receptor positive (AR+) or AR-dependent prostate cancer, AR-independent prostate cancer, carcinoma, castration-resistant prostate cancer (CRPC), hormone refractory prostate adenocarcinoma, and sarcoma); testis (e.g., adenomatoid tumors, choriocarcinoma, embryonal carcinoma, fibroadenoma, fibroma, interstitial cell carcinoma, lipoma, sarcoma, seminoma, teratoma, and teratocarcinoma); ureteral cancer, and urethra (e.g., adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma). Exemplary gynecological cancers include, but are not limited to, cancers of the cervix (e.g., adenocarcinoma, adenosquamous carcinoma, cervical carcinoma, cervical squamous cell carcinoma (CESC), glassy cell carcinoma, neuroendocrine tumor, pre-tumor cervical dysplasia, small cell carcinoma, squamous cell carcinoma, and villoglandular adenocarcinoma); fallopian tubes (e.g., carcinoma); labia; ovaries (e.g., dysgerminoma, granulosa-thecal cell tumors, malignant teratoma, ovarian carcinoma (e.g., endometroid tumor, high-grade serous ovarian cancer (HGSOC), high-grade serous carcinoma (HGSC), mucinous cystadenocarcinoma, serous cystadenocarcinoma, and unclassified carcinoma), and Sertoli-Leydig cell tumors); uterus (e.g., carcinosarcoma, clear cell endometrial carcinoma, endometrial carcinoma, grade 3 endometriod endometrial cancer, serous endometrial cancer (SEC), uterine carcinosarcoma (UCS), and uterine corpus endometrial carcinoma (UCEC)); vagina (e.g., botryoid sarcoma (embryonal rhabdomyosarcoma), clear cell carcinoma, and squamous cell carcinoma); and vulva (e.g., adenocarcinoma, fibrosarcoma, intraepithelial carcinoma, melanoma, and squamous cell carcinoma). Exemplary head and neck cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, eye cancer (e.g., intraocular malignant melanoma, ocular melanoma, and retinoblastoma), glioblastoma, lymphosarcoma, melanoma, nasal and paranasal cancer, nasal cavity cancer, oral cancer or mouth cancer (e.g., lip cancer, salivary gland cancer, and tongue cancer), osteosarcoma, pituitary adenoma, rhabdosarcoma, sinus cancer, squamous cell carcinoma, throat cancer (e.g., hypopharngx, oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer), parathyroid cancer, and thyroid cancer (e.g., medullary and papillary). Exemplary hematological cancers include, but are not limited to, lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenic lymphoma, chronic myelogenous leukemia (CML), cutaneous T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), hairy cell lymphoma, Hodgkin lymphoma, mantle cell lymphoma, Non-Hodgkin lymphoma (e.g., follicular lymphoma, relapsed or refractory NHL, and recurrent follicular), multiple myeloma (MM), myelodysplasia syndrome (MDS), myelofibrosis (PMF), myeloproliferative diseases (e.g., primary polycythemia vera (PV), and essential thrombocytosis (ET)), T-cell acute lymphoblastic lymphoma (T-ALL), and Waldenstrom's Macroglubulinemia. Exemplary liver cancers include, but are not limited to, hepatoma e.g., angiosarcoma, cholangiocarcinoma (also referred to as bile duct cancer), hemangioma, hepatoblastoma, hepatocellular adenoma, and hepatocellular carcinoma (HCC). Exemplary nervous system cancers include, but are not limited to, cancers of the brain (e.g., astrocytoma, brain lower grade glioma (LGG), brain stem glioma,d congenital tumors, ependymoma, germinoma (pinealoma), glioma, glioblastoma, glioblastoma multiforme (GBM), medulloblastoma, and oligodendroglioma); central nervous system lymphoma; Lhermitte-Duclos disease; meninges (e.g., gliomatosis, meningioma, and meningiosarcoma); neuroblastoma; schwannoma; spinal cord (e.g., glioma, meningioma, neurofibroma, sarcoma, and spinal axis tumor); and skull (e.g., granuloma, hemangioma, osteitis deformans, osteoma, and xanthoma). Exemplary respiratory tract cancers include, but are not limited to, epidermoid carcinoma; lung cancer including, but not limited to, alveolar (bronchiolar) carcinoma; bronchial adenoma; bronchogenic carcinoma (e.g., adenocarcinoma, squamous cell, undifferentiated small cell, and undifferentiated large cell); chondromatous hamartoma; epidermal growth factor receptor mutant positive (EGFRm+) non-small cell lung cancer; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC); and pleuropulmonary blastoma; and mesothelioma. Exemplary sarcomas include, but are not limited to, angiosarcoma, chondrosarcoma, epithelioid sarcoma, Ewing’s sarcoma, fibroma, fibrosarcoma, harmatoma, Kaposi’s sarcoma, lipoma, liposarcoma, myxoma, osteosarcoma (e.g., chondroblastic osteosarcoma), rhabdomyoma, rhabdomyosarcoma, and teratoma. Exemplary skin cancers include, but are not limited to, angioma, basal cell carcinoma, BRAF and HSP90 inhibition-resistant melanoma, cutaneous melanoma, dermatofibroma, lipoma, Kaposi’s sarcoma, keloids, melanoma, Merkel cell carcinoma, metastatic malignant melanoma, moles dysplastic nevi, sebaceous gland carcinoma, and squamous cell carcinoma. In embodiments of the methods provided herein, the cancer is anal cancer, bladder cancer, brain cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer, urothelial cancer, or uterine cancer. In embodiments of the methods provided herein, the cancer is anal cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, liver cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, or uterine cancer. In some embodiments of the cancers and methods disclosed herein, the cancer is characterized by an elevation or an amplification of the cyclin E1 (CCNE1) gene and / or cyclin E2 (CCNE2) gene (e.g., based on copy number) and / or a level of CCNE1 and / or CCNE2 higher than a control level of CCNE1 (referred to herein as a “change in the levels of CCNE1 and / or CCNE2”). In some embodiments of the cancers and methods disclosed herein, the cancer is characterized by high microsatellite instability (MSIhigh). In some embodiments of the cancers and methods disclosed herein, the cancer is characterized by Genomic Identification of Significant Targets in Cancer (GISTIC). In some embodiments, the cancer is pheochromocytoma and paraganglioma (PCPG). In some embodiments, the cancer is a refractory cancer, which is also referred to as a treatment-resistant cancer. In some embodiments, the cancer is platinum-resistant and / or platinum-refractory. In some embodiments, the cancer has progressed despite treatment with a platinum agent. In some embodiments of the cancers and methods disclosed herein, the cancer is breast cancer (BC). In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is HR+ / HER2- BC. In some embodiments, the breast cancer is ER+ / HER2- BC. In some embodiments, the breast cancer is PR+ / HER2- BC. In some embodiments, the breast cancer is TNBC. In some embodiments, the breast cancer is refractory. In some embodiments, the breast cancer is chemotherapy resistant breast cancer, endocrine resistant breast cancer, radiotherapy resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is responsive to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer has progressed despite treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer has progressed despite a first treatment with palbociclib, ribociclib, and / or fulvestrant and a second treatment with abemaciclib and / or fulvestrant. In some embodiments of the methods disclosed herein, the method further comprises administering to the patient a therapeutically acceptable amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the cancer is (a) ovarian cancer; (b) characterized by a change in the levels of CCNE1 and / or CCNE2; or (c) both (a) and (b). In some embodiments, the ovarian cancer is selected from dysgerminoma, a granulosa-thecal cell tumor, malignant teratoma, endometroid tumor, HGSOC, HGSC, mucinous cystadenocarcinoma, serous cystadenocarcinoma, and unclassified carcinoma. In some embodiments, the ovarian cancer is HGSOC. In some embodiments, the cancer is (a) endometrial cancer; (b) characterized by a change in the levels of CCNE1 and / or CCNE2; or (c) both (a) and (b). In some embodiments, the endometrial cancer is selected from carcinosarcoma, clear cell endometrial carcinoma, endometrial carcinoma, grade 3 endometriod endometrial cancer, and SEC. In some embodiments, the endometrial cancer is SEC. In some embodiments, the cancer is (a) lung cancer; (b) characterized by a change in the levels of CCNE1 and / or CCNE2; or (c) both (a) and (b). In some embodiments, the lung cancer is NSCLC. In some embodiments, the lung cancer is SCLC. In some embodiments, cancers treatable with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, include advanced / relapsed tumors; platinum- resistant or platinum-refractory ovarian cancer; endometrial cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; gastric cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; and HR+ / HER2- BC (including both ER+ / HER2- BC and PR+ / HER2- BC) that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In some embodiments, cancers treatable with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, include platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer; CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies; CCNE1 amplified advanced / relapsed tumors that do not belong to the other groups; HR+ / HER2- BC that has progressed despite CDK4 / 6i; and platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer. In one embodiment, the subject has CCNE1 amplified advanced / relapsed tumors. In one embodiment, the subject has CCNE1 amplified platinum-resistant or platinum-refractory ovarian cancer. In one embodiment, the subject has endometrial cancer (with prior platinum therapy, e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy). In one embodiment, the subject has CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies (which may include a prior platinum therapy). In one embodiment, the subject has gastric cancer (with prior platinum therapy e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy). In one embodiment, the subject has HR+ / HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In one embodiment, the subject has TNBC that has progressed despite one or more lines of therapies. In one embodiment, the subject has AR+ prostate cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has pancreatic cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has PDAC that has progressed despite one or more lines of therapies. In one embodiment, the subject has CCNE1 elevated lung cancer. In one embodiment, the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). In one embodiment, the subject has CCNE1 elevated NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). Combination Therapies Compounds of the disclosure or pharmaceutically acceptable salts thereof can be administered as the sole pharmaceutical agent or in combination with one or more other anti- cancer agents for the treatment of cancer, where the combination causes no unacceptable adverse effects. In some embodiments, the other anti-cancer agents are standard of care agents appropriate for the particular cancer. The term “additional anticancer therapeutic agent” as used herein means any one or more therapeutic agent, other than a compound described herein (e.g., Formulae (I), (Ia), (II), (III), or subformulas thereof), or a pharmaceutically acceptable salt thereof, that is or can be used in the treatment of cancer. In some embodiments, the additional anticancer agent is a protein kinase B (PKB) or AKT inhibitor including, but not limited to, afuresertib, capivasertib, ipatasertib, miransertib, and temsirolimus. In some embodiments, the AKT inhibitor is capivasertib. In some embodiments, the additional anticancer agent is an agent that inhibits the androgen receptor (AR) signaling pathway including, but not limited to, abiraterone, bicalutamide, enzalutamide, flutamide, ketoconazole, and niltamide. In some embodiments, the agent that inhibits the androgen receptor signaling pathway is enzalutamide. In some embodiments, the additional anticancer agent is an antibody including, but not limited to, atezolizumab, bevacizumab, margetuximab (e.g., margetuximab-cmkb), pembrolizumab, pertuzumab, ramucirumab, sacituzumab, and trastuzumab. In some embodiments, the antibody is trastuzumab. In some embodiments, the additional anticancer agent is an antibody-drug conjugate (ADC) including, but not limited to, anetumab ravtasine, belantamab mafodotin, brentuximab vedotin, datopotamab deruxtecan, disitamab vedotin, farletuzumab ecteribulin, gemtuzumab ozogamicin, inotuzumab ozogamicin, ladiratuzumab vedotin, enfortumab vedotin, loncastuximab tesirine, luveltamab tazevibulin, moxetumomab pasudotox, mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx), patritumab deruxtecan, polatuzumab vedotin, praluzatamab ravtansine, raludotatug deruxtecan, sacituzumab govitecan (e.g., sacituzumab govitecan-hziy), tisotumab vedotin (e.g., tisotumab vedotin-tftv), trastuzumab deruxtecan (e.g., fam-trastuzumab deruxtecan-nxki), trastuzumab duocarmazine, trastuzumab emtansine (e.g., ado-trastuzumab emtansine), tusamitamab ravtasine, upifitamab rilsodotin, and XMT-2056. In some embodiments, the ADC is sacituzumab govitecan, trastuzumab deruxtecan, or trastuzumab emtansine. In some embodiments, the ADC is trastuzumab deruxtecan. In some embodiments, the additional anticancer agent is a CDK4 / 6 inhibitor including, but not limited to, abemacicilb, BPI-16350, CS3002, dalpiciclib, ETH-155008, FCN-437c, HS-10342, lerociclib, palbociclib, P276-00, PF-07224826, PRT3645, ribociclib, SHR6390, SPH4336, trilaciclib, TQB3616, and XZP-3287. In some embodiments, the CDK4 / 6 inhibitor is abemacicilb, lerociclib, palbociclib, or ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is lerociclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the additional anticancer agent is a chemotherapeutic agent including, but not limited to, cyclophosphamide, doxorubicin, epirubicin, eribulin, ixabepilone, liposomal doxorubicin, methotrexate, platinum agents (e.g., carboplatin, cisplatin, and oxaliplatin), pyrimidine antagonists (e.g., 5-fluorouracil (5-FU), capecitabine, cytarabine, and gemcitabine), taxanes (e.g., cabazitaxel, docetaxel, and paclitaxel), sabizabulin, thiotepa, vinblastine, and vinorelbine. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor (e.g., anastrozole, exemestane, fadrozole, formestane, and letrozole), a luteinizing hormone-releasing hormone (LHRH) receptor agonist (e.g., leuprolide, and leuprorelin), a Selective Estrogen-Receptor Downregulator (SERD) (e.g., amcenestrant, camizestrant, elacestrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, taragarestrant, and ZB716), or a Selective Estrogen Receptor Modulator (SERM) (e.g., afimoxifene, arzoxifene, bazedoxifene, clomiphene, fispemifene, lasofoxifene, raloxifene, ormeloxifene, ospemifene, tamoxifen, tesmilifene, toremifene, and trilostane). In some embodiments, the endocrine agent is anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, toremifene, or a combination thereof. In some embodiments, the additional anticancer agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In some embodiments, the additional anticancer agent is a SERD. In some embodiments, the SERD is elacestrant or fulvestrant. In some embodiments, the SERD is elacestrant. In some embodiments, the SERD is fulvestrant. In some embodiments, the S In some embodiments, the additional anticancer agent is an epidermal growth factor receptor (EGFR) inhibitor including, but not limited to, afatinib, dacomitinib, erlotinib, gefitinib, neratinib, osimertinib, poziotinib, pyrotinib, regorafenib, or vandetanib, or an EGFR antibody such as cetuximab, panitumumab, or necitumumab. In some embodiments, the EGFR inhibitor is neratinib or osimertinib. In some embodiments, the EGFR inhibitor is neratinib. In some embodiments, the EGFR inhibitor is osimertinib. In some embodiments, the additional anticancer agent is a human epidermal growth factor receptor 2 (HER2) inhibitor including, but not limited to, lapatinib, neratinib, pyrotinib, and tucatinib. In some embodiments, the HER2 inhibitor is lapatinib. In some embodiments, the HER2 inhibitor is neratinib. In some embodiments, the HER2 inhibitor is tucatinib. In some embodiments, the additional anticancer agent is a hormone therapy including, but not limited to, goserelin, and megestrol. In some embodiments, the additional anticancer agent is goserelin. In some embodiments, the additional anticancer agent is megestrol. In some embodiments, the additional anticancer agent is a polyadenosine 5’- diphosphoribose polymerase (PARP) inhibitor including, but not limited to, fluzoparib, niraparib, olaparib, rucaparib, and talazoparib. In some embodiments, the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is talazoparib. In some embodiments, the additional anticancer agent is a phosphatidylinositol-4,5- bisphosphate 3-kinase (PI3K) inhibitor including, but not limited to, alpelisib, BPI-21668, buparlisib, copanlisib, CYH33, duvelisib, gedatolisib, GSK2636771, HS-10352, idelalisib, inavolisib, LOXO-783, MEN-1611, RLY-2608, temsirolimus, taselisib, TQB-3525, and umbralisib. In some embodiments, the PI3K inhibitor is alpelisib, copanlisib, duvelisib, idelalisib, or umbralisib. In some embodiments, the PI3K inhibitor is alpelisib. In some embodiments, the additional anticancer agent is a vascular endothelial growth factor receptor (VEGFR) inhibitor including, but not limited to, anlotinib, apatinib, axitinib, famitinib, lenvatinib, pazopanib, and sunitinib. In some embodiments, the VEGFR inhibitor is apatinib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an AKT inhibitor or a PI3K inhibitor, an endocrine agent, and, optionally, a CDK4 / 6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with alpelisib or capivasertib, fulvestrant, and, optionally, abemacicilb, palbociclib, or ribociclib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an antibody, e.g., trastuzumab. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an antibody and, optionally, a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with bevacizumab, pertuzumab, or trastuzumab and, optionally, capecitabine, carboplatin, docetaxel, doxorubicin, paclitaxel, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with one or more chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with a pyrimidine antagonist and / or gemcitabine, and / or a platinum agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with 5-FU. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with gemcitabine. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with carboplatin, cisplatin, or oxaliplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with carboplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with cisplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more of a pyrimidine antagonist, gemcitabine, a CDK4 / 6 inhibitor, and a platinum agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with 5-FU, gembcitabine, ribociclib, and, optionally, cisplatin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and / or a CDK4 / CDK6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, e.g., an aromatase inhibitor, a SERM or a SERD. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with a CDK4 / CDK6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an endocrine agent and, optionally, a CDK4 / 6 inhibitor. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, or toremifene, and, optionally, abemacicilb, palbociclib, or ribociclib, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with anastrozole, exemestane, or letrozole and abemacicilb, palbociclib, or ribociclib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with letrozole. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant and ribociclib. In some embodiments, the combination further comprises a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with fulvestrant, ribociclib, carboplatin, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy following treatment with an EGFR inhibitor, e.g., osimertinib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with an EGFR inhibitor and, optionally, a chemotherapeutic agent. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with neratinib or osimertinib and, optionally, capecitabine, gemcitabine, paclitaxel, or a combination thereof. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with osimertinib. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with a HER2 inhibitor, a chemotherapeutic agent, and, optionally, an antibody. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with neratinib or tucatinib, capecitabine, and, optionally, trastuzumab. Methods of Administration and Dosage Forms The term “effective amount” or “therapeutically effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, an effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day. The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general the route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003). A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, PA. The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly, etc.) doses over a period of a few days to months, or even years. A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In some embodiments, the patient is an adult human. Biomarkers and Pharmacodynamics Markers The disclosure further provides predictive markers including, but not limited to, biomarkers and pharmacodynamic markers, which can be monitored based on levels including, but not limited to, DNA (e.g., cDNA); RNA (e.g., messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA)); gene copy number; gene expression; gene sequence; protein expression (e.g., protein overexpression); expression levels, enzyme activity, phosphorylation levels, or mutations, to identify those human subjects having, suspected of having, or at risk of developing a cancer for whom administering a CDK2 degrader is likely to be effective. In some embodiments, the biomarker is selected from cancer antigen 125 (CA-125); carcinoembryonic antigen (CEA); checkpoint kinase 1 (CHK1); cyclin A1 (CCNA1); cyclin A2 (CCNA2); cyclin D1 (CCND1); cyclin D2 (CCND2); cyclin D3 (CCND3); cyclin E1 (CCNE1); cyclin E2 (CCNE2); cyclin-dependent kinase 1 (CDK1); CDK2; cyclin-dependent kinase 3 (CDK3); CDK4; cyclin-dependent kinase 5 (CDK5); CDK6; cyclin-dependent kinase 18 (CDK18); cyclin-dependent kinase inhibitor 1A (CDKN1A); cyclin-dependent kinase inhibitor 1B (CDKN1B); cyclin-dependent kinase inhibitor 2A (CDKN2A, also referred to as “p16” and “p16-INK4a”); E2F transcription factor 1 (E2F1); E2F transcription factor 2 (E2F2); E2F transcription factor 3 (E2F3); EGFR; enhancer of zeste 2 polycomb repressive complex 2 (EZH2); ER; F-box and WD repeat domain containing 7 (FBXW7); Harvey rat sarcoma virus proto-oncogene, GTPase (HRAS); Kirsten rat sarcoma virus oncogene homolog (KRAS); marker of proliferation Ki-67 (MKI67 or Ki-67); myelocytomatosis (MYC) proto-oncogene; v-myc avian myelocytomatosis viral oncogene lung carcinoma derived (MYCL); v-myc avian myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN); neuroblastoma rat sarcoma virus oncogene homolog (NRAS); HER2; human epidermal growth factor receptor-3 (HER3); prostate-specific antigen (PSA); retinoblastoma transcriptional corepressor 1 (RB1); retinoblastoma transcriptional corepressor like 1 (RBL1); retinoblastoma transcriptional corepressor like 2 (RBL2); thymidine kinase 1 (TK1), and the corresponding proteins encoded by these genes. In some embodiments, the biomarker is selected from CA-125, CCNE1, CCNE2, CEA, KRAS, Ki-67 (or MKI67), p16 (or CDKN2A), RB, PSA, TK1, and the corresponding proteins encoded by these genes. In some embodiments, the levels of a biomarker are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, a biomarker is absent. In some embodiments, the modulation results in the loss of expression of the corresponding protein, a decrease in gene copy numbers, a decrease in phosphorylated protein, or a decrease in protein activity. In some embodiments, the biomarker has a mutation (e.g., a loss of function mutation). In some embodiments, a biomarker or a biomarker mutant is functional. In some embodiments, a change in the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is indicative / predictive that a subject having or at risk of developing a cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced. In some embodiments, the levels of the biomarker at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced. In another aspect, provided herein is a method of treating cancer in a patient in need thereof comprising: i. testing, or having tested, a first biological sample obtained from the patient with cancer, thereby measuring levels of one or more biomarkers in the patient’s cancer; ii. comparing the levels of the one or more biomarkers in step i. to levels of one or more biomarkers measured in a patient with a normally functioning pathway; iii. in response to determining that the patient’s cancer will be sensitive to a compound of the disclosure, or a pharmaceutically acceptable salt thereof, treating the subject with a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of monitoring a response in a patient having or at risk of developing cancer comprising: i. administering to the patient in need thereof a therapeutically effective amount a compound of the disclosure, or a pharmaceutically acceptable salt thereof; ii. testing, or having tested, a first biological sample obtained from the patient, thereby measuring levels of one or more biomarkers in the biological sample; iii. comparing the levels of the one or more biomarkers in step ii. to levels of one or more biomarkers measured in a patient with a normally functioning pathway; and iv. determining whether the patient having or at risk of developing cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, if the comparison in step iii shows a change in the levels of one or more biomarkers. In some embodiments, additional biological samples are obtained from the subject and compared to the levels of the biomarkers measured in a patient with a normally functioning pathway (a “control level”) to continue monitoring. In some embodiments, additional biological samples are obtained from the patient and compared to the levels of the biomarkers measured in the first biological sample to continue monitoring. In some embodiments, the biomarker is CA-125. CA-125 is a large transmembrane glycoprotein encoded by the MUC16 gene. In some embodiments, the cancer is ovarian cancer characterized by overexpression of CA-125. In some embodiments, the biomarker is CCNE1 or CCNE2. CCNE1 is encoded by the cyclin E1 (“CCNE1”) gene (GenBank Accession No. NM_001238). CCNE1 acts as a regulatory subunit of CDK2, and CCNE1 is a cell cycle factor essential for the control of the cell cycle at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol.15:2612-2624). In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, wherein the patient has an amplification of the CCNE1 gene (e.g., based on copy number) and / or has a higher level of CCNE1 than a control level of CCNE1. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the level of CCNE1 in a patient is higher before administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, than after said administration. In some embodiments, the expression level of CCNE1 may be the level of CCNE1 mRNA. In other embodiments, the expression level of CCNE1 may be the level of CCNE1 protein. In other embodiments, the expression level of CCNE1 may be an indirect measure of the level of CCNE1 mRNA or protein. In some embodiments, the biomarker is CEA. CEA is a heavily glycosylated protein encoded by carcinoembryonic antigen cell adhesion molecule 5 (CEACAM5). In some embodiments, the cancer is selected from breast cancer, colorectal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, and prostate cancer, In some embodiments, the biomarker is KRAS. In some embodiments, the cancer is colon cancer, lung cancer, or pancreatic cancer. In some embodiments, the cancer is colon cancer, lung cancer, or pancreatic cancer characterized by a higher level of KRAS than a control level of KRAS. In some embodiments, the biomarker is the marker of proliferation Ki-67. In some embodiments, the cancer characterized by a higher level of Ki-67 than a control level of Ki- 67. In some embodiments, the biomarker is p16. The gene CDKN2A encodes p16, which acts as a negative regulator of the proliferation of normal cells by interacting with CDK4 and CDK6. In some embodiments, the biomarker is RB1. Retinoblastoma protein (Rb or RB) is a tumor suppressor protein encoded by the gene RB transcriptional corepressor 1 (RB1). In some embodiments, the RB1 gene has a mutation (e.g., a loss of function mutation). Rb is activated upon phosphorylation by cyclin D-CDK4 / 6 at Ser780 and Ser795 and / or at Ser807 and / or Ser811 and by cyclin E / CDK2 at Ser807 and Ser811 and Thr821. In some embodiments, the contemplated biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation at the serine corresponding to amino acid position 780 (Ser780 or S780) and / or the serine corresponding to amino acid position 795 (Ser795 or S795). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the serine corresponding to amino acid position 807 (Ser807 or S807) and / or the serine corresponding to amino acid position 811 (Ser811 or S811). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 821 (Thr821 or T821). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 826 (Thr826 or T826). In some embodiments, the levels of phosphorylated Rb are reduced compared to a control level of phosphorylated Rb. In some embodiments, the biomarker is PSA. In some embodiments, the cancer is prostate cancer characterized by higher levels of PSA than a control level of PSA. In some embodiments, the biomarker is TK1. TK1 is a direct downstream target of Rb-E2F pathway. It is involved in cellular proliferation through the recovery of the nucleotide thymidine in the DNA salvage pathway. TK1 is important for DNA repair following DNA damage because TK1 is necessary for the formation of nucleotides outside of the S phase. In some embodiments, a TK1 mutant has a resistance mutation. In some embodiments, TK1 is differentially methylated. In some embodiments, TK1 is serum TK1. In some embodiments, the levels of TK1 enzyme activity are reduced compared to a control level of TK1 enzyme activity. Synthesis Compounds of the disclosure, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing compounds of the disclosure can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. Preparation of compounds of the disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1H or13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. Scheme 1 Hal is a halogen, typically I, Br, Cl or F The compound (X) may be alkylated by halide (XI) in the presence of an organic or inorganic base, such as DIPEA, TEA, Na2CO3or K2CO3in DMF, DCM, MeCN, DMSO or NMP, optionally in the presence of a catalyst such as KI, to give the compound (II). Alternatively, this alkylation reaction may occur under mild acid catalysis such as p-TsOH in a solvent such as IPA at elevated temperature. Alternatively, compound (II) may be obtained from halide (XI) and amine (X) by a palladium catalysed coupling reaction, such as a Buchwald-Hartwig type reaction, using a suitable palladium catalyst in the presence of phosphine ligands, in the presence of a suitable inorganic base, in a solvent at elevated temperature and optionally under microwave irradiation. Scheme 2 The compound (II) may be obtained by reaction of the amine (XIII) and halide (XII) by a palladium catalysed coupling reaction, such as a Buchwald-Hartwig type reaction, as previously described in Scheme 1.

[0010] Scheme 3 In Scheme 3, ring A is linked to L through a N atom. L” is -L1-X1-L2-(L3)p-(X3)q-L4-, or -X1-L2-(L3)p-(X3)q-L4-, or -L2-(L3)p-(X3)q-L4-, or -(L3)p- (X3)q-L4-, or -(X3)q-L4-, or -L4-, its analogues or pre-cursors. L” is a pre-cursor of L, such that reaction between compounds (XIV) and (XV) forms L, wherein L is connected to ring A through an amide bond, L’’ contains a terminal carboxylic acid. The carboxylic acid (XV) may be coupled with amine (XIV) using an amide coupling agent, such as PyBop or HATU, in the presence of an organic base, typically DIPEA, to give compound (II). Scheme 4 L’ is -L1-X1-L2-(L3)p-(X3)q-L4-, or -L1-X1-L2-(L3)p-(X3)q-, or -L1-X1-L2-(L3)p-, or - L1-X1-L2-, or -L1-X1-, or -L1-, its analogues or pre-cursors. In Scheme 4, L’ is a pre-cursor of L, such that reaction between (X) and (XI) forms L. In Scheme 4, wherein L’ is attached to ring B through a N atom, compound (II) may be obtained from halide (XVII) and amine (XVI) by a Buchwald type palladium catalysed coupling reaction as previously described in Scheme 1. Alternatively, compound (II) may be obtained by an alklyation reaction of amine (XVI) with halide (XVII) as previously described in Scheme 1. In Scheme 4, wherein L’ is attached to ring B through a *C2-C6alkynylene-(O)(s)- group, compound (II) may be obtained from the alkyne (XVI) and halide (XVII) by a Sonagashira type palladium and copper catalysed cross coupling reaction. Scheme 5 In Scheme 5, Y1is NH and W is CH. Compound (II) may be obtained from the amine (XVIII) and halide (XIX) by an alkylation reaction as previously described in Scheme 1. In scheme 6, L'and L’’react to form L. In Scheme 6, L’and L’’form L through a CH2-N bond. Compound (II) may be obtained by a reductive amination reaction between the aldehyde (XVI) and amine (XV), or amine (XVI) and aldehyde (XV) in the presence of a suitable reducing agent such as STAB or MP-cycanoborohydride. Alternatively, compound (II) may be obtained by an alkylation reaction between compound (XVI) that contains a suitable leaving group, such as a Br, Cl, I, F, mesylate or tosylate and amine (XV), or amine (XVI) and compound (XV) that contains a suitable leaving group, such as Br, Cl, I, F mesylate or tosylate, in the presence of a suitable organic or inorganic base, as previously described in Scheme 1. L’and L’’form L through an -SO2-N- bond. Compound (II) may be obtained by an alkylation reaction between sulfonyl chloride (XVI) and amine (XV) in the presence of a suitable organic or inorganic base, optionally at elevated temperature. L’and L’’form L through an -CO2-NH- bond. Compound (II) may be obtained by an amide bond forming reaction between amine (XVI) and carboxylic acid (XV), or carboxylic acid (XVI) and amine (XVI), as previously described in Scheme 3. L’and L’’form L by formation of a 5 to 12-membered arylheterocycle. Compound (II) may be obtained by a cycloaddition reaction between compounds (XV) and (XVI). For example, wherein the aylheterocycle is a 1,2,3-triazole, compound (II) may be obtained by reaction of azide (XVI) and acetylene (XV), or acetylene (XVI) and azide (XV) by a copper catalysed cycloaddition reaction. Compounds (XVI) may be converted to alternative compounds (XVI) by reaction with -X1-L2-(L3)p-(X3)q-L4-, or -L2-(L3)p-(X3)q-L4-, or -(L3)p-(X3)q-L4-, or -(X3)q-L4-, or - L4-, its analogues or pre-cursors, so that L’and L’’form L following the reactions described in Scheme 6. Compounds (XV) may be converted to alternative compounds (XV) by reaction with - its a nalogues or pre-cursors, so that L and L form L following the reactions described in Scheme 6. Scheme 7 In scheme 7, R6is H Compound (XXI) may be obtained from the nitro compound (XX) by a reduction reaction under catalytic hydrogenation conditions, typically Pd / C in H2, or by reaction with a reducing metal, such as Fe or Zn in the presence of a suitable acid in a solvent such as EtOH. Compound (XVI) may be obtained from the amine (XXI) and halide (XI) by an alkylation reaction or reaction under Buchwald-Hartwig coupling conditions, as previously described in Scheme 1. Scheme 8 Compound (XXIV) may be obtained by reaction of the halide (XXII) and boronate ester (XXIII) under Suzuki-type palladium catalysed cross coupling reaction conditions. Compound (XV) may be obtained from compound (XXIV) by a reduction reaction under catalytic hydrogenations conditions, as previously described in Scheme 7. Compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), and (XV) are commercially available or may be prepared by the methods described in the Intermediates and Examples below. Compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), and (XV) may undergo further reaction to provide alternative compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), and (XV) by chemical transformations known to those skilled in the art. These transformations include, but are not limited to, reduction of a C1-C4carboxylic ester to provide an alcohol, oxidation of a primary alcohol to provide an aldehyde, hydrolysis of a C1-C4 carboxylic ester to provide a carboxylic acid, hydrolysis of an acetal to provide an aldehyde, alkylation of a primary or secondary N or O atom to provide a secondary or tertiary amine or ether, and conversion of an alcohol to an azide via a leaving group, such as a tosylate, by reaction with NaN3. It will be appreciated by those skilled in the art that it may be necessary to utilise a suitable protecting group strategy for the preparation of compounds of Formula (II). Typical protecting groups may comprise, a carbamate, preferably a Boc or CBz group for the protection of primary or secondary aliphatic amines, tert-butyl for the protection of carboxylic acids and tosylate for the protection of primary aliphatic alcohols. It will be appreciated that it may be necessary and / or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention. Compounds that contain one or more stereocenters may be separated into their separate stereoisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Intermediates and Examples below. EXAMPLES The following examples are intended to be illustrative and are not intended to be limiting in any way to the scope of the disclosure. Abbreviations ACN acetonitrile AcOH acetic acid aq. aqueous ATP adenosine-5’-triphosphate BEH ethylene bridged hybrid particle BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene Boc tert-butoxy carbonyl br broad BrettPhos Pd G3 [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′- biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonate BrettPhos Pd G4 bs broad singlet BSA bovine serum albumin °C degrees Celsius d doublet DCE dichloroethane DCM dichloromethane dd doublet of doublets DIBAL-H diisobutylaluminium hydride DIPEA N-ethyldiisopropylamine or N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide dq doublet of quartets DTT dithiothreitol EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N’,N’-tetraacetic acid Et3N or TEA triethylamine Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol equiv. equivalent(s) FBS fetal bovine serum g gram(s) GST glutathione S-transferase h hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Hex hexane1H-NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography HTRF homogeneous time resolved fluorescence IPA isopropanol LAH lithium aluminium hydride LCMS liquid chromatography mass spectrometry µL microliter(s) µm micrometer(s) µmol micromole(s) m multiplet M molar mAb monoclonal antibody MeCN acetonitrile MeOH methanol mg milligram(s) MHz megahertz min minute(s) mL milliliter(s) mM millimolar mmol millimole(s) MTBE methyl tert-butyl ether m / z mass to charge ratio nL nanoliter(s) nm nanometer(s) NMP N-methyl pyrrolidine PBS phosphate buffered saline Pd / C palladium on charcoal Pd2(dba)3  tris(dibenzylideneacetone)dipalladium (0) Pd(dppf)Cl2 [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(OAc)2 palladium acetate Pd(PPh3)2Cl2palladium(II)bis(triphenylphosphine) dichloride PE petroleum ether prep-TLC preparative thin layer chromatography psi pounds per square inch PTSA p-toluenesulfonic acid PyBOP benzotriazol-1-yloxytripyrrolindinophosphonium hexafluorophosphate q quartet RPMI Roswell Park Memorial Institute rt room temperature s singlet sat. saturated SFC supercritical fluid chromatography STAB sodium triacetoxyborohydride t triplettBuOH tert butanol t-BuOK potassium tert-butoxide TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TsOH p-toluenesulfonic acid U unit(s) UPLC ultra performance liquid chromatography Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl HPLC Codes. Organic gradient 0-100%, optimised for each sample. HPLC-A (X-BRIDGE-C18 (150 x 19 mm), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-B (X-SELECT-C18 (250 x 19 mm), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-C (X-BRIDGE-C18 (250 x 19 mm), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-D (SUNFIRE-C18 (250 x 10 mm), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-E (KROMOSIL-C18 (150 x 25 mm), 10 ^m 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-F 9YMC TRIART (50 x 2.1 mm) 1.7 ^m; 0-100% MeCN (0.05% TFA) / H2O (0.05% TFA)); HPLC-H (KROMOSIL-C18 (150 x 25 mm), 10 ^m; 0-100% MeCN / H2O (10 mM NH4HCO3)); HPLC-I (SUNFIRE-C18 (150 x 19 mm), 5 ^m 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-J (X-BRIDGE-C18 (250 x 10 mm), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-K (X-BRIDGE C18 (150 x 4.6 mm), 3.5 µm 0-100% MeCN / H2O (10 mM NH4OAc)); HPLC-L (INERTSIL ODS-3 (250 x 20 mm), 5 ^m; 0-100% MeOH / H2O (0.1% TFA)); HPLC-M (X-BRIDGE C18 (150 x 30 mm), 5 ^m 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-N (Atlantis-T3 (250 x 19 mm) 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-O (YMC Diol (250 x 10 mm), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-P (X-BRIDGE Prep C18 (150 x 30 mm), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-Q (Acquity UPLC BEH C18 (100 x 2.1 mm) 1.7 ^m) 0-100% MeCN / H2O (0.05% HCO2H)); HPLC-R (Atlantis-T3- (250 x 21.2), 5 ^m; 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-S (YMC HYDROSPARE C18 (150 x 25 mm) 10 µm 0-100% MeCN / H2O (0.1% HCO2H)); HPLC-T (GEMINI NX C18 (250 x 21 mm) 7 ^m, 0-100% MeCN / H2O (0.1 % HCO2H)). Intermediate 1. Synthesis of 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol- 1-yl)-2-methylpropan-2-ol To a stirred solution of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)propan-2-ol (5.0 g, 18.79 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (8.99 g, 41.33 mmol) in dioxane (45 mL ) was added solution of sodium carbonate (5.97 g, 56.36 mmol) in water (25 mL) at rt. The reaction mixture was purged with N2 for 15 min and Pd(dppf)Cl2.DCM (860 mg, 0.939 mmol) added at rt and the resulting reaction mixture stirred under N2at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-30% EtOAc / Hex) to afford the title compound as a brown solid (1.50 g, 25%). LCMS m / z = 321 [M+H]+. Intermediate 2. 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carbonitrile A mixture of 2,4-dichloropyrimidine-5-carbonitrile (1 g, 5.74 mmol), 1-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.20 g, 5.74 mmol), Pd(dppf)Cl2 (168 mg, 230 µmol), K2CO3(1.18 g, 8.61 mmol) in dioxane (30 mL) and water (6 mL) was stirred at 50℃ for 3 h. The reaction mixture was evaporated to dryness and the residue purified by silica gel chromatography (1% MeOH / DCM) to afford the title compound as a yellow solid (450 mg, 36%). LCMS m / z = 220 [M+H]+. Intermediate 3. 2,5-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine A mixture of 2,4,5-trichloropyrimidine (1 g, 5.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.69 g, 8.17 mmol), Pd(dppf)Cl2(100 mg, 122 µmol), Cs2CO3 (3.55 g, 10.9 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 50℃ for 2 h. The reaction mixture was evaporated to dryness and the residue purified by silica gel chromatography to afford the title compound as an off-white solid (450 mg, 36%). LCMS m / z = 229 [M+H]+. Intermediate 4. 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde Step 1. Synthesis of ethyl 1-((4-((tert-butoxycarbonyl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carboxylate To a stirred solution of ethyl piperidine-4-carboxylate (4.0 g, 25.44 mmol) and tert-butyl piperidin-4-ylcarbamate (5.09 g, 25.44 mmol) in DCM (125 mL) and THF (125 mL) were added triethylamine (14.30 mL, 101.7 mmol) followed by sulfuryl chloride (2.05 mL, 25.44 mmol) in dropwise manner over 30 min at 0 °C and the resulting mixture stirred for 2h at same temperature. The reaction was quenched with water (300 mL) and extracted with DCM (2x 150 mL). The combined organics was washed with brine solution (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 30-40% EtOAc / PE) to afford the title compound as a white solid (4.9 g, 46%). LCMS m / z = 420 [M+H]+. Step 2. Synthesis of ethyl 1-((4-aminopiperidin-1-yl)sulfonyl)piperidine-4-carboxylate hydrochloride To a stirred solution of ethyl 1-((4-((tert-butoxycarbonyl)amino)piperidin-1- yl)sulfonyl)piperidine-4-carboxylate (Step 1, 2.0 g 4.77 mmol) in DCM (20 mL) was added dropwise over 5 min 4.0 M HCl in dioxane (15 mL) at 0 °C. The reaction mixture was allowed to stir at rt for 2 h and concentrated and co-distilled with DCM (2x 50mL) under reduced pressure to obtain the title compound as a white solid (2.0 g) which was used without purification. LCMS m / z = 320 [M+H]+. Step 3. Synthesis of ethyl 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate A 48 mL sealed tube was charged with ethyl 1-((4-aminopiperidin-1-yl)sulfonyl)piperidine- 4-carboxylate hydrochloride (Step 2, 2.0 g, 5.62 mmol), 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 1.26 g, 3.93 mmol) in dioxane (15 mL) and DIPEA (2.95 mL 16.86 mmol) at rt and the resulting reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with DCM (2x 100 mL). The combined organics were washed with brine solution (150 mL), dried (Na2SO4), concentrated under reduced and the residue purified by column chromatography (SiO2, 40-50% EtOAc / PE) to afford the title compound as a brown, sticky liquid (1.72 g, 50 %). LCMS m / z = 604 [M+H]+. Step 4. Synthesis of 1-(4-(2-((1-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol To a stirred solution of ethyl 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate (Step 3, 1.71 g, 2.83 mmol) in THF (60 mL) was added LAH (2.0M in THF, 4.18 mL, 99 mmol) dropwise over 10 min at 0° C and stirred for 1h. The reaction was quenched with saturated NH4Cl solution (250 mL) and extracted with EtOAc (2x 80 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to obtain the title compound (1.27 g, 80%) which was used without purification. LCMS m / z = 562 [M+H]+. Step 5. Synthesis of 1-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde To a stirred solution of 1-(4-(2-((1-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Step 4, 1.27 g, 2.26 mmol) in DCM (40 mL) was added portion wise Dess-Martin periodinane (1.92 g, 4.52 mmol) at 0° C and the reaction stirred at rt for 2h. The reaction mixture was filtered through celite bed and washed with DCM (100 mL). The filtrate was washed with water (150 mL) and saturated NaHCO3solution (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 50%- 60% EtOAc / PE) to afford the title compound as a sticky off-white solid (0.72 g, 57%). LCMS m / z = 560 [M+H]+. Intermediate 5. N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide. Step 1. Synthesis of methyl (1r,4r)-4-((4-((tert-butoxycarbonyl)amino)piperidine)-1- sulfonamido)cyclohexane-1-carboxylate To the stirred solution of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate (1 g, 6.36 mmol), tert-butyl piperidin-4-ylcarbamate (1.274 g, 6.36 mmol) in DCM (20 mL) was added Et3N (644 mg, 6.36 mmol) and the resulted mixture cooled to -15 °C and sulfuryl chloride (858 mg, 6.36 mmol) and stirred for 2 h at -15 °C. The reaction mixture was diluted with water (30 mL) and extracted with DCM (3x 45 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, 30% EtOAc / PE) to afford the title compound as a white solid (250 mg, 9.4%). LCMS m / z = 420 [M+H]+. Step 2. Synthesis of methyl (1r,4r)-4-((4-aminopiperidine)-1-sulfonamido)cyclohexane-1- carboxylate hydrochloride To a stirred solution of methyl (1r,4r)-4-((4-((tert-butoxycarbonyl)amino)piperidine)-1- sulfonamido)cyclohexane-1-carboxylate (Step 1, 1 g, 2.38 mmol) in DCM (30 mL) was added, 4M HCl in dioxane (20 mL) at 0 °C and the resulting mixture stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as white solid (600 mg, 71%) which was used without further purification. LCMS m / z = 320 [M+H]+. Step 3. Synthesis of methyl (1r,4r)-4-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine)-1-sulfonamido)cyclohexane-1- carboxylate To a solution of methyl (1r,4r)-4-((4-aminopiperidine)-1-sulfonamido)cyclohexane-1- carboxylate hydrochloride (Step 2, 1.8 g, 5.64 mmol), 1-(4-(2-chloro-5- (trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 813 mg, 2.54 mmol) in dioxane (20 mL) was added DIPEA (3 mL, 16.9 mmol) and the resulting mixture heated to 90 °C for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3x 40 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 2% MeOH / DCM) to afford the title compound as a gummy solid (1.36 g, 40%). LCMS m / z = 604 [M+H]+. Step 4. Synthesis of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperidine- 1-sulfonamide Lithium aluminium hydride (2M in THF, 2.80 mL, 4.307 mmol) was added dropwise to a stirred solution of methyl (1r,4r)-4-((4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine)-1-sulfonamido)cyclohexane-1- carboxylate (Step 3, 1.3 g, 2.15 mmol) in THF (20 mL) at -5 °C. The reaction mixture was allowed to stir at rt for 2 h. The reaction was quenched with sat. NH4Cl solution (20 mL) and extracted with EtOAc (3x 30 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 3% MeOH / DCM to afford the title compound as a gummy solid (1.1 g, 89%). LCMS m / z = 576 [M+H]+. Step 5. Synthesis of N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-sulfonamide To the stirred solution of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)piperidine- 1-sulfonamide (Step 4, 1.1 g, 1.91 mmol) in DCM (30 mL) was added Dess-Martin periodinane (1.62 g, 3.82 mmol) at 0 °C and then allowed to warm to rt for 1h. The reaction mixture was filtered through a pad of celite and the filtrate diluted with water (30 mL) and extracted into DCM (3x 40 mL). The combined organics were dried (Na2SO4) and concentrated under reduced. The residue was purified by column chromatography on neutral alumina (4% MeOH / DCM) to afford the title compound as a light brown gummy solid (630 mg, 57%). LCMS m / z = 574 [M+H]+. Intermediate 6. 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2-yl)piperidine- 2,6-dione. Step-1: Synthesis of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate Cesium carbonate (2.52 g, 7.74 mmol) was added to a stirred solution of 3-(5-bromo-1- oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.10 mmol) and tert-butyl 4-(prop-2-yn-1- yloxy)piperidine-1-carboxylate (1.11 g, 4.64 mmol) in DMF (10 mL) and the mixture purged with nitrogen for 15 min. To this were added dichlorobis (triphenylphosphine)palladium (217 mg, 0.31 mmol) and copper(I) iodide (118 mg, 0.62 mmmol) under nitrogen and the mixture stirred at 70 °C for 16 h. The reaction mixture was quenched with cold water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with ice cold water (3x 30 mL), saturated ammonium chloride solution (2x 30 mL), dried over (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc / PE) to afford the title compound as a brown solid (1.3 g, 87 % yield).1H-NMR (400 MHz, DMSO-d6): 11.00 (s, 1H), 7.72 (d, 2H), 7.58 (d, 1H), 5.14-5.09 (dd, 1H), 4.49-4.44 (m, 3H), 4.36-4.32 (m, 1H), 3.73-3.71 (m, 1H), 3.68-3.61 (m, 2H), 3.18-3.16 (m, 2H), 3.06 (m, 1H), 2.62 (m, 1H), 2.49-2.38 (m, 1H), 2.16-1.99 (m, 1H), 1.87-1.73 (m, 2H), 1.42 (br s, 9H), 1.39-1.34 (m, 2H). Step-2: Synthesis of 3-(1-oxo-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione To a stirred solution of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 1.3 g, 2.70 mmol) in DCM (13 mL) was added 4.0 M HCl in dioxane (6.5 mL) at 0 °C and allowed to stir at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue quenched with saturated sodium bicarbonate (30 mL) and extracted with 20% IPA / CHCl3(3x 30 mL). The combined organics was dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as a brown solid (900 mg, 87%). LCMS m / z = 382 [M+H]+. Intermediate 7. (1r,4r)-4-(bromomethyl)cyclohexan-1-amine hydrochloride. To a stirred solution of tert-butyl ((1r,4r)-4-(bromomethyl)cyclohexyl)carbamate [ACS Medicinal Chemistry Letters (2012), 3(2), 129-134)] (10 g, 34.22 mmol) in DCM (30.0 mL) was added 4 M HCl in dioxane (20 mL) at 0 °C and the reaction mixture stirred at rt for 3 h. The reaction mixture was concentrated and co-distilled with DCM (2x 50 mL) under reduced pressure. The residue was washed with diethyl ether and dried under vacuum to afford the title compound as a tan solid (9.0 g, 75%) as a light brown semi solid.1 (400 MHz, DMSO-d6): 7.93 (s, 1H), 3.43-342 (d, 2H), 2.92-2.89 (m, 1H), 1.91-1.89 (m, 2H), 1.86-1.84 (m, 2H), 1.56-1.54 (m, 1H), 1.31-1.28 (m, 2H), 1.12-1.02 (m, 2H). Intermediate 8. 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid. Step 1. Synthesis of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)acetate To a stirred solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.50 g, 1.8 mmol) in DMF (5 mL) was added tert-butyl 2-bromoacetate (0.48 g, 2.40 mmol) at rt and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by RP column chromatography using C18 column (7-80% MeCN / H2O (0.1% HCO2H) to afford the title compound as a brown solid (1.50 g, 25%). LCMS m / z = 375 [M+H]+. Step 2: Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)acetic acid To a stirred solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)acetate (Step 1, 0.30 g, 0.82 mmol) in DCM (5 mL) was added TFA (3 mL) at 0 °C and the mixture stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (0.20g, 80%). LCMS m / z = 319 [M+H]+. Intermediate 9. 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione. Step 1. Synthesis of tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate To a stirred solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (5 g, 19.7 mmol) in DCM (100 mL) was added (4-bromophenyl)boronic acid (7.90 g, 39.3 mmol) and triethylamine (8.20 mL, 59.0 mmol). The solution was purged with O2 gas for 15 min. Copper (II) acetate (1.43 g, 7.86 mmol) was added to the reaction mixture and the reaction stirred at rt for 16 h. Water (150 mL) was added and the reaction mixture filtered through a pad of celite and washed with DCM (2x 200 mL). The combined organics were dried (Na2SO4) and concentrated under the reduced pressure and the residue purified by silica gel chromatography (SiO2, 10-50% EtOAc / PE) to afford the title compound as a semi-solid (8 g; 75%). LCMS m / z = 409 [M+H]+. Step 2. Synthesis of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate Potassium phosphate (10.37 g, 48.9 mmol) was added to a stirred solution of tert-butyl 9-(4- bromophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 8 g, 19.5 mmol), 2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (12.2 g, 29.3 mmol) in dioxane / water (176 mL, 10 / 1) and the mixture degassed with argon for 20 min. PdCl2(dppf).DCM (798 mg, 0.98 mmol) was added to the reaction mixture and the solution again purged with argon and heated for 3h at 110°C. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with water (4x 100 mL) and brine (2x 100 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by silica gel chromatography (SiO2, 0-6% EtOAc / PE) to afford the title compound as a colourless semi-solid (7g, 79%). LCMS m / z = 620 [M+H]+. Step 3. Synthesis of tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a suspension of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (Step 2, 4.5 g, 7.26 mmol) in EtOH (200 mL) was added Palladium on activated carbon, 10% Pd, (50% wet with water), unreduced (4 g). The reaction mixture was stirred at room temperature under H2 (120 psi) for 48 h. The reaction mixture was filtered through a pad of celite, washed with MeOH (2x 20 mL). The filtrate was concentrated under the reduced pressure and the residue was purified by Combi-flash chromatography (SiO2, 20-60% EtOAc / PE) to afford the title compound as an off-white solid (1.9 g, 59%). LCMS m / z = 442 [M+H]+. Step 4. Synthesis of 3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione 4N HCl in Dioxane (10 mL) was added to a stirred solution of tert-butyl 9-(4-(2,6- dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 3, 3.4 g, 4.60 mmol) in DCM (60 mL), at 0 ºC and the reaction was stirred at rt for 3 h. The reaction mixture was concentrated and co-distilled with dichloromethane (2x 50mL) under reduced pressure and the residue diluted with sat aq NaHCO3(25 mL) and extracted with 10% IPA / CHCl3 (5x 100 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as an off-white solid (2.4g, 91%). LCMS m / z = 342 [M+H]+. Intermediate 10. 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione.

[0011] Step 1. Synthesis of tert-butyl 9-(3-bromophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate To a stirred solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (5 g, 19.7 mmol) in DCM (100 mL) were added (3-bromophenyl)boronic acid (7.90 g, 39.3 mmol) and triethylamine (8.19 mL, 59 mmol) and O2 gas was purged through the solution for 15 min. Copper (II) acetate (1.43 g, 7.86 mmol) was added to the reaction mixture and the reaction was stirred at rt for 16 h. The reaction was quenched with water (150 mL), filtered through a pad of celite and washed with DCM (2x 200 mL). The combined organics were dried (Na2SO4) and concentrated under the reduced pressure. The residue was purified by Combflash chromatography (SiO2, 10-50% EtOAc / PE) to afford the title compound as an off-white solid (6.4 g; 80%). LCMS m / z = 409 [M+H]+. Step 2. Synthesis of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a stirred solution of tert-butyl 9-(4-bromophenyl)-3,9-diazaspiro[5.5]undecane-3- carboxylate (Step 1, 8 g, 19.5 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (12.23 g, 29.3 mmol) and potassium phosphate (10.37 g, 48.86 mmol) in dioxane / water (176 mL, 10:1) and the mixture degassed with argon for 20 min. PdCl2(dppf).DCM (798 mg, 0.98 mmol) was added and the solution purged with argon and heated for 3 h at 110°C. The reaction mixture was diluted with water (150 mL) and filtered through a pad of celite. The celite pad was washed with DCM (2x 200 mL) and the combined organics dried (Na2SO4) and concentrated under the reduced pressure to afford the title compound as an off-white solid (6.5 g, 67%). LCMS m / z = 620 [M+H]+. Step 3. Synthesis of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate To a suspension of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9- diazaspiro[5.5]undecane-3-carboxylate (Step 2, 6 g, 9.68 mmol) in Ethanol (100 mL) was added Palladium on activated carbon, 10% Pd, (50% wet with water, 6 g) and the reaction mixture stirred at room temperature under H2(120 psi) atmosphere for 48 h. The reaction mixture was filtered through a pad of celite and washed with methanol (4x 100 mL). The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (SiO2, 10-50% EtOAc / PE) followed by silica gel chromatography (SiO2, 20- 60% EtOAc / PE) to afford the title compound as an off-white solid (2.6 g, 61%). LCMS m / z = 442 [M+H]+. Step 4. Synthesis of 3-(3-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione 4N HCl in dioxane (5 mL) was added to a stirred solution of tert-butyl 9-(3-(2,6- dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 3, 2.6 g, 5.89 mmol) in DCM (40 mL), at 0 ºC. After completion of reaction the reaction mixture was concentrated under reduced pressure and the residue diluted with sat aq NaHCO3 (25 mL) and extracted with 10% IPA / CHCl3. The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as an off-white solid (1.9 g, 94%). Intermediate 11. 1-(2-methyl-3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. Step 1. Synthesis of tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate A mixture of 1-(3-bromo-2-methylphenyl)dihydropyrimidine-2,4(1H,3H)-dione (WO2015197028 A1, 1.5 g, 5.30 mmol.), tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1- carboxylate (1.90 g, 7.95 mmol.) and Cs2CO3 (4.32 g, 13.25 mmol.) in MeCN (15 mL) at rt was purged with nitrogen gas for 15 min and BrettPhos Pd G4 (488 mg, 0.53 mmol.) and copper(I) iodide (202 mg, 1.06 mmol.) were added under N2 and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction mixture was evaporat4ed to dryness under reduced and the residue was purified by silica gel chromatography (SiO2, 50-60% EtOAc / PE) to afford the title compound as a brown solid (1.2 g, 51%). LCMS m / z = 442 [M+H]+. Step 2. Synthesis of 1-(2-Methyl-3-(3-(piperidin-4-yloxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Formic acid (12 mL) was added to tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)-2-methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 1.2 g, 2.49 mmol) at rt room temperature and stirred at rt for 2 h. The reaction mixture was evaporated to dryness and the residue diluted with water (50 mL) and extracted with 10% MeOH / CHCl3 (3x 50 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound was a brown gum (780 mg, 84%). LCMS m / z = 342 [M+H]+. Intermediate 12. 3-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione.

[0012] Step 1. Synthesis of tert-butyl 4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate To a stirred solution of 3-(3-iodophenyl)piperidine-2,6-dione (1.0 g, 3.17 mmol) and tert- butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.37 g, 5.71 mmol) in DMF (10 mL) was added cesium carbonate (2.59 g, 7.93 mmol) and purged with nitrogen gas for 15 min. To this was added dichlorobis(triphenylphosphine)palladium (0.223 g, 0.32 mmol) and copper (I) Iodide (121 mg, 0.64 mmol) and stirred at 70 °C for 4h. The reaction was quenched with cold water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with ice cold water (3x 50 mL), saturated ammonium chloride solution (2x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 50-60% EtOAc / PE) to afford the title compound as a brown solid (1.2 g, 88%). LCMS m / z = 427 [M+H]+. Step 2. Synthesis of 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione To a stirred solution tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 1.2 g, 2.81 mmol) in DCM (12 mL) was added 4.0 M HCl in dioxane (6 mL) drop-wise at 0° C and then stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue quenched with saturated sodium bicarbonate (30 mL) and extracted with 20% IPA / CHCl3(3x 30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (700 mg, 76%). LCMS m / z = 327 [M+H]+. Step 3. Synthesis of tert-butyl 4-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate DIPEA (1.2 mL, 1.92 mmol) was added to a stirred solution of 3-(3-(3-(piperidin-4- yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione (Step 2, 250 mg, 0.77 mmol) and 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (211 mg, 0.92 mmol) in DMF (5 mL) at 0 °C and stirred for 5 min before HATU (524 mg, 1.38 mmol) was added and the reaction mixture stirred at rt for 16 h. The reaction was quenched with cold water (20 mL) and extracted with 10 % MeOH / DCM (3x 25 mL). The combined organics were washed with water (2x 25 mL), brine (25 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (SiO2, 60-70% EtOAc / PE) to afford the title compound as a brown solid (300 mg, 73%). LCMS m / z = 538 [M+H]+. Step 4. Synthesis of 3-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)piperidine-2,6-dione To a stirred solution of tert-butyl 4-(4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate (Step 3, 300 mg, 0.56 mmol) in DCM (3 mL), was added 4.0 M HCl in dioxane (1.5 mL) drop-wise at 0° C and the reaction mixture stirred at rt for 4h. The reaction was concentrated under reduced pressure and the residue quenched with cold water (50 mL) and extracted with Et2O (3x 50 mL). The aqueous layer was basified with saturated sodium bicarbonate (50 mL) and extracted with 20% IPA / CHCl3(3x 50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (180 mg, 74%). LCMS m / z = 438 [M+H]+. Intermediate 13. 1-(2-methyl-3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn- 1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. Step 1: Synthesis of tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (262 mg, 1.142 mmol) and HATU (434 mg, 1.142 mmol) in DMF (15 mL) was added 1-(2-methyl-3-(3- (piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 11, 325 mg, 0.952 mmol) followed by DIPEA (0.497 mL, 2.856 mmol) at rt and the resulting reaction mixture was stirred for 16 h at rt. The reaction mixture was diluted with ice-cold water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were dried (Na2SO4) and evaporated under reduced pressure and the residue purified by combi-flash (SiO2, 50% EtOAc / PE) to afford the title compound as a red solid (0.10 g, 19%). LCMS m / z = 556 [M+H]+. Step 2: Synthesis of 1-(2-methyl-3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1- yn-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione A solution of tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2- methylphenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate (0.1 g, 0.18 mmol) in formic acid (3 mL) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a red solid (0.08 g, 98%). LCMS m / z = 453 [M+H]+. Intermediate 14. Mixture of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide.

[0013] Step 1. Synthesis of methyl (1r,4r)-4-((3-fluoro-4-nitrophenyl)sulfonamido)cyclohexane-1- carboxylate To a solution of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate (10 g, 63.61 mmol) in DCM (80 mL) was added 3-fluoro-4-nitrobenzenesulfonyl chloride (22.86 g, 95.41 mmol) and TEA (19.31 g, 191 mmol) at -10 ºC and stirred for 2h. The reaction was quenched with cold water (100 mL) and extracted with DCM (3x 150 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure and the residue was purified by column chromatography (SiO2, 25-30% EtOAc / PE) to afford the title compound as a yellow solid (7 g). LCMS m / z = 361 [M+H]+. Step 2. Synthesis of methyl (1r,4r)-4-((4-amino-3-fluorophenyl)sulfonamido)cyclohexane-1- carboxylate Fe powder (26.35 g, 472 mmol) and NH4Cl (25.23 g, 472 mmol) were added to a stirred solution of methyl 4-((3-fluoro-4-nitrophenyl)sulfonamido)cyclohexane-1-carboxylate (Step 1, 8.5 g, 23.6 mmol) in EtOH (60 mL) and H2O (60 mL) and the reaction mixture stirred at 80 ºC for 4 h. The reaction mixture was filtered through a pad of celite bed the filtrate extracted with 10% MeOH / DCM. The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford methyl (1s,4s)-4-((4-amino-3- fluorophenyl)sulfonamido)cyclohexane-1-carboxylatethe title compound (6 g, 77%). LCMS m / z = 331 [M+H]+. Step 3. Synthesis of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carboxylate To a stirred solution of methyl (1r,4r)-4-((4-amino-3-fluorophenyl)sulfonamido)cyclohexane- 1-carboxylate (Step 2, 0.9 g, 2.72 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 1.05 g, 3.27 mmol) in dioxane (10 mL) was added Cs2CO3 (2.66 g, 8.17 mmol) at rt . The reaction mixture was purged with N2for 10 min and Pd(OAc)2 (183 mg, 0.82 mmol) and BINAP (509 mg, 0.82 mmol) were added at rt. The resulting mixture was stirred under Ar at 100 °C for 2 h in the microwave. After 2h the reaction mixture was quenched with cold water (150 mL) and extracted with EtOAc (3x 80 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 35% EtOAc / PE) to afford the title compound as a brown solid (0.75 g, 45%). LCMS m / z = 615 [M+H]+. Step 4. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-((1r,4r)-4- (hydroxymethyl)cyclohexyl)benzenesulfonamide To a stirred solution of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carboxylate (Step 3, 3.0 g, 4.88 mmol) in THF (50 mL) was added LiAlH4(14.6 mL, 9.76 mmol) at -5°C and the reaction mixture stirred at rt for 2 h. The reaction was quenched with saturated NH4Cl solution (250 mL) and extracted with EtOAc (2x 80 mL). The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as a brown solid (2.7 g, 94%) which was used without further purification. LCMS m / z = 587 [M+H]+. Step 5. Synthesis of 3-fluoro-N-((1r,4r)-4-formylcyclohexyl)-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide and 3-fluoro-N-((1s,4s)-4-formylcyclohexyl)-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide To a solution of methyl 4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylate (Step 4, 2.7 g, 4.60 mmol) in DCM (50 mL) was added DMP (3.90 g, 9.21 mmol) and the mixture stirred for 2 h. The reaction mixture filtered through celite bed and the filtrate evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 45% EtOAc / PE) to afford the title compounds as a 2:1 mixture of trans to cis isomers as a brown solid (900 mg, 33%). LCMS m / z = 585 [M+H]+.1H NMR (400 MHz, DMSO-d6): 10.10 (s, 1H), 9.50 (s, 1H), 9.49 (bs, 1H), 8.25 (s, 1H), 8.10-8.01 (m, 3H), 4.94 (s, 1H), 4.18 (s, 1H), 4.11 (s, 1H), 4.03-4.02 (s, 2H), 2.99-2.98 (s, 1H), 2.96-2.95 (m, 1H), 1.85-1.83 (m, 2H), 1.72-1.67 (m, 2H), 1.23-1.15 (s, 4H), 1.08 (s, 6H). Intermediate 15. (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid. To a stirred solution of methyl (1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carboxylate (Intermediate 14, Step 3, 350 mg, 0.57 mmol) in THF (8 mL) and H2O (2 mL) was added LiOH.H2O (119 mg, 2.85 mmol) at 0 °C and the reaction mixture stirred at rt for 4 h. The reaction mixture was neutralised with 1M HCl solution and extracted with EtOAc (3x 40 mL). The combined organics were evaporated to dryness to afford the title compound as a brown solid (300 mg, 88%). LCMS m / z = 601 [M+H]+. Intermediate 16. 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione.

[0014] Step 1. Synthesis of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate To a stirred solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.10 mmol) and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.111 g, 4.64 mmol) in DMF (10 mL) was added cesium carbonate (2.521 g, 7.74 mmol) and the resulting solution purged with nitrogen gas for 15 min. To this was added dichlorobis (triphenylphosphine)palladium (217 mg, 0.31 mmol) and copper(I) iodide (118 mg, 0.62 mmol) under nitrogen and the resulting reaction mixture stirred at 70 °C for 16h. The reaction was quenched with cold water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with saturated ammonium chloride solution (2x 30 mL) and dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc / PE) to afford the title compound as a brown solid (800 mg, 53%). LCMS m / z = 482 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione To a stirred solution of tert-butyl 4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (Step 1, 500 mg, 1.038 mmol) in DCM (5 mL) at 0 ºC was added 4.0 M HCl in dioxane (2.5 mL) and the reaction mixture stirred at rt for 3h. The reaction mixture was evaporated to dryness under reduced pressure and the residue and diluted with cold water (30 mL) and washed with Et2O (3x 30 mL). The aqueous layer was treated with saturated sodium bicarbonate (50 mL) and extracted with 20% IPA / CHCl3(3x 30 mL). The combined extracts were dried (Na2SO4) and evaporated to dryness under reduced pressure to afford the title compound as a brown solid (290 mg, 73%) as brown solid. LCMS m / z = 382 [M+H]+. Intermediate 17. 4-((2-(2-(2-azidoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione. To a solution of 2-(2-(2-azidoethoxy)ethoxy)ethan-1-amine (0.35 g, 2.00 mmol) and 2-(2,6- dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (RSC Med Chem, 2021, 12, 1381-1390, 0.55 g, 2.00 mmol) in DMF (5 mL) was added DIPEA (0.54 mL, 3.01 mmol) at 25 °C and the reaction mixture stirred at 90 °C for 16 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3x 15 mL). The combined organics were dried (Na2SO), concentrated under reduced pressure and the residue purified using column chromatography (SiO2, 35% EtOAc / PE to afford the title compound as a yellow solid (0.22 g, 25%). LCMS m / z = 431 [M+H]+. Intermediate 18. 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylic acid. Step 1. Synthesis of tert-butyl 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylate To a stirred solution of tert-butyl 1-((4-amino-3-fluorophenyl)sulfonyl)piperidine-4- carboxylate (0.60 g, 1.67 mmol) and 2-amino-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)pyrimidine-5-carbonitrile (Intermediate 107, 0.53 g, 1.67 mmol) in dioxane (6 mL) was added Cs2CO3(1.63 g, 5.02 mmol) at rt. The reaction mixture was purged with nitrogen for 10 min and Pd(OAc)2 (0.037 g, 0.167 mmol) added and stirred under argon at 100 °C for 1 h in a microwave. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3x 150 mL). The combined organics were washed with water (2x 150 mL), brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 30% EtOAc / PE) to afford the title compound as a brown liquid (400 mg, 37%). LCMS m / z = 643 [M+H]+. Step 2. Synthesis of 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carboxylic acid To a stirred solution of tert-butyl 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4- carboxylate (Step 1, 0.40 g, 0.62 mmol) in DCM (5 mL) was added TFA (2 mL) at 0 C and the reaction mixture stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown solid (0.35 g, 95%). LCMS m / z = 587 [M+H]+. Intermediate 19. 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide. Step 1. Synthesis of 4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide To a stirred solution of 2-(prop-2-yn-1-yloxy)ethan-1-amine (0.67 g, 6.77 mmol), 4- nitrobenzenesulfonyl chloride (1.50 g, 6.77 mmol) in DCM (2 mL) was added triethylamine (2.36 mL, 16.9 mmol) at rt and stirred for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 13% EtOAc / PE) to afford the title compound as a pale yellow solid (0.50 g, 26%) as pale yellow solid. LCMS m / z = 283 [M+H]+. Step 2. Synthesis of 4-amino-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide To a stirred solution of 4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 1, 0.50 g, 1.76 mmol) in ethanol (2.5 mL) and water (2.5 mL), were added Ammonium Chloride (1.882 g, 35.2 mmol), Iron Powder (1.964 g, 35.2 mmol) at rt and the reaction mixture heated at 80 ºC for 4 h. The mixture was cooled to rt, diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure to afford the title compound (0.40 g, 89%) which was used without further purification. LCMS m / z = 255 [M+H]+. Step 3. Synthesis of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide To a stirred solution of 4-amino-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 2, 0.250 g, 0.983 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)-2-methylpropan-2-ol (Intermediate 1, 0.315 g, 0.983 mmol) in IPA (2 mL) was added 4- methylbenzenesulfonic acid (0.169 g, 0.983 mmol) and heated at 90 ºC for 16 h. The reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3x 5 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 50% EtOAc / PE) to afford the title compound as a pale brown solid (0.18 g, 34%). LCMS m / z = 539 [M+H]+. Intermediate 20. 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-N-(prop-2-yn-1- To a stirred solution of aminoethanol (2.50 g, 40.92 mmol) in DCM (50 mL) was added 3- fluoro-4-nitrobenzenesulfonyl chloride (10.78 g, 45.01 mmol) and triethylamine (11.4 mL, 81.9 mmol) at 0 °C and stirred for 1 h at rt. The reaction was quenched with water (50 mL) and extracted with DCM (3 x 40 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 45-50% EtOAc / PE) to afford the title compound (4.70 g, 43%) as a yellow solid. LCMS m / z = 263 [M-H]+ Step 2. Synthesis of 3-fluoro-N-(2-hydroxyethyl)-4-nitro-N-(prop-2-yn-1- yl)benzenesulfonamide To a stirred solution of 3-fluoro-N-(2-hydroxyethyl)-4-nitrobenzenesulfonamide (Step 1, 2.20 g, 8.33 mmol) and t-butylammonium bromide (0.537 g, 1.67 mmol) in THF (30 mL) were added propargyl bromide (1.25 mL, 16.7 mmol) and potassium hydroxide (0.561 g, 9.99 mmol) at rt and stirred for 16 h at rt. The reaction was quenched with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organic were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 35-40% EtOAc / PE) to afford the title compound as a yellow solid (1.4 g, 56%). LCMS m / z = 303 [M+H]+Step 3. Synthesis of 4-amino-3-fluoro-N-(2-hydroxyethyl)-N-(prop-2-yn-1- yl)benzenesulfonamide To a stirred solution of 3-fluoro-N-(2-hydroxyethyl)-4-nitro-N-(prop-2-yn-1- yl)benzenesulfonamide (Step 2, 0.60 g, 1.98 mmol) in ethanol (20 mL) and water (20 mL) was added iron powder (2.21 g, 39.7 mmol) and ammonium chloride (2.12 g, 39.7 mmol) and the mixture stirred at 80 °C for 2 h. The reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound as an orange solid (0.50 g, 92%). LCMS m / z = 273 [M+H]+Step 4. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)-N-(prop-2-yn-1- yl)benzenesulfonamide To the stirred solution of 4-amino-3-fluoro-N-(2-hydroxyethyl)-N-(prop-2-yn-1- yl)benzenesulfonamide (Step 3, 0.50 g, 1.84 mmol) in IPA (10 mL) were added 1-(3-(2- chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (0.59 g, 1.84 mmol) and 4-methylbenzenesulfonic acid (0.32 g, 1.84 mmol) and the resulting mixture stirred at 90 °C for 16 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were dried (Na2SO4) and concentrated under reduced. The residue was purified by column chromatography (SiO2, 35-40% EtOAc / PE) to afford the title compound as a yellow solid (0.14 g, 13%). LCMS m / z = 557 [M+H]+Intermediate 21. 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide.

[0015] Step 1: Synthesis of 3-fluoro-4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide. To a stirred solution of 2-(prop-2-yn-1-yloxy)ethan-1-amine hydrochloride (1.50 g, 11.06 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (3.98 g, 16.59 mmol) in DCM (7.5 mL) was added triethylamine (4 mL, 27.66 mmol) dropwise at 0 °C and the resulting reaction mixture stirred at rt for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (3x 20 mL). The combined organics were washed with brine (40 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by combi-flash chromatography (SiO2, 20-30% EtOAc / PE) to afford the title compound as a semi-solid (2.2 g, 66%).1H NMR (400 MHz, CDCl3): 8.21 (t, 1H), 7.86-7.81 (m, 2H), 5.07 (t, 1H), 4.13 (d, 2H), 3.61 (t, 2H), 3.31 (q, 2H), 2.48 (t, 1H). Step 2: Synthesis of 4-amino-3-fluoro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide Iron powder (16.3 g, 291 mmol) and ammonium chloride (15.6 g, 291 mmol) were added to a stirred solution of 3-fluoro-4-nitro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 1, 4.40 g, 14.6 mmol) in ethanol (22 mL) and water (22 mL) and stirred at 80 °C for 2 h. The reaction mixture was filtered through a pad of celite and washed with methanol (2x 30 mL). The filtrate was concentrated under reduced pressure and the remaining aqueous solution extracted with DCM (50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown gum (3.80 g, 96%). LCMS m / z = 273 [M+H]+Step 3: Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.46 g, 1.43 mmol) was added at room temperature to a stirred solution of 4- amino-3-fluoro-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (Step 2, 0.30 g, 1.10 mmol) and p-toluenesulfonic acid (0.21 g, 1.10 mmol) in IPA (3 mL) and the resulting mixture stirred at 90 °C for 16 h. The reaction mixture was evaporated under reduced pressure and the residue purified by combi-flash chromatography (SiO2, 30-40% EtOAc / PE) to afford the title compound as a yellow gum (0.29 g, 47%). LCMS m / z = 557 [M+H]+. Intermediate 22. 4-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione. Step 1. Synthesis of tert-butyl 9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To a stirred solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.50 g, 9.83 mmol) in acetonitrile (25 mL) at rt was added sequentially 2-azidoethyl 4- methylbenzenesulfonate (2.85 mL, 11.79 mmol) and potassium carbonate (4.08 g, 29.5 mmol) and the resulting reaction mixture stirred for 18 h at 80 °C. The reaction was quenched with cold water (50 mL) and extracted with ethyl acetate (2x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25-30% EtOAc / PE) to afford the title compound as a yellow liquid (2.10 g, 66%). LCMS m / z = 324 [M+H]+. Step 2. Synthesis of 3-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane To a stirred solution of tert-butyl 9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 0.23 g, 0.65 mmol) in DCM (3 mL) was added 4N HCl in dioxane (2 mL) at 0 °C and the resulting mixture stirred for 1 h at rt. The reaction mixture was evaporated to dryness under reduced pressure and the residue was triturated with diethyl ether (5 mL) to afford the title compound as a brown liquid (0.18 g, 96%).1H-NMR (400 MHz, DMSO-d6): 10.45 (br, 1H), 8.85 (br, 2H), 1.86 (m, 2H), 3.37-3.32 (m, 5H), 3.08-3.01 (m, 6H), 1.82-1.77 (m, 4H), 1.72-1.65 (m, 2H), 1.53-1.51 (m, 2H) Step 3. Synthesis of 4-(9-(2-azidoethyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione To a stirred solution of 3-(2-azidoethyl)-3,9-diazaspiro[5.5]undecane (Step 2, 0.48 g, 1.85 mmol) in DMSO (10 mL) at rt were added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione (0.61 g, 2.22 mmol) and DIPEA (1.65 mL, 9.24 mmol) and the resulting reaction mixture stirred for 18 h at 120 °C. The reaction mixture was quenched with cold water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 70-80% EtOAc / PE) to afford the title compound as a yellow solid (0.60 g, 68%). LCMS m / z = 480 [M+H]+. Intermediate 23. 5-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione. Step 1. Synthesis of tert-butyl 1'-(2-azidoethyl)-[4,4'-bipiperidine]-1-carboxylate To a stirred solution of tert-butyl [4,4'-bipiperidine]-1-carboxylate (2.00 g ,7.45 mmol) and 2- azidoethyl 4-methylbenzenesulfonate (2.70 g, 11.2 mmol) in MeCN (20 mL) at room temperature was added potassium carbonate (3.09 g, 22.4 mmol) and the resulting mixture stirred at 80 °C for 16 h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure the residue purified by column chromatography (SiO2, 50-60% EtOAc / PE) to afford the title compound as a brown liquid (1.70 g, 68 %). LCMS m / z = 338 [M+H]+. Step 2. 1-(2-azidoethyl)-4,4'-bipiperidine hydrochloride (17b) To a stirred solution of tert-butyl 1'-(2-azidoethyl)-[4,4'-bipiperidine]-1-carboxylate (Step 1, 0.50 g, 1.48 mmol) in DCM (10 mL) was added 4.0 M HCl in dioxane (6 mL) dropwise at 0° C. After addition was completed the reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether and DCM to afford the title compound as an off-white solid (0.35 g, 87%). Step 3. Synthesis of 5-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Intermediate 17) To a stirred solution of 1-(2-azidoethyl)-4,4'-bipiperidine hydrochloride (Step 2, 0.70 g, 2.58 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.66 g, 2.30 mmol) in DMSO (15 mL) was added DIPEA(1.42 mL 7.67 mmol) at rt under nitrogen atmosphere and the resulting mixture stirred at 120 °C for 16 h. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (2× 50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 70-80% EtOAc / PE) to afford the title compound as a yellow solid (0.40 g, 32 %). LCMS m / z = 494 [M+H]+. Intermediate 24. 4-(1'-(2-azidoethyl)-[4,4'-bipiperidin]-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione. To a stirred solution of 1-(2-azidoethyl)-4,4'-bipiperidine (0.11 g, 0.40 mmol) in DMSO (1.5 mL), were added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (88.8 g, 0.32 mmol) and DIPEA (0.18 mL, 1.00 mmol) at rt and the resulting mixture stirred for 18 h at 120 °C. The reaction mixture was quenched with cold water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 2-8% MeOH / DCM) to afford the title compound as a yellow semi-solid (0.08 g, 40%). LCMS m / z = 494 [M+H]+. Intermediate 25. ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine.

[0016] Step 1. Synthesis of tert-butyl ((3-fluoro-4-nitrophenyl)sulfonyl)glycinate. A solution of tert-butyl glycinate (2.00 g, 15.3 mmol) and triethylamine (3.86 g, 38.2 mmol) in DCM (20 mL) was stirred for 15 min at rt and cooled to 0 °C before 3-fluoro-4- nitrobenzenesulfonyl chloride (5.48 g, 22.9 mmol) was added and stirring continued at 0 °C for 2 h. The reaction mixture was quenched with ice-cold water (20 mL) and extracted with DCM (3x 25 mL). The combined organics were dried (Na2SO4), concentrated under the reduced pressure and the residue purified by Biotage column chromatography (SiO2, 25-30% EtOAc / PE) to afford the title compound as a brown solid (4.00 g, 78%). LCMS m / z = 333 [M+H]+. Step 2: Synthesis of tert-butyl ((4-amino-3-fluorophenyl)sulfonyl)glycinate. To a stirred solution of tert-butyl ((3-fluoro-4-nitrophenyl)sulfonyl)glycinate (Step 1, 2.0 g, 5.98 mmol) in EtOH / H2O (1:1, 40 mL) were added ammonium chloride (6.4 g, 120 mmol) and Iron powder, (6.68 g, 120 mmol) at rt and the resulting reaction mixture stirred at 80 °C for 3 h. The reaction mixture was filtered through a pad of celite, washed with EtOH (2x 20 mL). The filtrate was concentrated under the reduced pressure to obtain the title compound (1.7 g, 93%). LCMS m / z = 303 [M+H]+. Step 3: Synthesis of tert-butyl ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4- yl)-5-(trifluoromethyl)pyrimidin-2-yl) amino) phenyl) sulfonyl) glycinate. To a stirred solution of tert-butyl ((4-amino-3-fluorophenyl)sulfonyl)glycinate (Step 2, 0.80 g, 2.63 mmol), 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (Intermediate 1, 0.67 g, 2.10 mmol) and BINAP (0.33 g, 0.53 mmol) in dioxane (8 mL) was added Cs2CO3 (2.57 g, 7.89 mmol) at rt and the mixture purged with argon for 15 min. Palladium(II) acetate, (0.24 g, 1.05 mmol) was added and again purged with nitrogen for 5 min and the reaction mixture stirred at 120 °C for 3 h under microwave irradiation. The reaction was quenched with ice-cold water (20 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-30% EtOAc / PE) to afford the title compound (0.30 g, 19%). LCMS m / z = 589 [M+H]+. Step 4: Synthesis of ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine. To a stirred solution of tert-butyl ((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl) amino) phenyl) sulfonyl) glycinate (Step 3, 0.3 g, 0.60 mmol) in DCM (3 mL) was added TFA (1.5 mL) at rt and the resulting reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with PE (20 mL) and further purified by flash chromatography (SiO2, 2-5% MeOH / DCM) to afford the title compound (0.3 g, 95%). LCMS m / z = 533 [M+H]+. Intermediate 26. 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione. Step 1. Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate. To a stirred solution of tert-butyl 4-(piperazin-1-ylmethyl)piperidine-1-carboxylate (1.00 g, 3.53 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.17 g, 4.23 mmol) in DMSO (10 mL) was added DIPEA (1.37 g, 10.6 mmol) under inert atmosphere at rt and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 10-40 % EtOAc / PE) to afford the title compound (1.2 g, 63%). LCMS m / z = 540 [M+H]+. Step 2. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperidin-4-ylmethyl)piperazin-1- yl)isoindoline-1,3-dione. To a stirred solution of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Step 1, 1.20 g, 2.22 mmol) in DCM (12 mL) was added 4 M HCl in dioxane (4.8 mL) at rt and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with DCM (2 x10 mL) to afford the title compound as a pale yellow solid (1.00 g, 94%). LCMS m / z = 440 [M+H]+. Intermediate 27. 2-methyl-1-(4-(2-((1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4- yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol. Step 1. Synthesis of tert-butyl (1-((3-chloropropyl)sulfonyl)piperidin-4-yl)carbamate 3-chloropropane-1-sulfonyl chloride (1.06 g, 5.99 mmol) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (1.00 g, 4.99 mmol) and triethylamine (1.99 ml, 14.98 mmol) in DCM (20 mL) at -10 ºC under nitrogen. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 15% EtOAc / PE) to afford the title compound as a white solid (1.50 g, 77%). LCMS m / z = 241 [M+H]+. Step 2. Synthesis of tert-butyl (1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4- yl)carbamate Prop-2-yn-1-ol (0.32 g, 5.72 mmol) was added to a stirred solution of tert-butyl (1-((3- chloropropyl)sulfonyl)piperidin-4-yl)carbamate (Step 1, 1.30 g, 3.81 mmol) and Cs2CO3(3.11 g, 9.53 mmol) in MeCN (10 mL) at rt under nitrogen atmosphere and the resulting mixture stirred at 80 °C for 16 h. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were washed with water (2x 50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 27 % EtOAc / PE) to afford the title compound as a brown liquid (1.30 g, 94%). LCMS m / z = 305 [M+H]+. Step 3. Synthesis of 1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4-amine hydrochloride (14c) To a stirred solution tert-butyl (1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4- yl)carbamate (Step 2, 0.2 g, 0.56 mmol) in DCM (12 mL) was added 4.0 M HCl in dioxane (6 mL) drop-wise at 0° C. After addition was completed the reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a brown solid (150 mg, 91%).1 NMR (400 MHz, DMSO-d6,): 8.03 (bs, 2H), 4.125 (d, 2H), 3.56-3.53 (m, 3H), 3.08-3.07 (m, 2H), 3.07-3.06 (m, 2H), 2.89-2.87 (m, 2H), 1.97-1.90 (m, 5H), 1.53-1.51 (m, 3H). Step 4. Synthesis of 2-methyl-1-(4-(2-((1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin- 4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol. To a stirred solution of 1-((3-(prop-2-yn-1-yloxy)propyl)sulfonyl)piperidin-4-amine hydrochloride (Step 3, 0.30 g, 1.01 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4- yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 389 mg, 1.21 mmol) in dioxane (3 mL) was added DIPEA (0.514 mg, 3.032 mmol) and heated at 90 ºC for 16 h. The mixture was diluted with water (2x 15 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 25-30% EtOAc / PE) to afford the title compound as a brown liquid (0.30 g, 54%). LCMS m / z = 545 [M+H]+. Intermediate 28. 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione. Step 1. Synthesis of 2,6-bis(benzyloxy)-3-(4-nitrophenyl)pyridine. To a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (5.0 g, 13.5 mmol), 4- nitrophenyl boronic acid (2.48 g, 14.9 mmol) in dioxane (100 mL) was added solution of potassium phosphate (5.73 g, 27 mmol) in H2O (10 mL) and degassed with argon for 20 min. To the resulting solution was added PdCl2(dppf). DCM (1.10 g, 1.35 mmol) and purged with argon for 2 min and the reaction mixture heated for 16 h at 110°C. The reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (2x 50 mL) and brine (50 mL). The combined organics were evaporated under reduced pressure and the residue purified by chromatography (SiO2, 0-3 % EtOAc / PE) to afford the title compound as a yellow solid (4.7 g, 84%). LCMS m / z = 413 [M+H]+. Step 2. Synthesis of 3-(4-aminophenyl)piperidine-2,6-dione. A 100 mL steel pressure vessel was charged with 2,6-bis(benzyloxy)-3-(4- nitrophenyl)pyridine (Step 1, 9.4 g, 22.8 mmol) in EtOH (180 mL) and 10% Palladium on carbon (1.29 g) was added under a nitrogen atmosphere. The vessel was charged with H2 gas (50m psi) and heated at 55 ºC for 24 h. After completion of reaction, the reaction mixture was filtered through a pad of celite and washed with MeOH (200 mL). The combined organics were concentrated under reduced pressure and the residue triturated with Et2O (50 mL) to afford the title compound as a white solid (2.00 g, 81%). LCMS m / z = 205 [M+H]+. Step 3. Synthesis of 3-(4-iodophenyl)piperidine-2,6-dione. To the stirred solution of 3-(4-aminophenyl)piperidine-2,6-dione (Step 2, 2.50 g, 12.24 mmol) in water (40 mL) were added, at 0 ºC, sodium nitrate (2.53 g, 36.72 mmol) and sulfuric acid (3.27 mL, 61.2 mmol) and the resulting mixture stirred at rt for 20 min. To this was added KI (10.16 g, 61.2 mmol) in water (20 mL) and the reaction mixture stirred at 80 ºC for 3 h. The reaction mixture was extracted with ethyl acetate (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-30% EtOAc / PE) to afford the title compound as a brown solid (1.90 g, 49%).1H NMR (400 MHz, DMSO-d6,): 10.97 (s, 1H), 7.72 (d, 2H), 7.05 (d, 2H), 3.86-3.83 (m, 1H), 2.69-2.51 (m, 1H), 2.48-2.47 (m, 1H), 2.20-2.17 (m, 1H), 2.03-1.99 (m, 1H). Step 4. Synthesis of tert-butyl 4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate. 3-(4-iodophenyl)piperidine-2,6-dione (0.50 g, 1.58 mmol) and tert-butyl 4-(prop-2-yn-1- yloxy)piperidine-1-carboxylate (0.684 g, 2.56 mmol), Cs2CO3 (1.55 g, 4.76 mmol) in DMF (5 mL) was purged with N2for 15 min. Pd(PPh3)2Cl2(0.11 g, 0.15 mmol) and CuI (0.060 g, 0.32 mmol) were added under N2and the mixture stirred at 70 °C for 4 h. The reaction was quenched with cold water (25 mL) and extracted with EtOAc (3x 25 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, 40-50% EtOAc / PE) to afford the title compound as a brown solid (0.43 g, 63%). LCMS m / z = 371 [M-56]+. Step 5. Synthesis of 3-(4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl 4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidine-1-carboxylate (Step 4, 1.0 g, 2.35 mmoL) in DCM (10.0 mL) was added 4.0 M HCl in dioxane (5 mL) at 0 °C and the reaction mixture stirred at rt for 4 h. The reaction mixture was evaporated to dryness and the residue quenched with saturated sodium bicarbonate (20 mL) and extracted with 20% IPA / CDCl3 (3x 20 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.90 g). LCMS m / z = 327 [M+H]+. Intermediate 29. 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylic acid. Step 1. Synthesis of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4- nitrobenzenesulfonamide. To a stirred solution of (1r,4r)-4-(bromomethyl)cyclohexan-1-amine hydrochloride (Intermediate 7, 1.00 g, 5.2 mmol) in DCM (60 mL) were added Et3N (2.25 mL, 15.60 mmol) and 3-fluoro-4-nitrobenzenesulfonyl chloride (1.50 g, 6.25 mmol) at 0 °C and the resulting reaction mixture stirred at 0 °C for 1 h. The reaction mixture was diluted with water (70 mL) and extracted with DCM (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20% EtOAc / PE) to afford the title compound as a brown solid (1.20 g, 58%). LCMS m / z = 394 [M+H]+. Step 2. Synthesis of 4-amino-N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3- fluorobenzenesulfonamide. To a stirred solution of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4- nitrobenzenesulfonamide (Step 1, 1.20 g, 3.03 mmol) in EtOH (50 mL) and water (50 mL) was added NH4Cl (3.24 g, 60.7 mmol) and iron powder (3.39 g, 60.7 mmol) at rt and the resulting reaction mixture stirred at 60 °C for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (1.00 g, 90%). LCMS m / z = 365 [M+H]+. Step 3. Synthesis of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide. 4-methylbenzenesulfonic acid (2.55 g, 14.8 mmol) was added to a stirred solution of 4- amino-N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluorobenzenesulfonamide (Step 2, 1.80 g, 4.93 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2- methylpropan-2-ol (Intermediate 1, 1.58 g, 4.93 mmol) in THF (20 mL) at rt and stirred at 90 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 40 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 20-30% EtOAc / PE) to afford the title compound as a white solid (1.70 g, 53%). LCMS m / z = 649 [M+H]+. Step 4. Synthesis of tert-butyl 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylate. To a stirred solution of N-((1r,4r)-4-(bromomethyl)cyclohexyl)-3-fluoro-4-((4-(1-(2-hydroxy- 2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)benzenesulfonamide (Step 3, 0.4 g, 0.62 mmol) in dioxane (40 mL) were added Cs2CO3(0.40 g, 1.23 mmol), KI (0.05 g, 0.31 mmol), and tert-butyl piperidine-4-carboxylate hydrochloride (0.68 g, 3.08 mmol) at rt and the resulting mixture heated at 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure and the residue diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford a residue that was purified by column chromatography (SiO2, 24% EtOAc / PER) to afford the title compound as an off- white solid (0.30 g, 65%). LCMS m / z = 754 [M+H]+. Step 5. Synthesis of 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylic acid. TFA (2 mL) was added to a stirred solution of tert-butyl 1-(((1r,4r)-4-((3-fluoro-4-((4-(1-(2- hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexyl)methyl)piperidine-4-carboxylate (0.30 g, 0.398 mmol) in DCM (2 mL) at 0 °C and stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown liquid (0.20 g, 72%). LCMS m / z = 698 [M+H]+. Intermediate 30. 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carbaldehyde. Step 1. Synthesis of 4-(1,3-dioxolan-2-yl)-1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidine To a stirred solution of 4-(1,3-dioxolan-2-yl)piperidine (2 g,12.7 mmol) and 3-fluoro-4- nitrobenzenesulfonyl chloride (3.66 g, 15.3 mmol) in DCM (60 mL) was added trimethylamine (18.4 mL, 127 mmol) dropwise at 0 °C and the resulting reaction mixture stirred for 1 h at rt. The reaction mixture was quenched with water (60 mL) and extracted with DCM (3x 50 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20-25% EtOAc / PE) to give the title compound as a yellow solid (2.5 g, 54%). LCMS m / z = 361 [M+H]+. Step 2. Synthesis of 4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2-fluoroaniline To a stirred solution of 4-(1,3-dioxolan-2-yl)-1-((3-fluoro-4-nitrophenyl)sulfonyl)piperidine (Step 2, 3 g, 5.23 mmol) in MeOH (80 mL) was added Palladium on carbon (0.84 g, 7.85 mmol) at rt and the mixture stirred under the atmosphere of H2 (120 PSI) for 6 h at rt. The reaction mixture was filtered through a pad of celite and washed with MeOH (3x 60 mL). The combined filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid (2 g, 87%). LCMS m / z = 331 [M+H]+. Step 3. Synthesis of 1-(4-(2-((4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2- fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2- ol To a stirred solution of 4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2-fluoroaniline (Step 2, 0.30 g, 0.91 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 0.23 g, 0.73 mmol) in dioxane (5 mL) was added Cs2CO3 (0.89 g , 2.72 mmol) at 0 °C and the mixture purged with argon for 15 min. To this was added at rt BINAP (0.06 g, 0.09 mmol) and Pd(OAc)2(0.02 g, 0.09 mmol) and resulting mixture heated at 100 °C under microwave irradiation for 2 h. The reaction mixture was filtered through a pad of celite washed with EtOAc (3x 30 mL). The filtrate was diluted with water (60 mL) and extracted with EtOAc (2x 30 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 40-50% EtOAc / PE) to afford the title compound as a white semi-solid (0.20 g, 36%). LCMS m / z = 615 [M+H]+. Step 4. Synthesis of 1-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidine-4-carbaldehyde To a stirred solution of 1-(4-(2-((4-((4-(1,3-dioxolan-2-yl)piperidin-1-yl)sulfonyl)-2- fluorophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2- ol (Step 3, 0.70 g, 1.14 mmol) in DCM (15 mL) was added TFA (6 mL) at 0 °C and the resulting reaction mixture stirred for 18 h at rt. The reaction mixture was diluted with ice- cold saturated NaHCO3(20 mL) and extracted with DCM (2x 30 mL). The combined organics were washed with water (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 40-50% EtOAc / PE) to afford the title compound as a brown solid (0.55 g, 85%). LCMS m / z = 571 [M+H]+. Intermediate 31. (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid. Step 1. Synthesis of tert-butyl 4-((3-fluoro-4-nitrophenyl)sulfonamido)piperidine-1- carboxylate To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (4 g, 20.0 mmol) in DCM (20 mL) was added triethylamine (6.06 g, 59.9 mmol) at rt and cooled to 0 °C (solution A). Then a solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (5.742 g, 23.966 mmol, 1.2 equiv.) in DCM (20 mL) (solution B) maintained at 0 °C was added to the solution A at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. After completion of reaction, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with DCM (3×50 mL). The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound (5.20 g). The crude was purified by flash chromatography, using (100-200 mesh) silica and ethyl acetate in pet ether (50-60%) as eluent to afford 22a (4.20 g, 52.13%) as yellow solid. LCMS m / z = 348 [M+H]+. Step 2. Synthesis of tert-butyl 4-((4-amino-3-fluorophenyl)sulfonamido)piperidine-1- carboxylate 10% Palladium on activated carbon, (3.20 g) was added to a solution of tert-Butyl 4-((3- fluoro-4-nitrophenyl)sulfonamido)piperidine-1-carboxylate (Step 1, 4.0 g, 9.91 mmol) in methanol (60 mL) at rt and reaction mixture was stirred at rt under H2 atmosphere (15 PSI) for 4 h. The reaction mixture was filtered through a celite bed and washed with 30% MeOH in DCM (2x 100 mL). The combined organics were concentrated under reduced pressure to afford the title compound as a brown solid (3.5 g, 94%). LCMS m / z = 372 [M+H]+. Step 3. Synthesis of tert-butyl 4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidine-1- carboxylate To a stirred solution of tert-butyl 4-((4-amino-3-fluorophenyl)sulfonamido)piperidine-1- carboxylate (Step 2, 2.0 g, 5.36 mmol) and 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1, 2.58 g, 8.03 mmol) in THF (20 mL) was added p-toluene sulfonic acid monohydrate (1.12 g, 5.89 mmol) at rt and the mixture stirred at 100 °C for 16 h. After completion of the reaction the reaction mixture was diluted with water (50 mL) and extracted with 20% MeOH in DCM (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (1.50 g; 40%). LCMS m / z = 558 [M-100]+. Step 4. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(piperidin-4-yl)benzenesulfonamide A solution of tert-butyl 4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidine-1-carboxylate (Step 3, 3.0 g, 4.56 mmol) and formic acid (30 mL) was stirred at 0 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with saturated NaHCO3solution and extracted with 20% IPA / CHCl3(2100 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (2.50 g, 98%). LCMS m / z = 558 [M+H]+. Step 5. Synthesis of methyl (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylate To a stirred solution of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)-N-(piperidin-4-yl)benzenesulfonamide (Ste p4, 1.00 g, 1.79 mmol) and methyl (1r,4r)-4-formylcyclohexane-1-carboxylate (0.46 g, 2.69 mmol) in MeOH (10 ml), was added acetic acid (0.01 mL, 0.18 mmol) and MP-Cyanoborohydride (1.00 g) portion wise at room temperature and stirred at rt for 16 h. The reaction mixture was filtered through celite bed and washed with MeOH (2x 20 mL). The filtrate was concentrated under reduced pressure and the residue purified by column chromatography (15% MeOH / DCM) to afford the title compound as a pale brown solid (1.0 g, 78% ). LCMS m / z = 712 [M+H]+. Step 6. Synthesis of (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid To a stirred solution of methyl (1r,4r)-4-((4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)- 1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)piperidin-1- yl)methyl)cyclohexane-1-carboxylate (Step 5, 0.60 g, 0.84 mmol) in THF (7 mL) and water (7 mL) was added lithium hydroxide (0.14 g, 5.90 mmol) portion wise at rt and the resulting reaction mixture stirred at the same temperature for 4 h. The reaction mixture was washed with diethyl ether (3x 20 mL). Then the aqueous layer was acidified to pH 5 with 1N HCl and extracted with 20% IPA / CHCl3) (3x 100 mL). The combined organics were washed with saturated brine solution (50 mL), dried (Na2SO4) and concentrated in vacuo to afford the title compound as a pale brown solid (0.50 g; 85%). LCMS m / z = 698 [M+H]+. Intermediate 32.3-(4-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2 dione. Step 1. Synthesis of tert-butyl 1'-(4-bromophenyl)-[4,4'-bipiperidine]-1-carboxylate. To a stirred solution of tert-butyl [4,4'-bipiperidine]-1-carboxylate (3.00 g, 11.18 mmol) in DCM (60 mL) were added (4-bromophenyl)boronic acid (2.25 g, 11.18 mmol) followed by TEA (4.65 mL, 33.53 mmol) at rt. The reaction mixture was degassed with O2 gas for 15 min and copper (II) acetate (0.81 g, 4.47 mmol) added and stirred at rt for 16 h. The reaction mixture was diluted with water (150 mL) and filtered through a pad of celite and washed with DCM (2x 200 mL). The combined organics were dried (Na2SO4) and concentrated under the reduced pressure. The residue was purified by chromatography (SiO2, 10-50% EtOAc / PE) to afford the title compound as a white solid (3.50 g, 74%). LCMS m / z = 423 [M+H]+. Step 2. Synthesis of tert-butyl 1'-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-[4,4'- bipiperidine]-1-carboxylate To a stirred solution of tert-butyl 1'-(4-bromophenyl)-[4,4'-bipiperidine]-1-carboxylate (Step 1, 3.50 g, 8.27 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (5.18 g, 12.40 mmol) in dioxane / water (55 mL, 10:1) was added potassium phosphate (4.39 g, 20.67 mmol). The reaction mixture was purged with Ar for 20 minute and PdCl2(dppf).DCM (0.34 g, 0.41 mmol) added and the resulting reaction mixture stirred for 3 h at 110 °C. The reaction mixture was filtered through a pad of celite and washed with EtOAc (3x 50 mL). The filtrate was washed with water (4x 100 mL), brine (2x 100 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by chromatography (SiO2, 0-20% EtOAc / PE) to afford the title compound as an off-white solid (2.50 g, 48%). LCMS m / z = 634 [M+H]+. Step 3. Synthesis of tert-butyl 1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1- carboxylate To a suspension of tert-butyl 1'-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-[4,4'- bipiperidine]-1-carboxylate (Step 2, 2.50 g, 3.94 mmol) in ethanol (50 mL) was added 10% Palladium on activated carbon (2.50 g) and the reaction mixture stirred at rt under H2 (120 psi) atmosphere for 48 h. The reaction mixture was filtered through a pad of celite and washed with methanol (4x 100 mL). The filtrate was concentrated under reduced pressure and the residue triturated with Et2O to afford the title compound as a white solid (1.00 g, 56%). LCMS m / z = 456 [M+H]+. Step 4. Synthesis of 3-(4-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione To a stirred solution of tert-butyl 1'-(4-(2,6-dioxopiperidin-3-yl)phenyl)-[4,4'-bipiperidine]-1- carboxylate (Step 3, 1.00 g, 2.19 mmol) in DCM (10 mL) was added 4N HCl in dioxane (5 mL) dropwise at rt and stirred for 3h. The reaction mixture was evaporated to dryness under the reduced pressure and the residue diluted with saturated solution of aqueous sodium bicarbonate (25 mL) and extracted with 10% IPA / CHCl3. The combined organics were combined, dried (Na2SO4) and evaporated to dryness to afford the title compound as an off- white solid (700 mg, 90%). LCMS m / z = 356 [M+H]+. Intermediate 33. 3-(3-([4,4'-bipiperidin]-1-yl)phenyl)piperidine-2,6-dione. The title compound was prepared as a pale yellow liquid (900 mg) from (3- bromophenyl)boronic acid and tert-butyl [4,4'-bipiperidine]-1-carboxylate using an analogous 3-Step procedure as described for Intermediate 32. LCMS m / z = 356 [M+H]+. Intermediate 34. 3-(3-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione. Step 1. Synthesis of tert-butyl (1-((4-(iodomethyl)piperidin-1-yl)sulfonyl)piperidin-4- yl)carbamate To a stirred solution of 4-(iodomethyl)piperidine (6.00 g, 26.7 mmol) in DCM (60 mL) was added triethylamine (11.2 mL, 80 mmol) and tert-butyl (1-(chlorosulfonyl)piperidin-4- yl)carbamate (Intermediate 39, 7.96 g, 26.7 mmol) at 0 °C under nitrogen atmosphere and the reaction mixture stirred at rt for 3 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3x 100 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 35-45% EtOAc / PE) to afford the title compound as a white solid (5.00 g, 38%). LCMS m / z = 488 [M+H]+. Step 2. Synthesis of tert-butyl (1-((4-((4-((3-(3-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1- yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 3-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)piperidine-2,6- dione (0.5 g, 1.53 mmol) in dioxane (5 mL) was added DIPEA (0.82 mL, 4.60 mmol) and tert-butyl (1-((4-(iodomethyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 1, 1.12 g, 2.30 mmol) and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organics were washed with brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 4-5% MeOH / DCM) to afford the title compound as a brown oil (0.80 g, 76%). LCMS m / z = 686 [M+H]+. Step 3. Synthesis of 3-(3-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)phenyl)piperidine-2,6-dione hydrochloride 4M HCl in 1,4-dioxane (4 mL) was added to a stirred solution of tert-butyl (1-((4-((4-((3-(3- (2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidin-1- yl)sulfonyl)piperidin-4-yl)carbamate (Step 2, 0.89 g, 1.30 mmol) in DCM (4 mL) at 0 °C and the reaction mixture stirred for 2 h at rt. The reaction mixture was evaporated under reduced pressure and the residue triturated with Et2O (5 mL) to afford the title compound as a brown solid (0.80 g, 98%). LCMS m / z = 586 [M+H]+. Intermediate 35. 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-sulfonyl chloride.

[0017] Step 1. Synthesis of Synthesis of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidine A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.8 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.87 g, 13.8 mmol), Pd(dppf)Cl2(112 mg, 0.138 mmol), K2CO3 (1.90 g, 13.8 mmol) in dioxane (30 mL) and water (8 mL) was stirred at 50 °C for 3 h. The reaction mixture was evaporated to dryness and the residue purified on silica gel column (25% EtOAc / PE) to afford the title compound as a white solid (1.5 g, 41%). LCMS m / z = 263 [M+H]+; Step 2. Synthesis of tert-butyl 4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate A solution of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Step 1, 1.5 g, 5.71 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.48 g, 7.42 mmol), DIPEA (1.10 g, 8.56 mmol) in IPA (30 mL) was stirred at 80 °C for 3 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue purified by column chromatography (SiO2, 5% MeOH / DCM) to afford the title compound as a colourless oil (2.2 g, 90%). LCMS m / z = 427 [M+H]+. Step 3. Synthesis of 4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine To a solution of tert-butyl 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-carboxylate (Step 2, 2.2 g, 5.15 mmol) in DCM (20 mL) was added TFA (8 mL) and the reaction mixture stirred at rt for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with DCM. Washed with sat. Na2CO3. The organic layer was separated and dried over Na2SO4. Filtered and concentrated to dryness to afford title compound (1.2 g, yield=71.4%) as a light-yellow oil. LCMS m / z = 327 [M+H]+. Step 4. Synthesis of 4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidine-1-sulfonyl chloride To a solution of 4-(1-methyl-1H-pyrazol-4-yl)-N-(piperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (Step 3, 300 mg, 0.919 mmol) and TEA (371 mg, 3.67 mmol) in DCE (6 mL) was added sulfuroyl dichloride (371 mg, 2.75 mmol) at 0oC and then at 50oC for 16 h. The reaction mixture was quenched with water and extracted with DCM. The combined organics was dried (Na2SO4) and concentrated to dryness to afford title compound as a yellow solid (300 mg, 77%). LCMS m / z = 425 [M+H]+. Intermediate 36. 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione. Step 1: Synthesis of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine- 1-carboxylate. To a solution of benzyl 4-formylpiperidine-1-carboxylate (20 g, 80.9 mmol) and tert-butyl piperazine-1-carboxylate (15.06 g, 80.9 mmol) in DCM (400 mL) was added NaBH(OAc)3(34.28 g, 162 mmol) and HOAc (5.83 g, 97.1 mmol) and the mixture stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with H2O (300 mL) and extracted with EtOAc (3x 300 mL). The combined organics were washed with brine (2x 150 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-40% THF / PE) to afford the title compound as a white solid (33.1 g, 93%). LCMS m / z = 418 [M+H]+. Step 2. Synthesis of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate. A mixture of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1- carboxylate (Step 1, 33 g, 79.03 mmol) and Pd / C (4.21 g, 3.95 mmol, 10% purity) in IPA (400 mL) was degassed and purged with H2(3x) and the mixture stirred at 25 °C for 10 h under H2. The mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (21 g, 85%).1H NMR (400MHz, DMSO-d6): 4.53 (br s, 2H), 3.34-3.22 (m, 4H), 2.94 (br d, 2H), 2.48-2.43 (m, 1H), 2.25 (br t, 4H), 2.08 (br d, 2H), 1.67- 1.53 (m, 3H), 1.38 (s, 9H), 1.05-0.96 (m, 2H). Step 3. Synthesis of tert-butyl 4-((1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4- yl)methyl)piperazine-1-carboxylate. A mixture of 5-bromoisobenzofuran-1(3H)-one (17.5 g, 82.15 mmol), tert-butyl 4-(piperidin- 4-ylmethyl)piperazine-1-carboxylate (Step 2, 20.95 g, 73.93 mmol), Pd2(dba)3 (3.76 g, 4.11 mmol), Xantphos (2.85 g, 4.93 mmol) and K3PO4 (17.44 g, 82.15 mmol) and tri-tert- butylphosphonium tetrafluoroborate (1.19 g, 4.11 mmol, 0.05 equiv.) in dioxane (400 mL) was degassed and purged with N2 (3x) and the mixture stirred at 100 °C for 18 h under N2. The reaction mixture was concentrated under reduced pressure and the residue diluted with H2O (300 mL) and extracted with DCM (3x 300 mL). The combined organics were washed with brine (2x 250 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-10% MeOH / DCM) to afford the title compound as a yellow solid (13 g, 37%). LCMS m / z = 416 [M+H]+. Step 4. Synthesis of 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2- (hydroxymethyl)benzoic acid. To a solution of tert-butyl 4-((1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperidin-4- yl)methyl)piperazine-1-carboxylate (Step 3, 13 g, 31.28 mmol) in MeOH (90 mL) and H2O (30 mL) was added NaOH (5.01 g, 125 mmol) and the mixture stirred at 50 °C for 3h. The reaction mixture was concentrated under reduced pressure, the pH adjusted to 3-4 with aqueous HCl (2M) and extracted with EtOAc (3x 150 mL). The combined organic layers were washed with H2O (2x 150 mL), dried (Na2SO4) and concentrated under reduced to afford the title compound as a yellow solid (12 g, 82%) which was used without further purification. Step 5. Synthesis of tert-butyl 4-((1-(3-(hydroxymethyl)-4- (methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate. To a solution of 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2- (hydroxymethyl)benzoic acid (Step 4, 13 g, 29.98 mmol) in MeOH (50 mL) and EtOAc (50 mL) was added trimethylsilyldiazomethane (2 M, 22.5 mL) and the mixture stirred at -10 °C for 10 min. The reaction mixture was concentrated under reduced pressure and the residue diluted with H2O (100 mL) and extracted with EtOAc (3x 100 mL). The combined organics were washed with brine (2x 100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-40% THF / PE) to give the title compound as a yellow solid (12.5 g, 80%). Step 6. Synthesis of tert-butyl 4-((1-(3-formyl-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-((1-(3-(hydroxymethyl)-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (Step 5, 12.5 g, 28 mmol) in DCM (130 mL) were added NaHCO3 (2.35 g, 28 mmol, 1.09 mL) and Dess-Martin (10.98 g, 25.9 mmol, 8.01 mL) and the mixture stirred at 0 °C for 1h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, 0-50% THF / PE) to afford the title compound as a yellow oil (7.95 g, 69%). Step 7. Synthesis of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidin-4-yl)methyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-((1-(3-formyl-4-(methoxycarbonyl)phenyl)piperidin-4- yl)methyl)piperazine-1-carboxylate (6.4 g, 14.36 mmol) and 3-aminopiperidine-2,6-dione (3.78g, 23.0 mmol) and NaOAc (3.54 g, 43.1 mmol) in MeOH (40 mL) was added NaBH3CN (1.35 g, 21.5 mmol) and the mixture was stirred at 20-40 °C for 10 h. The reaction mixture was concentrated under reduced pressure and the residue purified by flash chromatography (SiO2, 0-10% MeOH / DCM) to afford the title compound was a white solid (3.5 g, 49%). Step 8. Synthesis of 3-(1-oxo-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindolin-2- yl)piperidine-2,6-dione trifluoroacetate. A solution of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazine-1-carboxylate (3.2 g, 5.97 mmol) in DCM (21 mL) and TFA (7 mL) was stirred at 0 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (2.8 g, 85%). LCMS m / z = 426 [M+H]+. Intermediate 37. 3-(1-oxo-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2- yl)isoindolin-2-yl)piperidine-2,6-dione.

[0018] Step 1. Synthesis of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate A mixture of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1 g, 3.09 mmol), tert- butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (488 mg, 2.16 mmol), Pd-PEPPSI-IHeptCl 3- chloropyridine (120 mg, 123 µmol), Cs2CO3(3 g, 9.26 mmol) in dioxane (40 mL) was stirred at 100 ℃ for 3 h. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified using column chromatography to afford title compound as a yellow solid (700 mg, 69%). LCMS m / z = 469 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine- 2,6-dione To a solution of tert-butyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonane-7-carboxylate (700 mg, 1.49 mmol) in DCM (20 mL) was added TFA (8 mL) and stirred at 25 ℃ for 5 h. The reaction mixture was evaporated to dryness and the residue diluted with MTBE (20 mL) and the solid collected by filtration to afford title compound as an off-white solid (650 mg, TFA salt). LCMS m / z = 369 [M+H]+. Step 3. Synthesis of tert-butyl 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate To a solution 3-(1-oxo-4-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine-2,6-dione (250 mg, 678 µmol), tert-butyl 4-formylpiperidine-1-carboxylate (287 mg, 1.35 mmol), DIPEA (350 mg, 2.71 mmol) in DCM (12 mL) was added STAB (430 mg, 2.03 mmol) and the mixture stirred at 25 ℃ for 3 h. The reaction was quenched with water, evaporated to dryness and the residue purified by prep-TLC (25 / 1 DCM / MeOH) to afford title compound as a yellow solid (300 mg, 78%). LCMS m / z = 566 [M+H]+. Step 4. Synthesis of 3-(1-oxo-4-(7-(piperidin-4-ylmethyl)-2,7-diazaspiro[3.5]nonan-2- yl)isoindolin-2-yl)piperidine-2,6-dione To a solution of tert-butyl 4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2,7- diazaspiro[3.5]nonan-7-yl)methyl)piperidine-1-carboxylate (300 mg, 530 µmol) in DCM (8 mL) was added TFA (3 mL). Stirred at 25℃ for 3 h. Concentrated to dryness. The residue was diluted with MTBE (10 mL). Filtered. The solid was dried in vacuum to afford title compound (200 mg, TFA salt) as an off-white solid. LCMS m / z = 466 [M+H]+. Intermediate 38. 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidin-1- yl)methyl)cyclohexane-1-carboxylic acid. Step 1. Synthesis of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidine-1-carboxylate To a solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (2 g, 7.68 mmol) and tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (4.27 g, 15.3 mmol) in DMF (20 mL) was added t-BuOK (1.71 g, 15.3 mmol) and the mixture stirred at 100 ºC for 3 h. The reaction mixture was evaporated to dryness and the residue purified by column chromatography (SiO2, 5% MeOH / DCM) to afford the title compound as a light brown solid (1.2 g, 35%). LCMS m / z = 444 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate To a solution of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidine-1-carboxylate (Step 1, 1.2 g, 2.70 mmol) in DCM (15 mL) was added TFA (8 mL) and the mixture stirred at 25 ºC for 2 h. The reaction mixture was evaporated to dryness and the residue diluted with MTBE (30 mL). The solid was collected by filtration to afford the title compound as an off-white solid (1.1 g, TFA salt). LCMS m / z = 344 [M+H]+. Intermediate 39. tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl N-(piperidin-4-yl)carbamate (300 mg, 1.49 mmol) and TEA (452 mg, 4.47 mmol) in DCM (10 mL) was added SO2Cl2 (402 mg, 2.98 mmol) dropwise at 0°C and the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was washed with water and the combined organics evaporated to dryness to afford the title compound as an off-white solid (300 mg, crude) which was used without further purification. Intermediate 40. 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. Step 1. Synthesis of tert-butyl 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate To a solution of 3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6-dione (Intermediate 38, 800 mg, 2.32 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (989 mg, 4.64 mmol), DIPEA (1.19 g, 9.28 mmol) in DCM (20 mL) was added STAB (1.96 g, 9.28 mmol) at 0 ºC and the reaction mixture stirred at 25 ºC for 3 h. The reaction mixture was diluted with water, evaporated to dryness and the residue purified by column chromatography (SiO2, 10% MeOH / DCM) to afford the title compound as a light brown solid (750 mg, 60%). LCMS m / z = 541 [M+H]+. Step 2. Synthesis of 3-(1-oxo-4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)isoindolin-2- yl)piperidine-2,6-dione trifluoroacetate To a solution of tert-butyl 4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate (Step 1, 750 mg, 1.38 mmol) in DCM (10 mL) was added TFA (4 mL) and stirred at 25 ºC for 2 h. The reaction mixture was evaporated to dryness and the residue triturated with MTBE (15 mL). The solid was collected by filtration to afford the title compound as a light brown solid (600 mg) which was used without further purification. LCMS m / z = 441 [M+H]+. Step 3. Synthesis of tert-butyl (1-((4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate To a solution of 3-(1-oxo-4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)isoindolin-2- yl)piperidine-2,6-dione trifluoroacetate (Step 2, 200 mg, 0.45 mmol), tert-butyl (1- (chlorosulfonyl)piperidin-4-yl)carbamate (Intermediate 39, 200 mg, crude) in MeCN (15 mL) was added TEA (136 mg, 1.35 mmol) and stirred at 50°C for 16 h. The solution was concentrated to dryness and the residue was purified on prep-TLC (20:1 DCMMeOH) to afford the title compound as an off-white solid (200 mg, 63%). LCMS m / z = 703 [M+H]+. Step 4. Synthesis of 3-(4-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione trifluoroacetate To a solution of tert-butyl (1-((4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate (Step 3, 200 mg, 0.284 mmol) in DCM (8 mL) was added TFA (3 mL) and stirred at 25 ºC for 1 h. The reaction mixture was evaporated to dryness and the residue triturated with MTBE (10 mL). The solid was collected by filtration to afford the title compound as a white solid (100 mg). LCMS m / z = 603 [M+H]+. Intermediate 41. 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol- 4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylic acid.

[0019] Step 1. Synthesis of ethyl 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylate. HATU (80.17 mg, 0.21 mmol) was added to a stirred solution of (1r,4r)-4-((3-fluoro-4-((4-(1- (2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carboxylic acid (Intermediate 15, 150 mg, 0.250 mmol), DIPEA (0.13 mL, 0.75 mmol) and ethyl piperidine-4-carboxylate (39.3 mg, 0.250 mmol) in dry DMF (3 mL) 0 °C and the reaction mixture warmed to rt and stirred for 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with ethyl acetate (3x 15 mL). The combined organics were washed with water (2x 15 mL), brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (0-3% MeOH / DCM) to afford the title compound as an off-white solid (100 mg, 82%). LCMS m / z = 740 [M+H]+. Step 2. Synthesis of 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H- pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonamido)cyclohexane-1- carbonyl)piperidine-4-carboxylic acid. The title compound was prepared from ethyl 1-((1r,4r)-4-((3-fluoro-4-((4-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)phenyl)sulfonamido)cyclohexane-1-carbonyl)piperidine-4-carboxylate (Step 1) using an analogous method to that described for Intermediate 15. LCMS m / z = 712 [M+H]+. Intermediate 42. 1-methyl-3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6- dione hydrochloride. Step 1. Synthesis of tert-butyl 4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)piperidine-1-carboxylate. A mixture of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidine- 1-carboxylate (Intermediate 38, Step 1; 0.30 g, 0.68 mmol) and cesium carbonate (0.44 g, 1.35 mmol) in DMF (5 mL) was stirred for 10 min at rt. MeI (0.5 mL, 1.01 mmol) was added and stirred rt for 16 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2x 15 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to obtain the title compound (220 mg, 71%). Step 2. Synthesis of 1-methyl-3-(1-oxo-4-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6- dione. The title compound was prepared (100 mg, 58%) from tert-butyl 4-((2-(1-methyl-2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)piperidine-1-carboxylate (Step 1) using an analogous method to that described for Intermediate 54, Step 2. LCMS m / z = 358 [M+H]+. Intermediate 43. 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde. Step 1. Synthesis of ethyl 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate To a stirred solution of 2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine (Intermediate 35, Step 1, 2 g, 7.62 mmol) and ethyl 1-((4-aminopiperidin-1- yl)sulfonyl)piperidine-4-carboxylate (Intermediate 4, Step 2, 2.68 g, 8.38 mmol) in DMSO (30 mL) was added DIPEA (7.96 mL, 22.8 mmol) and the reaction mixture stirred at 80 ºC for 16 h. The reaction was diluted with water (40 mL) and extracted with EtOAc (2x 120 mL). The combined organics were concentrated under reduced pressure and the residue purified using column chromatography (SiO2, 50-60% EtOAc / PE) to afford the title compound as a yellow solid. (1.5 g, 36%). LCMS m / z = 546 [M+H]+. Step 2. Synthesis of (1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methanol To a stirred solution of ethyl 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carboxylate (Step 1, 2.0 g, 3.67 mmol) in THF (30 mL) at 0oC was added dropwise LAH (2.M solution in THF, 5.4 mL, 11 mmol). The reaction was quenched with sat. ammonium chloride solution and extracted with EtOAc (2x 75 mL). The combined organics evaporated to dryness to afford the title compound (1.4 g, 76%). LCMS m / z = 504 [M+H]+. Step 3. Synthesis of 1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidine-4-carbaldehyde A stirred solution of (1-((4-((4-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methanol (Step 2, 1.5 g, 2.98 mmol) and 2- iodoxybenzoic acid (3.34 g, 11.9 mmol, contains stabilizer, 45 wt. %) in DMSO (15 mL) was at rt overnight. The reaction was quenched with ice cold water (20-30 mL) and the solid collected by filtration. The solid was dissolved in EtOAc (100 mL) and washed with 1M sodium bicarbonate solution. The combined organics were dried (Na2SO4) and evaporated to dryness under reduced pressure to obtain the title compound (1 g, 67%). LCMS m / z = 502 [M+H]+. Intermediate 44. 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione. Step 1. Synthesis of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine To a stirred solution of 1-bromo-4-iodobenzene (0.6 g, 2.12 mmol) and 2,6-bis(benzyloxy)-3- (4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridine (1.07 g, 2.55 mmol) in dioxane (5.4 mL) and H2O) (0.6 mL) was added potassium phosphate (1.125 g, 5.30 mmol) and degassed with nitrogen stream for 5 min. Pd(dppf)Cl2.DCM (87 mg, 0.11 mmol) was added and the mixture stirred at 100 °C for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2x 45 mL). The combined organics were dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (SiO2, 5-10% EtOAc / PE) to afford the title compound. LCMS m / z = 446 [M+H]+. Step 2. Synthesis of tert-butyl 6-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate To a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (0.5 g, 1.12 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.244 g, 1.23 mmol) in dioxane (10 mL) were added TEA (0.178 mL, 1.23 mmol) and sodium tert-butoxide (0.355 g, 3.70 mmol) and degassed with nitrogen stream for 5 minutes. Tris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.056 mmol) and BINAP (0.070 g, 0.112 mmol) were added and the resulting reaction mixture was heated at 110 °C for 12 h. The reaction was quenched with water (70 mL) and extracted with ethyl acetate (2x 55 mL). The combined organics were dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography using (SiO2, 5-10% EtOAc / PE) to afford the title compound. LCMS m / z = 564 [M+H]+. Step 3. Synthesis of tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6- diazaspiro[3.3]heptane-2-carboxylate 10 % Pd / C (0.4 g) was added to a stirred, degassed solution of tert-butyl 6-(4-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Step 2, 0.4 g, 0.71 mmol) in EtOH (4 mL) and EtOAc (2 mL) and hydrogenated at 120 PSI H2 and stirred at rt for 16 h. The reaction mixture filtered through a pad of celite and washed with MeOH (3x 50 mL) and evaporated to dryness under reduced pressure afford the title compound as a clear oil (0.25 g, 91%). LCMS m / z = 386 [M+H]+. Step 4. Synthesis of 3-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione A solution of tert-butyl 6-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (Step 3, 0.23 g, 0.60 mmol) in formic acid (2.5 mL) was stirred at rt for 4 h. The reaction mixture was quenched with sat. bicarbonate solution and extracted with EtOAc (2x 50 mL). The combine organics were dried and evaporated to dryness to afford the title compound (160 mg, 94%). LCMS m / z = 286 [M+H]+. Intermediate 45. 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione. Step 1. Synthesis of 1-(3-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione Acrylic acid (5.17 mL, 75.6 mmol) was added to a solution of 3-bromoaniline (10 g, 58.13 mmol) in toluene (100 mL) at rt and the reaction mixture stirred at 100 °C for 16 h. The toluene was removed under vacuum and AcOH (49.9 mL, 872 mmol) and urea (52.37 g, 872 mmol) added at rt and the reaction mixture stirred at 120 °C for 24 h. The reaction mixture was cooled to 0 °C and ice cold water (100 mL) added and stirred for 15 min. The solids were collected by filtration and washed with ice cold water and diethyl ether to afford the title compound (9.2 g, 61%).1H NMR (400 MHz, DMSO-d6): 10.45 (s, 1H), 7.59 (s, 1H), 7.43- 7.40 (m, 1H), 7.35 (d, 2H), 3.79 (t, 2H), 2.72-2.50 (t, 2H). Step 2. Synthesis of tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)prop- 2-yn-1-yl)oxy)piperidine-1-carboxylate A mixture of 1-(3-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione (2.00 g, 7.43 mmol), tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (2.69 g, 11.15 mmol) and caesium carbonate (6.05 g, 18.58 mmol) in DMF (20 mL) at rt was purged with nitrogen for 15 min. Pd(PPh3)2Cl2 (0.52 g, 0.74 mmol) and copper(I) iodide (0.28 g, 1.49 mmol) were added under nitrogen atmosphere and the resulting reaction mixture stirred at 70oC for 16 h. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3x 100 mL). The combined organics were washed with brine solution (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 50-60% EtOAc / PE) to afford to the title compound as a brown solid (1.20 g, 51%). LCMS m / z = 428 [M+H]+. Step 3. Synthesis of 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione Formic acid (6 mL) was added to tert-butyl 4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (1.2 g, 2.81 mmol) at rt and stirred for 2 h. The formic acid was removed under reduced pressure and the residue diluted with water (20 mL) and extracted with 10% MeOH / CHCl3(3x 50 mL). The combined organics were washed with brine solution (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.68 g, 74%). LCMS m / z = 328 [M+H]+. Intermediate 46. 1-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione. Step 1. Synthesis of tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate To a stirred solution of 1-(3-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)phenyl)dihydropyrimidine- 2,4(1H,3H)-dione Intermediate 45 (0.30 g, 0.92 mmol) and 1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (0.25 g, 1.10 mmol) in DMF (3 mL) were added HATU (0.69 g, 1.83 mmol) and DIPEA (0.48 mL, 2.75 mmol) at rt and the reaction mixture stirred for 16 h. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (3x 25 mL). The combined organics were washed with brine solution (15 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.26 g, 53%). LCMS m / z = 539 [M+H]+. Step 2. Synthesis of 1-(3-(3-((1-(piperidine-4-carbonyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione Formic acid (1.3 mL) was added to tert-butyl 4-(4-((3-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)phenyl)prop-2-yn-1-yl)oxy)piperidine-1-carbonyl)piperidine-1-carboxylate (Step 1, 0.26 g, 0.48 mmol) at rt and stirred for 2 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue diluted with water (20 mL) and extracted with 10% MeOH / CHCl3 (3x 20 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a brown solid (0.12 g, 55%). LCMS m / z = 439 [M+H]+. Intermediate 47. 4-amino-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluorobenzenesulfonamide. Step 1. Synthesis of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (Chem. Comm., 2017, 53, 7577-7580, 1.00 g, 3.64 mmol), sodium bicarbonate (0.30 g, 3.64 mmol) and 5-(tert-butoxycarbonyl)-2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl 4- methylbenzenesulfonate (Org. Lett., 2004, 6, 3715-3718, 1.99 g, 3.64 mmol) in DMF (20 mL) added potassium bromide (0.86 g, 7.29 mmol) at rt and the resulting reaction mixture heated at 70oC for 16h. The reaction mixture was quenched with sat. NH4Cl solution (50 mL) and extracted with EtOAc (2x 20 mL). The combined organics were washed with water (2x 20 mL), brine solution (2x 20 mL), dried (Na2SO4) and concentrated under the reduced pressure. The residue was purified by flash chromatography (SiO2, 1-5% MeOH / DCM) to afford the title compound as a semi-solid (1.40 g, 59 %). LCMS m / z = 648 [M+H]+Step 2: Synthesis of 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride To a stirred solution of tert-butyl (tert-butoxycarbonyl)(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (0.70 g, 2.55 mmol) in DCM (14 mL) was added 4.0 M HCl in dioxane (2.5 mL) at 0 °C and the reaction mixture allowed to warm to rt and stirred for 3h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to afford the title compound as an off-white foam (0.55 g, 36 %). LCMS m / z = 650 [M+H]+Step 3: Synthesis of N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluoro-4-nitrobenzenesulfonamide To a stirred solution 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride (0.50 g, 1.02 mmol) in DCM (10 mL) was added triethylamine (0.42 mL, 3.08 mmol) dropwise at -10 °C and stirred for 15 min at same temperature. To this solution was added a solution of 3-fluoro-4- nitrobenzenesulfonyl chloride (0.49 g, 2.05 mmol) in DCM (10 mL) drop wise at -10 °C and the resulting reaction mixture was stirred for 1h at same temperature. The reaction mixture was diluted with water (25 mL) and extracted with DCM (3x 20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-3% MeOH / DCM) to afford the title compound as a pale orange solid (0.40 g, 60%). LCMS m / z = 653 [M+H]+Step 4: Synthesis of 4-amino-N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluorobenzenesulfonamide To a stirred solution of N-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-3-fluoro-4-nitrobenzenesulfonamide (0.35 g, 0.53 mmol) in EtOH (10 mL) and water (10 mL) was added ammonium chloride (0.57 g, 10.72 mmol) and iron powder (0.59 g, 10.72 mmol) at 0 °C and the resulting reaction mixture stirred at 60 °C for 16h. The reaction mixture was filtered through a pad of celite and washed with EtOAc (2x 10 mL). The filtrate was diluted with water (10 mL) and extracted with EtOAc (20 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure and the residue purified by combi flash chromatography (neutral alumina, 0-3% MeOH / DCM) to afford the title compound as a brown semi-solid (0.12 g; 36 %). LCMS m / z = 623 [M+H]+Intermediate 48. 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

[0020] Step 1: Synthesis of tert-butyl (1-((4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) piperidin-1-yl) sulfonyl) piperidin-4-yl) carbamate To a stirred solution of 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 16, 0.16 g, 0.28 mmol) in DCM (5 mL) and tert-butyl (1-(chlorosulfonyl) piperidin-4-yl) carbamate (0.12 g, 0.42 mmol) was added triethylamine (0.19 mL, 1.40 mmol) under inert atmosphere at rt and the resulting reaction mixture heated at 35 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2, 70-100% EtOAc / PE) to afford the title compound as a brown solid (0.17 g, 82%). LCMS m / z = 742 [M+H]+. Step 2: Synthesis 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4- yl)methyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a stirred solution of tert-butyl (1-((4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 4-yl) prop-2-yn-1-yl) oxy) piperidin-1-yl) methyl) piperidin-1-yl) sulfonyl) piperidin-4-yl) carbamate (0.17 g, 0.23 mmol) in DCM (3 mL) was added TFA (0.42 mL, 5.52 mmol) at 0 °C and the resulting reaction mixture stirred at rt for 8 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with diethyl ether (3x 10mL) to afford the title compound as a brown solid (0.14 g, 83.3%) which was used without purifcation. Intermediate 49. 3-(1-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1- yl)isoindolin-2-yl)piperidine-2,6-dione.

[0021] Step 1: Synthesis of tert-butyl 4-((4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate To a stirred solution of 3-(1-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione (Intermediate 16, 0.30 g, 0.79 mmol) and tert-butyl 4- formylpiperidine-1-carboxylate (0.21 g, 1.02 mmol) in MeOH (3 mL) were added a...

Claims

What is claimed is:

1. A compound of Formula (II),or a pharmaceutically acceptable salt thereof, wherein R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independentlyselected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2; L is a linker moiety; Ring B is:Each Y1is independently selected from C(Rd5)2and NRc12; Y2is C(Re3)2 or C(=O); W is CH or N; Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc13and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1or Rb2attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc12, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd5is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re3is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; and t is an integer from 0 to 4.

2. The compound of claim 1, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt thereof, wherein R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 to 3 Ra1, wherein C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb1, wherein the 3 to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc1and then is optionally substituted on a ring carbon with 1 to 4 Rb1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2; R3is selected from H, D, halo, CN, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, C5- C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl, C5-C12spirocycloalkyl, and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 12-membered heterocyclyl, 5 to 12-membered spiroheterocyclyl, and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2;L1is selected from a covalent bond, -S(=O)2-, -*NRc3-S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2- NRc3-(C(Rd1)2)n-, -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-, -*NRc3-S(=O)2-(C(Rd1)2)n-O- (C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb3, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 4 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 4 Rb4; or X1– L2– X2form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb5, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 4 Rb5; L3is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; Each X3is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12- membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb6, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ringheteroatoms each independently selected from O, S, N, and NRc9and then are optionally substituted on a ring carbon with 1 to 4 Rb6; or X2– L3– X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7; or Two X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7; L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, - *(C(Rd4)2)n-C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O- (C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, - *NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n- NRc11-C(=O)- wherein * denotes the point of attachment of L4to Ring B; wherein no more than three of L1, X1, L2, X2, and L4can simultaneously be a covalent bond; Ring B isEach Y1is independently selected from C(Rd5)2 and NRc12; Y2is C(Re3)2 or C(=O); W is CH or N; Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the C3-C6cycloalkyl is optionally substituted with D, OH, or -CH2OH, and wherein the 3 to 6-membered heterocyclyl has 1 to 4 ringheteroatoms each independently selected from O, S, N, and NRc13and then is optionally substituted on a ring carbon with D, OH, or -CH2OH; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2Rb3, Rb4, Rb5, Rb6, or Rb7attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc12, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 4 groups each independently selected from D and OH; Each Rd1, Rd2, Rd3, Rd4, and Rd5is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3is independently selected from H, D, and C1-C4alkyl; m is 0, 1, or 2; n is an integer from 0 to 8; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 4.

3. The compound of claim 2, wherein the compound is of Formula (IV):wherein t is an integer from 0 to 4, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein the compound is of Formula (IVa),(IVb), (IVc), or (IVd):or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2, wherein the compound is of Formula (V):wherein t is an integer from 0 to 3, 6. The compound of claim 5, wherein the compound is of Formula (Va), (Vb), (Vc), (Vd), (Ve), or (Vf):or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 2 to 6, wherein R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6- membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN;R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; orX1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; X3is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then are optionally substituted on a ring carbon with 1 to 3 Rb6; or X2– L3– X3form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, and -*NRc11-(C(Rd4)2)n-C(=O)- wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2or C(=O); Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb1, Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb1, Rb2Rb3, Rb4, Rb5, Rb6, or Rb7attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN;Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, Rc11, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Each Rd1, Rd2, Rd3, and Rd4is independently selected from H, D, halo, OH, C1-C4alkyl, and C3-C6cycloalkyl; Each Re1, Re2, and Re3is independently selected from H, D, and C1-C4alkyl; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3.

8. The compound of any one of claims 2 to 6, wherein R1is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, and C1-C4alkyl; R4is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6is H or D; R7is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms eachindependently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(R2d)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L3is selected from -O-, -(C(Rd3)2)n-, -*NRc8-(C(Rd3)2)n-, -*C(=O)-(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-, wherein * denotes the point of attachment of L3to X2; X3is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb6, and wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then are optionally substituted on a ring carbon with 1 to 3 Rb6; orX2– L3– X3form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 3 Rb7; or L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2 or C(=O); Each Ra1and Ra2is independently selected from H, D, OH, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, Rb6, Rb7, and Rb8is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2Rb3, Rb4, Rb5, Rb6, or Rb7attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc8, Rc9, Rc10, and Rc11is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4is independently selected from H, D, and C1-C4alkyl; Each Re1, Re2, and Re3is independently H or D; n is an integer from 0 to 4; p is 0 or 1; q is 0, 1, or 2; r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3.

9. The compound of claim 2, wherein the compound is of Formula (VI):or a pharmaceutically acceptable salt thereof.

10. The compound of claim 2, wherein the compound is of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 4.

11. The compound of claim 10, wherein the compound is of Formula (VIIa) or (VIIb):or a pharmaceutically acceptable salt thereof.

12. The compound of claim 2, wherein the compound is of Formula (VIII):or a pharmaceutically acceptable salt thereof, wherein t is an integer from 0 to 3.

13. The compound of claim 12, wherein the compound is of Formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), or (VIIIf):or a pharmaceutically acceptable salt thereof.

14. The compound of claim 2, wherein the compound is of Formula (IX):or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 10 to 14, wherein R1is selected from C1-C6alkyl, C3-C6cycloalkyl, and 3 to 6-membered heterocyclyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1, and wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc1; R2is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, C1-C4alkyl, and C3-C6cyclcoalkyl; R4is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R5is selected from H, D, halo, OH, CN, C1-C4alkyl, C1-C4alkoxy, and C3-C6cyclcoalkyl, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; R6is H or D; R7is selected from H, D, C1-C4alkyl, and C(=O)-C1-4alkyl; Ring A is selected from C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb2, and wherein the 3 to 10-membered heterocyclyl, 5 to 10-membered spiroheterocyclyl, and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-, -*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3;L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C8cycloalkyl, 3 to 10-membered heterocyclyl, 6 to 10-membered aryl, and 5 to 10-membered heteroaryl, wherein the C3-C8cycloalkyl and 6 to 10-membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 10-membered heterocyclyl and 5 to 10-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -* NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2 or C(=O); Each Ra1and Ra2is independently selected from D, halo, OH, C3-C6cycloalkyl, and 3 to 6- membered heterocyclyl, wherein the 3 to 6-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc13; Each Rb2, Rb3, Rb4, Rb5, and Rb8is independently selected from D, halo, OH, CN, N(Rc14)2, C1-C4alkyl, and C1-C4alkoxy, or two Rb2Rb3, Rb4, or Rb5attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc1, Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14is independently selected from H, D, C1-C4alkyl, and C(=O)C1-4alkyl; Each Rd1, Rd2, and Rd4is independently selected from H, D, halo, OH, C1-C4alkyl, and C3- C6cycloalkyl; Each Re1and Re3is independently selected from H, D, and C1-C4 alkyl;n is an integer from 0 to 4; r is an integer from 1 to 6; s is 0 or 1; and t is an integer from 0 to 3.

16. The compound of any one of claims 10 to 14, wherein R1is C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra1; R2is selected from H, D, and C1-C4alkyl, wherein the C1-C6alkyl is optionally substituted with 1 or 2 Ra2; R3is selected from H, D, and C1-C4alkyl; R4is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R5is selected from H, D, halo, OH, CN, and C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from D, halo, OH, and CN; R6is H or D; R7is selected from H, D, and C1-C4alkyl; Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6-membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6-membered aryl are each optionally substituted with 1 to 3 Rb2, wherein the 3 to 6-membered heterocyclyl and 5 or or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 3 Rb2; L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-NRc3-(C(Rd1)2)n-,-*S(=O)2- (C(Rd1)2)n-O-(C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-, wherein * denotes the point of attachment of L1to Ring A; X1is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatomseach independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3; L2is selected from a covalent bond, -(C(Rd2)2)n-, -*NRc5-(C(Rd2)2)n-, -*(C(Rd2)2)n-C(=O)-, - *(C(Rd2)2)n-O-(C(Rd2)2)n-, and -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, wherein * denotes the point of attachment of L2to X1; X2is selected from a covalent bond, C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb4, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 3 Rb4; or X1– L2– X2form a 5 to 10-membered spiroheterocyclyl, wherein the 5 to 10-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc7and then are optionally substituted on a ring carbon with 1 to 3 Rb5; L4is selected from a covalent bond, -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*C2-C6alkenylene-(O)s-, -*C2- C6 alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O-(C(Rd4)2)n-C(=O)-NRc11-, -*NRc11- (C(Rd4)2)n-C(=O)-NRc11-, wherein * denotes the point of attachment of L4to Ring B; wherein at least one of X1and X2is not a covalent bond; Y2is C(Re3)2 or C(=O); Each Ra1and Ra2is independently selected from H, D, and C1-C4alkyl; Each Rb2, Rb3, Rb4, Rb5, and Rb8is independently selected from D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, or two Rb2, Rb3, Rb4, or Rb5attached to the same atom, form a =O, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 3 groups each independently selected from D, halo, OH and CN; Each Rc2, Rc3, Rc4, Rc5, Rc6, Rc7, Rc11, Rc13, and Rc14is independently selected from H, D, and C1-C4alkyl; Each Rd1, Rd2, Rd3, and Rd4is independently selected from H, D, and C1-C4alkyl; Each Re1and Re3is independently H or D; n is an integer from 0 to 4;r is an integer from 1 to 6; s is 1; and t is an integer from 0 to 3.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C6alkyl optionally substituted with 1 or 2 Ra1.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1is C1-C6alkyl optionally substituted with OH.

19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R1is CH3 or CH2C(CH3)2OH.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R2is H or C1-C4alkyl, wherein the C1-C4alkyl is optionally substituted with 1 to 3 Ra2.

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R2is H.

22. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R3is H.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4is C1-C4alkyl, CN, or halo, wherein said C1-C4alkyl is optionally substituted with 1 to 3 groups each independently selected from halo.

25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4is CH3, CHF2, CF3, CN, or Cl.

26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4is CF3.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R5is selected from H, D, halo, OH, CN, C1-C4alkyl, and C1-C4alkoxy, wherein the C1-C4alkyl and C1-C4alkoxy are each optionally substituted with 1 to 4 groups each independently selected from D, halo, OH and CN.

28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R5is selected from H, D, halo, OH, and CN.

29. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R5is H.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R6is H.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7is selected from H, D, and C1-C4alkyl.

32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7is H or C1-C4alkyl.

33. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

34. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, wherein R7is H.

35. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, C5-C12spirocycloalkyl, 5 to 12-membered spiroheterocyclyl, phenyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl, C5-C12spirocycloalkyl, and phenyl are each optionally substituted with 1 to 4 Rb2, and wherein the 3 to 6-membered heterocyclyl, 5 to 12- membered spiroheterocyclyl, and 5 or 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc2and then are optionally substituted on a ring carbon with 1 to 4 Rb2.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from C3-C6cycloalkyl optionally substituted with 1 to 4 Rb2.

37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl optionally substituted with 1 to 4 Rb2.

38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl.

39. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with 1 to 4 Rb2.

40. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

41. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 4 Rb2.

42. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1 to 4 Rb2.

43. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl.

44. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 5 to 12-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2.

45. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is 6 to 11-membered spiroheterocyclyl optionally substituted with 1 to 4 Rb2.

46. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is 2-azaspiro[3.3]heptanyl optionally substituted with 1 to 4 Rb2.

47. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is 2-azaspiro[3.3]heptanyl.

48. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 4 Rb2.

49. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl optionally substituted with 1 to 4 Rb2.

50. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl.

51. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Ring A is cyclohexyl, phenyl, piperidinyl, 2-azaspiro[3.3]heptanyl, or pyridinyl, each of which is optionally substituted with 1 to 4 Rb2.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein Rb2is selected from C1-C4alkyl and halo.

53. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein Rb2is C1-C4alkyl.

54. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt thereof, wherein Rb2is selected from F and methyl.

55. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is selected from -S(=O)2-, -*S(=O)2-NRc3-, -*S(=O)2-(C(Rd1)2)n-O- (C(Rd1)2)n-, and -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-.

56. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is selected from -S(=O)2- and -*S(=O)2-NRc3-.

57. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is selected from -S(=O)2- and -*S(=O)2-NH-.

58. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is -S(=O)2-.

59. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is -*S(=O)2-NRc3-.

60. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is -*S(=O)2-(C(Rd1)2)n-O-(C(Rd1)2)n-.

61. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is -*S(=O)2-(CH2)3-O-CH2-.

62. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is -*S(=O)2-NRc3-(C(Rd1)2)n-O-(C(Rd1)2)n-.

63. The compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, wherein L1is -*S(=O)2-NH-(CH2)2-O-CH2-.

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is a covalent bond.

65. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, 6- membered aryl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl and 6- membered aryl are each optionally substituted with 1 to 3 Rb3, and wherein the 3 to 6- membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3.

66. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 or 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 3 Rb3, wherein the 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc4and then are optionally substituted on a ring carbon with 1 to 3 Rb3.

67. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb3.

68. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is cyclobutyl or cyclohexyl.

69. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb3.

70. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is pyrrolidinyl, piperidinyl, or piperazinyl.

71. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb3.

72. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein X1is 1,2,3-triazolyl.

73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is selected from -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-, -(C(Rd2)2)n-, - *(C(Rd2)2)n-C(=O)-, -*NRc5-(C(Rd2)2)n-, and -*(C(Rd2)2)n-O-(C(Rd2)2)n-.

74. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is selected from -*(CH2CH2O)r-(CH2)n-, -(CH2)n-, -*(CH2)n-C(=O)-, - *NRc5-(CH2)n-, and -*(CH2)n-O-(CH2)n-.

75. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is -*(C(Re1)2C(Re1)2O)r-(C(Rd2)2)n-.

76. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is -*(CH2CH2O)r-(CH2)n-.

77. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is -(C(Rd2)2)n-.

78. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is -(CH2)n-.

79. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is -*(C(Rd2)2)n-O-(C(Rd2)2)n-.

80. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt thereof, wherein L2is -*(CH2)n-O-(CH2)n-.

81. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is a covalent bond.

82. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is selected from C3-C10cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 12-membered aryl, and 5 to 12-membered heteroaryl, wherein the C3-C10cycloalkyl and 6 to 12-membered aryl are each optionally substituted with 1 to 4 Rb4, and wherein the 3 to 12-membered heterocyclyl and 5 to 12-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 4 Rb4.

83. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is selected from C3-C6cycloalkyl, 3 to 6-membered heterocyclyl, and 5 to 6-membered heteroaryl, wherein the C3-C6cycloalkyl is optionally substituted with 1 to 4 Rb4, and wherein the 3 to 6-membered heterocyclyl and 5 to 6-membered heteroaryl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc6and then are optionally substituted on a ring carbon with 1 to 4 Rb4.

84. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is selected from C3-C6cycloalkyl optionally substituted with 1 to 3 Rb4.

85. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is cyclohexyl.

86. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is selected from 3 to 6-membered heterocyclyl optionally substituted with 1 to 3 Rb4.

87. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is azetidinyl, piperidinyl, or piperazinyl.

88. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is selected from 5 or 6-membered heteroaryl optionally substituted with 1 to 3 Rb4.

89. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2is 1,2,3-triazolyl.

90. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is selected from -O-, -*C(=O)-(C(Rd3)2)n-, -(C(Rd3)2)n-, and - *(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-.

91. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is -O-.

92. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is -*C(=O)-(C(Rd3)2)n-.

93. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is -*C(=O)-(CH2)n-.

94. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is -(C(Rd3)2)n-.

95. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is -(CH2)n-.

96. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is -*(C(Re2)2C(Re2)2O)r-(C(Rd3)2)n-.

97. The compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, wherein L3is -*(CH2CH2O)r-(CH2)n-.

98. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein X3is selected from 3 to 6-membered heterocyclyl having 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRc9and then is optionally substituted on a ring carbon with 1 to 3 Rb6.

99. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein X3is selected from piperazinyl and piperidinyl, each optionally substituted on a ring carbon with 1 to 3 Rb6.

100. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein X3is selected from piperazinyl and piperidinyl.

101. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2– L3– X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7.

102. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2– L3– X3form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12- membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7.

103. The compound of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, wherein X2– L3– X3form a 10 to 11-membered spiroheterocyclyl, wherein the 10 to 11-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from N and NRc10.

104. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein two X3form a C5-C12spirocycloalkyl or 5 to 12-membered spiroheterocyclyl, wherein the C5-C12spirocycloalkyl is optionally substituted with 1 to 4 Rb7, and wherein the 5 to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7.

105. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein two X3form a 5 to 12-membered spiroheterocyclyl, wherein the 5 to 12- membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRc10and then are optionally substituted on a ring carbon with 1 to 4 Rb7.

106. The compound of any one of claims 1-97, or a pharmaceutically acceptable salt thereof, wherein two X3form 3,9-diazaspiro[5.5]undecane optionally substituted on a ring carbon with 1 to 4 Rb7.

107. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is a covalent bond.

108. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is selected from -O-, -C(=O)-, -(C(Rd4)2)n-, -NRc11-, -*NRc11-(C(Rd4)2)n-, -*(C(Rd4)2)n-NRc11-, -*O-(C(Rd4)2)n-, -*(C(Rd4)2)n-O-, -*C(=O)-(C(Rd4)2)n-, -*(C(Rd4)2)n- C(=O)-, -*C2-C6alkenylene-(O)s-, -*C2-C6alkynylene-(O)s-, -*O-(C(Rd4)2)n-C(=O)-, -*O- (C(Rd4)2)n-C(=O)-NRc11-, -*O-(C(Rd4)2)n-NRc11-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-, - *NRc11-(C(Rd4)2)n-C(=O)-, and -*NRc11-(C(Rd4)2)n-NRc11-C(=O)-.

109. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is selected from -O-, -NRc11-, -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-, -*C2- C6alkynylene-(O)s-, -*NRc11-(C(Rd4)2)n-, -*O-(C(Rd4)2)n-C(=O)-, -*NRc11-(C(Rd4)2)n-C(=O)-, and -*O-(C(Rd4)2)n-C(=O)-NRc11-.

110. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is selected from -O-, -NH-, -*NH-(CH2)n-C(=O)-NH-, -*C2- C6alkynylene-(O)s-, -*NH-(CH2)n-, -*O-(CH2)n-C(=O)-, -*NH-(CH2)n-C(=O)-, and -*O- (CH2)n-C(=O)-NH-.

111. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is selected from -O- and -NRc11-.

112. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is -*NRc11-(C(Rd4)2)n-C(=O)-NRc11-.

113. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is -*O-(C(Rd4)2)n-C(=O)-NRc11-.

114. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is -*C2-C6alkynylene-O-.

115. The compound of any one of claims 1-106, or a pharmaceutically acceptable salt thereof, wherein L4is -*C2-C6alkynylene-.

116. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with 1 to 4 Rb2and L1is -*S(=O)2- NRc3-.

117. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with 1 to 4 Rb2, L1is -*S(=O)2-NRc3- , and X1is C3-C8cycloalkyl.

118. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1 to 4 Rb2and L1is - S(=O)2-.

119. The compound of any one of claims 1-115, or a pharmaceutically acceptable salt thereof, wherein Ring A is piperidinyl optionally substituted with 1 to 4 Rb2, L1is -S(=O)2-, and X1is 3 to 10-membered heterocyclyl.

120. The compound of any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein Ring.

121. The compound of any one of claims 1-119, or a pharmaceutically acceptable salt thereof, wherein Ring122. The compound of any one of claims 1-121, or a pharmaceutically acceptable salt thereof, wherein Rb8is halo or C1-C4alkyl.

123. The compound of any one of claims 1-121, or a pharmaceutically acceptable salt thereof, wherein Rb8is F or methyl.

124. The compound of any one of claims 1-121, or a pharmaceutically acceptable salt thereof, wherein Rb8is methyl.

125. The compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, wherein W is CH.

126. The compound of any one of claims 1-124, or a pharmaceutically acceptable salt thereof, wherein W is N.

127. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1is C(Rd5)2.

128. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1is CH2.

129. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1is NRc12.

130. The compound of any one of claims 1-126, or a pharmaceutically acceptable salt thereof, wherein Y1is NH.

131. The compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, wherein Y2is C(Re3)2.

132. The compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, wherein Y2is CH2.

133. The compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, wherein Y2is C(=O).

134. The compound of any one of claims 1-133, or a pharmaceutically acceptable salt thereof, wherein m is 0.

135. The compound of any one of claims 1-133, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

136. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is 0.

137. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 8.

138. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 4.

139. The compound of any one of claims 1-135, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 2.

140. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof, wherein p is 0.

141. The compound of any one of claims 1-139, or a pharmaceutically acceptable salt thereof, wherein p is 1.

142. The compound of any one of claims 1-141, or a pharmaceutically acceptable salt thereof, wherein q is 0.

143. The compound of any one of claims 1-141, or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

144. The compound of any one of claims 1-143, or a pharmaceutically acceptable salt thereof, wherein r is an integer from 1 to 3.

145. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt thereof, wherein s is 0.

146. The compound of any one of claims 1-144, or a pharmaceutically acceptable salt thereof, wherein s is 1.

147. The compound of any one of claims 1-146, or a pharmaceutically acceptable salt thereof, wherein t is 0.

148. The compound of any one of claims 1-146, or a pharmaceutically acceptable salt thereof, wherein t is an integer from 1 to 3.

149. The compound of claim 1, wherein the compound is selected from the following:HO N N N F N F F, or a pharmaceutically acceptable salt of any of the aforementioned.

150. A pharmaceutical composition comprising a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

151. A method of degrading CDK2, comprising contacting CDK2 with a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof.

152. A method of treating cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-149, or a pharmaceutically acceptable salt thereof.

153. The method of claim 152, wherein the cancer is selected from anal cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, liver cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, and uterine cancer.

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