Bifunctional compounds containing thiazolyl derivatives for degrading certain cyclin-dependent kinase via ubiquitin proteasome pathway

Abstract

The present disclosure provides certain bifunctional compounds containing thiazolyl derivatives that cause degradation of Cyclin-dependent kinase 2 (CDK2) and / or Cyclin-dependent kinase 4 (CDK4) via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by CDK2 and / or CDK4. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

[0001]Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT BIFUNCTIONAL COMPOUNDS CONTAINING THIAZOLYL DERIVATIVES FOR DEGRADING CERTAIN CYCLIN-DEPENDENT KINASE VIA UBIQUITIN PROTEASOME PATHWAY 5 Cross-reference to Related Applications This International Patent Application claims the benefit of U.S. Provisional Application No.63 / 643,889, filed on May 7, 2024; the entire contents of which are hereby incorporated by reference. 10 Field of the disclosure The present disclosure provides certain bifunctional compounds containing thiazolyl derivatives that cause degradation of Cyclin-dependent kinase 2 (CDK2) and / or Cyclin-dependent kinase 4 (CDK4) via ubiquitin proteasome pathway and are therefore useful for the treatment of 15 diseases mediated by CDK2 and / or CDK4. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. Background Cyclin-dependent kinases (CDKs) are essential cellular serine / threonine kinases that play 20 an important role in orchestrating signaling events, such as DNA replication and protein synthesis, to ensure faithful eukaryotic cell division and proliferation. The regulation of CDK activity is tightly controlled by the fluctuating levels of various cyclins, which form heterodimeric complexes with CDKs to activate them. Out of the 21 identified CDKs, CDK1 / Cyclin B, CDK2 / Cyclin E, CDK2 / Cyclin A, CDK4 / Cyclin D, CDK6 / Cyclin D complexes are well known to 25 be vital regulators of cell cycle progression. Other CDKs are involved in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D. O. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291). In the canonical model of cell cycle, mitogenic signaling upregulates D-type cyclins, which directly bind and activate CDK4 / 6. Active CDK4 / 6-cyclin D complexes partially phosphorylate Rb, disrupting the Rb / E2F interaction and de-repressing E2F activity,30 leading to upregulation of cyclin E, a CDK2 activator. Cdk2-cyclin E further hyper- phosphorylates Rb, releasing E2F to transcribe genes required for S-phase entry. During S-phase, cyclin E is degraded and CDK2 forms a complex with cyclin A to promote phosphorylation of substrates essential for DNA replication and inactivation of E2F, completing S-phase (Asghar et al. Nat. Rev. Drug. Discov. (2015) 14: 130-146). CDK1-Cyclin A and CDK1-Cyclin B complexes - 1 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT are activated in late S and G2 phases to drive the transition into and completion of mitosis, respectively (Katsuno et al., 2009; Lindqvist et al., 2009; Lohka et al., 1988). Due to their crucial roles in regulating cell cycle and other essential cellular processes, increased activity or temporally abnormal activation of CDKs has been shown to promote 5 tumorigenesis and disease progression (Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Nat. Med. (1995) 1:309-320; Hall M, Peters G. Adv. Cancer Res. (1996) 68:67-108). Genetic changes in CDK-cyclin complexes and the proteins that regulate them are widespread in various cancers and are often associated with poor clinical outcomes. Common alterations include amplifications / overexpression of cyclin D, cyclin E, CDK4 and CDK6; loss of 10 Rb; deficiency in CDK inhibitory regulators such as p16, p21, p27, and loss‑of‑function mutations in FBXW7, a component of SCFFbw7ubiquitin E3 ligase responsible for cyclin E degradation. (Smalley et al. Cancer Res. (2008) 68: 5743-52). Over the last two decades, there has been significant interest in developing CDK inhibitors for therapeutic purposes. In combination with endocrine therapies, selective reversible inhibitors 15 of CDK4 and CDK6 e.g., palbociclib, ribociclib, and abemaciclib have revolutionized the therapeutic management for hormone receptor-positive (HR+) metastatic breast cancer (MBC). Ongoing clinical trials are also investigating these CDK4 / 6 inhibitors as single agents or in combination with other therapeutics for various cancers. (O'Leary et al. Nature Reviews (2016) 13:417-430). 20 Despite their significant clinical efficacy in ER-positive metastatic breast cancer, CDK4 / 6 inhibitors have some limitations. One major drawback is the development of primary or acquired resistance over time. An important mechanism of resistance involves the abnormal activation of CDK2. This can occur due to an overactivated CDK2 / Cyclin E complex caused by elevated Cyclin E expression (Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561) or formation of the 25 noncanonical CDK2 / cyclin D1 complex in response to CDK4 / 6 inhibition (Herrera-Abreu MT et al, Cancer Res. (2006) 15: 2301), which bypasses the need for CDK4 / 6 for cell cycle reentry. Additionally, CDK4 / 6 inhibitors palbociclib and ribociclib exhibit relatively high hematological toxicity, primarily neutropenia. CDK6 is highly expressed in the blood system and plays a role in regulating the growth of hematopoietic cells. Therefore, it is generally believed that the inhibition 30 of CDK6 leads to neutropenia, while breast cancer cells mainly depend on CDK4 for proliferation. Abemaciclib exhibits weaker inhibition of CDK6 than CDK4, resulting in lower hematological toxicity. Currently, multiple CDK2 inhibitors are under clinical development in solid tumors including PF-07104091 (NCT04553133), BLU-222 (NCT05252416), INCB123667 - 2 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT (NCT05238922), INX-315 (NCT05735080), ARTS-021 (NCT05867251), AZD8421 (NCT06188520) and BG-68501 (NCT06257264). Thus far, PF-07104091 and BLU-222 have demonstrated single agent activities in CDK4 / 6 inhibitor refractory breast cancer patients In addition, a CDK4 specific inhibitor PF-07220060 (NCT04557449), in combination with endocrine 5 therapy, has demonstrated clinical responses and lower neutropenia adverse events in CDK4 / 6 inhibitor refractory breast cancer patients. Thus, a molecule blocking both CDK2 and CDK4 as single agent or in combination with endocrine therapy, may address the primary and acquired resistance to CDK4 / 6 inhibitors, leading to enhanced antitumor activities and reduced adverse effects to achieve greater therapeutic efficacy in HR+ HER2- breast cancer. 10 Considering these factors, developing a small molecule inhibitor or a proteolysis-targeting chimeric molecule (PROTAC) that specifically targets CDK4 and / or CDK2 could represent a therapeutic opportunity with reduced toxicity and improved overall therapeutic efficacy. PROTACs are bifunctional molecules comprised of target protein-recruitment moiety and a ligand for E3 ligase, connected by a biocompatible linker. PROTACs bring the protein of 15 interest and the E3 ligase into close proximity and induce ubiquitination and subsequent degradation of the target protein by proteasome. Compared to small molecule drugs that typically bind disease-relevant proteins and inhibit their function, PROTACs display several unique and attractive features that make them desirable drug candidates. For example, PROTACs have been shown to be more selective than their 20 inhibitor counterparts, potentially reducing off-target toxicity. Moreover, PROTACs can perform multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can function at sub-stoichiometric receptor occupancies. The E3 ligases used in PROTACs mainly include cereblon (CRBN), Von Hippel–Lindau-containing complex (VHL), inhibitor of apoptosis protein (IAP), and mouse double minute 2 (MDM2). 25 Therefore, PROTACs that could recruit CDK2 and / or CDK4 to a ubiquitin ligase, and thereby causing ubiquitylation and proteasomal degradation of CDK2 and / or CDK4 are desirable. The present disclosure fulfills this and related needs. Summary 30 In a first aspect, provided is a compound of Formula (I): 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT (I) wherein R1is alkyl, cycloalkyl, cycloalkylalkyl, bridged cycloalkyl, cycloalkoxy, heterocyclyl, alkoxy, aryl, arylalkyl, arylalkoxy, heteroaryl, halo, cyano, haloalkyl, haloalkoxy, hydroxy, 5 hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino, where each of the aforementioned rings, by itself or as part of another group, is substituted with one or two substitutions independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R2is hydrogen or deuterium; and 10 Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the aforementioned rings is substituted with Ra, Rb, and Rcindependently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; Degron is an E3 ubiquitin ligase ligand selected from: 15 (a) a group of formula (i): ( : 20 ( ): - 4 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT (d) a group of formula (iv): ( 5 ( 10 w Yais CH or N; Zais a bond, -CH2-, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is attached to Ya; - 5 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT ring A is a group of formula (a), (b), or (c): where: Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, 5 alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R4and R5are independently hydrogen or alkyl; or R4and R5together with the carbon to which they are attached form >C=O; M is -O- or -NR6-; and R6is hydrogen or alkyl; and 10 R6is hydrogen or alkyl; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein in each heteroarylene one to three ring atoms are independently selected from nitrogen or oxygen atoms and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted 15 with Reeand Rffindependently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and X1, X2, X3, and X4are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NRgg-alkylene)-, -(alkylene-NRhh)-, , -NH-, -N(alkyl)-, –C(=O)-, –NRjjC(=O)-, or –C(=O)NRkk- where Rgg, Rhh, Rjj, and Rkkare independently hydrogen, alkyl, or 20 cycloalkyl and each alkylene, itself or as part of another group, is optionally substituted with one or two fluoro; Ry, Ry1, and Ry2are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with Rdand Rfselected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino; and 25 Wais bond, O, S, or alkylene; and L is -Z1-Z2-Z3-Z4-Z5-Z6- where: Z1is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O)2NR-, -NR’S(O)2-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with Rhand Riindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, 30 haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; - 6 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Z2is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR’(CO)-, -(O-alkylene)b-, -(alkylene-O)b-, -O(CH2)7-, -O(CH2)8-, cycloalkylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rjand Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, 5 haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; Z3is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, -(O-alkylene)c-, -(alkylene-O)c-, cycloalkylene, spiro cyclolalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)- monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, unsaturated heterocyclylene, 10 heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, -spiro heterocyclylene-(alkylene)-, or 11 to 13 membered spiro heterocyclylene, where each ring, by itself or as part of another group, is substituted with Rmand Rnindependently 15 selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; Z4is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -(alkylene-NR”)-, -(NR”- alkylene)-, -O-, -C(O)-, -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, cycloalkylene, -(alkylene)- cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, 20 heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene- (alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene- (alkylene)-, where each ring, by itself or as part of another group, is substituted with Roand Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, 25 cyano, hydroxy, amino, alkylamino, and dialkylamino; Z5is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O)2-, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or unsaturated heterocyclylene, or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; and 30 Z6is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR’(CO)-, or -C(O)NR-; where each R, R’ and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z1-, -Z2-, -Z3-, -Z4-, -Z5- and -Z6-, by itself or as part of another group and heteroalkylene of -Z3- and -Z4- are independently - 7 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT substituted with Rs, Rt, and Ruwhere Rsis hydrogen, deuterium, or halo, Rtis hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halo, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or 5 bridged heterocyclyl (where cycloalkyl, either by itself or as part of cycloalkyloxy, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, either by itself or as part of heterocyclyloxy or heterocyclylcarbonyl, and bridged heterocyclyl are substituted with R7and R8independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano), and Ruis 10 hydrogen or halo; or when Rtand Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the alkylene or heteroalkylene, Rtand Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by Rtand Ruare substituted with R9and R10independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, 15 alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano), alkenylene of -Z3- and -Z4- are substituted with Rvselected from hydrogen, fluoro, and cyano, and alkynylene of -Z3- and -Z4- are substituted with Rwand Rxindependently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano; or when Rwand Rxare attached to the same carbon atoms of the alkynylene, they can combine to form cycloalkylene or heterocyclylene wherein the cycloalkylene and 20 heterocyclylene are substituted with R11and R12independently selected from hydrogen, alkyl, and halo; provided that at least one of -Z1-Z2-Z3-Z4-Z5-Z6- is not a bond; or a pharmaceutically acceptable salt thereof. In a second aspect, provided is a compound of Formulae (IB): 25 wherein: R1, R2, and Hy are as defined in Formula (I) above or any of the embodiments thereof herein below; L is a Linker (in one embodiment Linker is -Z1-Z2-Z3-Z4-Z5-Z6- as defined in Formula (I) 30 above) or any one of embodiments thereof herein below); and Degron is an E3 ubiquitin ligase ligand; or - 8 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT a pharmaceutically acceptable salt thereof. In a third aspect, provided is a method of treating a disease mediated by CDK2 and / or CDK4 in a patient, in one embodiment the patient is in need of such treatment, which method comprises administering to the patient, in one embodiment a patient in need of such treatment, a 5 therapeutically effective amount of a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the third aspect, the disease is cancer. In a second embodiment of the third aspect, the disease is cancer selected from lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial 10 adenoma, and / or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi sarcoma, and / or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and / or mouth), liver cancer (e.g., hepatocellular 15 carcinoma and / or cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g., exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, bone cancer, biliary tract cancer, vaginal cancer, astrocytoma, liposarcomas, glioblastoma, neuroblastoma and / or kidney cancer. In a third embodiment of the third aspect, the cancers are those that are resistant to CDK4 / 6 20 inhibitors through CDK2-mediated mechanisms e.g., breast cancer. In a fourth embodiment of the third aspect, the disease is an autoimmune disease, or a condition associated with an autoimmune disease, which method comprises administering to the patient, in one embodiment a patient in need of such treatment, a therapeutically effective amount of a compound of any one of first and second aspects (or any of the embodiments thereof described herein), or a pharmaceutically 25 acceptable salt thereof. In some embodiments, the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), uveitis, pemphigus vulgaris, and sepsis. In a fifth embodiment of the third aspect, the disease is gout. In a sixth embodiment of the third aspect, the therapeutically effective amount 30 of a compound of Formulas (I) and (IB) (or any embodiment thereof disclosed herein including specific compounds), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition. In a fourth aspect, provided is a method of treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss, which method comprises - 9 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT administering to a patient, in one embodiment a patient in need of such treatment, a therapeutically effective amount of a compound of any one of first and second aspects, (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In some embodiments of the fourth aspect, the amount of hearing loss is reduced when compared to an 5 age-matched control. In some embodiments, the hearing loss is prevented when compared to an age-matched control. In a fifth aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. 10 In a sixth aspect, provided is a compound of (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment of the sixth aspect, the compound of Formula (I) or (IB) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof is useful for the treatment of one or more diseases disclosed in the third and fourth aspects above. 15 In a seventh aspect, provided is the use of a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK2 and / or CDK4 contributes to the pathology and / or symptoms of the disease. In one embodiment of the seventh aspect, the disease is one or more diseases disclosed in the third or fourth aspect 20 above. In an eighth aspect, provided is a method of degrading CDK2 and / or CDK4 in a cell via ubiquitin proteasome pathway which method comprises contacting the cell with a compound of Formula (I) or (IB) (or embodiments thereof as disclosed herein, including specific compounds). In one embodiment of the eighth aspect, CDK2 and / or CDK4 are degraded in vitro. In another 25 embodiment of the eighth aspect, CDK2 and / or CDK4 are degraded in vivo. In another embodiment of the eighth aspect, CDK2 and / or CDK4 are degraded in a cell in a patient. In an embodiment of any one of the above aspects, CDK2 is selectively degraded over CDK1 by a compound of Formula (I) or (IB). In another embodiment of any one of above aspects, CDK2 is selectively degraded over CDK1 and CDK4; or CDK4 is selectively degraded over 30 CDK1 and CDK2 by a compound of Formula (I) or (IB). In some embodiments, both CDK2 and CDK4 are degraded by a compound of Formula (I) or (IB), including CDK2 and CDK4 are selectively degraded over CDK1. The ability of compounds of Formula (I) and (IB) to degrade CDK2 and CDK4 selectively over CDK1 was measured by determining potency of the compounds in inhibiting retinoblastoma - 10 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT protein (Rb) phosphorylation in OVCAR3 (CDK2 dependent cell line), T47D (CDK4 dependent cell line) and KYSE520 (CDK1 dependent cell line) as described in Biological Example 1 below, and then determining the ratio of Rb IC50 from OVCAR3 and KYSE520 and T47D and KYSE520, respectively. Additionally, although the compounds of Formula (I) and (IB) degrade 5 both CDK2 and CDK4, they can, however, cause degradation of CDK2 to a greater extent than CDK4 or visa-versa. The degree of degradation of CDK2 and CDK4 can be determined by determining the ratio of Rb IC50 from OVCAR3 and T47D. For sake of clarity, selectively degrade as used herein means the compound disclosed herein may cause degradation of one protein to a greater extent than the other. 10 In the aforementioned aspects involving the treatment of cancer, further embodiments are provided comprising administering the compound of any one of first aspect, second aspect, third aspect, and Formula (IB), or a pharmaceutically acceptable salt thereof (or any embodiments thereof disclosed herein) or the pharmaceutical composition of the seventh aspect, in combination with at least one additional anticancer agent. When combination therapy is used, the agents can be 15 administered simultaneously or sequentially. Detailed Description Definitions: Unless otherwise stated, the following terms used in the specification and claims are 20 defined for the purposes of this Application and have the following meaning: “Alkyl” means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. “Alkylene” means a linear or branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise stated. When alkylene contains three to six carbon atoms it is also 25 referred to herein as C3 to C6 alkylene, Examples include, but are not limited to, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like. “Alkenylene” means a linear or branched unsaturated divalent hydrocarbon radical of two to six carbon atoms containing a double bond, e.g., ethen-diyl, propen-diyl, 2-propen-diyl, buten- diyl, penten-diyl, and the like. 30 “Alkynylene” means a linear or branched unsaturated divalent hydrocarbon radical of two to eight carbon atoms containing a triple bond, e.g., , , and thelike. “Alkoxy” means a -ORzradical where Rzis alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. - 11 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Alkoxyalkyl” means alkyl as defined above that is substituted with alkoxy as defined above e.g., methoxymethyl, methoxyethyl, ethoxyethyl, and the like. “Alkoxycarbonyl” and “alkyloxycarbonyl” mean a –C(O)ORzradical where Rzis alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like. 5 “Alkylcarbonylamino” means a –NRz’C(O)Rzradical where Rzis alkyl and Rz’ is H or alkyl, as defined above, e.g., methylcarbonylamino, ethylcarbonylamino, and the like. “Acyl” means a –C(O)Rzradical where Rzis alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, as defined herein, e.g., methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, 10 cyclopropylcarbonyl, and the like. When Rzis alkyl, acyl is also referred to herein as “alkylcarbonyl.” “Amido” means an -NRzC(O)- or -C(O)NRz- group, where Rzis hydrogen or alkyl as defined above. “Sulfonamido” means an -NRzS(O)2- or -S(O)2NRz- group, where Rzis hydrogen or alkyl 15 as defined above. “Amino” means –NH2.“Aminocarbonyl” means -C(O)NH2. “Alkylaminocarbonyl” means -C(O)NHRzradical where Rzis alkyl as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like. 20 “Dialkylaminocarbonyl” means -C(O)NRz1Rzradical where Rzand Rz1are independently alkyl as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like. “Alkylamino” means -NHRzradical where Rzis alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like. 25 “Alkylsulfonyl” means -S(O)2Rzwhere Rzis alkyl as defined above e.g., methylsulfonyl, ethylsulfonyl, and the like. “Alkylamino” means -NHRzradical where Rzis alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like. “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 30 10 ring atoms e.g., phenyl or naphthyl. “Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene. “Aralkyl” means an –(alkylene)-Rzradical where Rzis aryl as defined above e.g. benzyl. “Arylalkoxy” means an -ORzradical where Rzis arylalkyl as defined above. - 12 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Bicyclic heterocyclylene” means a saturated or unsaturated, divalent fused bicyclic group of 8 to 12 ring atoms in which one, two, or three ring atoms are heteroatoms independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being carbon, unless stated otherwise. Additionally, one or two ring 5 carbon atoms of the bicyclic heterocyclylene ring can optionally be replaced by a –CO- group. More specifically the term bicyclic heterocyclylene includes, but is not limited to, isoindolin- diyl, decahydro-2,6-naphthyridin-diyl, octahydrocyclopenta[c]pyrrol-diyl, octahydro-1H- pyrrolo[3,4-c]pyridin-diyl, hexahydrofuro[3,2-b]furan-3,6-diyl, and the like. When the heterocyclylene ring is unsaturated it can contain one or two ring double bonds provided that the 10 ring is not aromatic. “Bridged cycloalkyl” means a saturated monovalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRzRz’)ngroup where n is an integer selected from 1 to 3 and Rzand Rz’ are independently H or methyl (also may be referred to herein as “bridging” group). Examples include, but are not limited to, bicyclo[1.1.1]pent-1-yl, 15 bicyclo[2.2.1]heptyl, (in one embodiment bicyclo[2.2.1]hept-2-yl), and the like. “Bridged cycloalkylene” means a saturated divalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRzRz’)n group where n is an integer selected from 1 to 3 and Rzand Rz’ are independently H or methyl (also may be referred to herein as “bridging” group). Bridged cycloalkyl is optionally substituted with one or two 20 substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to, bicyclo[2.2.1]heptylene (in one embodiment bicyclo[2.2.1]hept-2,5-ylene). “Bridged heterocyclyl” means a saturated monovalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRpRp’)ngroup where n 25 is an integer selected from 1 to 3 and Rpand Rp’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, NH, O, and S(O)n, where n is an integer selected from 0 to 2. Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano 30 unless stated otherwise. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo-[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 6-azabicyclo[3.1.1]heptanyl, 8-azabicyclo[3.2.1]octanyl, and the like. - 13 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Bridged heterocyclylene” means a saturated divalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRzRz’)ngroup where n is an integer selected from 1 to 3 and Rzand Rz’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, 5 including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2. Bridged heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octa-3,8- diyl, 7-oxabicyclo[2.2.1]heptan-diyl, 2,5-diazabicyclo[2.2.1]heptan-diyl, 3,6-diazabicyclo- 10 [3.1.1]heptan-diyl, 2,5-diazabicyclo[2.2.2]octan-diyl, 3,8-diazabicyclo[3.2.1]octan-diyl, 6-azabicyclo[3.1.1]heptan-diyl, 8-azabicyclo[3.2.1]octan-diyl, and the like. “Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. 15 “Cycloalkylalkyl” means an -(alkylene)-Rzradical where Rzis cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. “Cycloalkyloxy” and “cycloalkoxy” mean a -ORzradical where Rzis cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, 20 cyclohexyloxy, and the like. “Cycloalkylene” means a divalent saturated cyclic hydrocarbon radical of three to six carbon atoms, unless stated otherwise e.g., 1,1-cyclopropylene, 1,1-cyclobutylene, 1,4- cyclohexylene, and the like. “Carbonyl” means -C(O)-. 25 “Carboxy” means –COOH. “Cyclylaminylene” means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one or two ring atoms are nitrogen, the remaining ring atoms being carbon. More specifically, the term cyclylaminyl includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, piperazinylene, and the like. 30 “Cyanoalkyl” means alkyl as defined above that is substituted with a cyano e.g., cyanomethyl, cyanoethyl, and the like. “Cyanoalkoxy” and “cyanoalkyloxy” mean an -ORzradical where Rzis cyanoalkyl as defined above. Examples include, but are not limited to, cyanomethoxy, cyanoethoxy, and the like. - 14 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Deuterium” means refers to2H or D. “Dialkylamino” means a -NRzRzradical where each Rzis independently alkyl as defined above, e.g., dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-, iso-, or tert-butylmethylamino, and the like. 5 “Ether” means an -O- group. “Fused heterocyclylene” means a divalent bicyclic ring in which two adjacent ring atoms of a saturated or partially unsaturated (but not aromatic) monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl, 10 or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom is optionally oxidized or quaternized. The fused heterocyclylene can be attached at any two atoms of the ring. Representative examples include, but are not limited to, 1,2,3,4- tetrahydroquinolin-1,4-diyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-5,8-diyl, 3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-diyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-diyl, and the like. 15 “Halo” means fluoro, chloro, bromo, or iodo, in one embodiment fluoro or chloro. “Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this 20 Application as fluoroalkyl. “Haloalkoxy” means a –ORzradical where Rzis haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like. When Rzis haloalkyl where the alkyl is substituted with only fluoro (in some examples, one or more fluoro), it is referred to in this Application as fluoroalkoxy. “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon 25 atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both present on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2- 30 hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl (in one embodiment 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2- hydroxyethyl). “Heteroalkylene” means is a linear or branched saturated divalent hydrocarbon radical of (a) two to six carbon atoms where one carbon atom of the linear portion of the divalent - 15 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT hydrocarbon radical is replaced by Xawhere Xais -O-, -S-, -SO-, -SO2-, -CO-, or -NRq1- or (b) three to six carbon atoms where two adjacent carbon atoms of the linear portion of the divalent hydrocarbon radical are replaced by Xa1where Xa1is -NRq1CO-, -CONRq1-, -NRq1SO-, -SONRq1-, -NRq1SO2-, or -SO2NRq1- (where each Rq1is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl) and 5 furthermore wherein, when the linear portion of the hydrocarbon radical of (a) has 3 to 6 carbon atoms and the hydrocarbon radical of (b) has 4 to 6 carbon atoms, then an additional carbon atom in the linear portion of the hydrocarbon radical of (a) and (b) that is not adjacent to Xaand Xa1above, can be replaced by Xywhere Xyis -O- or -NRq2- (where each Rq2is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl). For sake of clarity, as used in this definition, the linear portion of 10 the heteroalkylene means the consecutive atoms of the heteroalkylene connecting Z2and Z4when Z3is heteroalkylene and Z3and Z5when Z4is heteroalkylene; e.g., in the structure , the atoms with * form the linear portion of C5 heteroalkylene. When the h ins only one or two -O-, it can be referred to herein as “oxoalkylene.” When the heteroalkylene contains only one or two -NRq– and / or -NRq1-, it can be referred to herein as 15 “aminylalkylene.” When the heteroalkylene contains only -S-, it can be referred to herein as “sulfanylalkylene.” When the heteroalkylene contains only -SO-, it can be referred to herein as “sulfinylalkylene.” When the heteroalkylene contains only -SO2-, it can be referred to herein as “sulfonylalkylene.” Representative examples, of heteroalkylene include, e.g., 20 a “Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being - 16 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, indazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2- a]pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. 5 As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5- or 6 ring atoms and is a monocyclic ring, it is also referred to herein as 5-or 6-membered monocyclic heteroaryl or monocyclic heteroarylene. When the heteroaryl ring contains 9- or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroaryl. 10 “Heteroarylene” means a divalent heteroaryl radical as defined above, unless stated otherwise. Representative examples include, but are not limited to, benzimidazoldiyl e.g., benzimidazole-1,5-diyl, and the like. When the heteroarylene ring contains 5- or 6 ring atoms and is a monocyclic ring, it is also referred to herein as monocyclic heteroarylene or as 5- or 6-membered monocyclic heteroarylene e.g., pyrazolyl-1.4-diyl. When the heteroarylene ring 15 contains 9- or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroarylene. “Heteroarylalkyl” and “heteroaralkyl” mean an –(alkylene)-Rzradical where Rzis heteroaryl as defined above. “Heterocyclyl” means a saturated, monovalent, monocyclic group of 4 to 8 ring atoms in 20 which one or two ring atoms are heteroatom independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO- group. More specifically the term heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 25 morpholinyl, piperazinyl, tetrahydro-furanyl, tetrahydro-pyranyl, thiomorpholinyl, and the like. When the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds provided that the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group. “Heterocyclylcarbonyl” means a -C(O)R radical where R is heterocyclyl as defined herein. 30 More specifically, the term heterocyclyl includes, but is not limited to, piperidinylcarbonyl, piperazinylcarbonyl, pyrrolidinylcarbonyl, azetidinylcarbonyl, and the like. “Heterocyclyloxy” means an –ORzradical where Rzis heterocyclyl as defined above e.g. 1-methylpyrrolidin-3-oxy, 1-methylpyrrolidin-2-oxy, piperidin-3-oxy, piperidin-4-oxy and the like. - 17 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Heterocyclylene” means a saturated or unsaturated, divalent, monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclylene ring can optionally 5 be replaced by a –CO- group. More specifically, the term heterocyclylene includes, but is not limited to, , piperidin-1,4-diyl, azetidin-1,3-diyl, and the like. The Linker ‘L’ ” is a connector with a linear non-hydrogen atom number in the range of 1 to 20 (preferably, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; more preferably, 8 to 16, 9 to 14, 9 to 13, 9 to 12; more preferably 8, 9, 10, 11, 12, or 13; most 10 preferably, 12 or 13). Linker “L” can contain one or more (preferably 2, 3, 4, 5, 6, 7, or 8; more preferably, 3 to 6 or 3, 4, 5, or 6; most preferably, 4 or 5), groups which are independently selected, such as, but not limited to, ether, polyether, thioether, -NH-, -N(alkyl)-, amido, sulfonamido, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, sulfinyl, sulfonyl, ureido, thioureido, cycloalkylene, bridged cycloalkylene, spiro cycloalkylene, arylene, 15 heteroarylene, heterocyclylene, bridged heterocycylene, spiro heterocyclylene, bicyclic heterocyclylene, or fused heterocyclylene, and wherein cycloalkylene, bridged cycloalkylene, spiro cycloalkylene, arylene, heteroarylene, heterocyclylene, bridged heterocycylene, spiro heterocyclylene, bicyclic heterocyclylene, and fused heterocyclylene are optionally substituted with one, two, or three substituents independently selected from deuterium, alkyl, alkoxy, halo, 20 haloalkyl, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino, and wherein alkylene is optionally substituted with one or two halo (in one embodiment fluoro). In some or any embodiments, Linker L contains 3 to 5 groups independently selected from -O-, -NH-, -N(CH3)-, sulfonyl, phenylene, alkylene (in one embodiment -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH(CH3)CH2-, -CH(CH3)-, -CH2C(CH3)2CH2-, heterocyclylene (in one 25 embodiment azetidin-diyl, piperidin-diyl, or piperazin-diyl), spiro heterocyclylene (in one embodiment 2,6-diazaspiro[3.3]heptan-diyl), and monocyclic heteroarylene (in one embodiment imidazolyl or pyridinyl; in another embodiment imidazolyl), wherein heterocyclylene, spiro heterocyclylene, and monocyclic heteroarylene are optionally substituted with one, two, or three substituents independently selected from halo (in one embodiment fluoro) and alkyl (in one 30 embodiment methyl), and wherein alkylene is optionally substituted with one or two halo (in one embodiment the group is -CH(CHF2)-. “Phenylene” means divalent phenyl. - 18 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Polyether” means a group where d is an integer selected from 2 to 5 and Rzis C2-6alkylene. The term “oxo,” as used herein, alone or in combination, means =(O). The phrase “optionally” or “optional” as used herein means that the subsequently 5 described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase “alkylene optionally substituted with halo” is intended to cover alkylene that is unsubstituted and alkyene that is substituted with halo. “Spiro cycloalkylene” means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 10 ring atoms wherein the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro cycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, spiro[3,5]nonandiyl e.g., spiro[3.5]nonane-2,7-diyl, and the like. 15 “Spiro heterocyclylene" means a saturated bicyclic divalent ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro heterocyclylene is optionally substituted with one or two 20 substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, 2-azaspiro[3.3]heptan-diyl, 2,6-diazaspiro[3.3]heptan-diyl, 1,7-diazaspiro[3.5]nonan-diyl, 2,7-diazaspiro[3.5]nonan-diyl, 3,9-diazaspiro[5.5]undecan-diyl, and the like. “11 to 13 membered spiro heterocyclylene” means a saturated bicyclic divalent ring 25 having 11 to 13 ring atoms in which one, two, or three ring atoms are heteroatom(s) selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). The 11 to 13 membered spiro heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, 30 alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, diazaspiro[5.5]undecan-diyl, 1-oxa-diazaspiro[5.5]undecan-diyl, and the like. “Sulfinyl” means an -S(O)- group. “Sulfonyl” means an -S(O)2- group. - 19 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT “Substituted sulfonyl” means an -S(O)2Rzwhere Rzis alkyl as defined above e.g., methyl or ethylsulfonyl. Substituted sulfonyl is also referred to herein as alkylsulfonyl. “Thioether” means an -S- group. “Thioureido” means an -NHC(S)NH- group. 5 “Ureido” means an -NHC(O)NH- group. “Unsaturated heterocyclylene” means divalent, monocyclic nonaromatic group of 5 to 8 ring atoms having one, two, or three double bonds and in which one or two ring atoms are heteroatom(s) independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring 10 carbon atoms in the heterocyclylene ring can optionally be replaced by a –C(=O)- group. The present disclosure also includes protected derivatives of compounds of first aspect, second aspect, or Formula (IB) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof. For example, when compounds of Formula (I) or (IB) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s), these 15 groups can be protected with suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5thEd., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art. 20 The present disclosure also includes polymorphic forms and deuterated forms of the compound of first aspect, second aspect, or Formula (IB) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof. The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (I) or (IB) (and any embodiment thereof disclosed herein including specific 25 compounds) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in 30 some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed - 20 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such 5 salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric 10 acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy- 2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, 15 lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, 20 N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety. The compounds of Formula (I) (and any embodiment thereof disclosed herein including 25 specific compounds) may have asymmetric centers. Compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products 30 followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically - 21 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa. Certain compounds of Formula (I) (and any embodiment thereof disclosed herein 5 including specific compounds) can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a 10 few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) are within the scope of this disclosure. The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also contain unnatural amounts of isotopes at one or more of the 15 atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question. that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present disclosure, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of 20 hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I, and1251, respectively. Isotopically labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes canbe useful for their ease of preparation and detectability. Further, substitution with (or25 isotopically enriched for) heavier isotopes such as deuterium (i.e., 2H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds, including in Table 1 below, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced 30 by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. - 22 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. 5 “A pharmaceutically acceptable carrier / excipient” as used in the specification and claims includes both one and more than one such excipient. The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the 10 term “about” should be understood to mean that range which would encompass ± 10%. In one embodiment, the range for “about” encompasses ± 5%. The recited value and the range is included. Certain structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any 15 atom of the ring to which it is attached, where chemically feasible and valency rules permitting. For example, in the structure: , the Raasubstituent, and similarly the Rbband X1substituents, can replace hydr hat is part of the benzo portion of the bicyclic ring that is not already substituted with Rbband X1(in the case of Raa), and similarly with Raaand X1(in the case of Rbb), and with Raaand Rbb(in the case of X1). 20 Additionally, as used throughout the application, including in the embodiments, when a group is drawn out as divalent, the left bond of the divalent group is attached to the group which is to its left in the remainder of the molecule, and the right bond of the divalent group is attached to the group which is to its right in the remainder of the molecule. For example, in Formula (IB), in the following divalent groups: 25 the bond on the l , g: - 23 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT an on the right side of (a), (b), and (c) (i.e., X1, X2, and X3) is attached to Z1of L of the following structure: . 5 L i.e, -Z1-Z2-Z3-Z4-Z5-Z6-, the left side in L (i.e., Z1) is attached to X1, X2, X3, or X4or point of attachment delineated in Degrons of formula (c), (d), (e), or (f) and Z6is attached to an atom of Hy. For example, when L is a group of formula: , and Degron is a group of formula (a), i.e., , the left bond in L (i.e., the -NH-10 group) is attached to X1and the right han -SO2-) is attached to an atom of the Hy . ease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its 15 parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous 20 manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, - 24 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. 5 The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. In one embodiment, the patient is a human. “Treating” or “treatment” of a disease includes: 10 (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or 15 (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. In one embodiment, treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms. A “therapeutically effective amount” means the amount of a compound of the present 20 disclosure and / or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. A “condition associated with an autoimmune disease” means a condition that a patient 25 with an autoimmune disease is susceptible to, e.g., sepsis, or a condition that is caused by the autoimmune disease, e.g., uveitis. The compounds of Formula (I) or (IB) can also inhibit CDK2 and / or CDK4. The term “inhibiting” and “reducing,” or any variation of these terms in relation to CDK2 and / or CDK4, includes any measurable decrease or complete inhibition of enzymatic activity of CDK2 and / or 30 CDK4, respectively, to achieve a desired result. For example, a compound of Formula (I) or (IB) may independently decrease about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, of CDK2 and / or CDK4 activity, compared to their / its normal activity. In some embodiments, the CDK2 and / or CDK4 activity is reduced by at least 40% in the presence - 25 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT of a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 and / or CDK4, respectively, in the absence of said compound. The inhibitory activity of a compound of Formula (I) or (IB) can be measure using Biological Example 1, by converting a compound of Formula ( (I) or (IB) to a 5 corresponding compound of Formula (I) or (IB) that cannot be degraded by the ubiquitin proteosome pathway e.g., by methylating the nitrogen atom group of ligase ligand (i) or (ii) present in the compound of Formula (I) or (IB). The term “degrading” and “degrade,” or any variation of these terms in relation to CDK2, CDK4, and CDK1, means any measurable decrease in the concentration of CDK2, CDK4, and 10 CDK1, respectively, over time in a sample containing of Formula (I) or (IB). For example, there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, in CDK2 and CDK4 concentration in a sample containing CDK2 or CDK4, respectively and a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as 15 compared to an equivalent sample comprising CDK2 or CDK4, in the absence of said compound. The % degradation can be determined as described in Biological Example 2 below. In one embodiment, the decrease in the concentration of CDK2 is ≥ 20%. In another embodiment, the decrease in the concentration of CDK2 is ≥ 40%. In another embodiment, the decrease in the concentration of CDK2 is ≥ 50%. In another embodiment, the decrease in the concentration of 20 CDK2 is ≥ 60%. In another embodiment, the decrease in the concentration of CDK2 ≥ 70%. In another embodiment, the decrease in the concentration of CDK2 is ≥ 80%. In one embodiment, the decrease in the concentration of CDK4 is ≥ 20%. In another embodiment, the decrease in the concentration of CDK4 is ≥ 40%. In another embodiment, the decrease in the concentration of CDK4 is ≥ 50%. In another embodiment, the decrease in the 25 concentration of CDK4 is ≥ 60%. In another embodiment, the decrease in the concentration of CDK4 ≥ 70%. In another embodiment, the decrease in the concentration of CDK4 is ≥ 80%. “E3 ubiquitin ligase” refers to a family of proteins that operate in conjunction with E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzyme, assist or directly catalyze the covalent ligation of ubiquitin to a lysine residue of a substrate protein. E3 ubiquitin ligases 30 directly bind to substrate proteins and thus confer substrate specificity for the ubiquitination process. Ubiquitination can serve as a versatile signal mark for substrate proteins, which are targeted to degradation by proteasome or other regulations ranging from translocation to - 26 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT transcription. The cereblon (CRBN) and von Hippel-Lindau (VHL) proteins are substrate recognition subunits of two ubiquitously expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). VHL is part of 5 the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbx1. “E3 ubiquitin ligase ligand” means a small molecule ligand (i.e., having a molecular weight of below 2,000, 1,000, 500, or 200 Daltons), which is capable of binding to an E3 ubiquitin ligase or a subunit of E3 ligase, such as Cereblon, VHL, IAP, or MDM2. 10 Embodiments: In embodiments A1 to A249, the present disclosure includes: A1. In embodiment A1, provided is a compound of Formula (I) or a pharmaceutically acceptable salt as described in the first aspect of the Summary. In one embodiment of embodiment A1, R1is alkyl, cycloalkyl, cycloalkoxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, 15 hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino. A2. In embodiment A2, the compound of embodiment A1, or a pharmaceutically acceptable salt thereof, is wherein R1is alkyl or cycloalkyl. A3. In embodiment A3, the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is alkyl. 20 A4. In embodiment A4, the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyl. A5. In embodiment A5, the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof, is wherein R1is halo, haloalkyl, or haloalkoxy. A6. In embodiment A6, the compound of any one of embodiments A1 or A5, or a 25 pharmaceutically acceptable salt thereof, is wherein R1is haloalkyl. A7. In embodiment A7, the compound of any one of embodiments A1 or A5, or a pharmaceutically acceptable salt thereof, is wherein R1is haloalkoxy. A8. In embodiment A8, the compound of any one of embodiments A1 or A5, or a pharmaceutically acceptable salt thereof, is wherein R1is halo. 30 A9. In embodiment A9, the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof, is wherein R1alkoxy. A10. In embodiment A10, the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof, is wherein R1is hydroxyalkyl. - 27 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A11. In embodiment A11, the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof, is wherein R1is alkoxyalkyl. A12. In embodiment A12, the compound of any one of embodiments A1, or a pharmaceutically acceptable salt thereof, is wherein R1is amino, alkylamino, or dialkylamino 5 A13. In embodiment A13, the compound of embodiment A1 or A12, or a pharmaceutically acceptable salt thereof, is wherein R1is amino. A14. In embodiment A14, the compound of embodiment A1 or A12, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylamino. A15. In embodiment A15, the compound of embodiment A1 or A12, or a 10 pharmaceutically acceptable salt thereof, is wherein R1is dialkylamino. A16. In embodiment A16, the compound of embodiment A1, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkoxy. A17. In embodiment A17, the compound of any one of embodiments A1 to A16, or a pharmaceutically acceptable salt thereof, is wherein R1is methyl, ethyl, isopropyl, methoxy, 15 ethoxy, propoxy, cyclopropyl, cyclopentyl, cyclopropoxy, cyclopentyloxy, chloro, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methyloxymethyl, methoxyethyl, methoxypropyl, amino, methylamino, ethylamino, or propylamino. A18. In embodiment A18, the compound of any one of embodiments A1, A2, A4 to A8, 20 and A17, or a pharmaceutically acceptable salt thereof, is wherein R1is cyclopropyl, chloro, trifluoromethyl, or trifluoromethoxy. A19. In embodiment A19, the compound of any one of embodiments A1, A5, A6, A17, and A18, or a pharmaceutically acceptable salt thereof, is wherein R1is trifluoromethyl. A20. In embodiment A20, the compound of any one of embodiments A1, A5, A7, A17, 25 and A18, or a pharmaceutically acceptable salt thereof, is wherein R1is trifluoromethoxy. A21. In embodiment A21, the compound of any one of embodiments A1, A5, A8, A17, and A18, or a pharmaceutically acceptable salt thereof, is wherein R1is chloro. A22. In embodiment A22, the compound of any one of embodiments A1, A10, A11, and A17, or a pharmaceutically acceptable salt thereof, is wherein R1is hydroxymethyl, 30 methyloxymethyl, methoxyethyl, or methoxypropyl. A23. In embodiment A23, the compound of any one of embodiments A1 to A22, or a pharmaceutically acceptable salt thereof, is wherein R2is hydrogen. A24. In embodiment A24, the compound of any one of embodiments A1 to A22, or a pharmaceutically acceptable salt thereof, is wherein one of R2is deuterium. - 28 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A25. In embodiment A25, the compound of any one of embodiments A1 to A24, or a pharmaceutically acceptable salt thereof, is wherein Hy is heterocyclylene, arylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from 5 hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. A26. In embodiment A26, the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is heterocyclylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. 10 A27. In embodiment A27, the compound of any one of embodiments A1 to A26, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is pyrrolidin-1,3- diyl or piperidin-1,4-diyl, where Hy is substituted with Ra, Rb, and Rcwhere Raand Rbare independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy, Rcis hydrogen, and L is attached to the nitrogen atom of the piperidin-1,4-diyl or pyrrolidin-1,3-diyl ring of Hy. 15 A28. In embodiment A28, the compound of any one of embodiments A1 to A27, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: where the N atom of -diyl rings is attached to L. A29. In embodiment A29, the compound of any one of embodiments A1 to A28, or a 20 pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: where the N atom of t ,4-diyl rings is attached to L. A29a. In embodiment A29a, the compound of any one of embodiments A1 to A29, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: 25 where the N atom of the piperidin-1, yl ring is attached to L. - 29 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A30. In embodiment A30, the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is bridged heterocyclylene substituted with Ra, Rb, and Rcindependently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. 5 A31. In embodiment A31, the compound of any one of embodiments A1 to A25, and A30, or a pharmaceutically acceptable salt thereof, is wherein the bridged heterocyclylene of Hy is a ring of formula: and each ri , and L is attached to 10 the nitrogen atom of each ring. A32. In embodiment A32, the compound of embodiment A30 or A31, or a pharmaceutically acceptable salt thereof, is wherein Raand Rbare independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy. A33. In embodiment A33, the compound of embodiment A30, A31, or A32, or a 15 pharmaceutically acceptable salt thereof, is wherein Rbis hydrogen. A34. In embodiment A34, the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is cycloalkylene substituted with Ra, Rb, and Rcwhere Rais deuterium, methyl, fluoro, methoxy, or hydroxy and Rband Rcare hydrogen. A35. In embodiment A35, the compound of any one of embodiments A1 to A25, and 20 A34, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is cyclohexylene. A36. In embodiment A36, the compound of any one of embodiments A1 to A25, A34, and A35, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is where denotes bond to NH and denotes bond of L. 25 A37. In embodiment A37, the co und of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is arylene wherein the arylene is phenylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. - 30 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A38. In embodiment A38, the compound of any one of embodiments A1 to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is spiro heterocyclylene substituted (such as 2-azaspiro[3.3]heptan-2-yl) with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. 5 A39. In embodiment A39, the compound of any one of embodiments A1 to A25, and A37, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Hy is 1,4- phenylene according to structure denotes bond to NH and denotes bond of L and where Rbis hydrogen (ia R is methoxy). A39a. In embodiment A39a, the compound of any one of embodiments A1 to A24, or a 10 pharmaceutically acceptable salt thereof, is wherein Hy is fused heterocyclylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. A39b. In embodiment A39b, the compound of any one of embodiments A1 to A24, or a pharmaceutically acceptable salt thereof, is wherein Hy is bicyclic heterocyclylene substituted 15 with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. A40A. In embodiment A40A, the compound of any one of embodiments A1 to A39b, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i) or (ii). 20 A40. In embodiment A40, the compound of any one of embodiments A1 to A40A, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i): . 25 A41. In embodiment A41, the compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a): - 31 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A42. In embodiment A42, the ny one of embodiments A1 to A41, or a pharmaceutically acceptable salt thereof, is wherein R4and R5are independently hydrogen or alkyl. 5 A43. In embodiment A43, the compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof, is wherein R4and R5are hydrogen. A44. In embodiment A44, the compound of any one of embodiments A1 to A42, or a pharmaceutically acceptable salt thereof, is wherein R4is hydrogen and R5is methyl. A45. In embodiment A45, the compound of any one of embodiments A1 to A41, or a 10 pharmaceutically acceptable salt thereof, is wherein R4and R5together with the carbon to which they are attached form >C =O. A46. In embodiment A46, the compound of any one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b): 15 where M is -NR6-. A47. In embodiment A47, the compound of any one of embodiments A1 to A40, and A46, or a pharmaceutically acceptable salt thereof, is wherein R6is hydrogen. A48. In embodiment A48, the compound of any one of embodiments A1 to A40, and 20 A46, or a pharmaceutically acceptable salt thereof, wherein R6is alkyl. In one embodiment, R6is methyl. A49. In embodiment A49, the compound of any one of embodiments A1 to A48, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 32 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A50. In , ts A1 to and A49, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: 5 . A51. In ts A1 to A50, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 33 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A52. In embodiment A52, the compound of any one of embodiments A1 to A51, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of 5 formula (i) is: i,e, Raais hydrogendd , and R are H. A52a. In embodiment A52a, the compound of any one of embodiments A1 to A41, A45, and A47 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 10 ubiquitin ligase ligand of formula (i) is: . A53. In embodiment A53, the ny one of embodiments A1 to A41, A45, and A47 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: - 34 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A54. In embodiment A54, th y one of embodiments A1 to A43 and A47 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: 5 . A55. In embodiment A55, th y one of embodiments A1 to A43 and A47 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: . 10 A56. In embodiment A56, t f any one of embodiments A1 to A40, A42 to A46, and A48 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: . A57. In embodiment A57, the ny one of embodiments A1 to A40, A42 to 15 A46, and A48 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: . A58. In embodiment A58, th ny one of embodiments A1 to A54, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently 20 selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. For sake of clarity, in - 35 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT embodiments A52 to A54, Raa, Rbb, Rcc, and / or Rddare hydrogen when they are not specifically drawn out in structures of formula (i) and (ii), respectively. A59. In embodiment A59, the compound of any one of embodiments A1 to A54, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently 5 selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano. A60. In embodiment A60, the compound of any one of embodiments A1 to A54, A58, and A59, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy. 10 A61. In embodiment A61, the compound of any one of embodiments A1 to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen and methyl. A62. In embodiment A62, the compound of any one of embodiments A1 to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare 15 independently selected from hydrogen and methoxy. A63. In embodiment A63, the compound of any one of embodiments A1 to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen and fluoro. A64. In embodiment A64, the compound of any one of embodiments A1 to A54, and 20 A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, trifluoromethyl, and difluoromethyl. A65. In embodiment A65, the compound of any one of embodiments A1 to A54, A58, and A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen and trifluoromethoxy. 25 A66. In embodiment A66, the compound of any one of embodiments A1 to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, fluoro, and trifluoromethyl. A67. In embodiment A67, the compound of any one of embodiments A1 to A40A, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of 30 formula (ii): - 36 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A68. In embodiment A68, the compound of any one of embodiments A1 to A40A and A67, or a pharmaceutically acceptable salt thereof, is wherein Yais CH. A69. In embodiment A69, the compound of any one of embodiments A1 to A40A, and A67, or a pharmaceutically acceptable salt thereof, is wherein Yais N. 5 A70. In embodiment A70, the compound of any one of embodiments A1 to A40A, and A67 to A69, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond, -NH-, -O-, or -NHC(O)-. A71. In embodiment A71, the compound of any one of embodiments A1 to A40A, and A67 to A70, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond, -NH-, 10 or -NHC(O)-. A72. In embodiment A72, the compound of any one of embodiments A1 to A40A, and A67 to A71, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond. A73. In embodiment A73, the compound of any one of embodiments A1 to A40A, and A67 to A71, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-, or -NHC(O)-. 15 A74. In embodiment A74, the compound of any one of embodiments A1 to A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-. A74a. In embodiment A74a, the compound of any one of embodiments A1 to A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Zais -NHC(O)-. A75. In embodiment A75, the compound of any one of embodiments A1 to A40A, and 20 A67 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is phenylene substituted with Reeand Rff. A76. In embodiment A76, the compound of any one of embodiments A1 to A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is cyclylaminylene substituted with Reeand Rff. 25 A77. In embodiment A77, the compound of any one of embodiments A1 to A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with Reeand Rff. 30 A78. In embodiment A78, the compound of any one of embodiments A1 to A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6- membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with Reeand Rff. - 37 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A79. In embodiment A79, the compound of any one of embodiments A1 to A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms (and not containing any additional heteroatoms) and substituted with Reeand Rff. 5 A80. In embodiment A80, the compound of any one of embodiments A1 to A40A, A67 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted with Reeand Rff. A81. In embodiment A81, the compound of any one of embodiments A1 to A40A, and 10 A67 to A80, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is: , . A82-1. In embo diments A1 to A40A, and 15 A67 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is: , , , - 38 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT w is cyclylaminylene. For sake of clarity, Reeand Rffare hydrogen if they are not s out in the above structures of embodiment A82-1. 5 A82. In embodiment A82, the compound of any one of embodiments A1 to A40A, and A67 to A82-1, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is: , , 10 , or w is cyclylaminylene and Rffis hydrogen when not drawn out in the above st - 39 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A82A. In embodiment A82A, the compound of any one of embodiments A1 to A40A, A67, A68, A70 to A72, A77, and A79 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formul . A83. In embodiment A83, the compou ents A1 to A40A, and 5 A67 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is: , 10 A83A. In embodiment A83A, the compound of any one of embodiments A1 to A40A, and A67, A69 to A72, A77, A79 to A82, and A83, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formul . 15 A84. In embodiment A84, the compou iments A1 to A40A, and A67 to A83A, or a pharmaceutically acceptable salt thereof, is wherein each Reeand Rffare independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy. - 40 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A85. In embodiment A85, the compound of any one of embodiments A1 to A40A, and A67 to A83A, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano. A86. In embodiment A86, the compound of any one of embodiments A1 to A40A, and 5 A67 to A85, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano. A87. In embodiment A87, the compound of any one of embodiments A1 to A40A, and 10 A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, and isopropyl. A88. In embodiment A88, the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen and methoxy. 15 A89. In embodiment A89, the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro. A90. In embodiment A90, the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein one of Reeand Rffis 20 hydrogen or fluoro and the other of Reeand Rffis selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl. A91. In embodiment A91, the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy. 25 A92. In embodiment A92, the compound of any one of embodiments A1 to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, chloro, fluoro, and trifluoromethyl. A93. In embodiment A93, the compound of any one of embodiments A1 to A40A, and A67 to A92, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare hydrogen. 30 A94. In embodiment A94, the compound of any one of embodiments A1 to A40A, A67 to A86, A89, and A92, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare chloro. - 41 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A95. In embodiment A95, the compound of any one of embodiments A1 to A40A, A67 to A86, A89, and A92, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare fluoro. A96. In embodiment A96, the compound of any one of embodiments A1 to A40A, A67 5 to A86, and A90, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently trifluoromethyl or 2,2,2-trifluoroethyl. A96a. In embodiment A96a, the compound of any one of embodiments A1 to A39b, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iii), (iv), (v), or (vi). 10 A96b. In embodiment A96b, the compound of any one of embodiments A1 to A39b, and A96a, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iv) or (v). A96c. In embodiment A96c, the compound of any one of embodiments A1 to A39b, A96a, and A96b, or a pharmaceutically acceptable salt thereof, is wherein Ry, Ry1, and Ry2are 15 1-fluorocycloprop-1-yl and Wais bond, S, or methylene. A96d. In embodiment A96d, the compound of any one of embodiments A1 to A39b and A96a to A96c, or a pharmaceutically acceptable salt thereof, is wherein Wais S. A97. In embodiment A97, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each a bond. 20 A98. In embodiment A98, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each independently selected from alkylene. In a subembodiment of embodiment A98, X1, X2, X3,and X4are each methylene. A99. In embodiment A99, the compound of any one of embodiments A1 to A96, or a 25 pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each -O-. A100. In embodiment A100, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each independently selected from -(O-alkylene)-. A101. In embodiment A101, the compound of any one of embodiments A1 to A96, or a 30 pharmaceutically acceptable salt thereof, is wherein X1, X2, X3,and X4are each independently selected from -(alkylene-O)-. A102. In embodiment A102, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3,and X4are each independently selected from -(NRgg-alkylene)-. - 42 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A103. In embodiment A103, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3,and X4are each independently selected from -(alkylene-NRhh)-. A104. In embodiment A104, the compound of any one of embodiments A1 to A96, or a 5 pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each . A105. In embodiment A105, the compound of any one of embodim A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each -NH-. A106. In embodiment A106, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each independently 10 selected from -N(alkyl)-. In a subembodiment of embodiment A106, X1, X2, X3,and X4are each independently -N(methyl)- or -N(ethyl)-. A107. In embodiment A107, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each -C(=O)-. A108. In embodiment A108, the compound of any one of embodiments A1 to A96, or a 15 pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each independently -NRjjC(=O)-. A109. In embodiment A109, the compound of any one of embodiments A1 to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3,and X4are each independently -C(=O)NRkk-. 20 A110. In embodiment A110, the compound of any one of embodiments A1 to A96, A102, A103, A108, and A109, or a pharmaceutically acceptable salt thereof, is wherein Rgg, Rhh, Rjj, and Rkkare each independently hydrogen or alkyl. A110a. In embodiment A110a, the compound of any one of embodiments A1 to A110 is wherein at least two of -Z1-Z2-Z3-Z4-Z5-Z6- are not a bond. In a sub-embodiment of A110a, the 25 compound is wherein at least three of -Z1-Z2-Z3-Z4-Z5-Z6- are not a bond. In a sub-embodiment of A110a, the compound is wherein at least four of -Z1-Z2-Z3-Z4-Z5-Z6- are not a bond. A111. In embodiment A111, the compound of any one of embodiments A1 to A110a, or a pharmaceutically acceptable salt thereof, is wherein Z6is -S(O)2-. A112. In embodiment A112, the compound of any one of embodiments A1 to A111, or a 30 pharmaceutically acceptable salt thereof, is wherein Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr. A113. In embodiment A113, the compound of any one of embodiments A1 to A112, or a pharmaceutically acceptable salt thereof, is wherein Z5is phenylene, monocyclic heteroarylene, or - 43 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT heterocycylene, where each ring is substituted with Rqand Rrand one and only one of Z1and X1is a bond, one and only one of Z1and X2is a bond, one and only one of Z1and X3, and one and only one of Z1and X4is a bond (for sake of clarity, when X1, X2, X3, and X4are not a bond, then X1, X2, X3, and X4are as described in any one of embodiments A1 and A98 to A110). 5 A114. In embodiment A114, the compound for use of any one of embodiments A1 to A96d and A111, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, and X4are independently a bond, -(O-alkylene)-, -(NRgg-alkylene)-, , -NH-, or -N(alkyl)-, where Rggis hydrogen or alkyl and each alkylene is independe onally substituted with one or two fluoro (or X1, X2, X3, and X4are absent in ligands (iii) to (vi)); 10 Z1is a bond, alkylene, -(CO)NR-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, or heterocyclylene, where each ring is substituted with Rhand Ri; Z2is a bond, alkylene, -(O-alkylene)b-, -(alkylene-O)b-, cycloalkylene, or heterocyclylene, where each ring is substituted with Rjand Rk; Z3is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, cycloalkylene, phenylene,15 -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)- monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)- heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, -spiro heterocyclylene-(alkylene)-, or monocyclic heteroarylene, where each 20 ring, by itself or as part of another group, is substituted with Rmand Rn; Z4is a bond, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene- (alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or 25 -spiro heterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, is substituted with Roand Rp; Z5is a bond; and Z6is -S(O)2-; and wherein each alkylene in Z1, Z2, Z3, and Z4, by itself or as part of another group, is 30 independently substituted with Rs, Rt, and Ru. A115. In embodiment A115, the compound of any one of embodiments A1 to A96d, A97, and A111, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, and Z1are each a bond; - 44 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Z2is a bond, alkylene, cycloalkylene, or heterocyclylene, where each ring is substituted with Rjand Rk; Z3is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, 5 fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn; Z4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Roand Rp; Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is 10 substituted with Rqand Rr; and Z6is -S(O)2-; and wherein each alkylene in Z2, Z3, and Z4is independently substituted with Rs, Rt, and Ru. A116. In embodiment A116, the compound of any one of embodiments A1 to A96d, A97, A111, and A115, or a pharmaceutically acceptable salt thereof, is wherein: 15 X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn; Z4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, 20 heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Roand Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and 25 Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, Rt, and Ru. A117. In embodiment A117, the compound of any one of embodiments A1 to A96d, A97, A111, A115, and A116, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; 30 Z3is heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; - 45 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Z4is alkylene, -O-, cycloalkylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Roand Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; 5 Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z6is -S(O)2-; and wherein alkylene in Z4is substituted with substituted with Rs, Rt, and Ru. 10 A118. In embodiment A118, the compound of any one of embodiments A1 to A96d, A97, A111, and A115 to A117, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, and X4, Z1, and Z2are each a bond; Z3is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, 15 hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z4is alkylene, -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with Roand Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy; Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is 20 substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, Rt, and Ru. A119. In embodiment A119, the compound of any one of embodiments A1 to A96d, A97, 25 A111, and A115 to A118, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is heterocyclylene, bridged heterocyclylene or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; 30 Z4is alkylene, -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with Roand Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy, (in one embodiment Roand Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy), (in a subembodiment Z4is alkylene or -O-); - 46 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z6is -S(O)2-; and 5 wherein alkylene in Z4is substituted with Rs, Rt, and Ru. A120. In embodiment A120, the compound of any one of embodiments A1 to A96d, A97, A111, and A115, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, and Z1are each a bond; Z2is cycloalkylene or heterocyclylene, where each ring is substituted with Rjand Rk10 independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z3is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; 15 Z4is a bond, alkylene, or -O-; Z5is phenylene, monocyclic heteroarylene (e.g., pyridindiyl), or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z6is -S(O)2-; and 20 wherein alkylene in Z4is substituted with Rs, Rt, and Ru. A121. In embodiment A121, the compound of any one of embodiments A1 to A96d, A97, A111, A115, and A120, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, and Z1are each a bond; Z2is heterocyclylene substituted with Rjand Rkindependently selected from hydrogen, 25 deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z3is heterocyclylene substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z4is a bond, alkylene, or -O-; Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rr30 independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, Rt, and Ru. - 47 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A122. In embodiment A122, the compound of any one of embodiments A1 to A96d, A97, A111, and A112, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, and Z1are each a bond; Z2is heterocyclylene substituted with Rjand Rk(in one embodiment Rjand Rkare 5 independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy); Z3is a bond, alkylene, or -O-; Z4is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Roand Rp( in one embodiment Roand Rpare independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy); 10 Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rr(in one embodiment Rqand Rrare independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy); and Z6is -S(O)2-; and wherein alkylene in Z3is substituted with Rs, Rt, and Ru. 15 A123. In embodiment A123, the compound of any one of embodiments A1 to A117 and A122, or a pharmaceutically acceptable salt thereof, is wherein Z4is heterocyclylene or spiro heterocyclylene, where each ring is substituted with Roand Rp(in one embodiment Roand Rpare independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy). 20 A124. In embodiment A124, the compound of any one of embodiments A1 to A96d, or a pharmaceutically acceptable salt thereof, is wherein one and only one of X1and Z1, or one and only one of X2and Z1, or one and only one of X3and Z1, or one and only one of X4and Z1is a bond. A125. In embodiment A125, the compound of any one of embodiments A1 to A96d, or a 25 pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, X4, and Z1are each a bond. A126. In embodiment A126, the compound of any one of embodiments A1 to A96d, A124, and A125, or a pharmaceutically acceptable salt thereof, is wherein Z2is heterocyclylene or bridged heterocyclylene, each ring substituted with Rjand Rk. A127. In embodiment A127, the compound of any one of embodiments A1 to A96d, 30 A124, and A125, or a pharmaceutically acceptable salt thereof, is wherein Z2is a bond. A128. In embodiment A128, the compound of any one of embodiments A1 to A96d, and A124 to A127, or a pharmaceutically acceptable salt thereof, is wherein: Z3is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene- - 48 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT (alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, or -spiro heterocyclylene-(alkylene), where each ring, by itself or as part of 5 another group, is substituted with Rmand Rn; Z4is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged 10 heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, is substituted with Roand Rp; Z5is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O)2-, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and 15 Z6is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR’(CO)-, or -C(O)NR-; and and each alkylene in Z3, Z4, Z5, and Z6, itself or as part of another group, is independently substituted with Rs, Rt, and Ru. A129. In embodiment A129, the compound of any one of embodiments A1 to A97, A111, 20 A112, A125, A127, and A128, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is -heterocyclylene-(alkylene)-, where heterocyclylene is substituted with Rmand Rnand alkylene is substituted with Rs, Rt, and Ru; Z4is phenylene or monocyclic heteroarylene, where each ring is substituted with Roand 25 Rp; Z5is phenylene substituted with Rqand Rr; and Z6is -S(O)2-. A130. In embodiment A130, the compound of any one of embodiments A1 to A112 and A124 to A128, or a pharmaceutically acceptable salt thereof, is wherein: 30 Z3is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro - 49 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT heterocyclylene, -(alkylene)-spiro heterocyclylene-, or -spiro heterocyclylene-(alkylene), where each ring, by itself or as part of another group, is substituted with Rmand Rn; Z4is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiro 5 cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, is substituted with Roand Rp; 10 Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and Z6is -S(O)2-; and and each alkylene in Z3and Z4, itself or as part of another group, is independently substituted with Rs, Rt, and Ru. 15 A131. In embodiment A131, the compound of any one of embodiments A1 to A111, A124 to A128, and A130, or a pharmaceutically acceptable salt thereof, is wherein: Z3is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn; Z4is alkylene, -O-, heterocyclylene, -(alkylene)-heterocyclylene-, -(alkylene)-bridged 20 heterocyclylene-, where each ring, by itself or as part of another group, is substituted with Roand Rp; Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and Z6is -S(O)2; and 25 and each alkylene in Z4, itself or as part of another group, is substituted with Rsand Rt. A132. In embodiment A132, the compound of any one of embodiments A1 to A96d and A111, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is -O-, -NR”- (where R”is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic 30 heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn; Z4is alkylene, alkenylene, alkynylene, heteroalkylene, where alkylene and heteroalkylene are substituted with Rs, Rt, and Ruand alkenylene is substituted with Rv; - 50 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Z5is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rqand Rr; and Z6is -S(O)2. A133. In embodiment A133, the compound of any one of embodiments A1 to A96d, 5 A111, and A132, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is -O-, -NR”- (where R”is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn; 10 Z4is alkylene, alkenylene, or heteroalkylene where alkylene and heteroalkylene substituted with Rs, Rt, and Ruand alkenylene is substituted with Rv; Z5is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rqand Rr; and Z6is -S(O)2. 15 A134. In embodiment A134, the compound of any one of embodiments A1 to A96d, A111, and A132, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is -O-, -NR”- (where R”is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro 20 heterocyclylene, where each ring is substituted with Rmand Rn; Z4is alkynylene where alkynylene substituted with Rwand Rx; Z5is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rqand Rr; and Z6is -S(O)2. 25 A134a. In embodiment A134a, the compound of any one of embodiments A1 to A97 and A111, or a pharmaceutically acceptable salt thereof, is wherein: X1, X2, X3, X4, Z1, Z2and Z5are each a bond; Z3is -O-, -NR”- (where R”is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro 30 heterocyclylene, where each ring is substituted with Rmand Rn; Z4is C3 to C6 alkylene substituted with Rs, Rt, and Ru; and Z6is -S(O)2. - 51 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A135. In embodiment A135, the compound of any one of embodiments A1 to A113 and A115 to A134, or a pharmaceutically acceptable salt thereof, is wherein -Z (i.e., Z5is phenylene where Z4and Z6are attached at meta position of the pheny bstituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, halo, 5 haloalkyl, and haloalkoxy. A136. In embodiment A136, the compound of any one of embodiments A1 to A113, A115 to A134, and A135, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is substituted with Rqand Rrindependently selected from hydrogen, deuterium, methyl, m no, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and 10 trifluoromethoxy. A137. In embodiment A137, the compound of any one of embodiments A1 to A113, A115 to A134, A135, and A136, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is . A A113, 15 A115 to A128, and A130 to A134, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is monocyclic heteroarylene (such as imidazol-1,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl) substituted with Rqand Rrindependently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. A139. In embodiment A139, the compound of any one of embodiments A1 to A113, 20 A115 to A128, A130 to A134, and A138, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each ring substituted with Rqand Rrindependently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy. 25 A140. In embodiment A140, the compound of any one of embodiments A1 to A113, A115 to A128, A130 to A134, A138, and A139, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each ring substituted with Rqand Rrindependently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy. - 52 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A141. In embodiment A141, the compound of any one of embodiments A1 to A113, A115 to A118, A120, A123 to A128, and A130 to A134, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is heterocyclylene substituted with Rqand Rrindependently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 5 difluoromethoxy, and trifluoromethoxy. A142. In embodiment A142, the compound of any one of embodiments A1 to A113, A115 to A118, A120, A123 to A128, A130 to A134, and A141, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl. A143. In embodiment A143, the compound of any one of embodiments A1 to A142, or a 10 pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1, Z2, Z3, Z4, Z5, and Z6, by itself and when present, is methylene, ethylene, propylene, or butylene, each substituted with Rs, Rt, and Ru. A144. In embodiment A144, the compound of any one of embodiments A1 to A134 and A135 to A143, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1, Z2, 15 Z3, Z4, Z5, and Z6, by itself and when present, is methylene substituted with Rs, Rt, and Ru. A145. In embodiment A145, the compound of any one of embodiments A1 to A134 and A135 to A142, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1, Z2, Z3, Z4, Z5, and Z6, by itself or as part of –(O-alkylene)a- in Z1, –(alkylene-O)a- in Z1, -(O- alkylene)b- in Z2, -(alkylene-O)b- in Z2, -(O-alkylene)c- in Z3, -(alkylene-O)c- in Z3, -(O- 20 alkylene)d- in Z4, and -(alkylene-O)d- in Z4, and -(alkylene-O)- in Z6, and when present, is ethylene or propylene; as part of –(alkylene-NR”)- and –(NR”-alkylene)- and when present, is methylene, ethylene or propylene; and as part of –(alkylene)-cycloalkylene-, -cycloalkylene- (alkylene)-, -(alkylene)-phenylene-, -phenylene-(alkylene)-, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, 25 -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene-, and -spiro heterocyclylene-(alkylene)- is methylene, ethylene, propylene, or butylene, wherein each of above alkylene group is substituted with Rs, Rt, and Ru. A146. In embodiment A146, the compound of any one of embodiments A1 to A134, 30 A135 to A142 and A145, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1, Z2, Z3, Z4, Z5, and Z6, by itself or as part of -(O-alkylene)a- in Z1, -(alkylene-O)a- in Z1, -(O- alkylene)b- in Z2, -(alkylene-O)b- in Z2, -(O-alkylene)c- in Z3, -(alkylene-O)c- in Z3, -(O- alkylene)d- in Z4, and -(alkylene-O)d- in Z4, and -(alkylene-O)- in Z6, and when present, is ethylene; as part of -(alkylene-NR”)-) and -(NR”-alkylene)- and when present, is methylene; and - 53 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT as part of -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, -(alkylene)-phenylene- , -phenylene-(alkylene)-, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene- (alkylene)-, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene-, 5 and -spiro heterocyclylene-(alkylene)- and when present, is methylene. A147. In embodiment A147, the compound of any one of embodiments A1 to A146, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of Z1, Z2, Z3, Z4, Z5, and Z6, when present, is independently hydrogen or methyl. A148. In embodiment A148, the compound of any one of embodiments A1 to A147, or a 10 pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of Z1, Z2, Z3, Z4, Z5, and Z6, when present, is hydrogen. A149. In embodiment A149, the compound of any one of embodiments A1 to A147, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of Z1, Z2, Z3, Z4, Z5, and Z6, when present, is methyl. 15 A150. In embodiment A150, the compound of any one of embodiments A1 to A149, or a pharmaceutically acceptable salt thereof, is wherein each cycloalkylene of Z2, Z3, and Z4, by itself or as part of –(alkylene)-cycloalkylene- and -cycloalkylene-(alkylene)-, and when present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. A151. In embodiment A151, the compound of any one of embodiments A1 to A150, or a 20 pharmaceutically acceptable salt thereof, is wherein each cycloalkylene of Z2, Z3, and Z4, by itself or as part of –(alkylene)-cycloalkylene and -cycloalkylene-(alkylene)-, and when present, is independently selected from 1,2-cyclopropylene, 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene. A152. In embodiment A152, the compound of any one of embodiments A1 to A134a, 25 A138, and A143 to A151, or a pharmaceutically acceptable salt thereof, is wherein heteroarylene is monocyclic heteroarylene and each monocyclic heteroarylene of Z1, Z3, Z4, and Z5, by itself or as part of -(alkylene)-monocyclic heteroarylene- and -monocyclic heteroarylene-(alkylene)-, and when present, is independently selected from imidazoldiyl, pyridindiyl and pyrimidindiyl. A153. In embodiment A153, the compound of any one of embodiments A1 to A134a, 30 A138, and A143 to A152, or a pharmaceutically acceptable salt thereof, is wherein heteroarylene is monocyclic heteroarylene and each monocyclic heteroarylene of Z1, Z3, Z4, and Z5, by itself or as part of -(alkylene)-monocyclic heteroarylene- and -monocyclic heteroarylene-(alkylene)-, and when present, is independently selected from imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, and pyridin-3,5-diyl. - 54 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A154. In embodiment A154, the compound of any one of embodiments A1 to A134a and A143 to A153, or a pharmaceutically acceptable salt thereof, is wherein each phenylene of Z1, Z3, and Z4, by itself or as part of -(alkylene)-phenylene- and -phenylene-(alkylene)-, and when present, is independently selected from 1,3-phenylene and 1,4-phenylene. 5 A155. In embodiment A155, the compound of any one of embodiments A1 to A141 and A143 to A154, or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z1, Z2, Z3, Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene- and -spiro 10 heterocyclylene-(alkylene)-, respectively, and when present, are independently selected from: re ethyl, unless stated otherwise in any of the embodiments above. A156. In embodiment A156, the compound of any one of embodiments A1 to A141 and 15 A143 to A155, or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene, of Z1, Z2, Z3, Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene- and -spiro heterocyclylene-(alkylene)-, respectively, and when present, are independently selected from: - 55 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT re ss stated otherwise in any of the embodiments above. A157. In embodiment A157, the compound of any one of embodiments A1 to A141 and 5 A143 to A156, or a pharmaceutically acceptable salt thereof, is wherein heterocyclylene of Z1, Z2, Z3, Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)- and when present, is selected from: nts A1 to A141 and 10 A143 to A157, or a pharmaceutically acceptable salt thereof, is wherein heterocyclylene of Z1, Z2, Z3, Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)- and when present, is A159. I t A159, the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, and A130 to A134, or a pharmaceutically acceptable salt thereof, is 15 wherein -Z3-Z4-Z5-Z6- is: - 56 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , , , 5 ; lo, haloalkyl, haloalkoxy, alkoxy, and cyano(i.e., Rris hydrogen). In a subembodiment, each Rqand Rmare independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, 10 difluoromethoxy, difluoromethyl, and trifluoromethyl. A160. In embodiment A160, the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, and A159, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: - 57 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , , or wh l, halo, 5 haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e., Rr is hydrogen). A161. In embodiment A161, the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: . 10 A162. In embodiment A162 one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: . A164. In embodiment A16 one of embodiments A1 to A112, 15 A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: . A165. In embodiment A16 one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable 20 salt thereof, is wherein -Z3-Z4-Z5-Z6- is: - 58 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT . A166. In embodiment A166, y one of embodiments A1 to A111, A115 to A120, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: 5 . A167. In embodiment A16 one of embodiments A1 to A111, A115 to A120, A124 to A128, A130 to A134, A159, A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: Z4SO2N . 10 A168A. In embodim nd of any one of embodiments A1 to A111, A115 to A120, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: . A168. In embodiment A16 one of embodiments A1 to A112, 15 A115 to A136, and A159 to 168A, or a pharmaceutically acceptable salt thereof, is wherein the p A128, A130, A131, A135 to A154, and A159 to A168, or a pharmaceutically acceptable salt thereof, is 20 wherein Z4is –(alkylene)-heterocyclylene-, where heterocyclylene is substituted with Roand Rp. - 59 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A170. In embodiment A170, the compound of any one of A1 to A114, A124 to A128, A130, A131, A135 to A154, and A159 to A169 or a pharmaceutically acceptable salt thereof, is wherein Z4is –(CH2)-heterocyclylene- where heterocyclylene is substituted with Roand Rp. A171. In embodiment A171, the compound of any one of A1 to A114, A124 to A128, 5 A130, A131, A135 to A154, and A159 to A170, or a pharmaceutically acceptable salt thereof, is wherein Z4is: A A112, A124 to A128, A130, A131, A135 to A137, and A143 to A171, or a pharmaceutically acceptable salt 10 thereof, is wherein -Z3-Z4-Z5-Z6- is: - 60 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 7 to A112, A124 to A128, A130, A131, A135 to A137, and A143 to A172, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is: 5 . 2, A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3 to C6 alkenylene substituted with Rvwhere Rvis hydrogen. A175. In embodiment A175, the compound of any one of embodiments A1 to A112, 10 A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3 to C6 alkenylene substituted with Rvwhere Rvis fluoro or cyano. A176. In embodiment A176, the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A133, A134a, and A135 to A168 (except for Z4in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z4is C3 to C6 alkylene 15 substituted with Rs, Rt, and Ruwhere Rs, Rt, and Ruare hydrogen. A177. In embodiment A177, the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A133, A134a, and A135 to A148 (except for Z4in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, Rt, and Ruwhere Rs, Rt, and Ruare hydrogen or halo, provided at least one of 20 Rg, Rh, and Riis halo, in one embodiment the halo is fluoro. - 61 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A178. In embodiment A178, the compound of any one of embodiments A1 to A112, A115 to A121, A124 to A128, A130 to A133, A134a, and A135 to A148 (except for Z4in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z4is C3 to C6 alkylene substituted with Rs, Rt, and Ruwhere Rtis other than hydrogen and Ruis hydrogen or when Rtand 5 Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C6 alkylene, Rtand Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by Rtand Ruare substituted with R9and R10. A179. In embodiment A179, the compound of embodiment A178, or a pharmaceutically10 acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, Rt, and Ruwhere Rtis other than hydrogen and Ruis hydrogen. A180. In embodiment A180, the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof, is wherein the C3 to C6 alkenylene and C3 to C6 alkylene of Z4are linear alkenylene and alkylene, respectively, and substituted as defined therein. 15 A181. In embodiment A181, the compound of any one of embodiments A174 to A180, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to C6alkenylene is -CH=C(Rv)CH2-, -CH2CH=CH-, -CH2CH2CH=CH-, -CH2CH=CHCH2-, and the linear alkylene of C3to C6alkylene of Z4is -CH2CH(Rt)CH2-, -CH2CH2CH(Rt)-, -CH2C(Rs)(Rt)CH2-, -CH2CH2C(Rs)(Rt)- where Rsand Rtare as defined therein and Ruis hydrogen. 20 A182. In embodiment A182, the compound of any one of embodiments A178 to A181, or a pharmaceutically acceptable salt thereof, is wherein the linear C3 to C6 alkylene of Z4is -CH2CH(Rt)CH2- where Rtis other than hydrogen. A183. In embodiment A183, the compound of any one of embodiments A178 to A182, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to C6alkylene of Z4is as 25 defined therein and Rtof linear C3 to C6 alkylene of Z4is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein unless stated otherwise. A184. In embodiment A184, the compound of any one of embodiments A178 to A183, or 30 a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to C6alkylene of Z4is hydrogen and Rtof linear C3 to C6 alkylene of Z4is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, each ring substituted as defined therein. A185. In embodiment A185, the compound of any one of embodiments A178 to A184, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclyl, and bridged - 62 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT heterocyclyl of Rtof linear C3 to C6 alkylene of Z4, when present, are five or six membered rings and each ring is substituted as defined therein. A186. In embodiment A186, the compound of any one of embodiments A178 to A185, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to C6alkylene of Z4is as 5 defined therein and Rtof linear C3 to C6 alkylene of Z4is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or tetrahydrofuranyl, where each ring of 10 Rtis substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano, unless stated otherwise. A187. In embodiment A187, the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof, is wherein the C3to C6alkenylene and C3to C615 alkylene of Z4are branched C4 to C6 alkenylene and C4 to C6 alkylene, respectively, and each is substituted as defined therein. A188. In embodiment A188, the compound of any one of embodiments A176 to A179 and A187, or a pharmaceutically acceptable salt thereof, is wherein Z4is branched C4to C6alkylene substituted as defined therein. 20 A189. In embodiment A189, the compound of any one of embodiments A174 to A179, A187, and A188, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6 alkenylene of Z4is -CH2CH2C(CH3)=C(Rv)-, -CH2CH2C(CH2Rv)=CH-, -CH2C(CH3)=C(Rv)-, or -CH2C(=CH2)CH2- and the branched C4 to C6 alkylene of Z4is -CH2C(CH3)(Rt)CH2-, -CH2C(C2H5)(Rt)CH2-, -CH2CH(CH2Rt)CH2-, -CH2CH(CH2CH2Rt)CH2-, 25 -CH2C(CH3)(CH2Rt)CH2-, -CH2C(C2H5)(CH2Rt)CH2-, -CH2C(CH3)(CH2CH2Rt)CH2-, -CH2CH(CH3)CH(CH2Rt)-, -CH2CH2C(CH3)(CH2Rt)-, -CH2CH(CH3)C(Rs)(Rt)-, -CH2CH(C2H5)C(Rs)(Rt)-. -CH2CH(C(Rs)(Rt)(Ru))CH(CH3)-, -CH2C(CH3)(C(Rs)(Rt)(Ru))CH(CH3)-, -CH2CH(C(Rs)(Rt)(Ru))CH2-, - CH2CH2CH(C(Rs)(Rt)(Ru))-, -CH2CH2CH(C(Rs)(Rt)(Ru))CH2-, 30 or -CH2CH2CH2CH(C(Rs)(Rt)(Ru))- where Rs, Rt, and Ruare as defined therein. A190. In embodiment A190, the compound of any one of embodiments A174 to A179 and A187 to A189, or a pharmaceutically acceptable salt thereof, is wherein the branched C4to C6alkenylene of Z4is -CH2C(CH3)=C(Rv)- or -CH2C(=CH2)CH2- and the branched C4to C6alkylene of Z4is -CH2C(CH3)(Rt)CH2-, -CH2CH(CH2Rt)CH2-, -CH2CH(CH2CH2Rt)CH2- - 63 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , -CH2CH(C(Rs)(Rt)(Ru))CH2-, -CH2CH2CH(C(Rs)(Rt)(Ru))CH2-, or -CH2CH2CH2CH(C(Rs)(Rt)(Ru))- where Rs, Rt, and Ruare as defined therein. A191. In embodiment A191, the compound of any one of embodiments A176 to A179 and A187 to A190, or a pharmaceutically acceptable salt thereof, is wherein the Rsand Ruof 5 branched C4 to C6 alkylene of Z4are independently hydrogen or halo (unless stated otherwise) and Rtof branched C4to C6alkylene of Z4is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of Rtis 10 substituted as defined therein. A192. In embodiment A192, the compound of any one of embodiments A176 to A179 and A187 to A191, or a pharmaceutically acceptable salt thereof, is wherein the Rsand Ruof branched C4 to C6 alkylene of Z4are hydrogen or fluoro (unless stated otherwise) and Rtof branched C4to C6alkylene of Z4is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, 15 alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of Rtis substituted as defined therein. A193. In embodiment A193, the compound of any one of embodiments A176 to A179 and A187 to A192, or a pharmaceutically acceptable salt thereof, is wherein Rsand Ruof branched 20 C4to C6alkylene of Z4are hydrogen or fluoro (unless stated otherwise) and Rtof branched C4to C6 alkylene of Z4is hydrogen, halo, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein. A194. In embodiment A194, the compound of embodiment A178, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, Rt, and Ruwhere Rt25 and Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C6alkylene and Rtand Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by Rtand Ruare substituted with R9and R10. A195. In embodiment A195, the compound of any one of embodiments A178 and A194, 30 or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, Rt, and Ruwhere Rtand Ruare attached to the same carbon atom of the linear portion of C3 to C6alkylene and together with the carbon atom to which they are attached can form cycloalkylene substituted with R9and R10.- 64 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A196. In embodiment A196, the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, Rt, and Ruwhere Rtand Ruare attached to the same carbon atom of the linear portion of the C3 to C6 alkylene and together with the carbon atom to which they are attached can form heterocyclylene 5 substituted with R9and R10. A197. In embodiment A197, the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3 to C6 alkylene substituted with Rs, Rt, and Ruwhere Rtand Ruare attached to adjacent carbon atoms of the linear portion of the C3to C6alkylene and together with the carbon atoms to which they are attached can form cycloalkylene 10 substituted with R9and R10. A198. In embodiment A198, the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, Rt, and Ruwhere Rtand Ruare attached to adjacent same carbon atoms of the linear portion of the C3 to C6alkylene and together with the carbon atoms to which they are attached can form 15 heterocyclylene substituted with R9and R10. A199. In embodiment A199, the compound of any one of embodiments A178 and A194 to A196, or a pharmaceutically acceptable salt thereof, is wherein Rtand Ruare attached to the same carbon atom of the linear portion C3to C6alkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: 20 o w ment, R9is hydrogen, halo, methyl or ethyl and R10is hydrogen. 25 A200. In embodiment A200, the compound of any one of embodiments A178, A194, A197, and A198, or a pharmaceutically acceptable salt thereof, is wherein Rtand Ruare attached to adjacent carbon atoms of the linear portion of the C3to C6alkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: - 65 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT or heterocyclylene of formula: , w mbodime9 nt R is hydrogen, halo, 5 methyl or ethyl and R10is hydrogen. A201. In embodiment A201, the compound of any one of embodiments A1 to A112, A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof, is wherein the Z4is C3to C6heteroalkylene substituted with Rs, Rt, and Ru. A202. In embodiment A202, the compound of embodiment A201, or a pharmaceutically10 acceptable salt thereof, is wherein the Z4is C3to C6heteroalkylene substituted with Rs, Rt, and Ruwhere Rs, Rt, and Ruare hydrogen. A203. In embodiment A203, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein the Z4is C3 to C6 heteroalkylene substituted with Rs, Rt, and Ruwhere Rs, Rt, and Ruare hydrogen or halo, provided at least one of Rs, Rt, and Ruis halo. 15 A204. In embodiment A204, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6heteroalkylene substituted with Rs, Rt, and Ruwhere Rtis other than hydrogen and Ruis hydrogen, or when Rtand Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3to C6heteroalkylene, Rtand Rutogether with the carbon atom to which they are attached can form cycloalkylene or 20 heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R9and R10. A205. In embodiment A205, the compound of embodiment A204, or a pharmaceutically acceptable salt thereof, is wherein Rtand Ruare attached to the same carbon atom of the linear portion of the C3 to C6 heteroalkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: 25 o - 66 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT w ment, R9is hydrogen, halo, methyl or ethyl and R10is hydrogen. A206. In embodiment A206, the compound of embodiment A204, or a pharmaceutically 5 acceptable salt thereof, is wherein Rtand Ruare attached to adjacent carbon atoms of the linear portion of the C3 to C6 heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: , 10 w mbodiment, R9is hydrogen, halo, methyl or ethyl and R10is hydrogen. A207. In embodiment A207, the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof, is wherein the C3 to C6 heteroalkylene of Z4is linear C3 15 to C6heteroalkylene substituted with Rs, Rt, and Ru. A208. In embodiment A208, the compound of any one of embodiments A201 to A204, and A207, or a pharmaceutically acceptable salt thereof, is wherein the linear heteroalkylene of Z4is -CH2CH2XaCH2-, -CH2XaCH2CH2-, -CH2CH2CH2Xa-, -XaCH2CH2CH2-, - XyCH2CH2Xa-, -XyCH2CH2XaCH2-, -CH2CH2CH2XaCH2-, -CH2XaCH2-, -XaCH2CH2-, -CH2CH2Xa-, 20 -CH2CONRq1CH2-, -CH2SO2NRq1CH2-, -CH2NRq1COCH2-, -CH2NRq1SO2CH2-, -CH2CH2CH2NRq1CO-, -CH2CONRq1-, -CH2SO2NRq1-, -CH2NRq1CO-, -CH2NRq1SO2-, -CONRq1CH2-, -SO2NRq1CH2-, -NRq1COCH2-, or -NRq1SO2CH2- substituted with Rs, Rt, and Ruas defined therein and Xais -NRq1-, -O-, -S-, -SO-, -SO2-, or –CO-. A209. In embodiment A209, the compound of any one of embodiments A201 to A204, 25 A207, and A208, or a pharmaceutically acceptable salt thereof, is wherein Rq1is hydrogen, methyl, ethyl, methylcarbonyl, or methylsulfonyl. - 67 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A210. In embodiment A210, the compound of any one of embodiments A201 to A204, and A207 to 209, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to C6heteroalkylene of Z4is -CH2XaCH2-, -XaCH2CH2-, -CH2CH2Xa-, -CH2CH2CH2Xa-, -CH2CH(Rt)Xa-, -XaCH(Rt)CH2-, -CH2CONRq1-, -CH2SO2NRq1-, -CH2NRq1CO-, -CH2NRq1SO2-, 5 -CONRq1CH2-, -SO2NRq1CH2-, -NRq1COCH2-, or -NRq1SO2CH2- where Xais -S-, -SO2-, -O-, or -NRq1- substituted with Rs, Rt, and Ruas defined therein. A211. In embodiment A211, the compound of any one of embodiments A201 to A204, and A207 to 210, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to C6heteroalkylene of Z4is -CH2CH2CH2Xa- or -CH2CH2Xa- substituted with Rs, Rt, and Ruas defined 10 therein. A212. In embodiment A212, the compound of any one of embodiments A201 to A204, and A207 to A211, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to C6heteroalkylene of Z4is hydrogen or halo (unless stated otherwise therein above) and Rtof linear heteroalkylene of Z4is (unless stated otherwise therein above) hydrogen, halo, haloalkoxy, 15 cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein and Ruis hydrogen. A213. In embodiment A213, the compound of any one of embodiments A201 to A204, and A207 to A212, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3 to C6 20 heteroalkylene of Z4is hydrogen or fluoro (unless stated otherwise therein above) and Rtof linear heteroalkylene of Z4(unless stated otherwise therein above) is hydrogen halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein. A214. In embodiment A214, the compound of any one of embodiments A201 to A204, and A207 to A213, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, 25 heterocyclyl, and bridged heterocyclyl of Rtof linear C3 to C6 heteroalkylene of Z4, when present, are five or six membered ring and each ring is substituted as defined therein. A215. In embodiment A215, the compound of any one of embodiments A201 to A204, and A207 to A214, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear heteroalkylene of Z4, when present and unless stated otherwise herein above, is hydrogen, 30 deuterium, or fluoro, and Rtof linear heteroalkylene of Z4, unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, - 68 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT piperazinyl, tetrahydrofuranyl, each ring substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino, and cyano. A216. In embodiment A216, the compound of any one of embodiments A201 to A215, or 5 a pharmaceutically acceptable salt thereof, is wherein Xais -NRq1-, -O-, -S-, or -SO2-. In one embodiment, -NRq1- (where Rq1is hydrogen or methyl), -O-, or -S-. A217. In embodiment A217, the compound of any one of embodiments A201 to A216, or a pharmaceutically acceptable salt thereof, is wherein Xyis -O-. A218. In embodiment A218, the compound of any one of embodiments A201 to A216, or 10 a pharmaceutically acceptable salt thereof, is wherein Xyis -NH- or -NCH3-. A219. In embodiment A219, the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof, is wherein the C3to C6heteroalkylene of Z4is branched C4 to C6 heteroalkylene substituted with Rs, Rt, and Ru. A220. In embodiment A220, the compound of any one of embodiments A201 to A204,15 and A219, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6 heteroalkylene of Z4is -CH2XaCH(CH3)CH2-, -CH2XyCH2CH(CH3)Xa-, -CH2CH2CH(CH3)Xa-, -XaCH(CH3)CH2CH2-, -XyCH2CH(CH3)Xa-, -XyCH(CH3)CH2Xa-, -CH2CH2CH2CH(CH3)Xa-, -XaCH(CH2Rt)CH2-, -CH2CH(CH2Rt)Xa-, -XaCH(CH2CH2Rt)CH2-, -CH2CH(CH2CH2Rt)Xa-, -CH2C(CH3)(CH3)Xa-, -XaC(CH3)(CH3)CH2-, -CH(CH3)CH(CH3)Xa-, -CONRqCH2CH(CH3)Xa-, 20 -CH2NRqCOCH(CH3)CH2-, or -NRq1COCH(CH3)CH2- where Xais -NRq1-, -O-, -S-, -SO-, -SO2-, or –CO- and Rtis as defined therein above. A221. In embodiment A221, the compound of any one of embodiments A201 to A204, A219, and A220, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6 heteroalkylene of Z4is -CH2C(CH3)(CH3)Xa-, -CH(CH3)CH(CH3)Xa-, -XaCH(CH2CH2Rt)CH2-, 25 -CH2CH(CH2CH2Rt)Xa-, -XaCH(CH2Rt)CH2-, or -CH2CH(CH2Rt)Xa-. A222. In embodiment A222, the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof, is wherein the Rsand Ruof branched C4to C6heteroalkylene of Z4are hydrogen or halo (unless stated otherwise herein above) and Rtof branched C4 to C6 heteroalkylene of Z4is hydrogen, halo, haloalkoxy, cycloalkyl, 30 cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl substituted as defined therein. A223. In embodiment A223, the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof, is wherein Rsand Ruare - 69 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT hydrogen and Rtis hydrogen, heteroaryl, alkylaminocarbonyl, or cyano (unless stated otherwise herein above). A224. In embodiment A224, the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, 5 heterocyclyl of branched C4 to C6 heteroalkylene of Z4, by itself or as part of heterocyclyloxy, heterocyclylcarbonyl, and bridged heterocyclyl, when present, are five or six membered ring and each ring is substituted as defined therein. A225. In embodiment A225, the compound of any one of embodiments A201 to A204, and A219 to A224, or a pharmaceutically acceptable salt thereof, is wherein Rtof branched C4 to 10 C6heteroalkylene of Z4, when present and unless stated otherwise herein above, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyrrolidinyl, pyridinyl, piperidinyl, piperazinyl, or 15 tetrahydrofuranyl, where each ring is substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano. A226. In embodiment A226, the compound of any one of embodiments A201 to A204 and A219 to A225, or a pharmaceutically acceptable salt thereof, is wherein Xais -NRq1-, -O-, -S-, 20 or -SO2-. In one embodiment Xais -NRq1- or -O-. A227. In embodiment A227, the compound of any one of embodiments A1 to A112, A124 to A127, A132, and A134 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z4is alkynylene substituted with Rwand Rxindependently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano. 25 A228. In embodiment A228, the compound of any one of embodiments A227, or a pharmaceutically acceptable salt thereof, is wherein Z4is alkynylene substituted with Rwand Rxindependently selected from hydrogen, fluoro, difluoromethyl, trifluoromethyl, hydroxy, methoxy, and cyano. A229. In embodiment A229, the compound of embodiment A227, or a pharmaceutically 30 acceptable salt thereof, is wherein Z4is alkynylene substituted with Rwand Rxwhich are attached to the same carbon atoms of the alkynylene and are combined to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R11and R12independently selected from hydrogen, alkyl, and halo. - 70 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A230. In embodiment A230, the compound of any one of embodiments A227 to A229, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of Z4is: . 5 A embodiments A227, A228, and A230, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of Z4is: . A ound of any one of embodiments A174 to A226, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, and alkenylene 10 of Z4are selected from: - 71 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT - 72 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , re A233. In embodiment A233, the compound of any one of embodiments A174 to A226, and A232, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, 5 and alkenylene of Z4are selected from: - 73 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT re A234. In embodiment A234, the compound of any one of embodiments A174 to A226, 5 A232, and A233, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, and alkenylene of Z4are selected from: - 74 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , , O - 75 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT respe A235. In embodiment A235, the compound of any one of embodiments A174, A176, 5 A178, A179 to A184, A187 to A193, A201, A202, A204, A217, A219 to A223, A225, A226, and A232 to 234, or a pharmaceutically acceptable salt thereof, is wherein Z4is: 76, A178, A179 to A184, A187 to A193, A201, A202, A204, A217, A219 to A223, A225,A226, and 10 A232 to 235, or a pharmaceutically acceptable salt thereof, is wherein Z4is: - 76 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT to A194, A197, A200, to 202, A204, A207 to A213, A215 to A226, and A232 to 234, or a pharmaceutically acceptable salt thereof, is wherein Z4is: 5 d, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X1-L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: - 77 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 2 , - 78 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 5 - - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A23 to A96d and A238, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X1-L-, -X2-L-, -X3-L-, and -X4-L- (when the Degron is a group of formula 5 (i) or (ii)) are independently: - 80 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 6d, 5 A238, and A239, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X1-L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: - 81 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 6d and 5 A238 to A240, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X1-L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: . - 82 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A242. In embodiment A242, the compound of any one of embodiments A1 to A96d, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X1-L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: 5 , , , 10 ; lo, haloalkyl, haloalkoxy, alkoxy, and cyano (i.e., Rris hydrogen). In a subembodiment, each Rqand Rmare independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; and 15 Z4is alkylene, alkynylene, alkenylene, or heteroalkylene wherein alkylene and heteroalkylene are substituted with Rs, Rt, and Ru, alkenylene is substituted with Rvand alkynylene is substituted with Rwand Rxas defined in the first aspect of the Summary. - 83 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A243. In embodiment A243, the compound of any one of A1 to A96d and A242, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X1-L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: 5 , , or wherein ea haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e., Rris hydrogen). 10 A244. In embodiment A244, the compound of embodiment A242 or A243, or a pharmaceutically acceptable salt thereof, is wherein: ; and 15 ynylene is as provided in embodiment 231); and alkylene, alkenylene, and heteroalkylene of Z4are those as provided in embodiment A233. In one subembodiment alkylene, alkenylene, and heteroalkylene of Z4are those as provided in embodiment A234, respectively. In another subembodiment alkylene, alkenylene, and heteroalkylene of Z4are those as provided in embodiment A235, 20 respectively. In yet another subembodiment alkylene, alkenylene, and heteroalkylene of Z4are - 84 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT those as provided in embodiment A236, respectively. In one subembodiment alkylene, alkenylene, and heteroalkylene of Z4are those as provided in embodiment A237, respectively. A245. In embodiment A245, the compound of any one of embodiments A1 to A96d and A134a, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of 5 formula (iii) to (vi)); and -X1-L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: , w , haloalkyl, 10 haloalkoxy, alkoxy, and cyano; and Z4is C3to C6alkylene substituted with Rs, Rt, and Ru. A246. In embodiment A246, the compound of embodiment A245, or a pharmaceutically acceptable salt thereof, is wherein: e Rmand Rnare independently selected from hydrogen, 15 methyl, xy, difluoromethoxy, difluoromethyl, and trifluoromethyl; and Z4is propylene, butylene, or pentylene. A247. In embodiment A247, the compound of embodiment A245 or A246, or a pharmaceutically acceptable salt thereof, is wherein Z4is n-propylene. 20 A248. In embodiment A248, the compound of any one of embodiments A1 to A46, A48 to A56, A59 to A67, A69 to A75, A77 to A82, A83 to A93, A97, and A110a to A247, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand selected from: H O N O O F , - 85 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , , 5 , , , , , , hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. A249. In embodiment A249, the compound of any one of embodiments A1 to A46, A48 to A56, A59 to A67, A69 to A75, A77 to A82, A83 to A93, A97, and A110a to A248, or a 10 pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand selected from: H O N O O F , , - 86 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , and y g , y , y , y p py , , , y 5 hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. A250. In embodiment A250, the compound of embodiment A249, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ligase ligand selected from: 10 A250, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand is s hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and Rf ethyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. 15 A252. In embodiment A252, the compound of embodiment A250, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand is . - 87 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference to an embodiment includes combination of the embodiment and subembodiment(s) thereof. For example reference to embodiment A includes combination of embodiment A and subembodiment(s) thereof. For the sake of clarity, when an embodiment refers to more than one preceding 5 embodiments of varying scopes, the scope of the preceding embodiments control i.e., only those groups that fall within the scope of group(s) recited in a preceding embodiment(s) should be selected from the embodiment referring thereto. For example, of the groups recited in embodiment A17, while all the recited groups in A17 should be selected for embodiment A1, only fluoro, chloro, and bromo should be selected for embodiment A8 as scope of R1in A8 is limited to halo; 10 and only difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl should be selected for embodiment A6 as scope of R1in A6 is limited to haloalkyl. It is understood that the embodiments and subembodiments set forth above include all combinations of embodiments and subembodiments listed therein. 15 Representative compounds of Formula (I) are shown in Compound Table 1 below: Table 1 Mass Cpd Structure Name spec 1]+.3 .1 .0 - 88 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Mass C d Str t r Nm ec 1]+.3 .2 .4 .4 .2 .3 .5 - 89 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Mass C d Str t r Nm ec 1]+.4 .1 .2 .1 .1 .2 - 90 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Mass C d Str t r Nm ec 1]+.5 .4 .5 .1 .0 .2 - 91 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Mass C d Str t r Nm ec 1]+.2 .2 .9 .3 .2 .1 - 92 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Mass C d Str t r N m ec 1]+.0 General Synthetic Scheme Compounds Formula (I) (and any embodiment thereof disclosed herein including specific compounds) can be made by the methods depicted in the reaction schemes shown below. 5 The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, 10 Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds Formula (I)(and any embodiment thereof disclosed herein including specific compounds) can be 15 synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and 20 spectral data. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78oC to about 150oC, such as from about 0oC to about 125oC and further such as at about room (or ambient) temperature, e.g., about 20oC. Compounds of Formula (I), where Degron is an E3 ligase ligand of formula (i)-(vi) where 25 R3is hydrogen, ring Hy, R1, R2, and L are as defined in the first aspect of the Summary, can be prepared as described in Scheme 1 below. - 93 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Scheme 1 bromine and R1and R2are as defined in the first aspect of the Summary, with an amine of formula 1-2, 5 where Hy is as defined in the Summary and FG1is a suitable functional group such as an acid or amine, under conditions well known in the art (such as in the presence of TEA and ZnCl2 in tert- butanol), provides a compound of formula 1-3. A compound of formula 1-4 where L is as defined in the first aspect of the Summary with a suitable functional group (FG2), such as acid, amine, or alkyl halide, reacts with FG1in 1-3 to afford compound of Formula (I). For example, the reaction 10 is a peptide coupling reaction, where the resulting amide bond is part of L as defined in the Summary, and FG1and FG2are a combination of carboxylic acid and an amine, in the presence of suitable coupling reagents, such as a combination of HATU and DIPEA in DMF. Alternatively, a compound of Formula (I) such as where Hy is 1,4-piperidindiyl, Degron is 15 a group of formula (i) and L is attached to Degron (i) via heterocyclylene containing at least one nitrogen ring atom and to Hy via -SO2-, can be synthesized as illustrated and described in Scheme 2. Scheme 2 NH2R1 1R1RS S O A2AR1R2N L (I) 20 Trea ne or bromine, with a piperidine amine of formula 2-2 under conditions well known in the art, such as in the presence of TEA, and ZnCl2in tert-butanol, provides a compound of formula 2-3. An amine compound of formula 2-4, prepared by removal of the Boc protecting group of 2-3 in the presence - 94 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT of an acid, such as TFA, is converted to a sulfonamide compound of formula 2-6 by treating it with a sulfonyl halide of formula 2-5 where L’ is a precursor group of L in the compound of Formula (I) as defined in the Summary and A2is halogen such as chlorine and LG is a suitable leaving group such as halo or methylsulfonyl. 5 Treatment of a compound of formula 2-6 with an amine compound of formula 2-7, where ring A is defined as in the Summary and is heterocyclylene containing at least one nitrogen ring atom (e.g. piperidin-1,4-d basic conditions such as in the presence of DIPEA, provides a compound of formula (I). Compounds of formula 1-1, 2-5, and 2-7 are either commercially available or they can be 10 prepared by methods known in the art. A compound of Formula (I) such as where R2is hydrogen, Degron is a group of formula (i), Z1is heterocyclylene such as 4-piperidin-1-yl, Z2and Z3are bond, Z4is but-1-ynlene, Z5is aryl (Ar), and Z6is -SO2- can be synthesized as illustrated and described in Scheme 3. 15 Scheme 3 Tr ng group, such as chlorine or bromine, with an amine of formula 3-1 under basic or catalytic conditions known in the art provides an alkyne of formula 3-3. Coupling between alkyne 3-3 and compound 20 of formula 3-5, where A2is a halogen such as bromine or iodine, gives compound of formula 3-6, under conditions known in the art, such as a Sonogashira coupling in the presence of a palladium catalyst, a copper (I) cocatalyst, and an amine base. Removal of the Boc protecting group in compound 3-6 using an acid like TFA provides an amine compound of formula 3-7. Treatment of - 95 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT compound 3-7 with a thazole of formula 3-8 under suitable conditions well known in the art, provides a compound of Formula (I). Compounds of formula 3-2, 3-5, and 3-8 are either commercially available or they can be prepared by methods known in the art. 5 Compounds of Formula (I)) where R1, R2, Hy, L, and Degron are as defined in the Summary can be prepared as described in Scheme 3 below: Scheme 4 10 Treatme here R1, R2, Hy, L and Degron are as defined in the Summary, under suitable conditions such as acidic, basic or transition metal catalyzed reaction conditions well known in the art, provides a compound of Formula (I). Utility 15 The compound of Formula (I) or (IB) (and any embodiment thereof disclosed herein including specific compounds) i.e., compound of this disclosure can cause degradation of CDK2 and / or CDK4 proteins and hence are useful in the treatment of diseases mediated by CDK2 and / or CDK4. Increasing evidence suggests that overactivated CDK2 and / or CDK4 leads to abnormal 20 cell cycle regulation and proliferation in cancer cells. While CDK2 / 4 mutations are rarely found, the kinase activity of CDK4 / Cyclin D, CDK2 / Cyclin E or CDK2 / Cyclin A complexes is elevated via several mechanisms in human cancers. Aberrations of CDK4 / cyclin D regulation have been identified in many human cancers. For example, amplification or overexpression of cyclin D1 has been found in many cancers, including breast invasive ductal carcinoma, invasive breast 25 carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, and lung adenocarcinoma. Translocation of cyclin D1 Amplification of CDK4 is common in liposarcoma. CDK4 amplification has also been observed at lower frequency in other solid tumors and hematologic malignancies. Loss of the CDK4 inhibitor p16 (CDKN2A) is also a common event in many cancers, including glioblastoma multiforme, head and neck squamous cell carcinoma, 30 pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, lung squamous cell - 96 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT carcinoma, bladder urothelial carcinoma, skin cutaneous melanoma, diffuse large B-cell lymphoma, cholangiocarcinoma, lung adenocarcinoma, and stomach adenocarcinoma. Cyclin E has been found to be frequently amplified in cancers, for example, in uterine cancer, ovarian cancer, stomach cancer, and breast cancer. In some cancer types, loss-of-function 5 mutations in FBXW7 or overexpression of USP28, which control the turnover of cyclin E, leads to cyclin E overexpression and CDK2 activation. Alternatively, certain cancer cells express a hyperactive, truncated form of cyclin E or cyclin A. In addition, cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers. In some tumors, catalytic activity of CDK2 is increased following 10 loss of the expression or alteration of the location of the endogenous CDK2 inhibitor p27 or p21, or overexpression of SKP2, a negative regulator of p27. In addition, CDC25A and CDC25B, protein phosphatases responsible for the dephosphorylations that activate the CDK2, are overexpressed in various tumors. These various mechanisms of CDK2 activation have been validated using cancer cells or mouse cancer models. Furthermore, CDK2 / cyclin E phosphorylates 15 oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal to myc over-expressing cancer cells. In aneuploid cancer cells, for example KRAS-mutant lung cancer, CDK2 inhibition resulted in anaphase catastrophe and apoptosis. Moreover, inhibiting CDK2 effectively induced granulocytic differentiation in AML cell lines and arrested tumor 20 growth in AML mice models. CDK2 activation as a result of cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway to HR+ or HER2+ breast cancers treated by CDK4 / 6 inhibitors or trastuzumab. Accordingly, compounds of Formula (I) can be used in combination with CDK4 / 6 inhibitors or anti-HER2 therapies for the treatment of cancers that 25 become refractory to CDK4 / 6 inhibitors or anti-HER2 therapies. Therefore, a compound of this disclosure may be useful for treating tumors characterized by 1) overexpression of CDK2 and / or CDK4; 2) amplification / overexpression of cyclin D, cyclin E or cyclin A; 3) hyperphosphorylation of CDK2 (Thr160) or CDK4 (Thr172); 4) loss-of-function of mutation in FBXW7, depletion of AMBRA1, overexpression of USP28, or 30 amplification / overexpression of CDC25A or / and CDC25B; 5) expression of truncated cyclin E or cyclin A, 6) dysregulation of p16, p21 or p27, or overexpression of SKP2;and 7) hyperactive MYC / RAS; 8) Aneuploid cancers, and 9) CDK4 and / or CDK6 inhibitor refractory cancers. In some embodiments, the cancer is ovarian cancer (e.g. serous, clear cell, endometrioid, and mucinous ovarian carcinomas), uterine cancer (e.g. endometrial cancer and uterine sarcoma), - 97 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT stomach cancer (i.e. gastric cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), renal cancer (e.g. clear cell renal cell carcinomas, papillary renal cell carcinomas, and chromophobe renal cell carcinomas), brain cancer 5 (including astrocytoma, meningioma and glioblastoma), neuroblastoma, paraganglioma, pheochromocytoma, pancreatic neuroendocrine tumors, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, retinal cancers, hereditary leiomyomatosis, renal cell cancer, astrocytoma, skin cancer (e.g. melanoma, squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), bladder cancer 10 (including bladder urothelial carcinoma), cervical cancer, colorectal cancer (e.g., cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus), head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, tongue and mouth), liver cancer (e.g., hepatocellular carcinoma and cholangiocellular carcinoma), prostate cancer, testicular cancer, gall bladder cancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma and 15 neuroendocrine pancreatic cancer), thyroid cancer, and parathyroid cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, biliary tract cancer, esophageal cancer (e.g. esophageal squamous cell carcinoma and esophageal adenocarcinoma), sarcoma (e.g. liposarcoma and osteosarcoma), bone cancer, chondrosarcoma, leukemia (including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), 20 lymphoma (e.g. non-Hodgkin lymphoma NHL including mantel cell lymphoma, MCL and Hodgkin lymphoma) and multiple myeloma. In other embodiments, the cancer is breast cancer, including, e.g., ER-positive / HR-positive breast cancer, HER2-negative breast cancer; ER-positive / HR-positive breast cancer, HER2- positive breast cancer; ER-negative / HR-negative, HER2-positive breast cancer, triple negative 25 breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine resistant breast cancer, anti-HER2 therapy (e.g. trastuzumab) resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of 30 CCNE1 and / or CCNE2. Besides cancer, compounds of Formula (I) or (IB) as described in the Summary as described in the first aspect (or any of the embodiments thereof herein above) are useful in treating autoimmune diseases autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s - 98 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss. Testing CDK2 / 4 potency and CDK2 / 4 degradation activities of the compounds of the present 5 disclosure can be tested using the in vitro assays described in Biological Examples below. Pharmaceutical Compositions In general, the compounds Formula (I) (unless stated otherwise, reference to compound / compounds of Formula (I) herein includes any embodiments thereof described herein 10 or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable 15 dosage level may be from about 0.1 to about 250 mg / kg per day; about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to 20 about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds), i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of 25 the compound being utilized, the route and form of administration, and other factors. In general, compounds Formula (I) (and any embodiment thereof disclosed herein including specific compounds) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of 30 administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. - 99 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance. 5 The compositions are comprised of in general, a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). Such excipient may 10 be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may 15 be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. The compounds of Formula (I) (and any embodiment thereof disclosed herein 20 including specific compounds) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing 25 agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. 30 Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame - 100 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for 5 the preparation of highly concentrated solutions. In addition to the formulations described previously, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated as a depot preparation. Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, 10 for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise 15 the active ingredient in a flavored basis such as sucrose and acacia or tragacanth. The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. 20 Certain compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound 25 does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, 30 ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation. - 101 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT For administration by inhalation, compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, 5 trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may take the form of a dry powder composition, for example a powder mix of the compound and a 10 suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000). 15 The level of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) based on the total formulation, with the balance being one 20 or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %. Combinations and Combination Therapies The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may be used in combination with one or more other drugs in the treatment of 25 diseases or conditions for which compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). When a compound of Formula (I) (or any 30 embodiment thereof disclosed herein including specific compounds) is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is preferred. However, the combination therapy may also include therapies in which the compound of Formula (I) (or any embodiment thereof disclosed herein - 102 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT including specific compounds) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) and the other active ingredients may be used in lower doses 5 than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). The above combinations include combinations of a compound of Formula (I) (or any 10 embodiment thereof disclosed herein including specific compounds) not only with one other drug, but also with two or more other active drugs. Likewise, a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of Formula (I) (or any embodiment 15 thereof disclosed herein including specific compounds) is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). When a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is used contemporaneously with one or more 20 other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific 25 compounds). The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of Formula (I) (or any embodiment thereof disclosed herein 30 including specific compounds) in any combination with one or more other anti-cancer agents including but not limited to: MAP kinase pathway (RAS / RAF / MEK / ERK) inhibitors including but not limited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818), TQ-B3233, XL- 518 (Cas No.1029872-29-4, available from ACC Corp); trametinib, selumetinib (AZD6244), TQ- B3234, PD184352, PD325901, TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib - 103 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT (GDC-0973), AZD8330, BVD-523, LTT462, Ulixertinib, AMG510, ARS853, and any RAS inhibitors disclosed in patents WO2016049565, WO2016164675, WO2016168540, WO2017015562, WO2017058728, WO2017058768, WO2017058792, WO2017058805,WO2017058807, WO2017058902, WO2017058915, WO2017070256, 5 WO2017087528, WO2017100546, WO2017172979, WO2017201161, WO2018064510, WO2018068017, WO2018119183; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) TGF beta receptor kinase inhibitor such as LY2157299; BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (Gleevec®); Inilotinib 10 hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7); Saracatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-cyclobutylarmno)-5-(trifluoromethyl)-2- pyrimidinyl]amino]-l, 2,3,4-tetrahydronaphthalen-l,4-imin-9-yl]-2-oxoethyl]-acetamide (PF- 03814735, CAS 942487-16-3); 15 ALK inhibitors: PF-2341066 (XALKOPJ ®; crizotinib); 5-chloro-N4-(2- (isopropyl- sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiper azin-l-yl)piperidin-l- yl)phenyl)pyrimidine- 2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitors: 4-[2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l- yl]methyl]thieno[3,2-d]- pyrimidin-4-yl]morholine (also known as GDC 0941 and described in PCT Publication Nos. WO20 09 / 036082 and WO 09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8- (quinolin-3-yl)-2,3-dihydro- imidazo[4,5-c]quinolin-l-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06 / 122806); Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademark Avastin® by Genentech / Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2- 25 ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO 01 / 002369), Brivanib Alaninate ((S)-((R)-l-(4-(4-fluoro-2-methyl-lH-indol- 5-yloxy)-5-methylpyrrolo[2,l-f][l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4- pyridinyl- methyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 02 / 066470), 30 pasireotide (also known as SOM230, and described in PCT Publication No. WO 02 / 010192), sorafenib (sold under the tradename Nexavar®); AL-2846 MET inhibitor such as foretinib, carbozantinib, or crizotinib; FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib; - 104 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), 5 panitumumab (sold under the tradename Vectibix® by Amgen); HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech / Roche), Trastuzumab deruxtecan (sold under the trademark Enhertu), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7- ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 10 05 / 028443), lapatinib or lapatinib ditosylate (sold under the trademark Tykerb® by GlaxoSmithKline); Trastuzumab emtansine (in the United States, ado- trastuzumab emtansine, trade name Kadcyla) - an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1); HER dimerization inhibitors: Pertuzumab (sold under the trademark Omnitarg®, by 15 Genentech); CD20 antibodies: Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech / Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline); Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under the trademark Tarceva® by20 Genentech / Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No.6,780,996), dasatinib (sold under the tradename Sprycel® by 25 Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis); DNA Synthesis inhibitors: Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar® by Eli Lilly and Company), 30 nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline); Antineoplastic agents: oxaliplatin (sold under the tradename Eloxatin® ay Sanofi-Aventis and described in US Patent No.4,169,846); - 105 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename Neupogen® by Amgen); Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the 5 tradename Revlimid®), thalidomide (sold under the tradename Thalomid®); CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen / Genentech); Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)- 10 benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06 / 028958); Phospholipase A2 inhibitors: Anagrelide (sold under the tradename Agrylin®); BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]methyl]-l- piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-l-[(phenylthio)m ethyl]propyl]amino]-3- [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in 15 PCT Publication No. WO 09 / 155386); MCl-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991; Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®); 20 Topoisomerase I inhibitors: Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline); Topoisomerase II inhibitors: etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®); 25 mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E, 18R,19R,21R, 23S,24E,26E,28Z,30S,32S,35R)-l,18-dihydroxy-19,30- dimethoxy-15, 17, 21, 23, 29, 35-hexamethyl-2,3, 10, 14,20-pentaoxo-11, 36-dioxa-4- azatricyclo[30.3.1.04 ' 9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also 30 known as AP23573 and MK8669, and described in PCT Publication No. WO 03 / 064383), everolimus (sold under the tradename Afinitor® by Novartis); Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib; BET inhibitors such as INCB054329, OTX015, and CPI-0610; LSD1 inhibitors such as GSK2979552, and INCB059872; - 106 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT HIF-2α inhibitors such as PT2977 and PT2385; Osteoclastic bone resorption inhibitors: l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by 5 Pfizer / Wyeth); CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.); CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename Zevalin®); 10 Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®); Synthetic Interleukin-11 (IL-11): oprelvekin (sold under the tradename Neumega® by Pfizer / Wyeth); Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by 15 Amgen); Receptor Activator for Nuclear Factor κ B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen); Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename Nplate® by Amgen); 20 Cell growth stimulators: Palifermin (sold under the tradename Kepivance® by Amgen); Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No.934235-44-6); Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No.915296-00-3); CD52 antibodies: Alemtuzumab (sold under the tradename Campath®); 25 Histone deacetylase inhibitors (HDI): Voninostat (sold under the tradename Zolinza® by Merck); Alkylating agents: Temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough / Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine 30 mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under - 107 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®), 5 ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the tradename Thioplex®; Biologic response modifiers: bacillus calmette-guerin (sold under the 10 tradenames theraCys® and TICE® BCG), denileukin diftitox (sold under the tradename Ontak®); Anti-tumor antibiotics: doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the 15 tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence™), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®); Anti-microtubule agents: Estramustine (sold under the tradename Emcyl®); Cathepsin K inhibitors: Odanacatib (also known as MK-0822, N-(l-cyanocyclopropyl)-4- 20 fluoro-N-2-{(1S)-2,2,2-trifluoro-l-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03 / 075836); Epothilone B analogs: Ixabepilone (sold under the tradename Lxempra® by Bristol-Myers Squibb); Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxy- 25 geldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No.4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116 TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline); 30 Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® by Sanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cytadren®); Anti-androgens: Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename Fulexin™); Androgens: Fluoxymesterone (sold under the tradename Halotestin®); - 108 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDK11 / 12, or CDK16) inhibitors including but not limited to Alvocidib (pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4- chromenone, and described in US Patent No.5,621,002); 5 CDK4 / 6 inhibitors palbociclib, ribociclib, abemaciclib, and Trilaciclib; CDK9 inhibitors AZD 4573, P276-00, AT7519M, TP-1287; CDK2 / 4 / 6 inhibitor such as PF-06873600; SHP-2 inhibitor such as TNO155; MDM2 / MDMX, MDM2 / p53 and / or MDMX / p53 modulators; Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide 10 acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab); Taxane anti-neoplastic agents: Cabazitaxel (l-hydroxy-7, 10 -dimethoxy-9-oxo-5,20- epoxytax-l l-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{ [(tert- butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)- 15 4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-3- phenylpropanoyl}oxy)-l-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-l l-en-2-yl benzoate); 5HTla receptor agonists: Xaliproden (also known as SR57746, l-[2-(2-naphthyl)ethyl]-4- [3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No. 5,266,573); HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron 20 Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis); Anti-metabolites: Claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also 25 known as Liposomal Ara-C, sold under the tradename DepoCyt™), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin™), methotrexate (also known as amethopterin, methotrexate sodium (MTX), 30 sold under the tradenames Rheumatrex® and Trexall™), pentostatin (sold under the tradename Nipent®); Bisphosphonates: Pamidronate (sold under the tradename Aredia®), zoledronic acid (sold under the tradename Zometa®); Demethylating agents: 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®); - 109 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the 5 tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and Onxal™); Retinoids: Ali tretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename 10 Targretin®); Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R,10S,l lS,13S,14S,16R,17R)-9-fluoro-l l,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16- 15 trimethyl-6,7,8,9,10,l l,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®, Medralone®, 20 Medrol®, M-Prednisol® and Solu-Medrol®); Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin-11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®); Estrogen receptor downregulators: Fulvestrant (sold under the tradename 25 Faslodex®); and elacestrant and ARV-471(vepdegestrant); Anti-estrogens: tamoxifen (sold under the tradename Novaldex®); Toremifene (sold under the tradename Fareston®); Selective estrogen receptor modulators (SERMs): Raloxifene (sold under the tradename Evista®); 30 Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, sold under the tradename Megace®); - 110 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®); One or more immune checkpoint inhibitors CD27, CD28, CD40, CD122, CD96, CD73, 5 CD39, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137 and STING. In some embodiments, the immune checkpoint 10 molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors. 15 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab. 20 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab). 25 In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti- LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune 30 checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is - 111 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT MEDI0562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383 Compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) can also be used to increase or enhance an immune response, including 5 increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be used to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GVAX® (granulocyte- macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine). Anti-cancer 10 vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists. Other anti-cancer agents also include those that augment the immune system such as 15 adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation. A compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) can also be used in combination with the following adjunct therapies: anti- 20 nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). 25 Examples The following preparations of Intermediates (References) and compounds of Formula (I) (Examples) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof. - 112 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 1Synthesis of 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione, 2,2,2-trifluoroacetate 5 Step 1: tert-Butyl (14-((2-(2 olin-4-yl)amino)-3,6,9,12- tetraoxatetradecyl)carbamate A mi 0.0 mg, 1.81 mmol, 1.00 eq.), tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (609.0 mg, 1.81 10 mmol, 1.00 eq.), DIPEA (467.9 mg, 3.62 mmol, 2.00 eq.) in DMF (6.0 mL) was stirred for 16 h at 90oC under nitrogen atmosphere. The mixture was cooled, diluted with water, and then extracted with EtOAc. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1), to afford the title compound as a yellow solid. 15 Step 2: 4-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione, 2,2,2-trifluoroacetate -((2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate 20 (50 mg, 0.084 mmol, 1.00 eq.) in DCM (1.0 mL) at 0oC under nitrogen atmosphere. The mixture was stirred for 2 h, and then concentrated to give crude title compound as light yellow oil. - 113 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 2 Synthesis of 2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)- acetamido)ethoxy) ethoxy)ethyl methanesulfonate 5 Step 1: tert-Butyl 2-((2-(2,6-dio olin-4-yl)oxy)acetate A mixture of 2-(2,6 1,3-dione (1.5 g, 5.47 mmol, 1.00 eq.), tert-butyl 2-bromoacetate (1.3 g, 6.66 mmol, 1.22 eq.) and K2CO3 (1.1 g, 7.96 mmol, 1.46 eq.) in DMF (20.0 mL) was stirred at RT for 2 h. The mixture was diluted with H2O 10 and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, concentrated to get title compound as a white solid. Step 2: 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid A solution of tert-bu xoisoindolin-4-yl)oxy)- 15 acetate (1.0 g, 2.57 mmol, 1.00 eq.) and TFA (5.0 mL) in DCM (10.0 mL) was stirred at rt for 2 h. The mixture was concentrated and the residue was triturated with ether to get title compound as a white solid. Step 3: 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-hydroxyethoxy) ethoxy)ethyl)acetamide 20 HATU (51 ((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq.), 2-(2-(2-aminoethoxy)ethoxy)ethanol (201 mg, 1.35 mmol, 1.50 eq.) and DIPEA (348 mg, 2.69 mmol, 2.99 eq.) in DMF (6.0 mL) at 0oC and the mixture was stirred at RT for 1 h. The mixture 25 was diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated to get crude title compound as a yellow oil, which was used for next step without further purification. - 114 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 4: 2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy) ethoxy)ethyl methanesulfonate MsCl (2 2-(2,6- 5 dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-(2- hydroxyethoxy)ethoxy)ethyl)acetamide (800 mg, 1.73 mmol, 1.00 eq.) and TEA (524 mg, 5.18 mmol, 2.99 eq.) in DCM (8.0 mL) at 0oC and the mixture was stirred at 0oC for 1 h. The mixture was diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography 10 (DCM:MeOH = 50:1) to get title compound as a white solid. Reference 3 Synthesis of 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)oxy)acetamido)ethoxy)-ethyl methanesulfonate 15 Step 1: 2-((2-(2,6-Dioxopiperidi -yl)oxy)-N-(2-(2-hydroxyethoxy)- ethyl) acetamide A mixture of oxy)acetic acid (180 20 mg, 0.54 mmol, 1.00 eq.), 2-(2-aminoethoxy)ethan-1-ol (85 mg, 0.81 mmol, 1.50 eq.), HATU (308 mg, 0.81 mmol, 1.50 eq.) and DIPEA (209 mg, 1.62 mmol, 3.00 eq.) in DMF (5.0 mL) was stirred at 0oC for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4and concentrated to give crude title compound as a yellow oil, which was used for next step without further purification.25 Step 2: 2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)- ethyl methanesulfonate - 115 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT MsCl (16 n of 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-hydroxyethoxy)ethyl) acetamide (400 mg, 0.95mmol, 1.00 eq.) and TEA (288 mg, 2.85 mmol, 3.00 eq.) in DCM (8.0 mL) at 0oC. 5 The resulting mixture was stirred at 0oC for 1 h, diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and the residue was purified by flash silica gel chromatography (DCM:MeOH = 50:1) to give the title compound as a white solid. Reference 4 10 Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3- azatetradecan-14-yl methanesulfonate Step 1: 2-((2-(2,6-Dioxopiperidin oxy)-N-(2-(2-(2-(2- hydroxyethoxy) ethoxy)ethoxy)ethyl)acetamide 15 HAT 3.00 eq.) were added to a mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq.) and 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol (259 mg, 1.34 mmol, 1.49 eq.) in DMF (5.0 mL) at 0oC. The mixture was stirred at 0oC for 1h, diluted 20 with H2O, and then extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to get crude title compound as a yellow oil, which was used for next step without further purification. Step 2: 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3- azatetradecan-14-yl methanesulfonate 25 - 116 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT MsCl (271 mg, 2.37 mmol, 1.50 eq.) was added slowly to a stirred solution of 2-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-(2-(2-hydroxyethoxy)ethoxy)- ethoxy)ethyl)acetamide (800 mg, 1.58 mmol, 1.00 eq.) and TEA (479 mg, 4.73 mmol, 3.00 eq.) in DCM (8.0 mL) at 0oC. The mixture was stirred at 0oC for 1 h, diluted with H2O and extracted 5 with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH = 50:1) to get the title compound as a white solid. Reference 6 Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12,15- 10 tetraoxa-3- azaheptadecan-17-yl methanesulfonate Step 1: 2-((2-(2,6-Dioxopiper , )oxy)-N-(14-hydroxy-3,6,9,12- tetraoxatetradecyl)acetamide 15 A mixture o cetic acid (300 mg, 0.90 mmol, 1.00 eq.), 14-amino-3,6,9,12-tetraoxatetradecan-1-ol (320 mg, 1.35 mmol, 1.50 eq.), HATU (513 mg, 1.35 mmol, 1.50 eq.) and DIPEA (348 mg, 2.69 mmol, 2.99 eq.) in DMF (6.0 mL) was stirred at 0oC for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated to 20 get crude title compound as a yellow oil, which was used for next step without further purification. Step 2: 1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12,15-tetraoxa-3- azaheptadecan-17-yl methanesulfonate 25 Ms -((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N- (14-hydroxy-3,6,9,12- tetraoxatetradecyl)acetamide (800 mg, 1.45 mmol, 1.00 eq.) and TEA (479 mg, 4.73 mmol, 326 eq.) in DCM (8.0 mL) at 0oC. The reaction mixture was stirred at 0oC for 1 h, diluted with H2O - 117 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH = 50:1) to give the title compound as a white solid. Reference 7 5 Synthesis of 5-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6- dioxopiperidin-3-yl) isoindoline-1,3-dione Step 1: tert-Butyl (1-((4-fluoro arbamate 10 A solution of 4-fluorob mmol, 1.07 eq.) in DCM (10.0 mL) was added dropwise to a stirred solution of tert-butyl piperidin-4-ylcarbamate (2.5 g, 12.48 mmol, 1.00 eq.) in DCM (10.0 mL) and TEA (5.2 mL) at 0oC. The resulting mixture was stirred at RT overnight, concentrated and diluted with DCM. The mixture was stirred at RT for 1 h and filtered to give the title compound as a white solid. 15 Step 2: tert-Butyl (1-((4-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate To a stirred sol ol, 1.00 eq.) in THF (5.0 mL) was added NaH (60%, 251 mg, 6.28 mmol, 1.50 eq.) at 0oC under N2. The resulting mixture20 was stirred at RT for 15 min, then a solution of tert-butyl (1-((4-fluorophenyl)sulfonyl)piperidin-4- yl)carbamate (1.65 g, 4.60 mmol, 1.10 eq.) in THF (5.0 mL) was added slowly and the mixture was stirred at RT overnight. The mixture was diluted with H2O, and then extracted with DCM. The combined organic layer was washed with aq. NaCl, dried over Na2SO4, filtered, and then - 118 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT concentrated. The residue was purified by silica gel flash column (PE: EA = 3:1) to give the title compound as a white solid. Step 3: tert-Butyl (1-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 5 A mixture of tert- )phenyl)sulfonyl) piperidin- 4-yl)carbamate (500 mg, 0.87 mmol, 1.00 eq.), Pd(OH)2 (300 mg, 20% on carbon) in THF (20.0 mL) was stirred at 50oC under H2 (50 psi) overnight. The mixture was cooled, filtrated, concentrated. The residue was purified by silica gel flash column (DCM: MeOH = 10:1) to give the title compound as a white solid. 10 Step 4: tert-Butyl (1-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl) oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate A mix eridin-4-yl) carbamate (100 mg, 0.24 mmol, 1.00 eq.), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3- 15 dione (74 mg, 0.27 mmol, 1.13 eq.) and DIPEA (94 mg, 0.73 mmol, 3.04 eq.) in NMP (1.5 mL) was stirred at 140oC 2 h under microwave irradiation. The mixture was cooled, diluted with water, extracted with DCM, and then concentrated. The residue was purified by silica gel flash column (PE: EA = 1:1) to give the title product as a yellow solid. Step 5: 5-(3-(4-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- 20 yl) isoindoline-1,3-dione A mixtur ioxo-isoindolin-5- yl)- 119 -zetidine-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (144 mg, 0.21 mmol, 1.00 eq.), TFA (1.0 mL) in DCM (4.0 mL) was stirred at RT for 2 h. The mixture was concentrated to 25 give the title compound as a yellow oil, which was used for next step without further purification. - 119 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 8 Synthesis of 5-((3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-(2,6- dioxo-piperidin-3-yl)isoindoline-1,3-dione 5 Step 1: 5-(Bromomethyl)-2-(2,6 e-1,3-dione NBS (196 mg, 1.1 0 mmol, 0.20 eq.) were added to a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-1,3-dione (272 mg, 1.00 mmol, 1.00 eq.) in MeCN (15.0 mL) and the mixture was stirred at 80oC overnight under N2. The 10 mixture was cooled, and concentrated and the residue was purified by flash column chromatography (EA:PE = 0-100%) gave the title compound as a white solid. Step 2: tert-Butyl (1-((4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl) azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 15 A mix -4-yl)carbamate (100 mg, 0.24 mmol, 1.00 eq., from Reference 7, Step 3), 5-(bromomethyl)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1,3-dione (111 mg, 0.32 mmol, 1.33 eq.) and K2CO3(67 mg, 0.48 mmol, 2.00 eq.) in MeCN (2.0 mL) was stirred at 80oC overnight. The reaction mixture was cooled, concentrated and purified by silica gel flash column (DCM: MeOH = 20:1) to give the title 20 compound as a white solid. Step 3: 5-((3-(4-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-(2,6-dioxo- piperidin-3-yl)isoindoline-1,3-dione 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A mixture of tert-butyl (1-((4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl) methyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (33 mg, 0.048 mmol, 1.00 eq.) and TFA (1.0 mL) in DCM (4.0 mL) was stirred at RT for 3 h. The mixture was concentrated to give the title compound as a yellow solid. 5 Reference 9 Synthesis of 4-amino-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- ethoxy)ethoxy)ethyl)piperidine-1-sulfonamide 10 Step 1: tert-Butyl (2-(2-(2-((2-( oxoisoindolin-4-yl)amino)ethoxy)- ethoxy)ethyl)carbamate A mixtu (100 mg, 0.36 mmol, 1.10 eq.), tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (81.7 mg, 0.33 mmol, 15 1.00 eq.), DIPEA (127 mg, 0.98 mmol, 2.97 eq.) in NMP (1.5 mL) was stirred at 140oC under microwave for 2 h. The mixture was cooled and diluted with ethyl acetate, and then washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (EA:PE = 1:3) to give the title compound as a yellow oil. Step 2: 4-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- 20 dione A mixtu -isoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)carbamate (180 mg, 0.36 mmol, 1.00 eq.), TFA (0.5 mL) in DCM (2.0 mL) was stirred at RT for 2 h. The mixture was concentrated to give title compound as a 25 yellow oil, which was used for next step without further purification. - 121 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 3: tert-Butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate Sulfuryl dichloride (81 mg, 0 as added to a stirred solution of tert- butyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol, 1.00 eq.) and TEA (76 mg, 0.75 mmol, 1.50 5 eq.) in DCM (2.0 mL) at 0oC and the mixture was stirred at 0oC for 3 h. The mixture was diluted with water, and then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and then concentrated to give the title compound as a white solid, which was used for next step directly. Step 4: tert-Butyl (1-(N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- 10 ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate To a sti (2,6-dioxo- piperidin-3-yl)isoindoline-1,3-dione (70 mg, 0.17 mmol, 1.00 eq.) and tert-butyl (1-(chloro- sulfonyl)piperidin-4-yl)carbamate (51.9 mg, 0.17 mmol, 1.00 eq.) in DCM (2.0 mL) was added 15 TEA (52.4 mg, 0.52 mmol, 3.00 eq.). The mixture was stirred at 35oC overnight, and then concentrated. The residue was purified by silica gel chromatography (DCM:MeOH =30:1) to give the title compound as a yellow oil. Step 5: 4-Amino-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- ethoxy)ethoxy)ethyl)piperidine-1-sulfonamide 20 A mixtu 3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate (60 mg, 0.090 mmol, 1.00 eq.) in DCM (2.0 mL) and TFA (0.5 mL) was stirred at RT for 2 h. The mixture was concentrated to give the title compound as a yellow oil. 25 - 122 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 10 Synthesis of 4-amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)- propyl)-N-methylpiperidine-1-sulfonamide 5 Step 1: 4-Bromo-2-(2,6-dioxopip dione A mixture of ol, 1.00 eq.), 3-aminopiperidine-2,6-dione (18.0 g, 109.36 mmol, HCl, 1.09 eq.) and KOAc (29.4 g, 299.54 mmol, 2.98 eq.) in HOAc (200.0 mL) was stirred at 90 °C for 16 h. The reaction mixture was 10 cooled, diluted with ice water and then stirred at 0 °C for 1 h. The mixture was filtered and the filter cake was dried in vacuo to give the title compound as gray solid. Step 2: tert-Butyl methyl(3-(prop-2-yn-1-yloxy)propyl)carbamate A mixture of g, 15.85 mmol, 1.00 eq.) 15 in DCM (50.0 mL), 3-bromoprop-1-yne (3.0 g, 25.22 mmol, 1.59 eq.), 40% aqueous NaOH (30.0 mL) and tetrabutylammonium hydrogen sulfate (270 mg, 0.80 mmol, 0.050 eq.) was stirred at RT overnight under N2. The mixture was diluted with water, and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated. The residue was purified by flash column chromatography (EA:PE = 0 to 100%) to give the title compound as a 20 yellow oil. Step 3: tert-Butyl (3-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)oxy)propyl)(methyl)carbamate A mixture of 4 -dione (1.38 g, 4.09 25 mmol, 1.00 eq.), tert-butyl methyl(3-(prop-2-yn-1-yloxy)-propyl)carbamate (1.4 g, 6.16 mmol, - 123 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 1.51 eq.), CuI (78 mg, 0.41 mmol, 0.10 eq.), TEA (7.5 g, 74.12 mmol, 18.12 eq.) and Pd(PPh3)2Cl2(288 mg, 0.41 mmol, 0.10 eq.) in DMF (15.0 mL) was stirred at 80oC for 2h under N2. The mixture was cooled, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated. Purification by flash 5 column chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow oil. Step 4: tert-Butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)- (methyl)carbamate A mixture o isoindolin-4-yl)prop- 10 2-yn-1-yl)oxy)propyl)(methyl)carbamate (1.86 g, 3.85 mmol, 1.00 eq.), Pd(OH)2 / C (0.93 g, 50% w / w) in THF (50.0 mL) was stirred at RT overnight under H2atmosphere. The reaction mixture was filtered, concentrated and the residue was purified by flash chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow oil. Step 5: 2-(2,6-Dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)propyl)isoindoline-1,3-dione 15 A mixture of te xoisoindolin-4- yl)propoxy)propyl)(methyl)carbamate (1.45 g, 2.97 mmol, 1.00 eq.), TFA (1.0 mL) in DCM (10.0 mL) was stirred at RT for 2 h under N2. The mixture was concentrated and adjusted pH to 9 using aqueous Na2CO3, and then the mixture was extracted with DCM. The organic layer was washed 20 with water, brine, dried over Na2SO4, and then concentrated to give the title compound as a yellow oil. Step 6: tert-Butyl (1-(N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)- propyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate 25 A mixture of poxy)- propyl)isoindoline-1,3-dione (150 mg, 0.39 mmol, 1.00 eq.), tert-butyl (1-(chlorosulfonyl)- - 124 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT piperidin-4-yl)carbamate (173 mg, 0.58 mmol, 1.49 eq.) and TEA (118 mg, 1.17 mmol, 3.00 eq.) in DCM (2.0 mL) was stirred at 40oC overnight under N2. The mixture was cooled, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, concentrated to give the title compound as a yellow solid. 5 Step 7: 4-Amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)propyl)- N-methylpiperidine-1-sulfonamide To a stirred s in-3-yl)-1,3- dioxoisoindolin-4-yl)propoxy)propyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate (200 mg, 0.31 10 mmol, 1.00 eq.) in DCM (2.0 mL) was added TFA (0.5 mL). The resulting mixture was stirred at RT for 3h under N2, concentrated and adjusted pH to 9 using aqueous Na2CO3, and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated to give the title compound as a yellow oil, which was used for next step without further purification. 15 Reference 11 Synthesis of 4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione 20 Step 1: tert-Butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate NaH (1.2 g on of tert-butyl (2-(2- hydroxyethoxy)ethyl)carbamate (4.1 g, 19.98 mmol, 1.00 eq.) in THF (50.0 mL) in portions at 0 oC and the mixture was stirred for 1h. Then 3-bromoprop-1-yne (2.83 g, 23.79 mmol, 1.19 eq.) 25 was added at 0oC. The reaction mixture was warmed to RT and stirred for 16 h, poured into water and extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated and purified by flash column chromatography (EA:PE=0 to 100%) to give the title compound as a yellow oil. - 125 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 2: 4-Amino-N-(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)propoxy)ethoxy)ethyl)piperidine-1-sulfonamide g tert-Butyl 5(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate provided the title compound.Reference 12 Synthesis of 5-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione 10 Step 1: Benzyl (1-((3-methoxyphen yl)carbamate A solution of 3-met g, 15.68 mmol, 1.05 eq.) in DCM (20.0 mL) was added dropwise to a stirred solution of benzyl piperidin-4-ylcarbamate (3.5 15 g, 14.94 mmol, 1.00 eq.) and TEA (4.52 g, 44.82 mmol, 3.00 eq.) in DCM (50.0 mL) at 0oC and the mixture was stirred at RT for 3 h. The mixture was diluted with DCM and the organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (EA : PE = 1 : 3) gave the title compound as a white solid. Step 2: 3-((4-Aminopiperidin-1-yl)sulfonyl)phenol 20 The solution of b in-4-yl)carbamate (3.5 g, 8.66 mmol, 1.00 eq.) in CF3SO3H (20.0 mL) was stirred under N2 at 100oC for 3 h. The reaction - 126 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT mixture was cooled and concentrated to give the title compound as a brown oil, which was used for next step without further purification. Step 3: tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate 5 A solution of (B (5.0 mL) was added to a stirred solution of 3-((4-aminopiperidin-1-yl)sulfonyl)phenol (1.0 g, 3.91 mmol, 1.00 eq.) in DCM (20.0 mL) and TEA (1.18 g, 11.73 mmol, 3.00 eq.) at 0oC. The mixture was stirred at RT for 2 h, diluted with DCM and the organic layer was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by flash silica gel chromatography (ACN / water = (35%- 10 75%)) to give the title compound as a white solid. Step 4: 1-Benzhydrylazetidin-3-yl methanesulfonate To a stirred solution of g, 2.09 mmol, 1.00 eq.) in DCM (10.0 mL) was added TEA (633 mg, 6.27 mmol, 3.00 eq.) and MsCl (479 mg, 4.18 mmol, 15 2.00eq.) at 0oC. The mixture was stirred at RT overnight, diluted with DCM and then washed with water. The organic layer was washed with brine, dried over Na2SO4, concentrated and then purified by silica gel chromatography (EA : PE = 1 : 3) to give the title compound as a white solid. Step 5: tert-Butyl (1-((3-((1-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate 20 A mixture of t 4-yl)carbamate (533 mg, 1.49 mmol, 1.00 eq.), 1-benzhydrylazetidin-3-yl methanesulfonate (570 mg, 1.79 mmol, 1.20 eq.), Cs2CO3 (1.46 g, 4.49 mmol, 3.00 eq.) in DMSO (10.0 mL) was stirred at 90oC under N2 for 3 h. The mixture was cooled, diluted with EtOAc and the organic layer was washed with brine, dried 25 over Na2SO4, concentrated. The residue was purified by silica gel chromatography (EA:PE = 1:3) to give the title compound as a pale yellow solid. - 127 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 6: tert-Butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution o etidin-3-yl)oxy)phenyl)sulfonyl)- piperidin-4-yl)carbamate (400 mg, 0.69 mmol, 1.00 eq.) in MeOH (15.0 mL) were added 5 Pd(OH)2 / C (20 wt. %, 250 mg) and AcOH (0.5 mL) at RT. The resulting mixture was stirred at 50 oC under H2 (50 psi) overnight. The reaction mixture was cooled and filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (MeOH:DCM = 1:15) to give the title compound as a white solid. Step 7: tert-Butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)- 10 oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate Proceeding ana e, but using tert-butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and 2-(2,6-dioxopiperidin-3- yl)-5-fluoroisoindoline-1,3-dione provided the title compound. 15 Step 8: 5-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione Proceeding anal ve, but using tert-butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)phenyl)- 20 sulfonyl)piperidin-4-yl)carbamate provided the title compound. - 128 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 13 Synthesis of 3-(4-(3-((1-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4- yl)-oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6- dione 5 Step 1: tert-Butyl 4-((4-((3-(1-( yl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate A mixture o 1-yl)-2,3-dihydro-1H- 10 benzo[d]imidazol-1-yl)piperidine-2,6-dione (300 mg, 0.76 mmol, 1.00 eq., prepared by proceeding as described in Reference 11, Steps 1 and 2 above), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (421 mg, 1.51 mmol, 2.00 eq.), NaI (114 mg, 0.76 mmol, 1.00 eq.), K2CO3(634.8 mg, 4.59 mmol, 6.00 eq.) in ACN (5.0 mL) was stirred at 70oC overnight. The reaction mixture was cooled, concentrated and then purified with chromatograph 15 on silica gel (DCM / MeOH = 20 / 1) to give the title compound as a yellow solid. Step 2: 3-(3-Methyl-2-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3- dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Proceedin ut using tert-butyl 20 4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidine-1-carboxylate provided the title compound. - 129 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 3: tert-Butyl (1-((4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidin-1- yl)sulfonyl)piperidin-4-yl)carbamate 5 Proceedi t using 3-(3- methyl-2-oxo-4-(3-((1-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl(1-(chlorosulfonyl)piperidin-4- yl)carbamate provided the title compound. Step 4: 3-(4-(3-((1-((1-((4-Aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)- 10 oxy)prop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Proceedi t using tert-butyl (1-((4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate 15 provided the title compound. Reference 14 Synthesis of 3-(4-(3-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 20 Step 1: 3-Hydroxy-1-(4-methoxyb e t-BuOK (2.3 g, 20 ixture of N-(4- methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (5.0 g, 20.06 mmol,1.00 eq.) in THF (50.0 mL) at -78oC. After stirring at -78oC for 1h, the mixture was quenched with saturated aqueous - 130 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT NH4Cl and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and then purified with silica gel chromatograph (PE / EA = 3 / 1) to give the title compound as a white solid. Step 2: 1-(4-Methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate 5 Trifluoromethanesu 9 eq.) was added slowly to a stirred solution of 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (1.9 g, 7.62 mmol, 1.00 eq.) and pyridine (1.2 g, 15.17 mmol, 1.99 eq.) in DCM (40.0 mL) at 0oC. After stirring at 0oC for 2 h, the reaction mixture was quenched with water and then extracted with DCM. The organic 10 layer was washed with brine, dried over Na2SO4, concentrated and then purified by silica gel chromatograph (PE / EA = 5 / 1) to give the title compound as a yellow oil. Step 3: 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxy- benzyl)piperidine-2,6-dione 15 To a stirred solutio zol-2(3H)-one (1.1 g, 4.84 mmol, 1.23 eq.) in THF (30.0 mL) was added t-BuOK (632 mg, 5.63 mmol, 1.43 eq.) at 0oC. After stirring at 0oC for 0.5 h, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.5 g, 3.93 mmol, 1.00 eq.) in THF (10.0 mL) was added at 0oC. The reaction mixture was stirred at 0oC for 1 h, diluted with water and then extracted with EtOAc. 20 The organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was purified by silica gel chromatograph (PE / EA =2 / 1) to give the title compound as a white solid. Step 4: 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione A mixture of 3-(4- nzo[d]imidazol-1-yl)-1-(4- 25 methoxybenzyl)piperidine-2,6-dione (900 mg, 1.96 mmol, 1.00 eq.) in toluene / methanesulfonic acid =2 / 1 (3.0 mL) was stirred at 120oC for 3 h. The reaction mixture was cooled, concentrated - 131 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT and poured into ice water. The resulting mixture was filtered, and the cake was dried to give the title compound as a white solid. Step 5: tert-Butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate 5 NaH (60%, 240 mg, irred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 4.97 mmol, 1.00 eq.) in THF (20.0 mL) at 0oC, followed by 3-bromoprop-1-yne (704 mg, 5.92 mmol 1.19 eq.). The resulting mixture was stirred at RT for 2 h, quenched with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and then purified by silica gel chromatograph (PE / EA 10 =10 / 1) to give the title compound as a white solid. Step 6: tert-Butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate Proceeding analogo 3 above, but using 3-(4-bromo- 15 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate in DMF provided the title compound. Step 7: 3-(3-Methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione 20 Proceeding analogo above, but using tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2- yn-1-yl)oxy)piperidine-1-carboxylate provided the title compound. - 132 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 8: tert-Butyl (1-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate Proceeding a , but using 3-(3- 5 methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate in DMF provided the title compound. Step 9: 3-(4-(3-((1-((4-aminopiperidin-1-yl)sulfonyl)piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 10 Proceedi ut using tert-butyl (1-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)sulfonyl)piperidin-4-yl)carbamate provided the title compound. 15 Reference 15 Synthesis of 4-amino-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- cyclohexyl)-N-methylpiperidine-1-sulfonamide 2,2,2-trifluoroacetate Step 1: 4-Aminocyclohexanon 20 A mixture of tert-butyl (4-o (500 mg, 2.34 mmol,1.00 eq.) in a solution of HCl in ethyl acetate (1.0 M, 10.0 mL) was stirred at RT for 1 h. The reaction mixture - 133 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT was concentrated to give the title compound, which was used for next step without further purification. Step 2: 2-(2,6-Dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)isoindoline-1,3-dione 5 A mixture of 2-( 3-dione (276 mg.1.00 mmol, 1.00 eq.) and 4-aminocyclohexanone hydrochloride (300 mg, 2.00 mmol, 2.00 eq.) in NMP (2.5 mL) was stirred at 140oC under microwave for 3 h. The reaction mixture was cooled, diluted with DCM and then washed with brine. The organic layer was concentrated, and then the residue was triturated with DCM, filtered to give the title compound as a yellow solid. 10 Step 3: 2-(2,6-Dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione To a stirred mixt clohexyl)amino)- isoindoline-1,3-dione (200 mg, 0.54 mmol, 1.00 eq.) and methylamine (40% in MeOH, 210 mg, 2.71 mmol, 5.02 eq.) in MeOH / DCE (2.0 mL / 2.0 mL) was added one drop of AcOH. The 15 resulting mixture was stirred at RT for 1 h, and then NaBH(OAc)3(345mg, 1.63 mmol, 3.02 eq.) was added. The reaction mixture was stirred at RT overnight, diluted with DCM, washed with saturated aqueous NaHCO3and then brine. The organic layer was dried over Na2SO4and then concentrated to give the title compound as a yellow solid. Step 4: tert-Butyl (1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- 20 cyclohexyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate Proceedin ut using 2-(2,6- dioxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione and tert-butyl (1-(chlorosulfonyl)piperidin-4-yl)carbamate provided the title compound. - 134 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 5: 4-Amino-N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)- N-methylpiperidine-1-sulfonamide 2,2,2-trifluoroacetate Proc ing tert-butyl 5 (1-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexyl)-N- methylsulfamoyl)piperidin-4-yl)carbamate provided the title compound. Reference 16 Synthesis of tert-butyl 4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- 10 benzo[d]-imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate Step 1: tert-Butyl 4-((3-(1-(2,6-diox yl-2-oxo-2,3-dihydro-1H-benzo[d]- imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate 15 Procee using 3-(4-bromo- 3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate provided the title compound. Reference 17 20 Synthesis of 5-((3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione - 135 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 1: tert-Butyl (1-((3-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)- azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate Proceeding anal ve, but using tert-butyl 5 (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and 5-(bromomethyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione provided the title compound. Step 2: 5-((3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)methyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione 10 Proceed sing (1-((3-((1- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)oxy)phenyl)- sulfonyl)piperidin-4-yl)carbamate and TFA provided the title compound. Reference 18 15 Synthesis of 4-amino-N-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)propoxy)ethyl)piperidine-1-sulfonamide Step 1: tert-Butyl (2-(prop-2-yn-1- 20 Proceeding analogous p 2 above, but using tert-butyl (2-hydroxyethyl)carbamate and 3-bromoprop-1-yne provided the title compound. - 136 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 2: 4-Amino-N-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)propoxy)ethyl)piperidine-1-sulfonamide Proceeding ve, but using tert-butyl 5 (2-(prop-2-yn-1-yloxy)ethyl)carbamate provided the title compound. Reference 19 Synthesis of tert-butyl (1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate 10 Step 1: 1-(2,6-Dioxopiperidin-3-yl)- o-2,3-dihydro-1H-benzo[d]imidazole-4- carbaldehyde A mixture of 3-(4-br zo[d]imidazol-1-yl)- 15 piperidine-2,6-dione (700 mg, 2.07 mmol, 1.00 eq.), TEA (630 mg, 6.23 mmol, 3.01 eq.), Pd(dppf)Cl2(230.6 mg, 0.32 mmol, 0.15 eq.), Et3SiH (733 mg, 6.30 mmol, 3.04 eq.) in DMF (10 mL) was stirred at 80 oC under 15 psi carbon monoxide atmosphere overnight. The reactionmixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and then concentrated. The residue was purified by 20 chromatograph on silica gel (DCM / MeOH = 20 / 1) to give the title compound as a yellow oil. Step 2: tert-Butyl (1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate A mixture of 1-(2,6 3-dihydro-1H-benzo[d]- 25 imidazole-4-carbaldehyde (360 mg, 1.25 mmol, 1.00 eq.), tert-butyl N-methyl (piperidin-4- - 137 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT yl)carbamate (403 mg, 1.88 mmol, 1.50 eq. ) in THF / DMF = 2 / 1 (5 mL) was stirred at RT for 2h. NaBH(OAC)3(413 mg, 1.95 mmol, 1.60 eq.) was added at RT. After the reaction was complete, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4and then concentrated. The residue was purified by Prep-HPLC to 5 give the title compound as a yellow solid. Reference 20 Synthesis of tert-butyl (2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)(methyl)amino) benzyl)(methyl)amino)ethyl)(methyl)carbamate 10 Step 1: Dimethyl 3-iodophthala To a stirred mixture of 3 12 mmol, 1.00 eq.), Na2CO3(5.40 g, 50.95 mmol, 2.98 eq.) in DMF (30 mL) was added iodomethane (7.30 g, 51.43 mmol, 3.00 eq.) 15 at RT. The reaction mixture was stirred at 70oC overnight, cooled, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 10 / 1) to give the title compound as a white solid. Step 2: 4-(((tert-Butyldimethylsilyl)oxy)methyl)aniline 20 A mixture of (4-aminophen 4 mmol, 1.00 eq.), DMAP (595 mg, 4.87 mmol, 0.30 eq.), TEA (2.00 g, 19.76 mmol, 1.22 eq.) and TBSCl (2.70 g, 17.91 mmol, 1.10 eq.) in DMF (40 mL) was stirred at RT overnight. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, 25 filtered. and then concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 10 / 1) to give the title compound as a colorless oil. - 138 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 3: Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)phthalate A mixture of 3-iodo-pht , 9.37 mmol, 1.00 eq.), 4-(tert- butyl-dimethyl-silanyloxymethyl)-phenylamine (2.67 g, 11.25 mmol, 1.20 eq.), Pd2(dba)3 (436 5 mg, 0.48 mmol, 0.051 eq.), Cs2CO3(6.11 g, 18.75 mmol, 2.00 eq.), BINAP (143 mg, 0.23 mmol, 0.025 eq.) in toluene (30.0 mL) was stirred at 120oC overnight under nitrogen atmosphere. The reaction mixture was cooled, concentrated and the residue was purified by chromatograph on silica gel (PE / EA = 10 / 1) to give the title compound as a yellow oil. Step 4: Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)amino)phthalate 10 A mixture of dimethyl y)methyl)phenyl)- amino)phthalate (1.50 g, 3.49 mmol, 1.00 eq.), iodomethane (991 mg, 6.98 mmol, 2.00 eq.), Cs2CO3 (3.41 g, 10.47 mmol, 3.00 eq.) in DMF (30.0 mL) was stirred at 20oC for 8h under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The 15 organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 5 / 1) to give the title compound as a yellow oil. Step 5: 3-[(4-Hydroxymethyl-phenyl)-methyl-amino]-phthalic acid dimethyl ester 20 A solution of TBAF in T a stirred solution of dimethyl 3- ((4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-(methyl)amino)phthalate (500 mg, 1.13 mmol, 1.00 eq.) in THF (5.0 mL) at rt. After 2 h, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and then concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 2 / 1) to give the 25 title compound as a yellow oil. - 139 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 6: Dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate A mixture of 3-[(4-yy hthalic acid dimethyl ester (300 mg, 0.91 mmol, 1.00 eq.) and MnO2 (800 mg, 9.20 mmol, 10.11 eq.) in DCM (10.0 mL) was 5 stirred at rt overnight. The reaction mixture was filtered and concentrated to give the title compound as a yellow oil, which was used for next step without further purification. Step 7: Dimethyl 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl) phenyl)(methyl)amino)phthalate 10 A mixture of d ate (300 mg, 0.92 mmol, 1.00 eq.), methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (205 mg, 1.09 mmol, 1.18 eq.) and a drop of AcOH in DCE (5.0 mL) was stirred at RT for 2 h. NaBH(OAc)3 (290 mg, 1.37 mmol, 1.49 eq.) was then added and stirred for 4 h. The reaction mixture was concentrated and purified by prep-HPLC to give the title compound as a white solid. 15 Step 8: 3-((4-(((2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl)phenyl) (methyl)amino)phthalic acid A mixture of mino)ethyl)(methyl) amino)methyl)phenyl)(methyl)amino)phthalate (250 mg, 0.50 mmol, 1.00 eq.) and NaOH (40 mg, 20 1.00 mmol, 2.00 eq.) in EtOH / H2O =2 / 1 (5.0 mL) was stirred at 80oC for 5 h. The reaction mixture was concentrated and purified by prep-HPLC to give the title compound as a white solid. Step 9: tert-Butyl (2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)(methyl)amino) benzyl)(methyl)amino)ethyl)(methyl)carbamate - 140 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A mi l)amino)methyl) phenyl)(methyl)amino)phthalic acid (120 mg, 0.25 mmol, 1.00 eq.) and 3-aminopiperidine-2,6- dione hydrochloride (41 mg, 0.25 mmol, 1.00 eq.) in pyridine (3.0 mL) was stirred at 100oC 5 overnight. The reaction mixture was cooled and concentrated. The residue was purified by chromatograph on silica gel (DCM / MeOH = 30 / 1) to give the title compound as a yellow solid. Reference 21 Synthesis of tert-butyl (3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- 10 benzo[d]-imidazol-4-yl)piperidin-1-yl)propyl)(methyl)carbamate Step 1: tert-Butyl 4-(1-(2,6-dioxop thyl-2-oxo-2,3-dihydro-1H-benzo[d]- imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate 15 A mixt azol-1-yl)- piperidine-2,6-dione (100 mg, 0.30 mmol, 1.00 eq.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (119 mg, 0.38 mmol, 1.27 eq.), X-Phos-Pd-G3(38 mg, 0.045 mmol, 0.15 eq.), and K3PO4(191 mg, 0.90 mmol, 3.0 eq.) in 1,4-dioxane / H2O = 10 / 1 (2.2 mL) was stirred at 60oC for 3 h. The reaction mixture was diluted 20 with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by chromatograph on silica gel (DCM / MeOH = 20 / 1) to give the title compound as a brown solid. Step 2: tert-Butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidine-1-carboxylate 25 - 141 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A mixture of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (70 mg, 0.16 mmol, 1.00 eq.), 10% Pd / C (30 mg) and Pd(OH)2 (30 mg) in THF (10 mL) was stirred at 50oC under 50psi H2 pressure. The reaction mixture was filtered and then concentrated to give the title as a white solid. 5 Step 3: 3-(3-Methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-dione TFA salt A mixture o xo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidine-1-carboxylate (60 mg, 0.14 mmol, 1.00 eq.) and TFA (0.5 mL) 10 in DCM (2 mL) was stirred at RT for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil. Step 4: tert-Butyl (3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]- imidazol-4-yl)piperidin-1-yl)propyl)(methyl)carbamate 15 To a stirred m ihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione TFA salt (60 mg, 0.13 mmol, 1.00 eq.) in THF (5.0 mL) and DMF (1.0 mL) was added one drop of AcOH. After stirring at RT for 0.5h, tert-butyl methyl(3-oxopropyl)carbamate (63.6 mg, 0.34 mmol, 2.0 eq) was added at RT. The mixture was stirred at 20oC for 2 h followed by addition of NaBH(OAC)3 (72 mg, 0.34 mmol, 2.62 eq.). After 20 stirring at RT overnight, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by chromatograph on silica gel (DCM / MeOH = 50 / 1) to give the title compound as a yellow solid. - 142 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 22 Synthesis of tert-butyl (14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-14-oxo- 3,6,9,12-tetraoxatetradecyl)carbamate 5 Step 1: 2,2-Dimethyl-4-oxo- n-19-oic acid NaH ( tirred solution of tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl) carbamate (500 mg, 1.70 mmol, 1.00 10 eq.) in DMF (2 mL) at 0oC under nitrogen. After stirring at 0oC for 1 h, 2-iodoacetic acid (793 mg, 4.26 mmol, 2.51 eq.) was added at 0oC. The resulting mixture was slowly warmed to RT and then stirred overnight. This reaction mixture was quenched with H2O at 0oC, the pH was adjusted to 2~3 with 1 N aqueous HCl and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated to give the title compound as a yellow 15 oil. Step 2: tert-Butyl (14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-14-oxo- 3,6,9,12-tetraoxatetradecyl)carbamate ecan-19-oic 20 acid (372 mg, 1.06 mmol, 2.00 eq.) in THF (6 mL) was added isobutyl chloroformate (109 mg, 0.80 mmol, 1.51 eq.) and N-methylmorpholine (161 mg, 1.59 mmol, 3.00 eq.), followed by a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (145 mg, 0.53 mmol, 1.00 eq.) in DMF (2 mL) dropwise at 0oC. The resulting mixture was stirred at 30oC overnight, quenched with saturated NaHCO3, extracted with EtOAc. The organic layer was washed with 25 brine, dried over Na2SO4, filtered and then concentrated. The residue was purified by column chromatography on silica gel (PE : EA=1:1) to give the title compound as a yellow solid. - 143 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 23 Synthesis of tert-butyl (1-((3-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate O O HN O N ocNH 5 Step 1: Benzyl 4-(3-(3-((4-((te n-1-yl)sulfonyl)phenoxy)- azetidin-1-yl)piperidine-1-carboxylate A solut n-4-yl)carbamate (100 mg, 0.24 mmol, 1.00 eq.), benzyl 4-oxopiperidine-1-carboxylate (113 mg, 0.48 mmol, 2.00 10 eq.) and 1 drop of AcOH in THF (3.0 mL) was stirred at RT for 1h, followed by addition of NaBH(OAc)3 (102 mg, 0.48 mmol, 2.00 eq.). The reaction mixture was stirred at RT overnight, diluted with water and then extracted with DCM. The organic layer was concentrated and then purified by silica gel flash column (DCM / MeOH=20 / 1) to give the title compound as a white solid. 15 Step 2: tert-Butyl (1-((3-((1-(piperidin-4-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate To a stirr o)piperidin-1- yl)sulfonyl)phenoxy)azetidin-1-yl)piperidine-1-carboxylate (60 mg, 0.095 mmol, 1.00 eq.) in 20 MeOH(10.0 mL) was added 10% Pd / C (20 mg). The resulting mixture was stirred at 45oC under H2atmosphere overnight. The reaction mixture was filtered and concentrated to give the title compound as a white solid. - 144 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 3: tert-Butyl (1-((3-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate A enyl) 5 sulfonyl)piperidin-4-yl)carbamate (39.6 mg, 0.080 mmol, 1.00 eq.), 3-(5-bromo-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (38 mg, 0.12 mmol, 1.50 eq.), Cs2CO3(78 mg, 0.24 mmol, 3.00 eq.), Xantphos (15 mg, 0.027 mmol, 0.34 eq.) and Pd(OAc)2 (15 mg, 0.067 mmol, 0.84 eq.) in 1,4- dioxane (2.0 mL) was stirred at 100oC overnight under N2atmosphere.The mixture was cooled and then filtered. The filtrate was diluted with water and then extracted with DCM. The organic 10 layer was concentrated and then purified by prep-TLC (DCM / MeOH=10 / 1) to give the title compound as a yellow solid. Reference 24 Synthesis of tert-butyl (1-((3-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4- yl)-carbamate 15 Step 1: tert-Butyl (1-((3-(piperidin-4-y onyl)piperidin-4-yl)carbamate The title compound was prepared g as described in Reference 12, Steps 1 to 6 using 1-benzhydrylpiperidin-4-yl methanesulfonate. - 145 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 2: tert-Butyl (1-((3-((1-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate tert-Butyl (1-((3-(piperidin-4-yl onyl)piperidin-4-yl)carbamate was 5 converted to the title compound by proceeding analogously as described in Reference 27, Steps 1 and 2 above using benzyl 3-oxoazetidine-1-carboxylate. Reference 25 Synthesis of tert-butyl (1-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)- 10 oxy)ethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate HN Boc O O Step 1: Methyl 3-(2-hydroxyeth A mixture of methyl 3-hyd .50 g, 15.04 mmol, 1.00 eq.) and 1,3- 15 dioxolan-2-one (1.98 g, 22.48 mmol, 1.50 eq.), K2CO3 (2.07 g, 14.98 mmol, 1.00 eq.) in DMF (30.0 mL) was stirred at 120oC under N2for 2 h. The reaction mixture was cooled, diluted with water and then extracted with EtOAc. The organic layer was washed water, brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (EA:PE = 1:4) to give the title compound as a white solid. 20 Step 2: Methyl 2-(bromomethyl)-3-(2-hydroxyethoxy)benzoate O O O O Br H 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A mixture of methyl 3-(2-hydroxyethoxy)-2-methylbenzoate (1.50 g, 7.14 mmol, 1.00 eq.) in CCl4(45.0 mL), NBS (1.46 g, 8.20 mmol, 1.15 eq.) and AIBN (117 mg, 0.71 mmol, 0.10 eq was stirred under N2 at 75oC for 3 h. The mixture was cooled and then concentrated. The residue was purified by silica gel chromatography (EA PE = 1:3) to give the title compound as a white 5 solid. Step 3: 3-(4-(2-Hydroxyethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a stirred solution of me droxyethoxy)benzoate (2.00 g, 6.92 mmol, 1.00 eq.) in ACN (70.0 mL) was added 3-aminopiperidine-2,6-dione hydrochloride 10 (1.48 g, 8.99 mmol, 1.30 eq.) and TEA (1.04 g, 10.28 mmol, 1.49 eq.). The resulting mixture was stirred under N2at 80oC overnight, cooled and then concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the title compound as a blue solid. Step 4: 2-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl 4-methylbenzenesulfonate 15 To a stirred solution of olin-2-yl)piperidine-2,6-dione (500 mg, 1.64 mmol, 1.00 eq.) in DCM (10.0 mL) was added TEA (333 mg, 3.29 mmol, 2.00 eq.), TsCl (377 mg, 1.98 mmol, 1.21 eq.) and DMAP (20 mg, 0.16 mmol, 0.10 eq.) at 0oC. The resulting mixture was stirred at RT overnight, diluted with DCM, washed with water, brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel 20 chromatography (DCM:MeOH = 30:1) to give the title compound as a green solid. Step 5: Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate To a stirred solution of benzyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 8.50 mmol, 1.00 eq.) in DCM (20.0 mL) was added TEA (2.57 g, 25.40 mmol, 3.00 eq.) and MsCl (1.16 g, 25 10.13 mmol, 1.20 eq.) at 0oC. The resulting mixture was stirred at RT overnight, diluted with water and then extracted with DCM. The organic layer was washed with water, brine, dried over - 147 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Na2SO4, filtered, and concentrated to give the crude title compound as a yellow oil, which was used for next step without further purification. Step 6: tert-Butyl (1-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 5 Benzyl 4-((methylsulfo e was converted to the title compound by proceeding analogously as described in Reference 12, Steps 5-6 above. Step 7: tert-Butyl (1-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)oxy)ethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 10 A mixture o l)oxy)ethyl 4-methylbenzenesulfonate (50 mg, 0.11 mmol, 1.10 eq.), tert-butyl (1-((3-(piperidin-4- yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (44 mg, 0.10 mmol, 1.00 eq.), KI (15 mg, 0.090 mmol, 0.90 eq.) and DIPEA (35 mg, 0.27 mmol, 2.70 eq.) in ACN (2.0 mL) was stirred at 100oC under microwave for 3 h. The reaction mixture was cooled and concentrated, and the residue was 15 purified by silica gel chromatography (DCM:MeOH= 20:1) to give the title as a yellow oil. Reference 26 Synthesis of tert-butyl (1-((3-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)- ethyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate 20 - 148 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT tert-Butyl (1-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate was converted to the title compound by proceeding analogously as described in Reference 25, Step 7. Reference 275 Synthesis of tert-butyl (1-((3-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture of tert-butyl (1-((3 )sulfonyl)piperidin-4-yl) carbamate (300 mg, 0.93 mmol, 1.00 eq.), 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (448 mg, 10 1.02 mmol, 1.10 eq. ), Cs2CO3 (603 mg, 1.86 mmol, 2.00eq.), Pd(OAc)2 (41 mg, 0.19 mmol, 0.20 eq.) and X-Phos (176 mg, 0.37 mmol, 0.40 eq.) in 1,4-dioxane (10.0 mL) was stirred at 105oC under N2 for 2 days. The reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated. The residue was purified by flash chromatography gave title compound as a yellow solid. 15 Reference 28 Synthesis of tert-butyl (1-((3-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- piperidin-4-yl)methyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 20 Step 1: Benzyl 4-(3-((4-((tert-bu -1-yl)sulfonyl)phenyl)-5,6- dihydropyridine-1(2H)-carboxylate - 149 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A mixture of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (3.00 g, 7.18 mmol, 1.00 eq.), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate (3.20 g, 9.33 mmol, 1.30 eq.), X-Phos-Pd-G3 (608.0 mg, 0.72 mmol, 0.10 eq.) and K3PO4(4.57 g, 21.54 mmol, 3.00 eq.) in 1,4-dioxane (70.0 mL) and H2O (7.0 mL) was stirred 5 at 60oC under N2 for 6 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with PE / EtOAc (4:1), to afford the title compound as a yellow solid. Step 2: tert-Butyl (1-((3-(piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 10 A mixture of ben eridin-1-yl)sulfonyl)phenyl)- 5,6-dihydropyridine-1(2H)-carboxylate (4.00 g, 7.20 mmol, 1.00 eq.) and Pd / C (800 mg) in MeOH (40.0 mL) was stirred at 50oC under H2 (50 psi) for 16 h. The mixture was filtered and concentrated to afford the title compound as a white solid. Step 3: Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin- 15 1-yl)methyl)piperidine-1-carboxylate To a solutio peridin-4-yl)carbamate (3.00g, 7.10 mmol, 1.00 eq.) in DCE (20.0 mL) and MeOH (20.0 mL) was added benzyl 4-formylpiperidine-1-carboxylate (2.63 g, 10.65 mmol, 1.50 eq.) and AcOH (426.0 mg, 7.10 20 mmol, 1.00 eq.) and the solution was stirred at RT for 1 h. NaBH3CN (1.34 g, 21.30 mmol, 3.00 eq.) was added and the mixture was stirred at RT for 3 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (60:1), to afford the title compound as a white solid. - 150 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 4: tert-Butyl (1-((3-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate A mixtur n-1-yl)- 5 sulfonyl)phenyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (3.80 g, 5.81 mmol, 1.00 eq.) and Pd / C (800 mg) in MeOH (40.0 mL) was stirred at 50oC under H2 (50 psi) for 16 h. The mixture was filtered and concentrated to afford the title compound as a white solid. Step 5: Methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)- phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-cyanobenzoate 10 A solu enyl)- sulfonyl)piperidin-4-yl)carbamate (2.80 g, 5.40 mmol, 1.00 eq.), methyl 2-cyano-4-fluorobenzoate (1.06 g, 5.94 mmol, 1.10 eq.) and DIEA (2.09 g, 16.20 mmol, 3.00 eq.) in DMSO (30.0 mL) was stirred at 120oC under N2for 16 h. The mixture was cooled to RT, diluted with water, and then 15 extracted with EtOAc. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (100:1), to afford the title compound as a brown solid. Step 6: Methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)- phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-formylbenzoate 20 A mixt in-1-yl)- sulfonyl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-cyanobenzoate (1.01g, 1.50 mmol, 1.00 eq.), NaH2PO2.H2O (1.59 g, 15.00 mmol, 10.00 eq.) and Raney Ni (1.60 g) in pyridine (10.0 mL), H2O (5.0 mL) and AcOH (5.0 mL) was stirred for 16 h at 70oC under nitrogen atmosphere. The - 151 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT resulting mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (80:1), to afford the title compound as a light-yellow solid. Step 7: tert-Butyl (1-((3-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- 5 yl)methyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixt mmol, 1.30 eq.) and DIEA (184 mg, 1.43 mmol, 2.40 eq.) in dry DCM (5.0 mL) was stirred at RT for 10 min and then a solution of methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1- 10 yl)sulfonyl)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-formylbenzoate (400 mg, 0.59 mmol, 1.00 eq.) in dry DCM (5.0 mL) and AcOH (134 mg, 2.23 mmol, 3.80 eq.) was added. The mixture was stirred at 45oC under N2 for 3 h. The mixture was cooled to 0oC and NaBH(OAc)3 (375 mg, 1.77 mmol, 3.00 eq.) was added. The mixture was stirrd at rt for 1h and then at 45oC under N2for 16 h. The mixture was cooled, diluted with water, and then extracted with DCM. The combined 15 organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (40:1), to afford the title compound as a yellow solid. Reference 29 20 Synthesis of tert-butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1- yl)methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate Step 1: 3-5-Bromo-1-oxoisoindolin-2-ylpiperidine-2,6-dione 25 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (20.00 g, 64.91 mmol, 1.00 eq.) and 3-aminopiperidine-2,6-dione (11.71 g, 71.41 mmol, 1.10 eq.), K2CO3(26.87 g, 194.71 mmol, 3.00 eq.) in DMF was stirred at 70oC overnight under N2 atmosphere. The mixture was poured into water after the reaction was complete and extracted with DCM. The combined organic layer 5 was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (PE:EA=2:1) to give the title compound as a white solid. Step 2: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-5,6-dihydropyridine- 1(2H)-carboxylate 10 A mixtur .00 g, 3.11 mmol, 1.00 eq.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)- carboxylate (1.25 g, 4.04 mmol, 1.30 eq.), K3PO4(800 mg,3.73 mmol,1.20 eq) and Pd(dppf)Cl2(114 mg,0.16 mmol,0.05 eq) in DMF (10.0 mL) was stirred at 90oC for 12 h. The mixture was concentrated and purified by silica gel column chromatography eluting with PE / EA (1:2) to give 15 title compound as yellow solid. Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate To a stir oindolin-5-yl)-5,6- dihydropyridine-1(2H)-carboxylate (200 mg, 0.47 mmol, 1.00eq.) in THF (2.0 mL) was added 20 Pd / C(40 mg, 20%w / w). The resulting mixture was stirred at 40oC for 12 h under H2, filtered and concentrated to give the title compound as white solid. Step 4: 3-(1-Oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione DC (2,6- 25 dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1-carboxylate (100 mg, 0.234 mmol, 1.00 - 153 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT eq.) and the mixture was stirred at RT for 2 h. The mixture was concentrated to give the title compound as brown solid. Step 5: tert-Butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1- yl)methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 5 To a sti idine-2,6-dione (76.60 mg, 0.23 mmol, 1.00 eq) in THF (1.0 mL) was added DMF (1.0 mL), HCOOH(1 drop) and tert-butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (105.60 mg,0.23 mmol 1.00 eq). The resulting mixture was stirred at 45oC for 0.5 h. NaBH3CN (29.40 10 mg, 0.47 mmol, 2.00 eq) was added at RT and the reaction mixture was stirred at RT for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water and brine and concentrated. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (0~100%), to give the title compound as a white solid.15 Reference 30Synthesis of tert-butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin- 1-yl)-methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate Step 1: Benzyl 4-(dimethoxyme 20 To a mixture of benzy (1.00 g, 2.40 mmol, 1.00 eq.) in MeOH (9.0 mL) was added p-TsOH (38 mg, 0.20 mmol, 0.05 eq.) and trimethoxymethane (2.14 g, 20.22 mmol, 5.00 eq.). The mixture was stirred at RT for 12 h and then extracted with EtOAc. Purification of the crude product by silica gel column chromatography eluting with PE / EtOAc 25 (10:1) gave the title compound as a colorless oil. - 154 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 2: 4-(Dimethoxymethyl)piperidine To a mixture of benzyl e-1-carboxylate (948 mg, 3.23 mmol, 1.00 eq.) in MeOH (10.0 mL) was added Pd / C (400 mg) and the reaction mixture was 5 stirred at RT under H2for overnight. The resulting mixture was filtered through Celite and the filtrate was concentrated to give the title compound as a colorless oil. Step 3: tert-Butyl (1-((3-(4-(dimethoxymethyl) piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate 10 A mixture of 4-(d mol, 1.20 eq.), K2CO3 (215 mg, 1.56 mmol, 3.00 eq.), CuI (20 mg, 0.104 mmol, 0.20 eq.), L-proline (18 mg, 0.16 mmol, 0.30 eq.) and tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (219 mg, 0.52 mmol, 1.00 eq.) in DMSO (4.0 mL) was stirred at 90oC overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water and brine 15 and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the title compound as white solid. Step 4: tert-Butyl (1-((3-(4-formylpiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a mixture of te in-1-yl)phenyl)sulfonyl) 20 piperidin-4-yl)carbamate (640 mg, 1.29 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (4.0 mL) and the mixture was stirred at 45oC overnight. The reaction mixture was concentrated and dissolved in DCM (5.0 mL) followed by addition of TEA (261 mg, 2.58 mmol, 2.00 eq.) and (Boc)2O (562 mg, 2.58 mmol, 2.00 eq.). The solution was stirred at RT for 4 h, and concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to 25 give title compound as yellow solid. - 155 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 5: tert-Butyl (1-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)- methyl)piperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate The comp Step 5. 5 Reference 31 Synthesis of 3-(5-(azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione St 10 in DMA (3.0 mL) was added 1,2-dibromoethene (66 mg, 0.35 mmol, 0.10 eq.) and the mixture was stirred at 65oC under N2 for 30 min. The mixture was allowed to cool to RT and TMSCl (38 mg, 0.35 mmol, 0.10 eq.) was added. After stirring the mixture for 30 min., a solution of tert-butyl 3-iodoazetidine-1-carboxylate 15 (1.00 g, 3.53 mmol, 1.00 eq.) in DMA (1.0 mL) was added dropwise. The mixture was stirred at 65oC under N2 for 2 h, cooled to RT and used in next step without further purification. Step 2: tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-1-carboxylate A solut mg, 1.72 mmol, 20 3.00 eq.) in DMA was slowly added to a mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (185 mg, 0.57 mmol, 1.00 eq.), CuI (12 mg, 0.06 mmol, 0.10 eq.), Pd(dppf)Cl2 (44 mg, 0.06 mmol, 0.10 eq.) in DMA (2.0 mL). The mixture was stirred at 90oC under N2 overnight. The - 156 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT mixture was concentrated and purified by column chromatography on silica gel (EA) to give the title compound as a brown solid. Step 3: 3-(5-(Azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 5 To a soluti olin-5-yl)azetidine-1- carboxylate (44 mg, 0.11 mmol, 1.00 eq.) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise and the solution was stirred at RT for 3 h. The resulting mixture was concentrated to give the crude product as a brown oil. Reference 32 10 Synthesis of tert-butyl (1-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate Step 1: Benzyl 4-(3-((4-((ter l)sulfonyl)phenyl)piperazine-1- carboxylate 15 A mixture arbamate (5.00 g, 11.96 mmol, 1.00 eq.), K2CO3 (5.78 g, 41.86 mmol, 3.50 eq.), CuI (0.45 g, 2.39 mmol, 0.20 eq.), L-PRO (0.41 g, 3.59 mmol, 0.30 eq.) in DMSO (25.00 mL) and benzyl piperazine-1-carboxylate (3.43 g, 15.55 mmol, 1.30 eq.) was stirred at 100oC for 12 h. The mixture was quenched with 20 H2O and extracted with EtOAc. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound as white solid. Step 2: tert-Butyl (1-((3-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT The title compound was prepared analogously as described in Reference 30, Step 2. Step 3: Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin- 1-yl)methyl)piperidine-1-carboxylate 5 A m l)carbamate (1.07 g, 2.52 mmol, 1.00 eq.), AcOH (3 drops) and benzyl 4-formylpiperidine-1-carboxylate (933 mg, 3.78 mmol, 1.50 eq.) in MeOH (10.0 mL) was stirred at 45oC for 1 h. The solution cooled to RT and NaBH3CN (475 mg, 7.56 mmol, 3.00 eq.) was added. The mixture was stirred at RT for 12 h and then diluted with water and extracted with EtOAc. The combined organic layer was 10 washed with brine, dried over anhydrous Na2SO4,and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (60:1) to give the title compound as white solid. Step 4: tert-Butyl (1-((3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate 15 B yl)piperazin- 1-yl)methyl)piperidine-1-carboxylate was converted to the title compound using similar procedure as described in Reference 28, Step 4-7. 20 Reference 33 Synthesis of tert-butyl (1-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)-[1,4'-bipiperidin]-1'-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate - 158 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 1: tert-Butyl (1-((3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate A mixture o carbamate (1.00 g, 5 2.40 mmol, 1.00 eq.), K2CO3(1.16 g, 8.40 mmol, 3.50 eq.), CuI (91 mg, 0.480 mmol, 0.20 eq.), L-proline (83 mg, 0.72 mmol, 0.30 eq.) and 1,4-dioxa-8-azaspiro[4.5]decane (412 mg, 2.88 mmol, 1.20 eq.) in DMSO (10.0 mL) was stirred at 90oC overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column 10 chromatography eluting with PE / EtOAc (1:1) to give the title compound as yellow solid. Step 2: tert-Butyl (1-((3-(4-oxopiperidin-1-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture henyl)- sulfonyl)piperidin-4-yl)carbamate (624 mg, 1.30 mmol, 1.00 eq.), TsOH.H2O (49 mg, 0.26 mmol, 15 0.20 eq.) in acetone (6.0 mL) and H2O (12.0 mL) was stirred at 60oC overnight. The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting PE / EtOAc (1:1) to give the title compound as yellow solid. Step 3: tert-Butyl (1-((3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- 20 benzo[d]imidazol-4-yl)-[1,4'-bipiperidin]-1'-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-But rbamate (44 mg, 1.02 mmol, 0.90 eq.) and 1 drop of AcOH was added to a mixture of 3-(3-methyl-2-oxo-4- (piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (387 mg, 1.13 mmol, 25 1.00 eq.) in THF (5.0 mL). The reaction mixture was stirred at 40oC for 0.5 h. NaBH3CN (142 - 159 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT mg, 2.60 mmol, 2.00 eq.) was added at RT and stirred at RT overnight. The reaction mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the title compound as a yellow solid. 5 Reference 34 Synthesis of 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione Step 1: tert-Butyl 3-(1-(2,6-dioxopip l-2-oxo-2,3-dihydro-1H-benzo[d]- 10 imidazol-4-yl)azetidine-1-carboxylate A solution of (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc (II) iodide (600 mg, 1.72 mmol, 3.00 eq.) in DMA was slowly added to a mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H- 15 benzo[d]imidazol-1-yl)piperidine-2,6-dione (193 mg, 0.57 mmol, 1.00 eq.) in DMA (2.0 mL) CuI (12 mg, 0.06 mmol, 0.10 eq.) and Pd(dppf)Cl2 (44 mg, 0.06 mmol, 0.10 eq.). The mixture was stirred at 90oC under N2 overnight. The mixture was concentrated and purified by column chromatography on silica gel (EA) to the title compound as a yellow solid. Step 2: 3-(4-(Azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 20 2,6-dione O Boc O N N N NH N N To a solutio 2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)azetidine-1-carboxylate (23 mg, 0.055 mmol, 1.00 eq.) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise and the solution was stirred at RT for 3 h. The resulting 25 mixture was concentrated to give the crude product as a brown oil, which was used in next step without further purification. - 160 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Reference 35 Synthesis of tert-butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5- yl)piperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 5 Step 1: tert-Butyl 4-(5-bromo-2- henyl)piperazine-1-carboxylate A mixture of me 0 mmol, 1.00 eq.) and tert- butyl piperazine-1-carboxylate (2.23 g, 12.00 mmol, 1.50 eq.), K2CO3 (1.65 g, 12.00 mmol, 1.50 eq.) in DMA (6.0 mL) was stirred at 80oC overnight. The mixture was diluted with water and 10 extracted EA. The combined organic layer was washed with brine, dried over Na2SO4, concentrated. The residue was purified by flash chromatography (PE:EA=3:1) to give the title compound as a colorless oil. Step 2: tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate 15 A mixture of phenyl)-piperazine-1- carboxylate (1.50 g, 3.60 mmol, 1.00 eq.) and CuCN (484 mg, 5.40 mmol, 1.50 eq.) in DMF (6.0 mL was stirred at 100oC overnight. The mixture was extracted with EA and washed with NH3.H2O. The organic layer was washed with water and brine, dried over Na2SO4, concentrated and purified by flash chromatography (PE:EA=3:1) to give the title compound as a white solid.20 Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazine-1- carboxylate - 161 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate was converted to the title compound by proceeding analogously as described in Reference 28, Step 6-7. Step 4: 3-(6-Fluoro-1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 5 To a stirre oro-1-oxoisoindolin- 5-yl)piperazine-1-carboxylate (95 mg, 0.21 mmol, 1.00 eq.) in DCM (2.0 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil. 10 Step 5: tert-Butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperazin- 1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixtu dine-2,6-dione (74 mg, 0.33 mmol, 1.00 eq.), tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4- 15 yl)carbamate (138 mg, 0.32 mmol, 1.50 eq.), TEA (127 mg, 1.26 mmol, 6.00 eq.) in THF (5.0 mL) was stirred at 55oC overnight. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated, and the residue was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid. 20 Reference 36 Synthesis of tert-butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate - - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 1: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazine-1- carboxylate A mixture of , 1.00 eq.) and 2-(2,6- 5 dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (1.50 g, 5.10 mmol, 1.00 eq.), DIEA (1.97 g, 15.30 mmol, 3.00 eq.) in NMP (15.0 mL) was stirred at 110oC overnight. The mixture was diluted with water and extracted EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and the residue was purified by flash chromatography (PE:EA=1:2) to give the title compound as a yellow solid. 10 Step 2: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-1-yl)isoindoline-1,3-dione To a stirred solu -1,3- dioxoisoindolin-5-yl)piperazine-1-carboxylate (800 mg, 1.74 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (1.0 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was 15 concentrated to give the title compound as a yellow oil. Step 3: 3-(Bromomethyl)benzenesulfonyl chloride A mixture of 3-me 96 mol, 1.00 eq.) NBS (8.22 g, 46.16 mol, 1.10 eq.) and benzoyl peroxide (1.46 g, 4.20 mol, 0.01 eq.) in CCl4(80.00 mL) was 20 stirred at 80 ℃ for 12 h. The solution was filtered and the filtrate was concentrated to give crude product as white oil. Step 4: tert-Butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl piper in THF (20.00 mL) was 25 added to a stirred solution of 3-(bromomethyl)benzenesulfonyl chloride (3.79 g, 18.95 mol, 0.90 eq.) in THF (40.00 mL) and TEA (4.25 g, 42.10 mmol, 2.00 eq.) at 0oC. The resulting mixture - 163 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT was stirred at RT for 12 h, quenched with H2O and then extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1), to afford the title compound as white solid. 5 Step 5: tert-Butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5- yl)piperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture oindoline-1,3-dione (509 mg, 1.41 mmol, 1.00 eq.), tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)-piperidin-4- 10 yl)carbamate (916 mg, 2.12 mmol, 1.50 eq.) TEA (854 mg, 8.46 mmol, 6.00 eq.) in THF (10.0 mL) was stirred at 55oC overnight. The mixture was extracted DCM and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid. 15 Reference 37 Synthesis of tert-butyl (1-((3-((8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate Step 1: tert-Butyl 8-(2-(2,6-diox ioxoisoindolin-5-yl)-3,8-di- 20 azabicyclo[3.2.1]octane-3-carboxylate A mixture of ,3-dione (200 mg, 0.68 mmol, 1.00 eq.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (144 mg, 0.68 mmol, 1.00 eq.) and DIEA (263 mg, 2.04 mmol, 3.00 eq.) in NMP (3.0 mL) was stirred at 110oC overnight. 25 The reaction mixture was quenched with H2O and then extracted with DCM. The combined - 164 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give title compound as yellow solid. Step 2: tert-Butyl (1-((3-((8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)-3,8- 5 diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl n-5-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate was converted to the title compound proceeding analogously as described in Reference 36, Step 2-5. 10 Reference 38 Synthesis of tert-butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1- yl)-methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 15 Step 1: tert-Butyl 4-(3-cyano-4-( razine-1-carboxylate To a stirred soluti 0 g, 55.80 mmol, 1.00 eq.) in DMSO (150.0 mL) was added tert-butyl piperazine-1-carboxylate (11.40 g, 61.38 mmol, 1.10 eq.) and DIEA (34.70 g, 268.96 mmol, 4.80 eq.). The resulting mixture was stirred at 110oC for 20 12 h. The mixture was extracted with EtOAc washed with brine, concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound as yellow solid. - 165 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 2: tert-Butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate A mixture of t perazine-1-carboxylate (8.00 g, 23.20 mmol, 1.00 eq.) NaH2PO2.H2O (5.20 g, 48.70 mmol, 2.10 eq.) and Raney-Ni (5.10 5 g) in pyridine:H2O:AcOH=2:1:1 (80.0 mL) was stirred at 70oC for 12 h. The mixture was adjusted pH=7~8 with aq.NaHCO3, filtered, and extracted with EtOAc. The organic layer was washed with brine, concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound as yellow solid. Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate 10 A mixtu mmol, 1.20 eq.) DIEA (4.03 g, 31.22 mmol, 2.42 eq.), AcOH (10.63 g, 188.76 mmol, 13.78 eq.) and tert-butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4.50 g, 12.90 mmol, 1.00 eq.) in DCM (50.0 mL) was stirred at 35oC for 4 h and then NaBH(OAc)3 (8.20 g, 38.70 mmol, 3.00 15 eq.) was added at RT. The mixture was stirred at 40oC for 12 h and diluted with water and extracted with EtOAc. The organic layer was washed with brine, concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:2) to give the title compound as white solid. Step 4: 3-(1-Oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 20 To a soluti dolin-5-yl)piperazine- 1-carboxylate (72 mg, 0.17 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at RT for 2 h and then concentrated to give the title compound as yellow oil. - 166 - 1104266430\4\AMERICAS Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Step 5: tert-Butyl (1-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)- methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a sti dine-2,6-dione (55 5 mg, 0.17 mmol, 1.00 eq.) in THF (2.0 mL) were added TEA (52 mg, 0.51 mmol, 3.00 eq.) and tert-butyl (1-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (95 mg, 0.22 mmol, 1.30 eq.). The reaction mixture was stirred at 55oC overnight. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound as a yellow solid. 10 Reference 39 Synthesis of tert-butyl (1-((3-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7- diazaspiro-[3.5]nonan-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate 15 Step 1: tert-Butyl 7-(3-cyano- iazaspiro[3.5]nonane-2- carboxylate A mixture of me mol, 1.00 eq.) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.39 g, 6.14 mmol, 1.10 eq.) DIEA (719 mg, 16.74 20 mmol, 3.00 eq.) in DMSO (10.0 mL) was stirred at 110oC overnight. The mixture was diluted with water and extracted EA. The organic layer was washed with...

Claims

Attorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT What is Claimed:

1. A compound of Formula (I): 5 whereinR1is alkyl, cycloalkyl, cycloalkylalkyl, bridged cycloalkyl, cycloalkoxy, heterocyclyl, alkoxy, aryl, arylalkyl, arylalkoxy, heteroaryl, halo, cyano, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino, where each of the aforementioned rings, by itself or as part of another group, is substituted with one or two substitutions 10 independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R2is hydrogen or deuterium; and Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the 15 aforementioned rings is substituted with Ra, Rb, and Rcindependently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; Degron is an E3 ubiquitin ligase ligand selected from: (a) a group of formula (i): 20(b) a group of formula (ii):- 243 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT (c) a group of formula (iii): ( 5 (- 244 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT (f) a group of formula (vi):where: 5 Yais CH or N; Zais a bond, -CH2-, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is attached to Ya; ring A is a group of formula (a), (b), or (c): 10 where:Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R4and R5are independently hydrogen or alkyl; or R4and R5together with 15 the carbon to which they are attached form >C=O; M is -O- or -NR6-; and R6is hydrogen or alkyl; and R6is hydrogen or alkyl; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic 20 heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein in each heteroarylene one to three ring atoms are independently selected from nitrogen or oxygen atoms and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with Reeand Rffindependently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and - 245 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT X1, X2, X3, and X4are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NRgg-alkylene)-, -(alkylene-NRhh)-, , -NH-, -N(alkyl)-, –C(=O)-, -NRjjC(=O)-, or –C(=O)NRkk- where Rgg, Rhh, Rjj, ae independently hydrogen, alkyl, or cpart of another group, is optionally substituted with one 5 or two fluoro; Ry, Ry1, and Ry2are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with Rdand Rfselected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino; and Wais bond, O, S, or alkylene; and 10 L is -Z1-Z2-Z3-Z4-Z5-Z6- where: Z1is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O)2NR-, -NR’S(O)2-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with Rhand Riindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; 15 Z2is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR’(CO)-, -(O-alkylene)b-, -(alkylene-O)b-, -O(CH2)7-, -O(CH2)8-, cycloalkylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rjand Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; 20 Z3is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, -(O-alkylene)c-, -(alkylene-O)c-, cycloalkylene, spiro cyclolalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)- monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, unsaturated heterocyclylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic 25 heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, -spiro heterocyclylene-(alkylene)-, or 11 to 13 membered spiro heterocyclylene, where each ring, by itself or as part of another group, is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, 30 amino, alkylamino, and dialkylamino; Z4is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -(alkylene-NR”)-, -(NR”- alkylene)-, -O-, -C(O)-, -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, cycloalkylene, -(alkylene)- cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, - 246 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene- (alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene- (alkylene)-, where each ring, by itself or as part of another group, is substituted with Roand Rp5 independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; Z5is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O)2-, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or unsaturated heterocyclylene, or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, 10 haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; and Z6is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR’(CO)-, or -C(O)NR-; where each R, R’ and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z1-, -Z2-, -Z3-, -Z4-, -Z5- and 15 -Z6-, by itself or as part of another group and heteroalkylene of -Z3- and -Z4- are independently substituted with Rs, Rt, and Ruwhere Rsis hydrogen, deuterium, or halo, Rtis hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halo, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or 20 bridged heterocyclyl (where cycloalkyl, either by itself or as part of cycloalkyloxy, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, either by itself or as part of heterocyclyloxy or heterocyclylcarbonyl, and bridged heterocyclyl are substituted with R7and R8independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano), and Ruis 25 hydrogen or halo; or when Rtand Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the alkylene or heteroalkylene, Rtand Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by Rtand Ruare substituted with R9and R10independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, 30 alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano), alkenylene of -Z3- and -Z4- are substituted with Rvselected from hydrogen, fluoro, and cyano, and alkynylene of -Z3- and -Z4- are substituted with Rwand Rxindependently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano; or when Rwand Rxare attached to the same carbon atoms of the alkynylene, they can combine to form cycloalkylene or heterocyclylene wherein the cycloalkylene and - 247 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT heterocyclylene are substituted with R11and R12independently selected from hydrogen, alkyl, and halo; provided that at least one of -Z1-Z2-Z3-Z4-Z5-Z6- is not a bond; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 5 R1is alkyl, cycloalkyl, cycloalkoxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino.

3. The compound of any one of claims 2, or a pharmaceutically acceptable salt thereof, wherein R1is methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclopentyl, cyclopropoxy, cyclopentyloxy, chloro, fluoro, difluoromethyl, trifluoromethyl, 10 difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, methoxypropyl, amino, methylamino, ethylamino, or propylamino.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is methyl, ethyl, or trifluoromethyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt 15 thereof, wherein R2is hydrogen.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Hy is heterocyclylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. 20 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the heterocyclylene of Hy is: where the N atom of-diyl rings is attached to L.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt 25 thereof, wherein the Degron is an E3 ubiquitin ligase ligand of formula (i): .- 248 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: .

10. T, cally acceptable salt 5 thereof, wherein the Degron is an E3 ubiquitin ligase ligand of formula (ii):

11. The compound of any one of claims 1 to 7 and 10, or a pharmaceutically acceptable salt thereof, wherein the E3 ubiquitin ligase ligand of formula (ii) is: 10 , , ,1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT w cyclylaminylene.compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Z6is -S(O)2-.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt 5 thereof, wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn; 10 Z4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Roand Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is 15 substituted with Rqand Rr; and Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, Rt, and Ru.

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein: 20 X1, X2, X3, X4, and Z1are each a bond; Z2is heterocyclylene substituted with Rjand Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z3is heterocyclylene substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; 25 Z4is a bond, alkylene, or -O-; Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z6is -S(O)2-; and 30 wherein alkylene in Z4is substituted with Rs, Rt, and Ru.

15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein: X1, X2, X3, X4, and Z1are each a bond; - 250 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT Z2is heterocyclylene substituted with Rjand Rkare independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z3is a bond, alkylene, or -O-; Z4is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is 5 substituted with Roand Rp; Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rr; and Z6is -S(O)2-; and wherein alkylene in Z3is substituted with Rs, Rt, and Ru.

16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt 10 thereof, wherein: Z3is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn; Z4is alkylene, -O-, heterocyclylene, -(alkylene)-heterocyclylene-, -(alkylene)-bridged heterocyclylene-, where each ring, by itself or as part of another group, is substituted with Roand 15 Rp; Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and Z6is -S(O)2; and each alkylene in Z4, itself or as part of another group, is substituted with Rsand Rt. 20 17. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein: X1, X2, X3, X4, Z1, and Z2are each a bond; Z3is -O-, -NR”- (where R”is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro 25 heterocyclylene, where each ring is substituted with Rmand Rn; Z4is alkylene, alkenylene, alkynylene, heteroalkylene, where alkylene and heteroalkylene are substituted with Rs, Rt, and Ruand alkenylene is substituted with Rv; Z5is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rqand Rr; and 30 Z6is -S(O)2. - 251 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT 18. The compound of any one of claims 1 to 13, 16, and 17, or a pharmaceutically acceptable salt thereof, wherein -Z3-Z4-Z5-Z6- is: , 5 , ; lo,10 haloalkyl, haloalkoxy, alkoxy, and cyano 19. The compound of any one of claims 1 to 13 and 16 to 18, or a pharmaceutically acceptable salt thereof, wherein -Z3-Z4-Z5-Z6- is: - 252 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT , , or wh, halo, 5 haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the phenylene of Z5i and is selected from:ally 10 acceptable salt thereof, wherein Z4is –(alkylene)-heterocyclylene-, where heterocyclylene is substituted with Roand Rp.

22. The compound of any one of claims 1 to 14, and 16 to 20, or a pharmaceutically acceptable salt thereof, wherein Z4is C3to C6alkylene substituted with Rs, Rt, and Ruwhere Rs, Rt, and Ruare hydrogen. 15 23. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein -X1-L-, -X2-L-, -X3-L- and -X4-L- are independently: ,- 253 - 1104266430\4\AMERICASAttorney Docket No.119005.00283 Client Ref. No. NKT-24-003PCT wherein each Rmand Rnare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano; and Z4is C3 to C6 alkylene substituted with Rs, Rt, and Ru.

24. The compound of any one of claims 1 to 7 and 10 to 23, or a pharmaceutically 5 acceptable salt thereof, wherein Degron is the E3 ubiquitin ligase lig where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroe25. A pharmaceutical composition comprising a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

26. A method of treating cancer mediated by CDK2 and / or CDK4 in a patient in need 10 thereof which method comprises administering to the patient in need thereof, a therapeutically effective amount a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25. - 254 - 1104266430\4\AMERICAS

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