Bifunctional compounds containing pyrido[2,3-d]pyrimidin-7(8H)-one derivatives for degrading cyclin-dependent kinases 2, 4, and 6 via ubiquitin proteasome pathway

Abstract

The present disclosure provides certain bifunctional compounds that cause degradation of Cyclin-dependent kinase 2 (CDK2), Cyclin-dependent kinase 4 (CDK4), and Cyclin-dependent kinase 6 (CDK6) via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by CDK2, and / or CDK4, and / or CDK6. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

Attorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT BIFUNCTIONAL COMPOUNDS CONTAINING PYRIDO[2,3-d]PYRIMIDIN-7(8H)-ONE DERIVATIVES FOR DEGRADING CYCLIN-DEPENDENT KINASES 2, 4, and 6 VIA UBIQUITIN PROTEASOME PATHWAY Cross-reference to Related Applications This PCT International Patent Application claims the benefit of U.S. Provisional Application No.63 / 613,023, filed on December 20, 2023; the entire contents of which are hereby incorporated by reference. Field of the disclosure The present disclosure provides certain bifunctional compounds containing pyrido[2,3-d]- pyrimidin-7(8h)-one derivatives that cause degradation of Cyclin-dependent kinases 2, 4, and 6 (CDK 2 / 4 / 6) via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by these kinases. 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 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 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, 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 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 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 Rb; deficiency in CDK inhibitory regulators such as p16, p21, p27, and loss‑of‑function mutations in FBXW7, a - 1 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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 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). Despite their significant clinical efficacy in ER-positive metastatic breast cancer, CDK4 / 6 inhibitors have 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 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, acquired CDK6 amplification is found to promote breast cancer resistance to CDK4 / 6 inhibitors and loss of ER dependence (Yang, C., et al. Oncogene (2017) 36, 2255–2264). Considering these factors, developing a small molecule inhibitor or a proteolysis-targeting chimeric molecule (PROTAC) that targets CDK2 / 4 / 6 could represent a therapeutic opportunity with 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 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 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). Therefore, PROTACs that could recruit CDK2 / 4 / 6 to a ubiquitin ligase, and thereby causing ubiquitylation and proteasomal degradation of these kinases are desirable. The present disclosure fulfills this and related needs. - 2 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Summary In a first aspect,(I) wherein: R1is branched alkyl, branched haloalkyl, branched cyanoalkyl, branched hydroxylalkyl, branched alkoxyalkyl, branched haloalkoxyalkyl, cycloalkyl, or bridged cycloalkyl; wherein cycloalkyl and bridged cycloalkyl are substituted with 0, 1, 2, or 3 groups independently selected from halo, cyano, hydroxy, alkoxy, and haloalkoxy; R2is hydrogen, alkyl, halo, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl R2ais hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the aforementioned rings is substituted selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, Degron is selected from: (a) a(i); and (b) a group of formula (ii): (ii); 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) or (b): ; where: Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; - 3 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein one to three ring atoms of each heteroarylene ring are heteroatoms independently selected from nitrogen, oxygen, or sulfur 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 Z is -O-, -NR3- (where R3is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene and where each ring is substituted with Rdand Reindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; alk is C3to C6alkenylene substituted with Rfselected from hydrogen, fluoro, and cyano; C3to C6 alkylene or C3 to C6 heteroalkylene wherein the C3 to C6 alkylene and C3 to C6 heteroalkylene are substituted with Rg, Rh, and Riwhere Rgis hydrogen, deuterium or halo, Rhis hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halo, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or 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); or when Rgand Rhare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C6 alkylene or C3 to C6 heteroalkylene, Rgand Rhtogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by Rgand Rhare substituted with R9and R10independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano), and Riis hydrogen or halo; and the linear portion of C3to C6alkenylene, C3to C6alkylene, and C3to C6heteroalkylene, attaching Ar and Z, contains at least three atoms; Ar is phenylene, monocyclic heteroarylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each of the aforementioned ring is substituted with Rj, Rk, and Rmindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; or a pharmaceutically acceptable salt thereof. In a second aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. In a third aspect, provided is a method of treating a disease mediated by CDK2 and / or CDK4 and / or CDK6 in a patient, preferably the patient is in need of such treatment, which method - 4 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein below), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed herein. In a first embodiment of the third aspect, the disease is cancer. In a second subembodiment 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 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 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 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, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein below), or a pharmaceutically 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 fourth aspect, provided is a method of treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss, which method comprises administering to a patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof as disclosed therein. In some embodiments, the amount of hearing loss is reduced when compared to an 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 compound of Formula (I) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof for use in therapy. In one embodiment of the fifth aspect, the compound of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof is for use in the treatment of one or more of diseases disclosed in the third and / or fourth aspects above. In a sixth aspect, provided is the use of a compound of Formula (I) (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 and / or CDK6 contribute(s) to the pathology and / or symptoms of the disease. In one - 5 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT embodiment of the seventh aspect, the disease is one or more of diseases disclosed in the third and / or fourth aspects above. In a seventh aspect, provided is a method of degrading CDK2 / 4 / 6 in a cell via ubiquitin proteasome pathway which method comprises contacting the cell with a compound of Formula (I) (or embodiments thereof as disclosed herein). In one embodiment of the seventh aspect, the CDK2 / 4 / 6 are degraded in the cell in vitro. In another embodiment of the seventh aspect, the CDK2 / 4 / 6 are degraded in the cell in vivo. In yet another embodiment of the seventh aspect, the CDK2 / 4 / 6 are degraded in the cell of a patient. It has been surprisingly discovered that PROTACS of Formula (I) containing the -Z-alk-Ar- linker degrade CDK2 / 4 / 6 selectively over CDK1. In the aforementioned aspects involving the treatment of cancer, further embodiments are provided comprising administering the compound of first aspect and of Formula (I), or a pharmaceutically acceptable salt thereof (or any embodiments thereof disclosed herein) or the pharmaceutical composition of the third aspect, in combination with at least one additional anticancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially. Detailed Description Definitions: Unless otherwise stated, the following terms used in the specification and claims are 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. “Alkenyl” means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like. “Alkynyl” means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, 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 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. “Alkenyylene” means a linear or branched divalent hydrocarbon radical of two to six carbon atoms containing a double bond, e.g., ethenylene, propenylene, and the like. For sake of clarity, when alkenylene contains three to six carbon atoms it is also referred to herein as C3 to C6 alkenylene. “Alkoxy” means a -ORpradical where Rpis alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like. “Alkoxyalkyl” means a linear or a branched monovalent hydrocarbon radical of one to six carbons substituted with an alkoxy group as defined above. Representative examples include, but are not limited to, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, methoxypropyl, and the like. “Branched alkoxyalkyl” means a branched monovalent hydrocarbon radical of three to six carbons substituted with an alkoxy group as defined above. Representative examples include, but are not limited to, 3-methoxybut-2-yl, 1-(methoxymethyl)-2-methylpropyl, and the like. - 6 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT “Alkoxycarbonyl” or “alkyloxycarbonyl” means a –C(O)ORpradical where Rpis alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like. “Alkylcarbonylamino” means a –NRp’C(O)Rpradical where Rpis alkyl and Rp’ is H or alkyl, as defined above, e.g., methylcarbonylamino, ethylcarbonylamino, and the like. “Alkylcarbonyl” means a –C(O)Rpradical where Rpis as defined herein, e.g., methylcarbonyl, ethylcarbonyland the like. “Amino” means –NH2.“Aminocarbonyl” means -C(O)NH2. “Alkylaminocarbonyl” means -C(O)NHRpradical where Rpis alkyl as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like. “Alkylcarbonylamino” means -NHC(O)Rpradical where Rpis alkyl as defined above e.g., methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, and the like. “Alkylsulfonyl” means -S(O)2Rpradical where Rpis alkyl as defined above e.g., methylsulfonyl, ethylsulfonyl, and the like. “Dialkylaminocarbonyl” means -C(O)NRp1Rpradical where Rpand Rp1are independently alkyl as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like. “Alkylamino” means -NHRpradical where Rpis 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 10 ring atoms e.g., phenyl or naphthyl. “Aralkyl” or “arylalkyl” means –(alkylene)-Rpradical where Rpis aryl as defined above e.g., benzyl, phenethyl, and the like. “Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene. “Aryloxy” means a -O-Rpradical where Rpis aryl as defined above e.g., phenyloxy (or phenoxy), or naphthyloxy. “Aryloxyalkyl” means –(alkylene)-Rpradical where Rpis aryloxy as defined above e.g., benzyloxy, phenethyloxy, and the like. “Bicyclic heterocyclylene” means a saturated divalent fused bicyclic group of 8 to 12 ring atoms in which one, two, or three ring atoms are heteroatoms independently selected from N, NH, 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 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 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 (CRpRp’)n group where n 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). Examples include, but are not limited to, bicyclo[1.1.1]pent-1-yl, bicyclo[2.2.1]heptyl, preferably, bicyclo[2.2.1]hept-2-yl, and the like. - 7 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT “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’)n group where n 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 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. “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 (CRpRp’)n group where n 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 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-[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. “Cycloalkyloxy or cycloalkoxy” means a -ORpradical where Rpis cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. “Cycloalkylene” means a divalent saturated hydrocarbon radical of three to six carbon atoms, otherwise e.g., 1,1-cyclopropylene, 1,1-cyclobutylene, 1,4-cyclohexylene, and the like. “Carbonyl” means -C(O)-. “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 cyclylaminylene includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, piperazinylene, and the like. “Cyanoalkyl” means alkyl as defined above that is substituted with a cyano e.g., cyanomethyl, cyanoethyl, and the like. “Branched cyanoalkyl” means a branched monovalent hydrocarbon radical of three to six carbons substituted with a cyano group. Representative examples include cyano-isopropyl and cyano- isobutyl, and the like. - 8 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT “Cyanoalkyloxy” means an -ORpradical where Rpis cyanoalkyl as defined above, e.g., cyanomethyloxy, cyanoethyloxy, and the like. “Deuterium” means refers to2H or D. “Dialkylamino” means a -NRpRpradical where each Rpis alkyl as defined above and are independently selected, e.g., dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-, iso-, or tert-butylmethylamino, and the like. “Fused heterocyclyl” means a monovalent bicyclic ring in which two adjacent ring atoms of a saturated monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, NH, 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, or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom is optionally oxidized and further wherein one of the carbon ring atoms of the saturated monocyclic ring is optionally replaced by a –C(=O)- group. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro- 2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazinyl, and the like. “Fused heterocyclylene” means a divalent bicyclic ring in which two adjacent ring atoms of a saturated monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, NH, 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, or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom is optionally oxidized and further wherein one of the carbon ring atoms of the saturated monocyclic ring is optionally replaced by a –C(=O)- group. 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. “Halo” means fluoro, chloro, bromo, or iodo, e.g., 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 Application as fluoroalkyl. “Branched haloalkyl” means a branched monovalent hydrocarbon radical of three to six carbons 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. Representative examples include CF(CH3)2, and the like. When the branched haloalkyl is substituted with only fluoro, it can be referred to in this Application as branched fluoroalkyl. “Haloalkoxy” means an –ORpradical where Rpis haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like. When Rpis 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. “Branched haloalkoxyalkyl” means a branched monovalent hydrocarbon radical of three to six carbons substituted with a haloalkoxy group as defined above. Representative examples include, but - 9 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT are not limited to, 3-trifluoromethoxybut-2-yl, 1-(trifluoromethoxymethyl)-2-methylpropyl, and the like. “Hydroxyalkyl” means a linear or a branched monovalent hydrocarbon radical of one to six carbons substituted with a hydroxy group. 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, and the like. “Branched hydroxyalkyl” means a branched monovalent hydrocarbon radical of three to six carbons substituted with a hydroxy group. Representative examples include, but are not limited to, hydroxy-isopropyl, 1-(hydroxymethyl)-2-methylpropyl, hydroxy-isobutyl, and the like. “Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, NH, O, and S, the remaining ring atoms being carbon, unless otherwise stated. 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. 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 “five or six” or “5-or 6”-membered monocyclic heteroaryl. When the heteroaryl ring contains 9- or 10 ring atoms, it is also referred to herein as 9-or 10-membered fused bicyclic heteroaryl. “Heteroaryloxy” means –O-Rpradical where Rpis heteroaryl as defined above e.g., pyridinyloxy, pyrazolyloxy, imidazolyloxy, and the like. “Heteroarylalkyl” means –(alkylene)-Rpradical where Rpis heteroaryl as defined above e.g., pyridinylmethyl, pyrazolylmethyl, and the like. “Heteroaryloxyalkyl” means –(alkylene)-Rpradical where Rpis heteroaryloxy as defined above e.g., pyridinyloxymethyl, pyrazolyloxymethyl, imidazolyloxymethyl, and the like. “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-diyl (pyrazolyl-1.3-diyl, pyrazolyl-1.4-diyl, pyrazolyl-1.5- diyl and the like) and imidazol-diyl (imidazol-1,2-diyl, imidazol-1,4-diyl, imidazol-1,5-diyl). When the heteroarylene 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 heteroarylene. “Heterocyclyl” means a saturated, monovalent, monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, NH, 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 be replaced by a –C(=O)- group. More specifically, the term heterocyclyl includes, but is not limited to, oxetanyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, and the like. “Heterocyclylalkyl” means –(alkylene)-Rpradical where Rpis heterocyclyl as defined above e.g., piperidinylmethyl, pyrrolidinylmethyl, and the like. - 10 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT “Heterocyclylcarbonyl” means a -C(O)R group where R is heterocyclyl as defined herein. More specifically, the term heterocyclyl includes, but is not limited to, piperidinylcarbonyl, piperazinylcarbonyl, pyrrolidinylcarbonyl, azetidinylcarbonyl, and the like. “Heterocyclyloxy” means an -OR group where R is heterocyclyl as defined herein. More specifically, the term heterocyclyl includes, but is not limited to, piperidinyloxy, piperazinyloxy, pyrrolidinyloxy, azetidinyloxy, and the like. “Heterocyclylene” means a saturated, divalent, monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, NH, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless statedAdditionally, one or two ring carbon atoms in the heterocyclylene ring can by a –C(=O)- group. More specifically, the term heterocyclylene includes, but is not limited to, , piperidin-1,4-diyl, azetidin-1,3-diyl, and the like. “C3 to C6 heteroalkylene” means a linear or branched saturated divalent hydrocarbon radical of three to six carbon atoms where (a) one carbon atom of the linear portion of the divalent hydrocarbon radical is replaced by Xawhere Xais -O-, -S-, -SO-, -SO2-, -CO-, or -NRq- or (b) two adjacent carbon atoms of the linear portion of the divalent hydrocarbon radical are replaced by Xa1where Xa1is -NRqCO-, -CONRq-, -NRqSO-, -SONRq-, -NRqSO2-, or -SO2NRq- (where each Rqis hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl) and furthermore an additional carbon atom, that is not adjacent to Xaand in of the divalent hydrocarbon radical of (a) and (b) above can be replaced-O- or -NRq1- (where Rq1is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl), provided that the linear portion of C3to C6heteroalkylene attaching Z and Ar contains at least three atoms. For sake of clarity, as used in this definition, the linear portion of the C3 to C6 heteroalkylene means the consecutive atoms of the C3 to C6 heteroalkylene connecting Z and Ar e.g., in the structure , the atoms with * form the linear portion of C5 heteroalkylene. When the C3 to C6 heteroalkylene contains only one or two -O-, it can be referred to herein as “oxoalkylene.” When the C3to C6heteroalkylene contains only one or two -NRq– and / or -NRq1-, it can be referred to herein as “aminylalkylene.” When the C3to C6heteroalkylene contains only -S-, it can be referred to herein as “sulfanylalkylene.” When the C3 to C6 heteroalkylene contains only -SO-, it can be referred to herein as “sulfinylalkylene.” When the C3to C6heteroalkylene contains only -SO2-, it can be referred to herein as “sulfonylalkylene.” Representative examples, of C3to C6 heteroalkylene include, e.g., - 11 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCTand the like. “Phenylene” means divalent phenyl. The phrase “optionally” or “optional” as used herein means that the subsequently 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 alkylene that is substituted with halo. “Spiro heterocyclyl” means a saturated bicyclic monovalent 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 heterocyclyl 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, 2-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 3,9-diazaspiro[5.5]undecanyl, and the like. “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 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. “Unsaturated heterocyclylene” means divalent, monocyclic nonaromatic group of 6 to 8 ring atoms having one or two double bonds and 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 be replaced by a –C(=O)- group. - 12 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT The present disclosure also includes protected derivatives of compounds of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof. For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s), these 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. The present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof. Certain compounds of the present disclosure can exist as tautomers and / or geometric isomers. All possible tautomers forms and mixtures thereof are within the scope of this (I) having a hydroxy substituted pyridyl ring can exist as aThe term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (I) (and any embodiment thereof disclosed herein including specific 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 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 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 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 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, - 13 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, 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, 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 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 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 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 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 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 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 hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,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 - 14 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with (or isotopically enriched for) heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic 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 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. 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. “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 should be understood to mean that range which would encompass ± 10%, the recited value and the range is included. Certain structures drawn with one or more floating substituents. Unless provided otherwise orthe context, the substituent(s) may be present on any 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 Rbbsubstituent, can replace hydrogen of any CH bicyclic ring that is not already substituted with Rbb(in the case the case of Rbb). Additionally, as usedin the embodiments, when a group is drawn out as divalent, the left bond of the is attached to the group which is to its left in the remainder of the molecule, and the right divalent group is attached to the group which is to its right in the remainder of the molecule. For example, in the following divalent groups: of E3 ubiquitin ligase ligand group of formula (i), the bond on the left of (a) and (b) is attached to the following ring: - 15 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT, and the on the side of (a) and (b) is attached to Z of the Formula (I) structure:. Similarly, for -Z-alk-Ar-, the bond on left side (i.e., Z) is side i.e., ring A of formula (i) or ring B of formula (ii) and the bond on to -SO2- that is attached to an atom of Hy. For example, when-Z-alk- a group ,and ring A of Degron of formula (i) is a group of formula , the bond of piperidinyl is attached to benzo portion of ring (a) and the bond of phenyl is attached to -SO2- that is attached to Hy. The term “disease” 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 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 manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, 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. 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. Preferably, the patient is a human. - 16 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT “Treating” or “treatment” of a disease includes: (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 (stabilizing), or reducing the development or severity of the disease or its clinical symptoms; or (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 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 with an autoimmune disease is susceptible to, e.g., sepsis, or a condition that is caused by the autoimmune disease, e.g., uveitis. The term “degrading” and “degrade,” or any variation of these terms in relation to CDK2, CDK4, CDK6, and CDK1, means any measurable decrease in the concentration of CDK2, CDK4, CDK6, and CDK1, respectively, in a sample over time. 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, CDK4, and CDK6 concentration in a sample containing CDK2, CDK4, or CDK6, respectively, and a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2, CDK4, or CDK6, respectively, in the absence of said compound. The % degradation can be determined as described in Biological Example 2 below. A given degrader is considered to be selective for CDK2, CDK4, and CDK6 if its inhibitory activity, IC50, for CDK2, CDK4, and CDK6 are at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, or at least 100-fold more than its inhibitory activity, IC50,for a CDK that is other than CDK2, CDK4, and CDK6, e.g., CDK1. The IC50activity of a compound of Formula (I) in CDK1, CDK2, CDK4, and CDK6 can be determined as described in Biological Example 1 below using KYSE520, OVCAR3, T47D, and THP1 cell lines, respectively. “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 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 transcription. The cereblon (CRBN) and von Hippel-Lindau (VHL) proteins are substrate recognition subunits of two - 17 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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 the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbx1. Embodiments: Embodiment A In embodiments A1 to A207, the present disclosure includes: A1. In embodiment A1, provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described in the second aspect of the Summary. A2. In embodiment A2, the compound of embodiment A1, or a pharmaceutically acceptable salt thereof, is wherein R1is branched alkyl. A3. In embodiment A3, the compound of embodiment A1 or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is isopropyl, sec-butyl, or tert-butyl. A4. In embodiment A4, the compound of embodiment A1, A2, or A3, or a pharmaceutically acceptable salt thereof, is wherein R1is isopropyl or cyclopropyl. In a subembodiment of A4, the compound, or a pharmaceutically acceptable salt thereof, is wherein R1is isopropyl. A5. In embodiment A5, the compound of embodiment A1, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halo, cyano, hydroxy, alkoxy, and haloalkoxy, preferably selected from halo and hydroxy. A5a. In embodiment A5a, the compound of embodiment A1 or A5, or a pharmaceutically acceptable salt thereof, is wherein R1is unsubstituted cycloalkyl. A6. In embodiment A6, the compound of embodiment A1, A5, or A5a, or a pharmaceutically acceptable salt thereof, is wherein R1is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or unsubstituted cyclopentyl. A6b. In embodiment A6b, the compound of embodiment A1, or a pharmaceutically acceptable salt thereof, is wherein R1is bridged cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halo, cyano, hydroxy, alkoxy, and haloalkoxy, preferably the 0, 1, 2, or 3 groups are independently selected from selected from halo and hydroxy. A7-1. In embodiment A7-1, the compound of A1, or a pharmaceutically acceptable salt thereof, is wherein R1is branched haloalkyl, branched cyanoalkyl, branched hydroxylalkyl, branched alkoxyalkyl, or branched haloalkoxyalkyl. A7-2. In embodiment A7-1, the compound of A1, or a pharmaceutically acceptable salt thereof, is wherein R1is branched haloalkyl. A7-3. In embodiment A7-1, the compound of A1, or a pharmaceutically acceptable salt thereof, is wherein R1is branched hydroxylalkyl. A7. In embodiment A7, the compound of embodiment A1 to A7-3, or a pharmaceutically acceptable salt thereof, is wherein R2is hydrogen, halo, haloalkyl, alkyl, hydroxyalkyl, or alkoxyalkyl. - 18 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A8. In embodiment A8, the compound of embodiment A1 to A7-3, or a pharmaceutically acceptable salt thereof, is wherein R2is hydrogen, methyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxymethyl, methoxymethyl, or ethoxymethyl. In a subembodiment of A8, the compound, or a pharmaceutically acceptable salt thereof, is wherein R2is methoxymethyl or ethoxymethyl. A9. In embodiment A9, the compound of embodiment A1 to A7-3, or a pharmaceutically acceptable salt thereof, is wherein R2is difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxymethyl, methoxymethyl, or ethoxymethyl. In a subembodiment of A9, the compound, or a pharmaceutically acceptable salt thereof, is wherein R2is difluoromethyl, trifluoromethyl, or 2,2-difluoroethyl. A10. In embodiment A10, the compound of any one of embodiments A1 to A8, or a pharmaceutically acceptable salt thereof, is wherein R2is hydrogen. A11. In embodiment A11, the compound of any one of embodiments A1 to A7, or a pharmaceutically acceptable salt thereof, is wherein R2is alkyl. A12. In embodiment A12, the compound of any one of embodiments A1 to A7, and A11, or a pharmaceutically acceptable salt thereof, is wherein R2is methyl or ethyl. A13. In embodiment A13, the compound of any one of embodiments A1 to A8, A11, and A12, or a pharmaceutically acceptable salt thereof, is wherein R2is methyl. A14. In embodiment A14, the compound of any one of embodiments A1 to A7-3, or a pharmaceutically acceptable salt thereof, is wherein R2is cyanoalkyl, hydroxyalkyl, or alkoxyalkyl. A15. In embodiment A15, the compound of embodiment A1 to A7-3, and A14, or a pharmaceutically acceptable salt thereof, is wherein R2is cyanoalkyl. A16. In embodiment A16, the compound of any one of embodiments A1 to A7 and A14, or a pharmaceutically acceptable salt thereof, is wherein R2is hydroxyalkyl. A17. In embodiment A17, the compound of any one of embodiments A1 to A7 and A14, or a pharmaceutically acceptable salt thereof, is wherein R2is alkoxyalkyl. A18. In embodiment A18, the compound of any one of embodiments A1 to A9 and A14 to A17, or a pharmaceutically acceptable salt thereof, is wherein R2is cyanomethyl, hydroxymethyl, methoxymethyl, methoxyethyl, methoxypropyl, or ethoxymethyl, unless stated otherwise. A19. In embodiment A19, the compound of any one of embodiments A1 to A9 and A14 to A18, or a pharmaceutically acceptable salt thereof, is wherein R2is cyanomethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl, or ethoxymethyl, unless stated otherwise. A20. In embodiment A20, the compound of any one of embodiments A1 to A7, or a pharmaceutically acceptable salt thereof, is wherein R2is halo or haloalkyl. A21. In embodiment A21, the compound of any one of embodiments A1 to A7 and A20, or a pharmaceutically acceptable salt thereof, is wherein R2is halo. A22. In embodiment A22, the compound of any one of embodiments A1 to A7 and A20, or a pharmaceutically acceptable salt thereof, is wherein R2is haloalkyl. A22a. In embodiment A22a, the compound of any one of embodiments A1 to A9, A21, and A22, or a pharmaceutically acceptable salt thereof, is wherein R2is fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl, unless stated otherwise. - 19 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A22b. In embodiment A22b, the compound of any one of embodiments A1 to A9 and A21 to A22a, or a pharmaceutically acceptable salt thereof, is wherein R2is fluoro, difluoromethyl, trifluoromethyl, or 2,2-difluoroethyl, unless stated otherwise. A23. In embodiment A23, the compound of any one of embodiments A1 to A22b, or a pharmaceutically acceptable salt thereof, is wherein R2ais hydrogen. A24. In embodiment A24, the compound of any one of embodiments A1 to A22b, or a pharmaceutically acceptable salt thereof, is wherein R2ais deuterium. 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, phenylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from 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. 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 each ring being substituted with Ra, Rb, and Rcwhere Raand Rbare independently hydrogen, Rcis hydrogen, and -SO2- is attached to the nitrogen 1,3-diyl ring of Hy. A28. In embodimentA1 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 -SO2- A29. In embodiment A29, the compound of any one of embodiments A1 to A28, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is:where the N atom of the pyrrolidin-1,3-diyl or piperidin-1,4-diyl rings is attached to -SO2-. 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: where the N atom of the piperidin-1,4-diyl ring is attached to -SO2-. - 20 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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 Rcwhere Rcis hydrogen. A31. In embodiment A31, the compound of any one of embodiments A1 to A25 and A30, or a pharmaceutically of Hy is a ring of formula:where each ring is substituted with Ra, Rb, and Rcwhere Rcis hydrogen, and the nitrogen atom of each ring is attached to -SO2-. 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 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 A34, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is cyclohexylene. embodiment A36,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 -SO2-. A37. In embodiment A37, the compound 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. 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 (preferably, 2-azaspiro[3.3]heptan-2-yl) substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. A39. In embodiment A39, the compound of embodiment A37, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Hy is 1,4-phenylene according to structure - 21 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT where denotes bond to NH and denotes bond to -SO2-where Rais hydrogen, fluoro, methyl or methoxy and Rbis hydrogen. A39a. In embodiment A39a, the compound of any one of embodiments A1 to A24, or a 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 with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen. A40. In embodiment A40, the of embodiments A1 to A39b, or a pharmaceutically acceptable salt is an E3 ubiquitin ligase ligand of formula (i):. A41. In embodiment A41, the one of embodiments A1 to A40, or a pharmaceutically acceptable salt thereof,ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a): . A42. In embodiment A42, the compound of any one of embodiments A1 to A41, or a pharmaceutically acceptable salt thereof, is wherein R4and R5are independently hydrogen or alkyl. 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 42, 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 pharmaceutically acceptable salt thereof, is wherein R4and R5together with the carbon to which they are attached form >C =O. - 22 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A46a. In embodiment A46a, 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):. A46. In embodiment A46, the compound of any one of embodiments A1 to A40 and 46a, or a pharmaceutically acceptable salt thereof, ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b):. A47. In embodiment A47, the compound of any one of embodiments A1 to A40, A46a, 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, A46a, and A46, or a methyl. A49. In A1 to A48, or a pharmaceutically ligase ligand of formula (i) is:. A50. In A1 to A49, or a pharmaceutically ubiquitin ligase ligand of formula (i) is:. - 23 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A51. In embodiment A51, the compound of any one of embodiments A1 to A50, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:. A52. In A1 to A51, or a pharmaceutically ligase ligand of formula (i) is:; i.e., where Rbbis hydrogen. A52a. In embodiment A52a, the one of embodiments A1 to A52, or apharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rbbis hydrogen.A53. In embodiment A53, the compound of any one of embodiments A1 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rbbis hydrogen. - 24 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A54. In embodiment A54, the compound of any one of embodiments A1 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:i.e., where Rbbis hydrogen. A55. In embodiment A55, the compound of any one of embodiments A1 to A52, or a pharmaceutically acceptable salt thereof, A of the E3 ubiquitin ligase ligand of formula (i) is:i.e., where Raaand Rbbare hydrogen. A56. In embodiment A56, the one of embodiments A1 to A52, or a pharmaceutically acceptable salt thereof, A of the E3 ubiquitin ligase ligand offormula (i) is: i.e., where Rccand Rddare hydrogen. A57. In embodiment A57, the one of embodiments A1 to A52, or apharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rccand Rddare hydrogen. A58. In embodiment A58, the compound of any one of embodiments A1 to A54, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy, unless stated otherwise i.e., in embodiments A52 to A54, Rbb, Rcc, and Rddare hydrogen. A59. In embodiment A59, the compound of any one of embodiments A1to A54, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano, unless stated otherwise. 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, unless stated otherwise. - 25 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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, unless stated otherwise. 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 independently selected from hydrogen and methoxy, unless stated otherwise. 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, unless stated otherwise. A64. In embodiment A64, 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, trifluoromethyl, and difluoromethyl, unless stated otherwise. 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, unless stated otherwise. 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 stated otherwise. A67. In embodiment A67, the of embodiments A1 to A39b, or apharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (ii): (ii). A68. In embodiment A68, the compound of any one of embodiments A1 to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Yais CH. A69. In embodiment A69, the compound of any one of embodiments A1 to A39b and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Yais N. A70. In embodiment A70, the compound of any one of embodiments A1 to A39b and A41 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 A39b and A41 to A70, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond, -NH-, or -NHC(O)-. A72. In embodiment A72, the compound of any one of embodiments A1 to A39b and A41 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 A39b and A41 to A71, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-, or -NHC(O)-. A74. In embodiment A74, the compound of any one of embodiments A1 to A39b, A41 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-. - 26 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A74a. In embodiment A74a, the compound of any one of embodiments A1 to A39b, A41 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 A39b and A41 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 A39b, and A41 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is cyclylaminylene substituted with Reeand Rff. A77. In embodiment A77, the compound of any one of embodiments A1 to A39b and A41 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. A78. In embodiment A78, the compound of any one of embodiments A1 to A39b, A41 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. A79. In embodiment A79, the compound of any one of embodiments A1 to A39b, A41 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 substituted with Reeand Rff. A80. In embodiment A80, the compound of any one of embodiments A1 to A39b, A41 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10- membered fused bicyclic ring atoms and substituted with Reeand Rff. A81. In embodiment A1 to A39b and A41 to A80, or a pharmaceutically ubiquitin ligase ligand of formula (ii) is:, , , or . - 27 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A82-1. In embodiment A82-1, the compound of any one of embodiments A1 to A39b and A41 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of , ,, or Rffare / is and A41 to of ,, , , , , , , or where ring B is cyclylaminylene. - 28 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A82A. In embodiment A82A, the compound of any one of embodiments A1 to A39b and A41 to salt thereof, is wherein the E3 ubiquitin ligase ligand offormula (ii) is . A83. In embodiment A83, the compound of any one of embodiments A1 to A39b and A41 to A82, or a ligand of formula (ii) is: ,, , , , .any one of embodiments A1 to A39b and A41 to A83, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is or . A84. In embodiment A84, the compound of any one of embodiments A1 to A39b and A41 to A83A, or a pharmaceutically acceptable salt thereof, is wherein each Reeand Rffare independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy unless stated otherwise. A85. In embodiment A85, the compound of any one of embodiments A1 to A39b and A41 to A84, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano unless stated otherwise. A86. In embodiment A86, the compound of any one of embodiments A1 to A39b and A41 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 unless stated otherwise. - 29 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A87. In embodiment A87, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, and isopropyl unless stated otherwise. A88. In embodiment A88, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen and methoxy unless stated otherwise. A89. In embodiment A89, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro unless stated otherwise. A90. In embodiment A90, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein one of Reeand Rffis hydrogen or fluoro and the other of Reeand Rffis selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl unless stated otherwise. A91. In embodiment A91, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy unless stated otherwise. A92. In embodiment A92, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, chloro, fluoro, and trifluoromethyl unless stated otherwise. A93. In embodiment A93, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare hydrogen. A94. In embodiment A94, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare chloro unless stated otherwise. A95. In embodiment A95, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare fluoro unless stated otherwise. A96. In embodiment A96, the compound of any one of embodiments A1 to A39b and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently trifluoromethyl or 2,2,2-trifluoroethyl unless stated otherwise.A97. In embodiment A97, the compound of any one of A96, or a acceptable salt thereof, is wherein Ar is phenylene, monocyclic heteroarylene,or heterocyclylene, where each ring is substituted with Rj, Rk, and Rmwhere Rmis hydrogen. A98. In embodiment A98, the compound of any one of embodiments A1 to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is phenylene of formula or (i.e., Ar is phenylene where alk and SO2are attached at meta position or para position of the phenylene ring) substituted with Rj, Rk, and Rmwhere Rjand Rkare independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy and Rmis hydrogen. - 30 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A99. In embodiment A99, the compound of any one of embodiments A1 to A98, or a acceptable salt thereof, is wherein the phenylene of Ar is orsubstituted with Rj, Rk, and Rmwhere Rjand Rkare independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and Rmis hydrogen. A100. In embodiment A100, the compound of any one ofA1 to A99, or aacceptable salt thereof, is wherein the phenylene of Ar is or substituted with Rj, Rk, and Rmwhere Rjand Rkselected from hydrogen, fluoro, A1 to A100, or a. A101. In embodiment A101, the compound of any one of embodiments A1 to A100, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is . A102. In embodiment A102, the compound of any one of embodiments A1 to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is monocyclic heteroarylene (such as imidazol-1,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-2,5-diyl, or pyridin-3,5-diyl) substituted with Rj, Rk, and Rmwhere Rjand Rkare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, cyano, and haloalkoxy and Rmis hydrogen. A103. In embodiment A103, the compound of any one of embodiments A1 to A97, and A99 to A102, or a pharmaceutically acceptable salt thereof, is wherein the monocyclic heteroarylene of Ar is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-2,5-diyl, or pyridin-3,5-diyl, where each ring substituted with Rj, Rk, and Rmwhere Rjand Rkare independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy and Rmis hydrogen. A104. In embodiment A104, the compound of any one of embodiments A1 to A97 and A99 to A103, or a pharmaceutically acceptable salt thereof, is wherein the monocyclic heteroarylene of Ar is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, where each ring substituted with Rj, Rk, and Rmwhere Rjand Rkare independently selected from hydrogen, methyl, - 31 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and Rmis hydrogen. A105. In embodiment A105, the compound of any one of embodiments A1 to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is heterocyclylene substituted with Rj, Rk, and Rmwhere Rjand Rkare independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy and Rmis hydrogen. A106. In embodiment A106, the compound of any one of embodiments A1 to A97, A99 to A101, and A103 to A105, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Ar is divalent azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl. A107. In embodiment A107, the compound of any one of embodiments A1 to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is bridged heterocyclylene. A99 to A101,the bridged heterocyclylene of Ar is selected from: A109. In embodiment A109, the compound of any one of embodiments A1 to A108, or a pharmaceutically acceptable salt thereof, is wherein Z is cycloalkylene selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene and substituted as defined therein. A110. In embodiment A110, the compound of any one of embodiments A1 to A109, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Z is independently selected from 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene. A111. In embodiment A111, the compound of any one of embodiments A1 to A108 and A110, or a pharmaceutically acceptable salt thereof, is wherein Z is phenylene or monocyclic heteroarylene (such as imidazoldiyl, pyridindiyl and pyrimidindiyl) and substituted with Rdand Reas defined therein. A112. In embodiment A112, the compound of any one of embodiments A1 to A108 and A111, or a pharmaceutically acceptable salt thereof, is wherein Z is monocyclic heteroarylene selected from imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, and pyridin-3,5-diyl. A113. In embodiment A113, the compound of any one of embodiments A1 to A108 and A111, or a pharmaceutically acceptable salt thereof, is wherein Z is 1,3-phenylene or 1,4-phenylene. A114. In embodiment A114, the compound of any one of embodiments A1 to A108, or a pharmaceutically acceptable salt thereof, is wherein Z is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring substituted with Rdand Reas defined therein. - 32 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A115. In embodiment A115, the compound of any one of embodiments A1 to A108 and A114, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene, bridgedrespectively, wherein each ring is substituted with Rdand Reindependently selected from hydrogen, A1 to A108, A114, and bridgedrespectively. A1 to A108 and A114 to is heterocyclylene selected from:- 33 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A118. In embodiment A118, the compound of any one of embodiments A1 to A108 and A114 to acceptable salt thereof, is wherein Z is heterocyclylene,. A119. In embodiment A119, the compound of any one of embodiments A1 to A108 or a pharmaceutically acceptable salt thereof, is wherein Z is -O-, -NH-, or –NCH3-. and A114, or ahaloalkyl, A114, and A120,haloalkyl, haloalkoxy,A98, A114, and A120, or a pharmaceutically acceptable salt thereof, is wherein -Z-alk-Ar-SO2- is: - 34 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT wherein each Rd, Re, and Rkare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and Rjis hydrogen. A123. In embodiment A123, the compound of any one of embodiments A1 to A98, A114, A120, and A121, or a is wherein -Z-alk-Ar-SO2- is:wherein Rd, Re, and Rkare as defined therein. A124. In embodiment A124, of embodiments A1 to A98, A114, A120, and A121, or a is wherein -Z-alk-Ar-SO2- is:wherein Rd, Re, and Rkare as defined A125. In embodiment A125, of embodiments A1 to A98, A114, A120, and A121, or ais wherein -Z-alk-Ar-SO2- is: wherein Rd, Re, and Rkare as definedA126. In embodiment A126, the compound of any one of embodiments A1 to A98, A114, A120, and A121, or a pharmaceutically acceptable salt thereof, is wherein -Z-alk-Ar-SO2- is:wherein Rd, Re, and Rkare as defined therein. A127. In embodiment A127, the compound of any one of embodiments A1 to A98, A114, A120, and A121, or a pharmaceutically acceptable salt thereof, is wherein -Z-alk-Ar-SO2- is:wherein Rd, Re, and Rkare as defined therein. A128. In embodiment A128, the compound of any one of embodiments A1 to A98, A114, A120, and A122, or a pharmaceutically acceptable salt thereof, is wherein -Z-alk-Ar-SO2- is: wherein Rd, Re, and Rkare as defined therein. - 35 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A129. In embodiment A129, the compound of any one of embodiments A1 to A98, A114, A120, and A122, or a is wherein -Z-alk-Ar-SO2- is:wherein Rd, Re, and Rkare as defined therein. A130. In embodiment A130, of embodiments A1 to A98, A114, A120, and A122, or a is wherein -Z-alk-Ar-SO2- is:wherein Rd, Re, and Rkare as defined A131. In embodiment A131, of embodiments A1 to A98, A114,A120, and A122, or a is wherein -Z-alk-Ar-SO2- is: wherein Rd, Re, and Rkare as definedA132. In embodiment A132, of embodiments A1 to A98, A114, A120, and A122, or a pharmaceutically acceptable salt thereof, is wherein -Z-alk-Ar-SO2- is:wherein Rd, Re, and RkA133. In A1 to A98, A114, A120, A121, and A123 to is wherein (i.e. Ar) is:. A134. In embodiment A134, the compound of any one of embodiments A1 to A98, A114, A120, A121, A123 to A127, and A133, or a pharmaceutically acceptable salt thereof, is wherein (i.e. Ar) is , , or . A135. In embodiment A135, the compound of any one of embodiments A1 to A134, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to C6 alkenylene substituted with Rfwhere Rfis hydrogen. - 36 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A136. In embodiment A136, the compound of any one of embodiments A1 to A134, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to C6 alkenylene substituted with Rfwhere Rfis fluoro or cyano. A137. In embodiment A137, the compound of any one of embodiments A1 to A134, or a pharmaceutically acceptable salt thereof, is wherein alk is C3to C6alkylene substituted with Rg, Rh, and Riwhere Rg, Rh, and Riare hydrogen. A138. In embodiment A138, the compound of any one of embodiments A1 to A134, or a pharmaceutically acceptable salt thereof, is wherein alk is C3to C6alkylene substituted with Rg, Rh, and Riwhere Rg, Rh, and Riare hydrogen or halo, provided at least one of Rg, Rh, and Riis halo. A139. In embodiment A139, the compound of embodiment A138, or a pharmaceutically acceptable salt thereof, is wherein the halo of the at least one of Rg, Rh, and Riis fluoro. A140. In embodiment A140, the compound of any one of embodiments A1 to A134, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to C6 alkylene substituted with Rg, Rh, and Riwhere Rhis other than hydrogen and Riis hydrogen or when Rgand Rhare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3to C6alkylene, Rgand Rhtogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by Rgand Rhare substituted with R9and R10. A141. In embodiment A141, the compound of any one of embodiments A140, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to C6 alkylene substituted with Rg, Rh, and Riwhere Rhis other than hydrogen and Riis hydrogen. A142. In embodiment A142, the compound of any one of embodiments A1 to 141, or a pharmaceutically acceptable salt thereof, is wherein the C3 to C6 alkenylene and C3 to C6 alkylene of alk are linear alkenylene and alkylene, respectively, and substituted as defined therein. A143. In embodiment A143, the compound of any one of embodiments A1 to A136 and A140 to A142, or a pharmaceutically acceptable salt thereof, is wherein the linear C3 to C6 alkenylene of alk is -CH=C(Rf)CH2- and the linear C3 to C6 alkylene of alk is -CH2CH(Rh)CH2-, -CH2CH2CH(Rh)-, -CH2C(Rg)(Rh)CH2-, -CH2CH2C(Rg)(Rh)- where Rhis other than hydrogen and Riis hydrogen. A144. In embodiment A144, the compound of any one of embodiments A1 to A134 and A140 to A143, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to C6alkylene of alk is -CH2CH(Rh)CH2- where Rhis other than hydrogen and Riis hydrogen. A145. In embodiment A145, the compound of any one of embodiments A1 to A134 and A140 to A144, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3 to C6 alkylene of alk is hydrogen, deuterium, or halo and Rhof linear C3to C6alkylene of alk is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, where each ring substituted as defined therein unless stated otherwise. A146. In embodiment A146, the compound of any one of embodiments A1 to A134 and A140 to A145, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3 to C6 alkylene of alk is hydrogen and Rhof linear C3to C6alkylene of alk is halo, haloalkoxy, cycloalkyl, - 37 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT cycloalkyloxy, alkoxy, hydroxy, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, where each ring substituted as defined therein. A147. In embodiment A147, the compound of any one of embodiments A1 to A134 and A140 to A146, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3to C6alkylene of alk is hydrogen and Rhof linear C3to C6alkylene of alk is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, where each ring substituted as defined therein. A148. In embodiment A148, the compound of any one of embodiments A1 to A134 and A140 to A147, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl of Rhof linear C3 to C6 alkylene of alk, when present, are five or six membered ring and each ring is substituted as defined therein. A149. In embodiment A149, the compound of any one of embodiments A1 to A134 and A140 to A148, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3 to C6 alkylene of alk is hydrogen, deuterium, or fluoro unless stated otherwise and Rhof linear C3to C6alkylene of alk is 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 Rhis substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano, unless stated otherwise. A149A. In embodiment A149A, the compound of any one of embodiments A1 to A134 and A140 to A149, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3 to C6 alkylene of alk is hydrogen, deuterium, or fluoro, unless stated otherwise and Rhof linear C3to C6alkylene of alk is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrrazol-4-yl, pyridin-4-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, where each ring of Rhis substituted with R7and R8independently selected from hydrogen, deuterium, methyl, or fluoro, unless stated otherwise. A150. In embodiment A150, the compound of any one of embodiments A1 to A134, or a pharmaceutically acceptable salt thereof, is wherein alk is branched C4to C6alkylene substituted with Rg, Rh, and Ri. A151. In embodiment A151, the compound of any one of embodiments A1 to A138 and A150, or a pharmaceutically acceptable salt thereof, is wherein the C3 to C6 alkenylene and C3 to C6 alkylene of alk are branched C4to C6alkenylene and C4to C6alkylene, respectively, where the C4to C6 alkylene is substituted with Rg, Rh, and Rias defined therein. A152. In embodiment A152, the compound of any one of embodiments A1 to A138, A150, and A151, or a pharmaceutically acceptable salt thereof, is wherein the branched C4to C6alkenylene of alk is -CH2CH2C(CH3)=C(Rf)-, -CH2C(CH3)=C(Rf)-, or -CH2C(=CH2)CH2- and the branched C4 to C6 alkylene of alk is -CH2C(CH3)(Rh)CH2-, -CH2C(C2H5)(Rh)CH2-, -CH2CH(CH2Rh)CH2-, -CH2CH(CH2CH2Rh)CH2-, -CH2C(CH3)(CH2Rh)CH2-, -CH2C(C2H5)(CH2Rh)CH2-, -CH2C(CH3)(CH2CH2Rh)CH2-, -CH2CH(CH3)CH(CH2Rh)-, -CH2CH2C(CH3)(CH2Rh)-, - 38 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT -CH2CH(CH3)C(Rg)(Rh)-, -CH2CH(C2H5)C(Rg)(Rh)-. -CH2CH(C(Rg)(Rh)(Ri))CH(CH3)-, -CH2C(CH3)(C(Rg)(Rh)(Ri))CH(CH3)-, -CH2CH(C(Rg)(Rh)(Ri))CH2-, -CH2CH2CH(C(Rg)(Rh)(Ri))-, -CH2CH2CH(C(Rg)(Rh)(Ri))CH2-, or -CH2CH2CH2CH(C(Rg)(Rh)(Ri))- where Rg, Rh, and Riare as defined therein. A153. In embodiment A153, the compound of any one of embodiments A1 to A138 and A150 to 152, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6 alkenylene of alk is -CH2C(CH3)=C(Rf)- or -CH2C(=)CH2- and the branched C4to C6alkylene of alk is -CH2C(CH3)(Rh)CH2-, -CH2CH(CH2Rh)CH2-, -CH2CH(CH2CH2Rh)CH2-, -CH2CH(C(Rg)(Rh)(Ri))CH2-, -CH2CH2CH(C(Rg)(Rh)(Ri))CH2-, or -CH2CH2CH2CH(C(Rg)(Rh)(Ri))- where Rg, Rh, and Riare as defined therein. A154. In embodiment A154, the compound of any one of embodiments A1 to A138 and A150 to A153, or a pharmaceutically acceptable salt thereof, is wherein the Rgand Riof branched C4 to C6 alkylene of alk are independently hydrogen or halo (unless stated otherwise) and Rhof branched C4to C6alkylene of alk is 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 Rhis substituted as defined therein. A155. In embodiment A155, the compound of any one of embodiments A1 to A138 and A150 to A154, or a pharmaceutically acceptable salt thereof, is wherein the Rgand Riof branched C4 to C6 alkylene of alk are hydrogen or fluoro (unless stated otherwise) and Rhof branched C4 to C6 alkylene of alk is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of Rhis substituted as defined therein. A156. In embodiment A156, the compound of any one of embodiments A1 to A138 and A150 to A155, or a pharmaceutically acceptable salt thereof, is wherein Rgand Riof branched C4 to C6 alkylene of alk are hydrogen or fluoro (unless stated otherwise) and Rhof branched C4 to C6 alkylene of alk is hydrogen, halo, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein. A157. In embodiment A157, the compound of any one of embodiments A1 to A138 and A150 to A155, or a pharmaceutically acceptable salt thereof, is wherein alk is branched C4to C6alkylene substituted as defined therein and the heteroaryl, heterocyclyl, by itself or as part of heterocyclyloxy, heterocyclylcarbonyl, and bridged heterocyclyl of Rhof branched C4 to C6 alkylene of alk, when present, are five or six membered ring and each ring of Rhis substituted as defined therein. A158. In embodiment A158, the compound of any one of embodiments A1 to A138 and A150 to A157, or a pharmaceutically acceptable salt thereof, is Rgand Riof branched C4 to C6 alkylene of alk are independently hydrogen, deuterium, or fluoro (unless stated otherwise) and Rhof branched C4 to C6 alkylene of alk, 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, - 39 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT furanyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or tetrahydrofuranyl, where each ring of Rhis substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano, unless stated otherwise. A158A. In embodiment A158A, the compound of any one of embodiments A1 to A138 and A150 to A158, or a pharmaceutically acceptable salt thereof, is wherein Rgand Riof branched C4 to C6alkylene of alk, unless stated otherwise, is hydrogen or fluoro and Rhof branched C4to C6alkylene of alk, when present and unless stated otherwise, is hydrogen, fluoro, hydroxy, methoxy, cyano, pyrazolyl-1-yl, or methylaminocarbonyl. A159. In embodiment A159, the compound of any one of embodiments A1 to A134 and A140, or a pharmaceutically acceptable salt thereof, is wherein alk is C3to C6alkylene substituted with Rg, Rh, and Riwhere Rgand Rhare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C6 alkylene and Rgand Rhtogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by Rgand Rhare substituted with R9and R10. A160. In embodiment A160, the compound of any one of embodiments A1 to A134, A140, and A159, or a pharmaceutically acceptable salt thereof, is wherein alk is C3to C6alkylene substituted with Rg, Rh, and Riwhere Rgand Rhare attached to the same carbon atom of the linear portion of C3 to C6 alkylene and together with the carbon atom to which they are attached can form cycloalkylene substituted with R9and R10. A161. In embodiment A161, the compound of any one of embodiments A1 to A134, A140, and A159, or a pharmaceutically acceptable salt thereof, is wherein alk is C3to C6alkylene substituted with Rg, Rh, and Riwhere Rgand Rhare attached to the same carbon atom of the linear portion of the C3to C6alkylene and together with the carbon atom to which they are attached can form heterocyclylene substituted with R9and R10. A162. In embodiment A162, the compound of any one of embodiments A1 to A134, A140, and A159, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to C6 alkylene substituted with Rg, Rh, and Riwhere Rgand Rhare attached to adjacent carbon atoms of the linear portion of the C3 to C6 alkylene and together with the carbon atoms to which they are attached can form cycloalkylene substituted with R9and R10. A163. In embodiment A163, the compound of any one of embodiments A1 to A134, A140, and A159, or a pharmaceutically acceptable salt thereof, is wherein alk is C3to C6alkylene substituted are attached to adjacent same carbon atoms of the linear with the carbon atoms to which they are attachedcan form heterocyclylene substituted with R9and R10. A164. In embodiment A164, the compound of any one of embodiments A1 to A134, A140, and A159 to A161, or a pharmaceutically acceptable salt thereof, is wherein Rgand Rhare 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: - 40 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT orwhere each ring is substituted with R9and R10, preferably R9is hydrogen, halo, methyl or ethyl and R10is hydrogen. A165. In embodiment A165, the compound of any one of embodiments A1 to A134, A140, A159, A162, and A163, or a pharmaceutically acceptable salt thereof, is wherein Rgand Rhare attached to of the linear portion of the C3to C6alkylene and together with the carbon atomsattached can form cycloalkylene of formula: orwhere each ring is substituted with R9and R10, preferably R9is hydrogen, halo, methyl or ethyl and R10is hydrogen. A166. In embodiment A166, the compound of any one of embodiments A1 to A134, or a pharmaceutically acceptable salt thereof, is wherein the alk is C3 to C6 heteroalkylene substituted with Rg, Rh, and Ri. A167. In embodiment A167, the compound of any one of embodiments A1 to A134 and A166, or a pharmaceutically acceptable salt thereof, is wherein the alk is C3 to C6 heteroalkylene substituted with Rg, Rh, and Riwhere Rg, Rh, and Riare hydrogen. A168. In embodiment A168, the compound of any one of embodiments A1 to A134 and A166, or a pharmaceutically acceptable salt thereof, is wherein the alk is C3 to C6 heteroalkylene substituted with Rg, Rh, and Riwhere Rg, Rh, and Riare hydrogen or halo, provided at least one of Rg, Rh, and Riis halo. A169. In embodiment A169, the compound of any one of embodiments A1 to A134 and A166, or a pharmaceutically acceptable salt thereof, is wherein alk is C3 to C6 heteroalkylene substituted with Rg, Rh, and Riwhere Rhis other than hydrogen and Riis hydrogen, or when Rgand Rhare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C6 heteroalkylene, Rgand Rhtogether with the carbon atom to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R9and R10. A169a. In embodiment A169a, the compound of any one of embodiments A1 to A134 and A169, or a pharmaceutically acceptable salt thereof, is wherein Rgand Rhare attached to the same - 41 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT carbon atom of the linear portion of the C3to C6heteroalkylene and together with the carbon atom to which they of formula:orwhere each ring is substituted with R9and R10, preferably R9is hydrogen, halo, methyl or ethyl and R10is hydrogen. A169b. In embodiment A169b, the compound of any one of embodiments A1 to A134 and A169, or a salt thereof, is wherein Rgand Rhare attached to adjacent carbon atomsof the C3to C6heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula:or heterocyclylene of formula: where each ring is substituted with R9and R10, preferably R9is hydrogen, halo, methyl or ethyl and R10is hydrogen. A170. In embodiment A170, the compound of any one of embodiments A1 to A134, A166, and A169, or a pharmaceutically acceptable salt thereof, is wherein alk is C3to C6heteroalkylene substituted with Rg, Rh, and Riwhere Rhis other than hydrogen and Riis hydrogen. A171. In embodiment A171, the compound of any one of embodiments A1 to 134, A142 to A149A, A151 to A156, A158, A158A, and A166 to A170, or a pharmaceutically acceptable salt thereof, is wherein the C3to C6heteroalkylene of alk is linear C3to C6heteroalkylene. A172. In embodiment A172, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, A170, and A171, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to C6heteroalkylene of alk is -CH2CH2XaCH2-, -CH2XaCH2CH2-, -CH2CH2CH2Xa-, -XaCH2CH2CH2-, - XyCH2CH2Xa-, -XyCH2CH2XaCH2-, -CH2CH2CH2XaCH2-, -CH2XaCH2-, -XaCH2CH2-, -CH2CH2Xa-, -CH2CONRqCH2-, -CH2SO2NRqCH2-, -CH2NRqCOCH2-, -CH2NRqSO2CH2-, -CH2CH2CH2NRqCO-, -CH2CONRq-, -CH2SO2NRq-, -CH2NRqCO-, -CH2NRqSO2-, -CONRqCH2-, -SO2NRqCH2-, -NRqCOCH2-, or -NRqSO2CH2- substituted with Rg, Rh, and Rias defined therein and Xais -NRq-, -O-, -S-, -SO-, -SO2-, or –CO-. - 42 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A173. In embodiment A173, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A172, or a pharmaceutically acceptable salt thereof, is wherein Rqis hydrogen, methyl, ethyl, methylcarbonyl, or methylsulfonyl. A174. In embodiment A174, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A173, or a pharmaceutically acceptable salt thereof, is wherein the linear C3 to C6 heteroalkylene of alk is -CH2XaCH2-, -XaCH2CH2-, -CH2CH2Xa-, -CH2CH(Rh)Xa-, -XaCH(Rh)CH2-, -CH2CONRq-, -CH2SO2NRq-, -CH2NRqCO-, -CH2NRqSO2-, -CONRqCH2-, -SO2NRqCH2-, -NRqCOCH2-, or -NRqSO2CH2- where Xais -S-, -SO2-, -O-, or -NRq-. A175. In embodiment A175, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A174, or a pharmaceutically acceptable salt thereof, is wherein the linear C3 to C6 heteroalkylene of alk is -CH2CH2CH2Xa- or -CH2CH2Xa. A176. In embodiment A176, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A175, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3 to C6 heteroalkylene of alk is hydrogen or halo (unless stated otherwise) and Rhof linear C3to C6heteroalkylene of alk is (unless stated otherwise) hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, where each ring substituted as defined therein and Riis hydrogen. A177. In embodiment A177, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A176, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3to C6heteroalkylene of alk is hydrogen or fluoro (unless stated otherwise) and Rhof linear C3to C6heteroalkylene of alk (unless stated otherwise) is hydrogen halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein. A178. In embodiment A178, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A177, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl of Rhof linear C3to C6heteroalkylene of alk, when present, are five or six membered ring and each ring is substituted as defined therein. A179. In embodiment A179, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A176, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3to C6heteroalkylene of alk, when present and unless stated otherwise, is hydrogen, deuterium, or fluoro, and Rhof linear C3 to C6 heteroalkylene of alk, when present and 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, piperazinyl, or tetrahydrofuranyl, where each ring substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, - 43 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino, and cyano. A180. In embodiment A180, the compound of any one of embodiments A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A179, or a pharmaceutically acceptable salt thereof, is wherein Rgof linear C3to C6heteroalkylene of alk is hydrogen and Rhof linear C3 to C6 heteroalkylene of alk is fluoro, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrrazol-4-yl, pyridin-4-yl, pyrrolidin-1-yl, or 2-oxopyrrolidin-1-yl, where each ring substituted with R7and R8independently selected from hydrogen, deuterium, methyl, or fluoro. A181. In embodiment A181, the compound of any one of embodiments A172 to A180, or a pharmaceutically acceptable salt thereof, is wherein Xais -NRq-, -O-, -S-, or -SO2-, preferably -NRq-, -O-, or -S-. A182. In embodiment A182, the compound of any one of embodiments A172 to A181, or a pharmaceutically acceptable salt thereof, is wherein Xais -NRq- where Rqis hydrogen or methyl. A183. In embodiment A183, the compound of any one of embodiments A172 to A181, or a pharmaceutically acceptable salt thereof, is wherein Xais -O-. A184. In embodiment A184, the compound of any one of embodiments A172 to A181, or a pharmaceutically acceptable salt thereof, is wherein Xais -S-. A185. In embodiment A185, the compound of any one of embodiments A172 to A184, or a pharmaceutically acceptable salt thereof, is wherein Xyis -O-. A186. In embodiment A186, the compound of any one of embodiments A172 to A184, or a pharmaceutically acceptable salt thereof, is wherein Xyis -NH- or -NCH3-. A187. In embodiment A187, the compound of any one of embodiments A1 to 134, A166 to A169, and A170, or a pharmaceutically acceptable salt thereof, is wherein the C3to C6heteroalkylene of alk is branched C4 to C6 heteroalkylene. A188. In embodiment A188, the compound of any one of embodiments A1 to A134, A166 to A169, A170, and A187, or a pharmaceutically acceptable salt thereof, is wherein the branched C4to C6 heteroalkylene of alk is -CH2XaCH(CH3)CH2-, -CH2XyCH2CH(CH3)Xa-, -CH2CH2CH(CH3)Xa-, -XaCH(CH3)CH2CH2-, -XyCH2CH(CH3)Xa-, -XyCH(CH3)CH2Xa-, -CH2CH2CH2CH(CH3)Xa-, -XaCH(CH2Rh)CH2-, -CH2CH(CH2Rh)Xa-, -XaCH(CH2CH2Rh)CH2-, -CH2CH(CH2CH2Rh)Xa-, -CH2C(CH3)(CH3)Xa-, -XaC(CH3)(CH3)CH2-, -CH(CH3)CH(CH3)Xa-, -CONRqCH2CH(CH3)Xa-, -CH2NRqCOCH(CH3)CH2-, or -NRqCOCH(CH3)CH2- where Xais -NRq-, -O-, -S-, -SO-, -SO2-, or -CO-. A189. In embodiment A189, the compound of any one of embodiments A1 to 134, A166 to A169, A170, A187, and A188, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6 heteroalkylene of alk is -CH2C(CH3)(CH3)Xa-, -CH(CH3)(CHCH3)Xa-, -XaCH(CH2CH2Rh)CH2-, -CH2CH(CH2CH2Rh)Xa-, -XaCH(CH2Rh)CH2-, or -CH2CH(CH2Rh)Xa-. A190. In embodiment A190, the compound of any one of embodiments A1 to 134, A166 to A169, A170,A173, and A187 to A189, or a pharmaceutically acceptable salt thereof, is wherein the Rgand Riof branched C4to C6heteroalkylene of alk are hydrogen or halo (unless stated otherwise) and Rhof branched C4 to C6 heteroalkylene of alk is hydrogen, halo, haloalkoxy, cycloalkyl, - 44 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl substituted as defined therein. A191. In embodiment A191, the compound of any one of embodiments A1 to 134, A166 to A169, A170, A173, and A187 to A190,or a pharmaceutically acceptable salt thereof, is wherein the Rgand Riof branched C4 to C6 heteroalkylene of alk are hydrogen or fluoro (unless stated otherwise) and Rh(unless stated otherwise) is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl, substituted as defined therein. A192. In embodiment A192, the compound of any one of embodiments A1 to 134, A166 to A169, A170, A173, and A187 to A191, or a pharmaceutically acceptable salt thereof, is wherein Rgand Riare hydrogen and Rhis hydrogen, heteroaryl, alkylaminocarbonyl, or cyano. A193. In embodiment A193, the compound of any one of embodiments A1 to 134, A166 to A169, A170, A173, and A187 to A192, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, and heterocyclyl of branched C4 to C6 heteroalkylene of alk, 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. A194. In embodiment A194, the compound of any one of embodiments A1 to 134, A166 to A169, A170, A173, and A187 to A193, or a pharmaceutically acceptable salt thereof, is wherein Rhof branched C4to C6heteroalkylene of alk, 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, pyrrolidinyl, pyridinyl, piperidinyl, piperazinyl, or tetrahydrofuranyl, where each ring substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano. A195. In embodiment A195, the compound of any one of embodiments A188 to A194, or a pharmaceutically acceptable salt thereof, is wherein Xais -NRq-, -O-, -S-, or -SO2-, preferably -NRq- or -O-. A196. In embodiment A196, the compound of any one of embodiments A188 to A195, or a pharmaceutically acceptable salt thereof, is wherein Xais -NRq- where Rqis hydrogen or methyl. A197. In embodiment A197, the compound of any one of embodiments A188 to A195, or a pharmaceutically acceptable salt thereof, is wherein Xais -O-. A198. In embodiment A198, the compound of any one of embodiments A188 to A195, or a pharmaceutically acceptable salt thereof, is wherein Xais -S-. A199. In embodiment A199, the compound of any one of embodiments A188 to A198, or a pharmaceutically acceptable salt thereof, is wherein Xyis -O-. A200. In embodiment A200, the compound of any one of embodiments A188 to A198, or a pharmaceutically acceptable salt thereof, is wherein Xyis -NH- or -NCH3-. - 45 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A201. In embodiment A201, the compound of any one of embodiments A1 to A200, or a- 46 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCTor a- 47 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCTor aany one to or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand selected from: , , , , - 48 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT , ,, , and ; where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and Rffis hydrogen, methyl, fluoro, or or a selected from: , ,, , , , and ; where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and Rffis hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. - 49 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT A206. In embodiment A206, the compound of any one of embodiments A1 to A205, or a selected from:A207. In embodiment A207, the A67, A69 to A72, A77, A79 to A82, and A83 to iswherein Degron is the E3 ubiquitin ligase ligand is where each Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, preferably methyl and optionally wherein Rffis hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. “Unless stated otherwise” as used in the embodiments means that when an embodiment refers to more than one preceding embodiment of varying scopes, 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 R2groups recited in embodiment A18, while all the R2recited groups in A18 should be selected for embodiment A1, only R2as hydroxymethyl, from the list of groups is limited to hyd able 1 below: Cpd # [M+H]+ 1 867.9oxo e ra y ropyr m n- -y - 1-methyl-1H-indazol-6-yl)piperidin- 1-yl)-2-methylpropyl)benzonitrile 2 2-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin- 1-yl)-2-methylpropyl)-4-((4-((6- (ethoxymethyl)-8-isopropyl-7-oxo- 892.4 7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)piperidin-1- yl)sulfonyl)benzonitrile - 50 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Cpd # [M+H]+ 3 832.3 4 834.3 5 809.3 6 884.3 7 882.3 8 854.21-methyl-1H-indazol-6-yl)piperidin- 1-yl)ethoxy)benzonitrile 4-((4-((6-(cyanomethyl)-8- cyclopropyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2- 9 yl)amino)piperidin-1-yl)sulfonyl)-2- (3-(4-(3-(2,4- 871.3 dioxotetrahydropyrimidin-1(2H)-yl)- 1-methyl-1H-indazol-6-yl)piperidin- 1-yl)-2-methylpropyl)benzonitrile - 51 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Cpd # [M+H]+ 10 891.1 11 834.2, y py , d]pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)benzonitrile 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. 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, 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 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 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. - 52 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Compounds of Formula (I), where Degron is an E3 ligase ligand of formula (i) and (ii) and Hy, R1, R2, R2a, Ar, alk, and Z are as defined in the Summary (or an embodiment thereof hereinabove), can be prepared as described in Scheme 1.Treatment of a compound of formula 1-2 where A1is a leaving group, such as halogen (e.g. chlorine, or bromine) or methylsulfonyl, with an amine of formula 1-1 where Degron, Hy, R1, R2, R2a, Ar, alk, and Z are as defined in the Summary or an embodiment thereof hereinabove, under suitable conditions such as acidic, basic or transition metal catalyzed reaction conditions well known in the art, provides a compound of Formula (I). Alternatively, a compound of Formula (I) such as where R1, R2, Ar, and alk are as defined in the a group of each ring 2.Treatment of a compound of formula 2-1 where A1is a halogen such as chlorine or bromine and R1and R2are defined in the Summary (or an embodiment thereof herein above), with a piperidine amine of formula 2-2 under conditions well known in the art, such as in the presence of DIPEA in tert-butanol at elevated temperature, 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 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 A2is halogen such as chlorine and LG is a suitable leaving group such as halo or methylsulfonyl and Ar and alk are as defined in the Summary (or an embodiment thereof hereinabove). Treatment of a compound of formula 2-6 with an amine compound of formula 2-7 where is heterocyclyl, bridged heterocyclyl, or spiro heterocyclyl, each ring containing at least one nitrogen atom and ring A is defined as in the Summary or an embodiment - 53 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT thereof hereinabove, under basic conditions such as in the presence of DIPEA, provides a compound of Formula (I) where Degron is a group of formula (i). Proceeding as replacing a compound of formula 2-7 with acompound of formulawhere Ya, Za, and ring B are as defined in the Summary and is as defined above for compound 2-7, will provide a compound of Formula (I) where the Degron is a group of formula (ii) or any embodiment thereof. Compounds of formula 2-1, 2-5, 2-7, and 2-8 are either commercially available or they can be prepared by methods known in the art. Alternatively, a compound of Formula (I) such as where R1, R2, Ar, and alk are as defined in the Summary or an embodiment thereof, R2ais hydrogen, Degron is a group of formula (i) and Z is as illustratedCross coupling of a compound of formula 3-1, where A1is a halogen and ring A as defined in the Summary or an embodiment thereof hereinabove, with a tetrahydropiperidinyl of formula 3-2 where M is a metal, such as boronic ester or zinc, provides a compound of formula 3-3. The reaction typically proceeds in the presence of a palladium catalyst; for example, when M is a boronic ester, a Suzuki reaction is conducted in the presence of Pd(dppf)Cl2 and Na2CO3, in 1,4-dioxane and water. Reduction of the double bond in compound 3-3 under conditions well known in the art, such as in the presence of a palladium catalyst and under hydrogen atmosphere, provides compound of formula 3-4. Removal of the Boc protection group of 3-4 under acidic conditions provides an amine compound of formula 3-5. Reaction of 3-5 with an aldehyde of formula 3-6 where Ar and -CH2- [alk1]n-1is alk, each as defined in the Summary or an embodiment thereof hereinabove, under conditions well known in the art in the presence of a reducing agent, such as NaBH(OAc)3, in a suitable solvent, such as DCM, where Hy is as defined in the Summary or an embodiment thereof - 54 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT hereinabove and -CH2-(alk1)n-1is alk as defined in the Summary or an embodiment thereof hereinabove, provides compound of formula 3-7. Removal of the Boc protecting group in compound 3-7 using an acid like TFA provides an amine compound of formula 3-8. Treatment of compound 3-8 with a compound of formula 2-1 under suitable conditions such as acidic, basic or transition metal catalyzed reaction conditions well known in the art, provides a compound of Formula (I) where Degron is a group of formula (i). but replacing a compound of formula 3-5 with a of formulawhich can then be converted into a compound of Formula (I) where the Degron is a group of formula (ii) or any embodiment thereof. Utility The compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) could cause degradation of CDK2 / 4 / 6 proteins and hence are useful in the treatment of diseases mediated by CDK2, CDK4, and / or CDK6. Increasing evidence suggests that aberrant activation of G1 cell cycle kinases including CDK2, and / or CDK4 and / or CDK6 leads to abnormal cell cycle regulation and proliferation in cancer cells. While CDK2 and / or CDK4 and / or CDK6 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 and / or CDK6 and / or 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 carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, and lung adenocarcinoma. Translocation of cyclin D1 and / or 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 / 6 inhibitor p16 (CDKN2A) is also a common event in many cancers, including glioblastoma multiforme, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, lung squamous cell 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 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 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 - 55 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT mechanisms of CDK2 activation have been validated using cancer cells or mouse cancer models. Furthermore, CDK2 / cyclin E phosphorylates 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 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 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 and / or CDK6; 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 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), 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 (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, enal cell cancer, astrocytoma, skin cancer (e.g. melanoma, squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), bladder cancer (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 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), lymphoma (e.g. non-Hodgkin lymphoma NHL including mantel cell lymphoma, MCL and Hodgkin lymphoma) and multiple myeloma. - 56 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT In other embodiments, the cancer is breast cancer, including, e.g., ER-positive / HR- positiveHER2-negative breast cancer; ER-positive / HR-positive HER2-positive breast cancer; ER- negative / HR-negative, HER2-positive breast cancer, triple negative 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 CCND1 and / or CCNE1 and / or CCNE2. Besides cancer, compounds of Formula (I) 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 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 / 6 degradation activities of the compounds of the present 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) wherein includes any embodiments thereof described herein and / 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 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 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 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 administration - 57 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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. 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. 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 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 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 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 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. 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 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 the preparation of highly concentrated solutions. - 58 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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, 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 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. 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 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, 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. 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, 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 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 - 59 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000). 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 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 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 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 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 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 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 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 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 - 60 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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 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 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 (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, 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 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); 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. WO 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- 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), 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; - 61 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib; 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), panitumumab (sold under the tradename Vectibix® by Amgen); HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech / Roche), 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 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); Trastuzumab deruxtecan (trade name Enhertu); HER dimerization inhibitors: Pertuzumab (sold under the trademark Omnitarg®, by Genentech); TROP2 ADCs: Sacituzumab govitecan; datopotamab deruxtecan; 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® by 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 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), 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); 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 tradename Revlimid®), thalidomide (sold under the tradename Thalomid®); - 62 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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)- 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 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®); 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®); 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 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; 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 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®); 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 Amgen); - 63 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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); 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®); 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 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 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®), 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 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 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- 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); - 64 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxy- 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); 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®); CDK (CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, 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); CDK4 / 6 inhibitors pabociclib, 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 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)- 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 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 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), sold under the tradenames Rheumatrex® and Trexall™), pentostatin (sold under the tradename Nipent®); - 65 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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®); 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 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 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- 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®, 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®);

[0209] Estrogen receptor downregulators: Fulvestrant (sold under the tradename Faslodex®); 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®); Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, sold under the tradename Megace®); 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, 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 molecule is an - 66 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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. 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. 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). 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 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 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 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 sued 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 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 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-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and - 67 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). 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. Synthesis of 3-(5-(azetidin-3-yl)-1-2,6-dione 2,2,2-trifluoroacetate Step 1: (1-(tert-Butoxycarbonyl)To a mixture of Zn dust (300 mg, 4.59 mmol, 1.30 eq.) 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 eq.) was added. After stirring the carboxylate (1.00 g, 3.53 mmol, 1.00stirred at 65oC under N2for 2 h, and then cooled to rt. The solution was 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 solution of mg, 1.72 mmol, 3.00 eq.) in DMA was 2-yl)piperidine-2,6-dione (185 mg, 0.57 mmol,(44 mg, 0.06 mmol, 0.10 eq.) in DMA (2.0 mL). The mixture was stirred at 90oC under N2overnight. The mixture was concentrated and purified by column chromatography on silica gel (EtOAc) to give the title compound as a brown solid. Step 3: 3-(5-(Azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate To a solution of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-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 - 68 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT the solution was stirred for 3 h. The resulting mixture was concentrated to give the title product as a brown oil. Reference 2 Synthesis of 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-Step 1: tert-Butyl 3-(1- 1H-benzo[d]-imidazol- 4-yl)azetidine-1-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- 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 N2chromatography on silica gel (EtOAc) to Step 2: 3-(4-(Azetidin-1-yl)piperidine-2,6- dione 2,2,2-trifluoroacetate To a solution of tert-butyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)azetidine-1- mmol, 1.00 eq.) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise and the rt for 3 h. The resulting mixture wasconcentrated to give the title as a Synthesis of 3-(1-Oxo-5- dione 2,2,2-trifluoroacetateStep 1: tert-Butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate To a stirred solution of methyl 2-cyano-4-fluorobenzoate (10.00 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.), and the resulting mixture was stirred at 110oC for 12 h. - 69 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give the title compound as yellow solid. Step 2: tert-Butyl 4-(3-A mixture of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-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 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, and the mixture was filtered, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified (3:1) to give the title compound asStep 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate A mixture of 3-aminopiperidine-2,6-dione hydrochloride (2.60 g, 15.50 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. Then NaBH(OAc)3 (8.20 g, 38.70 mmol, 3.00 eq.) was added the above mixture, and the diluted with water and extracted with EtOAc. Na2SO4. After filtration,the filtrate was 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 2,2,2-trifluoroacetate razine-1- carboxy resultingmixture was stirred at rt for 2 h and then concentrated to give the title compound as yellow oil. The following reference compounds were synthesized by proceeding analogously as described in Reference 3. Ref # Structure Synthesis tert-butyl piperazine-1-carboxylate was Ref.4 replaced by tert-butyl 2,7-diazaspiro- [3.5]nonane-2-carboxylate in Step 1 - 70 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Reference 5 Synthesis of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione StepTo a stirred solution of 4-bromo-2-fluorobenzonitrile (10 g, 0.05 mol, 1.00 eq.) in EtOH (50.0 mL) was added methylhydrazine (57 g, 0.50 mol, 10.00 eq.) and the mixture was stirred at 100oC 30 h in sealed tube. Then the mixture was filtered to give the title compound as pale Step 2: Methyl 3-((6-bromo-Methyl acrylate (209.00 g, 2.43 mol, 10.00 eq.) was added to a solution of 6-bromo-1-methyl- 1H-indazol-3-amine (55.00 mol, 1.50 eq.), lactic acid (33.00 g, 0.36 mol, 1.50 eq.)oC 20 h under N2. The mixture was concentrated under by column chromatography on silica gel (EtOAc:PE = 0 tosolid. Step 3: Methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propanoate NaOCN (26.00 g, 0.32 of methyl 3-((6-bromo-1- methyl-1H-indazol-3-yl)amino) eq.) in AcOH (500.0 mL), and the mixture was stirred at 80oC with water and extracted with EtOAc. The organic layer wasAfter filtration, the filtrate was concentrated to give the title compound as yellow solid. Step 4: 1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione - 71 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT To a solution of methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propanoate (56.00 g, 0.16 mol, 1.00 eq.) in MeCN (500.0 mL) was added Tirton-B (7.90 g, 0.05 mol, 0.30 eq.) and stirred at rt for 20 h under N2. The mixture was concentrated, then diluted with water. The mixture was filtered and solid was washed with water, air dried to give the title compound as pale yellow solid. Step 5: tert-Butyl 4-(3- - - indazol-6-yl)-5,6- dihydropyridine-1(2H)-To a mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.10 g, 3.41 mmol, 1.00 eq.) in 1,4-dioxane / H2O (10 mL / 1 mL) was added tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.60 g, 5.11 mmol, 1.50 eq.), K3PO4 (2.20 g, 10.22 mmol, 3.00 eq.) and X-Phos-Pd G3 (289 mg, 0.34 mmol, 0.10 eq. ), and the mixture was stirred at 60oC under N2for 3 h. The mixture was diluted with DCM, and the organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated, and the silica gel (DCM:MeOH = 20 : 1) to give the title Step 6: tert-Butyl 4-(3- 1H-indazol-6- yl)piperidine-1-A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)-5,6-dihydropyridine-1 , Pd / C (150 mg, 50% wt) and Pd(OH)2(150 mg, 50oC and 50 psi overnight. The mixture was filtered column chromatography on silica gel (PE:EtOAc = 1Step 7: 1-(1-Methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2- 2,2,2-trifluoroacetate A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidine-1-carboxylate (100 mg, 0.25 mmol, 1.00 eq.) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as brown oil. - 72 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT The following Reference compounds were synthesized by proceeding analogously as describe Re eplaced e in Re eplacedy , e in Ref 7 Step 1 trifluoroacetateStep tert- - - A mixture of 1-bromo-4-nitrobenzene (1.0 g, 4.95 mmol, 1.00 eq), tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.30 g, 7.43 mmol, 1.50 eq.), K2CO3(1.37 g, 9.90 mmol, 2.00 eq.), and Pd(dppf)Cl2(724 mg, 0.99 mmol, 0.20 eq) in dioxane / H2O (15 mL, 5 / 1 ) was filtered and extracted with EtOAc. The combinedAfter filtration, the filtrate was concentrated. The residue was purified by silica flash column PE / EtOAc (10:1) to give the title compound as yellow solid. Step 2: tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate A mixture of -carboxylate (1.20 g, 3.95 mmol, 1.00 eq.), Pd / C stirred at 45 ℃ under H2 overnight. The mixtureresidue was purified by silica flash column PE / EtOAc (3:1) to give the title compound as yellow solid. Step 3: tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate A mixture of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (332 mg, 1.20 mmol, 1.00 eq.), 3-bromopiperidine-2,6-dione (242 mg, 1.26 mmol, 1.05 eq.) and NaHCO3 (302 mg, 3.60 mmol, - 73 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 3.00 eq.) in DMF (4.0 mL) was stirred at 70 ℃ overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica flash column PE / EtOAc (1:1) to give the title compound as yellow solid. Step 4: 3-((4-(Piperidin-4-yl) trifluoroacetateTFA (0.5 mL) was added to a mixture of tert-butyl 4-(4-((2,6-dioxopiperidin-3- yl)amino)phenyl)piperidine-1-carboxylate (100 mg, 0.26 mmol, 1.00 eq.) in DCM (2.0 mL) and the mixture was stirred at rt for 2 h. The mixture was concentrated to give the title compound as a yellow solid. Synthesis of 3-(4-(piperazin-1-2,6-dione 2,2,2-trifluoroacetate Step 1: 2,6-Bis(benzyloxy)-3-2-yl)pyridine A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (19.00 g, 0.05 mol, 1.00 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.60 g, 0.08 mol, 1.50 eq.), KOAc (10.00 g, 0.10 mol, 2.00 eq.), and 1,4-dioxane (200.0 mL) was stirred at 100oC for 25 h and extracted with EtOAc, and the combined organic After filtration, the filtrate was concentrated andchromatography eluting with EtOAc:PE= 0 to 100% to give the title compound as yellow solid. Step 4: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.42 g, 10.60 mmol, 1.20 eq.), 1-bromo-4-iodobenzene (2.50 g, 8.83 mol, 1.00 eq.), K3PO4 (5.63 g, 26.50 mmol, 3.00 eq.), and Pd(PPh3)4(510 mg, 0.44 mmol, 0.05 eq.) in 1,4-dioxane / H2O=10:1 (40.0 mL) was stirred at 100oC for 16 h under N2. The mixture was diluted with water and extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na2SO4. After filtration, - 74 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc:PE= 0 to 100% to give the title compound as yellow solid. Step 5: tert-Butyl 4-(4- 1-carboxylateA mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (500 mg, 1.12 mmol, 1.00 eq.), tert-butyl piperazine-1-carboxylate (417 mg, 2.24 mmol, 2.00 eq.), Cs2CO3(730 mg, 2.24 mmol, 2.00 eq.), Pd2(dba)3 (51 mg, 0.06 mmol, 0.05 eq.), and RuPhos (52 mg, 0.11 mmol, 0.10 eq.) in toluene (15.0 mL) was stirred at 110oC for 20 h under N2. The mixture was diluted with water and extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was gel column chromatography eluting as yellow solid. Step 6: tert-Butyl 4-(4-A mixture of tert- piperazine-1-carboxylate (260 mg, 0.47 mmol, 1.00 and 1,4-dioxane (5.0 mL) was stirred at rt for 20 h underconcentrated to give the title compound as yellow oil. Step 7: 3-(4-(Piperazin-1-yl)phenyl)piperidine-2,6-dione 2,2,2-trifluoroacetate TFA (0.5 mL) was added to a stirred solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperazine-1-carboxylate (160 eq.) in DCM (2.0 mL) and the mixture was stirred at rt for 2 h under N2. The to give the title compound as yellow oil.Synthesis of 1-(6-(piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 2,2,2-trifluoroacetate - 75 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Step 1: 6-Bromo-1-(2,2,2-NaH (2.10 g, 52.83 mmol, 2.00 eq.) was added to a stirred solution of 6-bromo-1H-indazol-3- amine (5.60 g, 26.42 mmol, 1.00 eq.) in DMF (20.0 mL) at 0oC and the mixture was stirred at 0oC for 1h.2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.7 g, 29.06 mmol, 1.10 eq.) was added and the mixture was stirred at rt for 3 h under N2. The mixture was poured into cold water and filtered. The solid was washed with water and dried to the title as yellow solid. Step 2: 1-(6-(Piperidin-4-yl)- dihydropyrimidine-2,4(1H,3H)- dione 2,2,2-trifluoroacetateThe title compound was analogously as described in Reference 5, Steps 2-7. Synthesis of 1-(1-methyl-6-(piperazin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneStep 1: Benzyl 4-(4-cyano-3-fluorophenyl)piperazine-1-carboxylate A mixture of 2,4- eq.), benzyl piperazine-1- carboxylate (20 g, 90.80 g, 181.6 mmol, 2.00 eq.) inACN (200.0 mL) was was filtered, and the filtrate was concentrated. 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: Benzyl 4-(3-amino-1H-indazol-6-yl)piperazine-1-carboxylate A mixture of benzyl 4-(4-cyano-3-fluorophenyl)piperazine-1-carboxylate (11.00 g, 32.40 mmol, 1.00 eq.) and N2H4 / H2O (10.14g, 161.99 mmol, 5.00 eq) in BuOH (100.0 mL) was stirred at - 76 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 100 ℃ under N2for 16 h. The mixture was concentrated and purified by flash chromatography to give the title compound as yellow solid. Step 3: Benzyl 4-(3-To a solution of benzyl 4-(3-amino-1H-indazol-6-yl)piperazine-1-carboxylate (4.00 g, 11.40 mmol, 1.00 eq.) in dry DMF (50.0 mL) at 0 ℃ was added NaH (0.91 g, 22.80 mmol, 2.00 eq.) under N2, and the mixture was stirred at rt for 30 min. The mixture was cooled to 0 ℃, CH3I (1.78 g, 12.54 mmol, 1.10 eq.) in dry DMF (10.0 mL) was added dropwise, and the mixture was stirred for 3 h. The mixture was quenched with water, extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH = (50:1) to give the title compound as yellow solid. Step 4: Benzyl 4-(3-(2,4- 1H-indazol-6-yl)-piperazine- 1-carboxylateThe title described in Reference 5, Steps 2-4. Step 5: 1-(1-Methyl-6-2,4(1H,3H)-dione azine-1- carboxy 82 mg, 10.81 m xture was filtereddescribed in Reference 11. Ref # Structure Synthesis Iodomethane was replaced by 2,2,2-trifluoroethyl trifluoromethane-sulfonate in Step 3 Ref.12 - 77 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Reference 13 Synthesis of 1-(6-(3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4Step 1: 1-(1-Methyl-6- indazol-3- yl)dihydropyrimidine-2,4A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (626 mg, 2.00 mmol, 1.00 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (762 mg, 3.00 mmol, 1.50 eq.), KOAc (589 mg, 6.00 mmol, 3.00 eq.) and Pd(dppf)Cl2 (146 mg, 0.20 mmol, 0.10 eq.) in 1,4-dioxane (10 mL) was stirred at 85oC under N2overnight. The mixture was filtered and the filtrated was on silica gel (DCM:MeOH = 100 : 1) Step 2: tert-Butyl 4-(3- 1H-indazol-6-yl)-3,3- difluoro-3,6-A mixture of 1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (800 mg, 2.00 mmol, 1.00 eq.), tert-butyl 3,3-difluoro-4- (( - 1 - 3.00 mmol, 1.50 eq.), Na2CO3eq.) and H2O (2.5 mL) in 1,4- was filtered and the filtrated wason silica gel (DCM:MeOH = 120 : 1) to give the title compound as a yellow solid. Step 3: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3- difluoropiperidine-1-carboxylate A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (940 mg, 2.00 mmol, 1.00 eq.), 10% Pd / C (900mg) and Pd(OH)2 (900mg) in MeOH (10.0 mL) was stirred at 50oC under H2 (50 PSI) overnight. - 78 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 1 : 1) to give the title as yellow solid. Step 4: 1-(6-(3,3-Difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 2,2,2-2,2,2-A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)-3,3-difluoropiperidine-1-carboxylate (102 mg, 0.22 mmol, 1.00 eq.) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at rt for 2h. The mixture was concentrated to give the title compound as brown oil. Synthesis of tert-butyl 6-(3-(2,4- (2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6- diazaspiro[3.3]trifluoroacetate Step 1: tert-Butyl 6-indazol-6-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg, 0.93 mmol, 1.00 eq.), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (570 mg, 2.32 mmol, 2.50 eq.), t-BuOK(627 mg, 5.6 mmol, 6.00 eq.), t-BuBrettphos Pd G3 (81mg, 0.093 mmol, 0.10 eq.) and t-BuXphos (76mg, 0.186 mmol, 0.20 eq.) in 1,4-dioxane (6 mL) was stirred at 100oC under N2for 3 h. washed with water and brine, dried the residue was purified by column the title compoundas yellow solid. Step 2: 1-(1-Methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate A mixture of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (90 mg, 0.204 mmol, 1.00 eq.) in TFA / DCM (0.5 mL / 2 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as brown oil. - 79 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Reference 15 Synthesis of 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl) piperidin-4- yl)-1-methyl-1H- -dione hydrochlorideStep 1: tert-Butyl (1-((3- 4-yl)carbamateA mixture of tert-butyl N-[1-[3-(bromomethyl)phenyl]sulfonyl-4-piperidyl]carbamate (1.0 g, 2.31 mmol), 2-methylpropanal (416 mg, 5.77 mmol), tetrabutylammonium iodide (85.24 mg, 0.23 mmol) and sodium hydroxide (323.06 mg, 8.08 mmol) in 1,4-dioxane (10 mL) was heated to 70 °C and stirred for 3 h under argon atmosphere. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by with 5% Step 2: tert-1H-indazol-6- yl)piperidin-1-yl)-2,2-dimethylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate Titanium tetraisopropanolate (1.24 g, 4.37 mmol) was added to a mixture of tert-butyl (1-((3- (2,2-dimethyl-3-oxopropyl)phenyl)sulfonyl) piperidin-4-yl)carbamate (530 mg, 1.25 mmol) and 1-(1- methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (408.7 mg, 1.25 mmol) in anhydrous N-methyl-2-pyrrolidone (5.3 mL), and the mixture was heated to 90 °C for 3 h under argon atmosphere. The mixture was cooled to rt and sodium cyanoborohydride (274.56 mg, mixture was diluted with washed with water, brine,and the residue was purified by silica gel chromatography, eluted with methanol / dichloromethane (0~5%) to afford the title compound as a white solid. Step 3: 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl) piperidin-4-yl)- 1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride To a stirred solution of tert-butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)-2,2-dimethylpropyl)phenyl) sulfonyl)piperidin-4- - 80 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT yl)carbamate (280 mg, 0.38 mmol) in dichloromethane (3 mL) was added 4 M hydrogen chloride in dioxane (1.5 mL) at 0 °C and stirred for 1 h. The mixture was concentrated under reduced pressure to afford the title compound as a white solid. Reference 16 Synthesis of 1-(6-(1-(2-(3-((4- butyl)piperidin-4-yl)-1-methyl- 1H-indazol-3- hydrochlorideStep 1: Ethyl (E)-2-(3-((4-( benzylidene)- butanoateEthyl 2-(diethoxyphosphoryl)butanoate (412 mg, 1.63 mmol, 1.20 eq.) was added to a stirred solution of NaH (60 % in mineral oil, 82 mg, 2.04 mmol, 1.50 eq.) in THF (10.0 mL) at 0oC and this mixture was stirred at 0oC for 30 min. tert-Butyl (1-((3-formylphenyl)-sulfonyl)piperidin-4- yl)carbamate (500 mg, 1.36 mmol, 1.00 eq.) in THF (10.0 mL) was added. The mixture was stirred at 0oC for 30 min, and then slowly warmed to rt and stirred for 12 h. The mixture was quenched with H2O at 0oC, and washed with brine, and dried over anhydrous under reduced pressure, and the residue waswith DCM:MeOH (0~5 %), to afford the title compound as a white solid. Step 2: Ethyl 2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzyl)butanoate A mixture of 1-yl)- sulfonyl)benzylidene) (200 mg) in MeOH (10.0mL) was stirred at rt was the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (0~5 %) to afford the title compound as a pale yellow oil. Step 3: tert-Butyl (1-((3-(2-(hydroxymethyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate LiAlH4(2.5 M in THF, 1.15 mL, 2.88 mmol, 3.00 eq.) was added to a stirred solution of ethyl 2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzyl)-butanoate (450 mg, 0.96 mmol, - 81 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 1.00 eq.) in THF (20.0 mL) at -10oC, and the mixture was stirred for 3 h. The mixture was diluted with DCM, quenched with H2O, and the resulting mixture was stirred at rt for 30 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with DCM:MeOH (0~5 %), to afford the title Step 4: tert-Butyl (1-((3-To a stirred solution of tert-butyl (1-((3-(2-(hydroxymethyl)butyl)phenyl)sulfonyl)- piperidin-4-yl)carbamate (150 mg, 0.35 mmol, 1.00 eq.) in DCM (7.0 mL) was added Dess- Martin periodinane (223 mg, 0.53 mmol, 1.50 eq.) at 0oC and the mixture was stirred under N2 for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by %), to afford the title Step 5: tert-Butyl 1H-indazol-6- yl)piperidin-1-yl)NaBH(OAc)3 (180 mg, 0.85 mmol, 2.5 eq.) in DMA (2.0 mL) was added to a mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (127 mg, 0.35 mmol, 1.00 eq.), TEA (106 mg, 1.05 mmol, 3.00 eq.) and tert- butyl (1-((3-(2-formylbutyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (149 mg, 0.35 mmol, 1.00 eq.) in DMA (6.0 mL) at 0oC, and the mixture was stirred at rt for 12h. The mixture was diluted with with brine, and under reducedgel, eluting with DCM:MeOH (0~5 %), to afford the title compound as a pale yellow solid. Step 6: 1-(6-(1-(2-(3-((4-Aminopiperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H- indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride HCl in EtOAc (2 M, 5.0 mL) was added to tert-butyl (1-((3-(2-((4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)- butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (170 mg, 0.23 mmol, 1.00 eq.) at rt and it was allowed to stir for 3h. The mixture was concentrated under reduced pressure to afford the title compound as a pale yellow solid. - 82 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Reference 17 Synthesis of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)- hydrochloride StepA mixture of 4-amino-2-bromobenzonitrile (5.0 g, 25.38 mmol, 1.00 eq.) in conc. HCl / H2O (60.0 mL / 225.0 mL) was warmed to 90oC until fully dissolved. The mixture was cooled to 0~5oC. A solution of NaNO2 (1.9 g, 27.54 mmol, 1.08 eq.) in H2O (5 mL) was added dropwise to above mixture then followed by addition of CuCl (0.2 g, 2.02 mmol, 0.08 eq.) in SOCl2 / H2O (8.0 mL / 50.0 mL) dropwise at 0~5oC. The resulting mixture was stirred at 0~5oC for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, and the organic layer was filtrate was concentrated under reduced pressure and chromatography, eluting with PE:EtOAc = 4: 1 to Step 2: tert-Butyl (1-((3-carbamate 3-Bromo-4-cyanobenzenesulfonyl chloride (500 mg, 1.79 mmol, 1.00 eq.) in DCM (5.0 mL) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (359.2 mg, 1.79 mmol, 1.00 eq.) and TEA (542.4 mg, 5.37 at 0 ℃. The mixture was stirred at rt for 2h. The DCM. The combined organic layer was washed filtration, the filtrate was concentrated and thethe title compound as brown solid. Step 3: tert-Butyl (1-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)-carbamate To a stirred solution of tert-butyl (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)- carbamate (400 mg, 0.90 mmol, 1.00 eq.) in DMF (8.0 mL) was added 2-(di-tert-butyl-phosphaneyl)- 1-phenyl-1H-indole (20 mg, 0.06 mmol, 0.06 eq.), N-cyclohexyl-N-methylcyclohexanamine (194.4 mg, 1.17 mmol, 1.1 eq.), 2-methylprop-2-en-1-ol (130 mg, 1.8 mmol, 2.00 eq.) and Pd2(dba)3 (16.8 mg, 0.02 mmol, 0.02 eq.). The mixture was purged with N2and stirred at 100oC for 5h. The mixture - 83 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT was poured into water, extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by flash chromatography to give the title compound as white solid. Step 4: 4-((4-Aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-The title compound was synthesized by proceeding analogously as described in Reference 16, Steps 5-6. Synthesis of (S)-1-(6-(1-(2-(3- propyl)piperidin-4-yl)-1- methyl-1H-indazol- -dione hydrochlorideStep 1: tert-Butyl(1-((3- sulfonyl)piperidin-4-yl) carbamateTo a stirred solution of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5 g, 11.92 mmol, 1 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.03 g, 11.92 mmol, 1 eq.) in 1,4- mmol, 0.1 eq.) and AcOK (3.51 g, 35.77 mmol, 3 mixture was stirred for 2 h at 80oC. The mixtureThe combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound as a yellow solid. Step 2: tert-Butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tert-butyl(1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- phenyl)sulfonyl)piperidin-4-yl) carbamate (9 g, 19.3 mmol, 1 eq.) in ACN (90 mL) was added H2O2(30%, 45 mL) at rt. The resulting mixture was stirred for 10 min at room temperature. The mixture was quenched with sat. Na2SO3 solution at 0°C and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After - 84 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-50%) to afford the title compound as a white solid. Step 3: Methyl (S)-2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)- propanoateTo a stirred mixture of tert-butyl (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate (2 g, 5.6 mmol, 1.0 eq.), PPh3(2.2 g, 8.4 mmol, 1.5 eq.) and methyl (2S)-2-hydroxypropanoate (600 mg, 5.78 mmol, 1.03 eq.) in THF (20 mL) was added DIAD (1.36 g, 6.73 mmol, 1.20 eq.) dropwise at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h at room temperature. The mixture was quenched with water and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with After filtration, the filtrate was concentrated under gel column chromatography, eluted as a white solid. Step 4: tert-Butyl (S)-(1-(piperidin-4-yl)-carbamate To a stirred solution of methyl (S)-2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1- yl)sulfonyl)phenoxy)propanoate (1.6 g, 3.62 mmol, 1.0 eq.) in THF (16 mL) was added 2 M LiAlH4in THF (3.6 mL, 7.2 2 for 2 h at 0°C. The mixture was was diluted with EtOAc, and the title compound as a yellow solid.Step 5: (S)-1-(6-(1-(2-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl- 1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride The title compound was synthesized by proceeding analogously as described in Reference 16, Steps 4-6. - 85 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Reference 19 Synthesis of 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)-piperidin- 4-yl)-1-methyl-1H- -dione hydrochlorideStep 1: tert-Butyl (1-((3-(2- 4-yl)carbamateA solution of tert-butyl (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate(5.1 g, 12.2 mmol, 1.0 eq.), Pd(AcO)2 (0.27 g, 1.2 mmol, 0.1 eq.), 2-methylprop-2-en-1-ol (2.6 g, 36.5 mmol, 3.0 eq.), NaHCO3 (2 g, 24.3 mmol, 2.0 eq.) and tetrabutylammonium bromide (19.6 g, 60.8 mmol, 5.0 eq.) in DMF (51 mL) was stirred for 3 h at 100°C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over anhydrous Na2SO4. After the filtrate was concentrated under reduced The residue was purified by silica gel to afford the title compound as a light Step 2: tert-Butyl (1-(methyl-1H-indazol-6- yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione hydrochloride (4.06 g, 11.2 mmol, 1.0 eq.) in DMAc (46 mL) was added TEA (5.7 g, 56 mmol, 5.0 eq.) at 0 °C. The resulting mixture was stirred for 5 min at rt. To the above mixture was added tert-butyl (1-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (4.6 g, 11.2 mmol, 1.0 eq.). The resulting mixture was stirred for 1 h at rt. Then NaBH(AcO)3 (5.3 g, 25.2 mmol, 2.25 eq.) was added in portions at 0 °C and stirred for 2 h at rt. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-100%) to afford the title compound as a white solid. - 86 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Step 3: 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1- methyl-1H-To a stirred solution of tert-butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)-carbamate (3.7 g, 5.1 mmol, 1.0 eq.) in DCM (37 mL) was added 4M HCl in 1,4-dioxane (18 mL) dropwise at 0 °C. The resulting mixture was stirred for 1 h at rt. The mixture was concentrated under reduced pressure t iv th titl m nd li ht ll w lid described in Refer Ref ndazol- )-dione Ref. methyl- -1H- ,6-dionen ep 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione Ref.19b hydrochloride was replaced by 3-(1-oxo-5- (piperidin-4-yl)isoindolin-2-yl)piperidine- in Step 2Synthesis of 1-(6-(1-(3-(3-((4- -2-hydroxy-2-methylpropyl)- piperidin-4-yl)-1- -dione hydrochlorideStep 1: tert-Butyl (1-((3-(2-methylallyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture of tert-butyl (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- sulfonyl)piperidin-4-yl)carbamate (3.3 g, 7.1 mmol, 1.0 eq.), 3-bromo-2-methylprop-1-ene (1.91 g, 14.2 mmol, 2.0 eq.), Pd(PPh3)2Cl2 (497 mg, 0.7 mmol, 0.1 eq.) and Na2CO3 (2.25 g, 21.2 mmol, 3.0 eq.) in THF (30 mL) and H2O (3 mL) was stirred for 4 h at 65 °C under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-30%) to afford the title compound as a yellow solid. - 87 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Step 2: tert-Butyl (1-((3-((2- piperidin-4-yl)carbamateTo a stirred solution of tert-butyl (1-((3-(2-methylallyl)phenyl)sulfonyl)piperidin-4- yl)carbamate (810 mg, 2.1 mmol, 1.0 eq.) in DCM (10 mL) was added m-CPBA (834 mg, 4.1 mmol, 2.0 eq., 85%) in portions at 0 °C. The resulting mixture was stirred for 4 h at rt. The reaction was quenched with aq NaHCO3 at 0 °C, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0~100%) to afford the title compound as a light yellow solid. Step 3: tert-Butyl (1- 1H-indazol-6- yl)piperidin-1-yl)-2-To a stirred solution of tert-butyl (1-((3-((2-methyloxiran-2-yl)methyl)phenyl)sulfonyl)- piperidin-4-yl)carbamate (650 mg, 1.6 mmol, 1.0 eq.) and 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (634 mg, 1.76 mmol, 1.1 eq.) in EtOH (6 mL) was added TEA (240 mg, 2.4 mmol, 1.5 eq.) and the mixture was stirred for 24 h at 80 °C. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and filtration, the filtrate was with EtOAc / PEStep 4: 1-(6-(1-(3-(3-((4-Aminopiperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)- piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride To a stirred solution of tert-butyl (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4- yl)carbamate (700 mg, 1 mmol, 1.0 eq.) in DCM (3 mL) was added 4 M HCl in 1,4-dioxane (3 mL) dropwise, and the mixture was stirred for 2 h. The resulting mixture was concentrated under vacuum to afford the title compound as a light yellow solid. - 88 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Reference 21 Synthesis of 1-(6-(1-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)- 1-methyl-1H-indazol-3- -dione hydrochlorideStep 1: tert-Butyl (1-((4-To a stirred solution of 4-bromobenzenesulfonyl chloride (10.0 g, 39.14 mmol, 1.00 eq.) in DCM (20.0 mL) was added tert-butyl piperidin-4-ylcarbamate (9.41 g, 46.96 mmol, 1.20 eq.) and TEA (7.92 g, 78.27 mmol, 2.00 eq.) at 0oC, and the mixture was stirred at rt for 2h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, and the organic layer the filtrate was concentrated under reduced gel column chromatography, eluting as a white solid. Step 2: tert-Butyl (1-((4-(2-4-yl)carbamate A mixture of tert-butyl (1-((4-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.20 mmol, 1.00 eq.), NaHCO3(201 mg, 2.39 mmol, 2.00 eq.), tetrabutylammonium bromide (77.1 mg, 0.239 mmol, 0.2 eq.), 2-methylprop-2-en-1-ol (172.4 mg, 2.39 mmol, 2.00 eq.), and Pd(OAc)2 (6 mg, 0.0239 mmol, 0.02 N2. The mixture was poured into water, with water and brine, dried over residue was purified by flashStep 3: tert-Butyl (1-((4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a stirred solution of tert-butyl (1-((4-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4- yl)carbamate (150 mg, 0.366 mmol, 1.00 eq.), 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3- - 89 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (133 mg, 0.366 mmol, 1.00 eq.) and TEA (110.9 mg, 1.1 mmol, 3.00 eq.) in DMA (2.0 ml) was added NaBH(OAc)3 (187.7 mg, 0.886 mmol, 2.5 eq.) at 0oC and the mixture was stirred at 0oC for 2 h. The mixture was poured into water and extracted with EtOAc. The combined organic layer was washed with water and brine, and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by flash chromatography to give the title compound as white solid. Step 4: 1-(6-(1-(3- piperidin-4-yl)-1- methyl-1H-HCl in EtOAc (2 M, 2.0 mL) was added to tert-butyl (1-((4-(3-(4-(3-(2,4-dioxotetrahydro- pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)- piperidin-4-yl)carbamate (110 mg, 0.15 mmol, 1.00 eq.) and the mixture was stirred at rt for 2h. The mixture was concentrated under reduced the title compound as a brown oil.Synthesis of 2- 7(8H)-oneStep 1: 8-Isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one To a stirred mixture of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 2.59 mmol, 1.00 eq.) in DMF (5.0 mL) was added 2-iodopropane (660 mg, 3.88 mmol, 1.50 eq.) and resulting mixture was stirred at 70oC for 16 h. The EtOAc. The combined organic layers was washedover anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc:PE (0 to 100%), to afford the title compound as a white solid. Step 2: 8-Isopropyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one To a stirred solution of 8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.85 mmol, 1.00 eq.) in DCM (3.0 mL) was added m-CPBA (276 mg, 1.36 mmol, 1.60 eq.) at rt, and the resulting mixture was stirred for 3 h. The mixture was diluted with water and extracted with - 90 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT DCM. The combined organic layers was washed with NH4Cl (aq.), brine, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as white solid. Reference 23 Synthesis of 6-chloro-8- pyrido[2,3-d]pyrimidin-7(8H)-oneStep 1: 6-Chloro-2-To a solution of NaH (213 mg, 5.33 mmol, 1.80 eq.) in THF (10.0 mL) was added ethyl 2- chloro-2-(diethoxyphosphoryl)acetate (1.15 g, 4.44 mmol, 1.50 eq.) dropwise at 0oC. After 1h, 4- amino-2-(methylthio)pyrimidine-5-carbaldehyde (500 mg, 2.96 mmol, 1.00 eq.) was added to the mixture dropwise at 0oC. The mixture was stirred at rt for 16 h. The mixture was quenched with sat. NH4Cl and extracted with over Na2SO4. After filtration, the filtrate was was purified by silica gel column chromatographyas off white solid. Step 2: 6-Chloro-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one To a solution of 6-chloro-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.44 mmol, 1.00 eq.) in DMF (5.0 mL) was added Cs2CO3(287 mg, 0.88 mmol, 2.00 eq.) and 2-iodopropane (112 mg, 0.66 mmol, 1.50 eq.), under N2for 12 h. The mixture was poured into organic layers were dried over Na2SO4. Afterpressure. The residue was concentrated and purified by silica gel column chromatography (PE:EtOAc = 3: 1) to give the title compound as yellow solid. Step 3: 6-Chloro-8-isopropyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one To a solution of 6-chloro-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.37 mmol, 1.00 eq.) in DCM (5.0 mL) was added m-CPBA (151 mg, 0.74 mmol, 2.00 eq.). The mixture was stirred at rt for 16 h. The mixture was concentrated and purified by prep-TLC (PE:EtOAc = 3: 1) to give the title compound as off-white solid. The following reference compound was synthesized by proceeding analogously as described in reference 23. - 91 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Reference 24 Synthesis of 8-cyclopropyl-2- [2,3-d]pyrimidin-7(8H)-oneStep 1: Ethyl 4-To a stirred mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2.0 g, 8.60 mmol, 1.00 eq.) in DMSO (20.0 mL) was added cyclopropanamine (589 mg, 10.32 mmol, 1.20 eq.), DIEA (6.55 g, 43.00 mmol, 5.00 eq.) and CsF (5.56 g, 43.0 mmol, 5.00 eq.), and the resulting mixture was stirred at 65oC for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na2SO4. After reduced pressure. The residue was purified by silica gel (0 to 100%), to afford the title compound as a whiteStep 2: (4- - To a stirred solution of ethyl 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (2.45 g, 9.67 mmol, 1.00 eq.) in THF (20.0 mL) was added 2.5M LiAlH4 in THF (5.80 mL, 14.51 mmol, 1.50 eq.) at 0 °C and rt. The mixture was diluted with water and extracted washed with water, brine, and the organic layer was dried filtrate was concentratedunder reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc=1:1), to afford the title compound as a yellow solid. Step 3: 4-(Cyclopropylamino)-2-(methylthio)pyrimidine-5-carbaldehyde To a stirred solution of (4-(cyclopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol (2.0 g, 9.48 mmol, 1.00 eq.) in CHCl3 (20.0 mL) was added MnO2 (16.48 g, 189.60 mmol, 20.00 eq.) at rt and the mixture was stirred for 16 h at 70 °C. The mixture was filtered, and the filtrate was diluted with water and extracted with DCM. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc=3:1), to afford the title compound as a white solid. - 92 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Step 4: 8-Cyclopropyl-2-To a stirred mixture of 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (1.00 g, 4.78 mmol, 1.00 eq.) in THF(10.0 mL) was added ethyl acetate (1.26 g, 14.34 mmol, 3.00 eq.) at - 75℃ and stirred for 15 mins. Then 1M LiHMDS in THF (9.56 mL, 9.56 mmol, 2.00 eq.) was added to the mixture at -75℃ and the mixture was allowed to warm to rt and stirred for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced gel column chromatography, eluting with EtOAc:PE (0 solid. Step 5: 8-Cyclopropyl-2--one To a stirred solution of 8-cyclopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.43 mmol, 1.00 eq.) in DCM (3.0 mL) was added m-CPBA (139 mg, 0.69 mmol, 1.60 eq.) at 25 °C and the resulting mixture was stirred for 3 h. The mixture was diluted with water and extracted with DCM. The combined organic NH4Cl (aq.), brine, and the organic layer was dried over anhydrous Na2SO4. was concentrated under reduced pressure to give the title compound asReference 25 Synthesis of 8- [2,3-d]pyrimidin-7(8H)-oneStep 1: 8-Isopropyl-2-(methylsulfonyl)-6-(difluoromethyl)pyrido[2,3-d]pyrimidin-7(8H)-one To a stirred solution of 8-isopropyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (267 mg, 1.00 mmol, 1.00 eq.) in DMSO (4.0 mL) was added TFA (114 mg, 1.00 mmol, 1.00 eq.), FeCl2 (63 mg, 0.50 mmol, 0.50 eq.), zinc difluoromethanesulfinate (444 mg, 1.50 mmol, 1.50 eq.) and TBHP (70% in H2O, 129 mg, 1.00 mmol, 1.00 eq.) at 0 °C and the mixture was stirred for 16 h at rt. The mixture was diluted with water and extracted with DCM. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE:EtOAc = 2:1), to afford the title compound as a yellow solid. - 93 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Example 1 Synthesis of 1-(6-(1-(3-(3-((4-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-Step 1: 1-(6-(1- 7-oxo- 2- yl)amino) 1H-indazol-3- yl)To a stirred solution of 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2- methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (86 mg, 0.14 mmol, 1.00 eq.) in DMSO (3.0 mL) was added 8-isopropyl-2- (methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (55 mg, 0.21 mmol, 1.50 eq.) and DIEA (36 mg, 0.28 mmol, 2.00 eq.), and the resulting mixture was stirred at 65 °C for 16 h. The mixture was diluted with water and extracted with DCM. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (0 to 10%), to afford the title as a solid. MS (ES, m / z): [M+1]+= 809.3. Synthesis of 4-((4-( [2,3-d]pyrimidin-2- yl)amino)piperidin-1-yl)- 1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrileStep 1: 4-((4-((6-Chloro-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin- 1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)-2-methylpropyl)benzonitrile - 94 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT To a stirred solution of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2- methylpropyl)benzonitrile hydrochloride (120 mg, 0.19 mmol, 1.00 eq.) in DMSO (3.0 mL) was added 6-chloro-8-isopropyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (56 mg, 0.19 mmol, 1.00 eq.) and DIEA (72 mg, 0.57 mmol, 3.00 eq.), and the resulting mixture was stirred for 12 h at 65oC. The mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford n Example 2. Ex 3 23 in 4 23 in5 Ref.22 replaced Ref.23 in Step 1. Biological Examples Biological Example 1 Phospho-Rb Measurement in Cells Phosphorylation of RB protein at S807 / 811 were measured using HTRF phospho-RB cellular kits (Cat# 64RBS807PEG) from Cisbio / Revvity. On Day 1, adherent cells, such as OVCAR3 (CDK2-dependent cell line) and T47D (CDK4- dependent) were seeded into 96-well tissue-culture treated plates at 20,000 cells / well in 200 µL media and suspension cells THP1 were seeded into sterile 384-well plates at 20,000 cells / well in 50 µL media. Cells were then incubated overnight at 37 °C in CO2 atmosphere. On Day 2, the cells were treated with test compounds at concentrations from 0.3 to 3,000 nM using Tecan D300e digital dispenser (HP Inc., CA, USA). Twenty-four hours after compound treatment, cell culture media of the adherent cells is removed by flicking the plate and tapping the plate against clean paper towel.30 µL 1X lysis buffer was supplemented from the kit was added to each well of adherent cells. For suspension cells, 16.7 µL 4X lysis buffer was directly added to 50 µL of cells in 384-well plates. The plates were then incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 µL cell lysate from cell culture plate was transferred to 384-well small volume white detection plate.2 µL premixed detection solution was added and the plate was covered with sealer. To prepare the detection solution, d2 conjugated-phospho-RB antibody and Eu-cryptate conjugated phosphor-RB antibody were diluted into detection buffer following manufacturer’s - 95 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT instruction. Detection plates were incubated for 4 h at room temperature and read on ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM / 620 nM) was plotted against the compound concentration and normalized to DMSO controls. Half maximal inhibition concentration (IC50) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA). In the table below, AA indicates a IC50 of less than to 1 nM; A indicates a IC50 of greater than or equal to 1 nM but less than or equal to 100 nM; B indicates a IC50of greater than 100 nM but less than or equal to 500 an or equal to 2.5 µM; D indicates a IC50 of (fr HP1 t )7 B AA A 8 A AA B 9 A AA A 10 A A A 11 A AA A Biological Example 2 High-throughput Measurement of Cellular Endogenous CDK1 / 2 / 4 / 6 Effects of compounds on cellular CDK levels were monitored by a high-throughput HTRF assay. To determine half maximal degradation concentration (DC50) and maximum degradation level (Dmax) values of compounds, cellular CDK level was measured in 96-well format using HTRF total CDK cellular kit (CDK1, Cat# 64CDK1TPEG; CDK2 Cat# 64CDK2TPEG; CDK4 Cat# 64CDK4TPEG; CDK6, Cat# 64CDK6TPEG) from Cisbio / Revvity. On Day 1, adherent cells were seeded into 96-well tissue-culture treated plates at 20,000 cells / well in 200 µL media and incubated overnight at 37°C in CO2atmosphere. On Day 2 cells were treated with compounds at concentration ranging from 0.1 to 1,000 nM using Tecan D300e digital dispenser (HP Inc., CA, USA).6 or 24 hours after compound treatment, cell culture media was removed by flicking the plate and tapping the plate against clean paper towel. Immediately 30 µL 1X lysis buffer was supplemented from the kit and added to each well and the plate is incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 µL cell lysate from 96-well cell culture plate was transferred to 384-well small volume white detection plate.2 µL premixed detection solution was added and the plate is covered with sealer. To prepare the detection solution, d2 conjugated-CDK antibody and Eu-cryptate conjugated CDK antibody were diluted into detection buffer following manufacturer’s instruction. Detection plates were incubated overnight at room temperature and read on ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM / 620 nM) was normalized to DMSO controls (100% CDK) and lysis buffer controls (0% CDK) to calculate the relative CDK level (%CDK relative to DMSO), which was - 96 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT then plotted against the compound concentration. Half maximal degradation concentration (DC50) and maximal degradation (Dmax) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA). Formulation Examples The following are representative pharmaceutical formulations containing a compound of the present disclosure. Tablet Formulation The following ingredients are mixed intimately and pressed into single scored tablets. Ingredient Quantity per tablet (mg) compound Formula (I) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. Ingredient Quantity per capsule (mg) Compound Formula (I) 200 lactose spray dried 148 magnesium stearate 2 Injectable Formulation Compound of Formula (I) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg / mL Inhalation Composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula (I) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration. Topical Gel Composition To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I) is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration. - 97 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT Ophthalmic Solution Composition To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound of Formula (I) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration. Nasal spray solution To prepare a pharmaceutical nasal spray solution, 10 g of a compound of Formula (I) is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 µL of spray for each application. - 98 - 1103234938\3\AMERICAS

Claims

Attorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT What is Claimed:

1. A compound(I) wherein: R1is branched alkyl, branched haloalkyl, branched cyanoalkyl, branched hydroxylalkyl, branched alkoxyalkyl, branched haloalkoxyalkyl, cycloalkyl, or bridged cycloalkyl; wherein cycloalkyl and bridged cycloalkyl are substituted with 0, 1, 2, or 3 groups independently selected from halo, cyano, hydroxy, alkoxy, and haloalkoxy; R2is hydrogen, alkyl, halo, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl; R2aare independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the aforementioned rings is substituted independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, Degron is ligand selected from: (a) a(i); or (b) a group of formula (ii): (ii); 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) or (b): ; where: Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; - 99 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 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; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein one to three ring atoms of each heteroarylene ring are heteroatoms independently selected from nitrogen, oxygen, or sulfur 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 Z is -O-, -NR3- (where R3is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene and where each ring is substituted with Rdand Reindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; alk is C3to C6alkenylene substituted with Rfselected from hydrogen, fluoro, and cyano; C3to C6 alkylene or C3 to C6 heteroalkylene wherein the C3 to C6 alkylene and C3 to C6 heteroalkylene are substituted with Rg, Rh, and Riwhere Rgis hydrogen, deuterium or halo, Rhis hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halo, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or 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); or when Rgand Rhare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3 to C6 alkylene or C3 to C6 heteroalkylene, Rgand Rhtogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by Rgand Rhare substituted with R9and R10independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano), and Riis hydrogen or halo; and the linear portion of C3to C6alkenylene, C3to C6alkylene, and C3to C6heteroalkylene, attaching Ar and Z, contains at least three atoms; Ar is phenylene, monocyclic heteroarylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each of the aforementioned ring is substituted with Rj, Rk, and Rmindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; or a pharmaceutically acceptable salt thereof. - 100 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is branched alkyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is R1is cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halo, cyano, hydroxy, alkoxy, and haloalkoxy.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is isopropyl, sec-butyl, tert-butyl, 2,2,2-trifluoroethyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, or unsubstituted cyclopentyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen, halo, haloalkyl, alkyl, hydroxyalkyl, or alkoxyalkyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2ais hydrogen.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Hy is heterocyclylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

8. The compound of any one of to 7, or a pharmaceutically acceptable saltthereof, wherein the heterocyclylene of Hy is: where the N atom of the to -SO2-.

9. The compound of any or a pharmaceutically acceptable saltthereof, wherein the Degron is an E3 ubiquitin ligase ligand of formula (i):

10. acceptable salt thereof, wherein (i) is:. - 101 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the Degron is an E3 ubiquitin (ii):(ii). salt ,, , , , , where ring B is cyclylaminylene.

13. The compound of any oneacceptable salt thereof, wherein Ar is phenylene, monocyclic heteroarylene, bridged heterocyclylene, or heterocyclylene, where each ring of Ar is substituted with Rj, Rk, and Rmwhere Rmis hydrogen.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Ar is phenylene of formula or substituted with Rj, Rk, and Rmwhere Rjand Rkare independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy and Rmis hydrogen.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Z is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring of Z is substituted with Rdand Re. - 102 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z are selected. selected 17. salt thereof,wherein each Rd, Re, and Rkare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and Rjis hydrogen.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein alk is C3 to C6 alkenylene substituted with Rfwhere Rfis hydrogen.

19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein alk is C3to C6alkylene substituted with Rg, Rh, and Riwhere Rg, Rh, and Riare hydrogen.

20. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein alk is C3to C6alkylene substituted with Rg, Rh, and Riwhere Rhis other than hydrogen and Riis hydrogen. - 103 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 alkenylene and C3 to C6 alkylene of alk are linear C3 to C6 alkenylene and linear C3 to C6 alkylene, respectively, where alk is substituted with Rg, Rh, and Ri.

22. The compound of any one of claims 121, or a pharmaceutically acceptable salt thereof, wherein the linear C3to C6alkenylene of alk is -CH=C(Rf)CH2- and the linear alkylene of C3to C6 alkylene of alk is -CH2CH(Rh)CH2-, -CH2CH2CH(Rh)-, -CH2C(Rg)(Rh)CH2-, -CH2CH2C(Rg)(Rh)- where Rhis other than hydrogen and Riis hydrogen.

23. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 alkenylene and C3 to C6 alkylene of alk are branched C4 to C6 salt -CH2C -CH2C CH2-, -CH2C- -, - -, - -, -CH2CH(C2H5)C(Rg)(Rh)-, -CH2CH(C(Rg)(Rh)(Ri))CH(CH3)-, -CH2C(CH3)(C(Rg)(Rh)(Ri))CH(CH3)-, -CH2CH(C(Rg)(Rh)(Ri))CH2-, -CH2CH2CH(C(Rg)(Rh)(Ri))-, -CH2CH2CH(C(Rg)(Rh)(Ri))CH2-, or -CH2CH2CH2CH(C(Rg)(Rh)(Ri))-.

25. The compound of any one of claims 1 to 20, 23, and 24, or a pharmaceutically acceptable salt thereof, wherein Rgand Riof branched C4to C6alkylene of alk are (unless stated otherwise) hydrogen, deuterium, or fluoro and Rhof branched C4to C6alkylene of alk, 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, piperazinyl, or tetrahydrofuranyl, where each ring of Rhis substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano, unless stated otherwise.

26. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein the alk is C3to C6heteroalkylene substituted with Rg, Rh, and Ri.

27. The compound of any one of claims 1 to 17 and 26, or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 heteroalkylene of alk is linear C3 to C6 heteroalkylene.

28. The compound of any one of claims 1 to 17, 26, and 27, or a pharmaceutically acceptable salt thereof, wherein the linear C3 to C6 heteroalkylene of alk is -CH2CH2XaCH2-, -CH2XaCH2CH2-, -CH2CH2CH2Xa-, -XaCH2CH2CH2-, -XyCH2CH2Xa-, -XyCH2CH2XaCH2-, -CH2CH2CH2XaCH2-, -CH2XaCH2-, -XaCH2CH2-, -CH2CH2Xa-, -CH2CONRqCH2-, -CH2SO2NRqCH2-, -CH2NRqCOCH2-, -CH2NRqSO2CH2-, -CH2CH2CH2NRqCO-, -CH2CONRq-, -CH2SO2NRq-, -CH2NRqCO-, -CH2NRqSO2-, -CONRqCH2-, -SO2NRqCH2-, -NRqCOCH2-, or -NRqSO2CH2substituted with Rg, Rh, and Riand Xais -NRq-, -O-, -S-, -SO-, -SO2-, or –CO-. - 104 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT 29. The compound of any one of claims 1 to 17 and 26, or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 heteroalkylene of alk is branched C4 to C6 heteroalkylene.

30. The compound of any one of claims 1 to 17, 26, and 29, or a pharmaceutically acceptable salt thereof, wherein the branched C4to C6heteroalkylene of alk is -CH2XaCH(CH3)CH2-, -CH2XyCH2CH(CH3)Xa-, -CH2CH2CH(CH3)Xa-, -XaCH(CH3)CH2CH2-, -XyCH2CH(CH3)Xa-, -XyCH(CH3)CH2Xa-, -CH2CH2CH2CH(CH3)Xa-, -XaCH(CH2Rh)CH2-, -CH2CH(CH2Rh)Xa-, -XaCH(CH2CH2Rh)CH2-, -CH2CH(CH2CH2Rh)Xa-, -CH2C(CH3)(CH3)Xa-, -XaC(CH3)(CH3)CH2-, -CH(CH3)CH(CH3)Xa-, -CONRzCH2CH(CH3)Xa-, -CH2NRqCOCH(CH3)CH2-, or -NRqCOCH(CH3)CH2- where Xais -NRq-, -O-, -S-, -SO-, -SO2-, or –CO-.

31. The compound of any one of claims 1 to 17, 26, 29, and 30, or a pharmaceutically acceptable salt thereof, wherein the Rgand Riof branched C4to C6heteroalkylene of alk are hydrogen or halo (unless stated otherwise) and Rhof branched C4 to C6 heteroalkylene of alk is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, with salt- 105 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT33. salt thereof,, , , , ,,- 106 - 1103234938\3\AMERICASAttorney Docket No. 119005.00279Client Ref. No. NKT-23-012PCT ,, , and ; where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and Rffis hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

34. A pharmaceutical composition comprising a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. A method of treating cancer in a patient which method comprises administering to the patient in need thereof, a therapeutically effective amount a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34. - 107 - 1103234938\3\AMERICAS

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