Bifunctional compounds containing 2,5-substituted pyrimidine derivatives for degradation of cyclin-dependent kinase 2 via the ubiquitin proteasome pathway

Abstract

The present disclosure provides certain bifunctional compounds that cause degradation of cyclin-dependent kinase 2 (CDK2) via the ubiquitin proteasome pathway and are therefore useful for treating diseases mediated by CDK2. Pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided. The present disclosure provides certain bifunctional compounds containing 2,5-substituted pyrimidine derivatives that cause degradation of cyclin-dependent kinase 2 (CDK2) via the ubiquitin proteasome pathway and are therefore useful for treating diseases mediated by CDK2.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT international patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 424,871, filed November 11, 2022; U.S. Provisional Patent Application No. 63 / 485,255, filed February 15, 2023; U.S. Provisional Patent Application No. 63 / 512,594, filed July 7, 2023; and U.S. Provisional Patent Application No. 63 / 528,596, filed July 24, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] The present disclosure provides certain bifunctional compounds containing 2,5-substituted pyrimidine derivatives that cause degradation of cyclin-dependent kinase 2 (CDK2) via the ubiquitin proteasome pathway and are therefore useful in treating diseases mediated by CDK2. Pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) are cellular kinases important for coordinating signaling events such as DNA replication and protein synthesis to ensure the division and proliferation of eukaryotic cells. To date, at least 21 mammalian CDKs have been identified (Malumbres M. Genome Biol. (2014): 15-122). Of these CDKs, at least the CDK1 / cyclin B, CDK2 / cyclin E, CDK2 / cyclin A, CDK4 / cyclin D, and CDK6 / cyclin D complexes are known to be important regulators of cell cycle progression. Meanwhile, other CDKs are important for regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, DO Annu. Rev. Cell. Dev. Biol. (1997), 13:261-291).

[0004] Due to the role of CDKs in regulating the cell cycle and other important cellular processes, increased activity or transient abnormal activation of CDKs has been shown to result in the development of various types of cancer. Human tumor development is generally associated with alterations in either the CDK protein itself or its regulators (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). For example, amplification of CDK and cyclin regulatory subunits, as well as mutations, gene deletions, or transcriptional silencing of endogenous CDK inhibitory regulators, have been reported (Smalley et al. Cancer Res. (2008) 68:5743-52). Extensive research has established the role of these alterations in promoting tumor initiation and progression. Therefore, over the past two decades there has been considerable interest in developing inhibitors of cyclin-dependent kinases (CDKs) for therapeutic purposes.

[0005] Selective CDK4 / 6 inhibitors have transformed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (MBC). Palbociclib, ribociclib, and abemaciclib, selective reversible inhibitors of CDK4 and CDK6, have been approved for hormone receptor-positive (HR+) metastatic breast cancer in combination with endocrine therapy. Additional clinical trials with these CDK4 / 6 inhibitors, either as monotherapy or in combination with other therapeutic agents, are ongoing in both breast cancer and other cancers. (O'Leary et al. Nature Reviews (2016) 13:417-430) CDK4 / 6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer; however, clinical benefit may be limited over time by the development of primary or acquired resistance.

[0006] An important mechanism of resistance to CDK4 / 6 inhibitors is abnormal activation of CDK2. High expression of cyclin E has been reported to result in an overactive CDK2 / cyclin E complex, which bypasses the requirement for CDK4 / 6 for cell cycle re-entry (Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561). In addition, when CDK4 / 6 is inhibited, a non-canonical CDK2 / cyclin D1 complex formation has been found to promote pRb phosphorylation recovery and drive cell cycle progression (Herrera-Abreu MT et al. Cancer Res. (2006) 15:2301).

[0007] The CDK2 / cyclin E complex plays a key role in regulating the G1 / S transition, histone biosynthesis, and centrosome duplication. Following initial phosphorylation of Rb by CDK4 / 6 / cyclin D, CDK2 / cyclin E further hyperphosphorylate p-RB, releasing E2F and transcribing genes required for S phase entry. During S phase, cyclin E is degraded, and CDK2 forms a complex with cyclin A to promote the phosphorylation of substrates that enable DNA replication and the inactivation of E2F, completing S phase (Asghar et al. Nat. Rev. Drug. Discov. (2015) 14:130-146). In addition to cyclin binding, CDK2 activity is also tightly regulated through interactions with negative regulators such as p21 and p27. In response to mitogenic stimuli, which signal an optimal cell cycle environment, p21 and p27 are phosphorylated and degraded, disrupting CDK2 / cyclin activation.

[0008] Cyclin E, a cyclin regulating CDK2, is frequently overexpressed in cancer, and its overexpression correlates with poor prognosis. For example, amplification or overexpression of cyclin E has been shown to be associated with poor outcomes in breast cancer (Keyomarsi et al., N Engl J Med. (2002) 347:1566-75). Overexpression of cyclin E2 (CCNE2) has been associated with endocrine resistance in breast cancer cells, and CDK2 inhibition has been reported to restore sensitivity to tamoxifen or CDK4 / 6 inhibitors in tamoxifen-resistant and CCNE2-overexpressing cells (Caldon et al., Mol Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Cancer Res. (2016) 76:2301-2313). Cyclin E amplification has also been reported to contribute to trastuzumab resistance in HER2+ breast cancer (Scaltriti et al. Proc Natl Acad Sci. (2011) 108:3761-6). Overexpression of cyclin E has also been reported to play a role in basal-like breast cancer, triple-negative breast cancer (TNBC), and inflammatory breast cancer (Elsawaf Z. et al. Breast Care (2011) 6:273-278; Alexander A. et al. Oncotarget (2017) 8:14897-14911).

[0009] Amplification or overexpression of cyclin E1 (CCNE1) is frequently observed in ovarian, gastric, endometrial, uterine, bladder, esophageal, prostate, lung, and other cancer types (Nakayama et al. Cancer (2010) 116:2621-34; Etemadmoghadam et al. Clin Cancer Res (2013) 19:5960-71; Au-Yeung et al. Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al. Modern Pathology (2017) 30:297-303; Ooi et al. Hum Pathol. (2017) 61:58-67; Noske et al. Oncotarget (2017) 8:14794-14805), and is often correlated with poor clinical outcomes.

[0010] In some cancers, SCF is involved in cyclin E degradation Fbw7 Loss-of-function mutations in FBXW7, a component of ubiquitin E3 ligase, also result in overexpression of cyclin E and activation of CDK2. Alternatively, certain cancer cells express a hyperactive truncated form of cyclin E. Furthermore, amplification and overexpression of cyclin A have also been reported in various cancers, such as hepatocellular carcinoma, colorectal cancer, and breast cancer.

[0011] In contrast to the frequent upregulation of cyclin E, the inhibitory regulators CDK2, p21, and p27 are often aberrantly downregulated in cancer. It has been hypothesized that loss or reduction of these important endogenous inhibitors leads to high and / or aberrant transient activation of CDK2, thereby promoting tumor growth.

[0012] Furthermore, the protein phosphatases CDC25A and CDC25B, which are responsible for the dephosphorylation that activates CDK2, are overexpressed in various tumors. These various mechanisms of CDK2 activation have been validated using mouse cancer models. Furthermore, CDK2 / cyclin E phosphorylates oncogenic Myc to counteract ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal to cancer cells overexpressing myc.

[0013] Recently, pharmacological inhibition or genetic deletion of CDK2 has been shown to preserve hearing function in animal models treated with cisplatin or noise (Teitz T et al. J Exp Med. 2018 Apr 2;215(4):1187-1203). Mechanistically, inhibition of CDK2 kinase activity reduces cisplatin-induced mitochondrial production of reactive oxygen species, thereby enhancing inner ear cell survival. Therefore, in addition to antitumor therapy, CDK2 inhibition may also be used as a promising preventative treatment for noise-, cisplatin-, or antibiotic-induced, or age-related hearing loss, for which there are currently no FDA-approved drugs.

[0014] Targeted protein degradation has emerged as a potential therapeutic approach to eliminate specific proteins by utilizing endogenous protein degradation systems (such as the ubiquitin-proteasome pathway or lysosomes) (Dale et al., 2021; Li and Crews, 2022). Proteins targeted for degradation by the ubiquitin-proteasome system are first "tagged" with ubiquitin through the ubiquitination process and then degraded by the proteasome, a large enzyme complex. The ubiquitination process is a sophisticated post-translational modification cascade in which three enzymes (ubiquitin-activating E1, ubiquitin-binding E2, and ubiquitin-protein E3 ligase enzymes) act sequentially to attach ubiquitin to substrate proteins. Because E3 ligases can directly bind to substrates and determine the specificity of ubiquitination, E3 ubiquitin ligases are the most diverse components of the ubiquitin-proteasome system, with approximately 600 members.

[0015] Protein degradation-targeting chimeric molecules (PROTACs) are bifunctional molecules composed of a target protein recruitment moiety and an E3 ligase ligand connected by a biocompatible linker. PROTACs can bring a protein of interest and an E3 ligase into close proximity, inducing ubiquitination and subsequent degradation of the target protein by the proteasome. Compared to traditional small molecule drugs, which typically bind to disease-related proteins and inhibit their function, PROTACs exhibit several unique and attractive features that make them desirable drug candidates. Because PROTACs are not limited to binding catalytic domains, they have the ability to target previously undruggable proteins. PROTACs have been shown to be more selective than their inhibitor counterparts, potentially reducing off-target toxicity. Furthermore, PROTACs can carry out multiple rounds of target ubiquitination and degradation. This catalytic mechanism allows PROTACs to function with substoichiometric receptor occupancy. E3 ligases used in PROTACs mainly include cereblon (CRBN), von Hippel-Lindau-containing complex (VHL), inhibitor of apoptosis proteins (IAPs), and mouse double minute 2 (MDM2). In contrast to inhibition, ablation of CDK2 protein would result in a loss of CDK2 activity and any protein interaction or scaffolding function of CDK2. Thus, there is a need for bifunctional molecules that can recruit CDK2 to ubiquitin ligases, thereby causing ubiquitination and proteasomal degradation of CDK2. The present disclosure meets this and related needs. [Prior art documents] [Non-patent literature]

[0016] [Non-Patent Document 1] Malumbres M.Genome Biol.(2014):15-122 [Non-patent document 2] Morgan,DOAnnu.Rev.Cell.Dev.Biol.(1997),13:261-291 [Non-patent document 3] Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560 [Non-patent document 4] Karp JE, Broder S. Nat. Med. (1995) 1:309-320 [Non-Patent Document 5] Hall M,Peters G.Adv.Cancer Res.(1996)68:67-108 [Non-patent document 6] Smalley et al. Cancer Res. (2008)68:5743-52 [Non-Patent Document 7] O'Leary et al.Nature Reviews(2016)13:417-430 [Non-patent document 8] Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561 Summary of the Invention [Means for solving the problem]

[0017] In a first aspect, there is provided a compound for use in the degradation and / or inhibition of CDK2, wherein the compound has formula (A1): [ka] (In the formula, R 1is alkyl, alkenyl, alkynyl, alkylthio, pentafluorothio, halo, haloalkyl, haloalkylthio, haloalkoxy, alkoxy, amino, alkylamino, dialkylamino, cyano, cycloalkyl, cycloalkoxy, cycloalkylalkyl, bridged cycloalkyl, bridged cycloalkoxy, bridged cycloalkylalkyl, cyanoalkyl, cyanoalkoxy, alkoxyalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkoxy, acyl, azidocarbonyl, alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, substituted sulfonyl, substituted sulfinyl, substituted ureido, aryl, aralkyl, aryloxy, heteroaryl, heteroaralkyl, heteroaryl aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, fused heterocyclyl, fused heterocyclyloxy, or fused heterocyclylalkyl, where cycloalkyl, by itself or as part of cycloalkoxy and cycloalkylalkyl, aryl, by itself or as part of aralkyl and aryloxy, heteroaryl, by itself or as part of heteroaralkyl and heteroaryloxy, heterocyclyl, by itself or as part of heterocyclylalkyl and heterocyclyloxy, bridged cycloalkyl, by itself or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and fused heterocyclyl, by itself or as part of fused heterocyclylalkyl and fused heterocyclyloxy, are substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R 2 and R 2a are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiroheterocyclylene, bridged heterocyclylene, or fused heterocyclylene, wherein each of the foregoing rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. a , R b , and R c or a pharmaceutically acceptable salt thereof; The compounds of formula (A1) degrade and / or inhibit CDK2, and the degradation of CDK2 occurs via the ubiquitin proteasome pathway.

[0018] In a first embodiment of the first aspect, the compound of formula (A1) degrades CDK2 via the ubiquitin proteasome pathway.

[0019] In a second embodiment of the first aspect, the compound of formula (A1) inhibits CDK2.

[0020] In a second aspect, there is provided a compound for use in the degradation of CDK2, wherein the compound has formula (A): [ka] (In the formula, R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano, or cycloalkyl, wherein the cycloalkyl is substituted with 1 to 3 halo; R 2 and R 2a are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiroheterocyclylene, bridged heterocyclylene, or fused heterocyclylene, wherein each of the foregoing rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano.a , R b , and R c or a pharmaceutically acceptable salt thereof; CDK2 is degraded via the ubiquitin proteasome pathway.

[0021] In a third aspect, the compounds of formula (A1) and (A) for use in the degradation of CDK2 as described in the first and / or second aspect have the formula (I): [ka] (In the formula, R 1 is as defined herein; R 2 and R 2a are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiroheterocyclylene, bridged heterocyclylene, or fused heterocyclylene, wherein each of the foregoing rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. a , R b , and R c is replaced by; L is a linker; Degrons are E3 ubiquitin ligase ligands); or a pharmaceutically acceptable salt thereof.

[0022] In a fourth aspect, a compound of formula (Ia): [ka] (In the formula, R 1is alkyl, alkenyl, alkynyl, alkylthio, pentafluorothio, halo, haloalkyl, haloalkylthio, haloalkoxy, alkoxy, amino, alkylamino, dialkylamino, cyano, cycloalkyl, cycloalkoxy, cycloalkylalkyl, bridged cycloalkyl, bridged cycloalkoxy, bridged cycloalkylalkyl, cyanoalkyl, cyanoalkoxy, alkoxyalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkoxy, acyl, azidocarbonyl, alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, substituted sulfonyl, substituted sulfinyl, substituted ureido, aryl, aralkyl, aryloxy, heteroaryl, heteroaralkyl, heteroaryl aryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, fused heterocyclyl, fused heterocyclyloxy, or fused heterocyclylalkyl, where cycloalkyl, by itself or as part of cycloalkoxy and cycloalkylalkyl, aryl, by itself or as part of aralkyl and aryloxy, heteroaryl, by itself or as part of heteroaralkyl and heteroaryloxy, heterocyclyl, by itself or as part of heterocyclylalkyl and heterocyclyloxy, bridged cycloalkyl, by itself or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and fused heterocyclyl, by itself or as part of fused heterocyclylalkyl and fused heterocyclyloxy, are substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R 2 and R 2a are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiroheterocyclylene, bridged heterocyclylene, or fused heterocyclylene, wherein each of the foregoing rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. a , R b , and R c is replaced by; Degron is (a) a group of formula (i): [ka] (b) a group of formula (ii): [ka] (c) a group of formula (iii): [ka] (d) a group of formula (iv): [ka] (e) a group of formula (v): [ka] (f) a group of formula (vi): [ka] an E3 ubiquitin ligase ligand selected from: R x and R x1 are hydrogen, respectively; Y a is CH or N; Z a is a bond, -CH2-, -NH-, -O-, or -NHC(O)-, where NH of -NHC(O)- is Y a It is bound to; Ring A is represented by formula (a), (b) or (c): [ka] where: R aa , R bb , R cc , and R dd is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R 4 and R 5 are independently hydrogen or alkyl; or R 4 and R 5 form >C=O with the carbon to which they are attached; R 6 is hydrogen or alkyl; Ring B is phenylene, cyclylaminylene, 5- or 6-membered monocyclic heteroarylene, or 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains 1 to 3 nitrogen ring atoms, and further wherein the phenylene, cyclylaminylene, and each heteroarylene has R independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. ee and R ff are independently substituted with; X 1 , X 2 , X 3 , and X 4 are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NR gg -alkylene)-, -(alkylene-NR hh )-, [ka] , -NH-, -N(alkyl)-, -C(=O)-, NR jj C(=O)- or -C(=O)NR kk -, where R gg , R hh , R jj , and R kkis independently hydrogen, alkyl, or cycloalkyl, each alkylene by itself or as part of another group optionally substituted with 1 or 2 fluoro; R y , R y1 , and R y2 R is independently alkyl, hydroxyalkyl, cycloalkyl, or heterocyclyl, where cycloalkyl and heterocyclyl are selected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino. d and R f is replaced by; W a is a bond, O, S, or alkylene; L -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -where: Z 1 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -S(O)2NR-, -NR'S(O)2-, -(O-alkylene) a -, -(Alkylene-O) a -, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. h and R i is replaced by; Z 2 represents a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR'(CO)-, -(O-alkylene) b -, -(Alkylene-O) b -, -O(CH2)7-, -O(CH2)8-, cycloalkylene, or -heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. j and Rk is replaced by; Z 3 represents a bond, alkylene, alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR''-, -(O-alkylene) c -, -(Alkylene-O) c -, cycloalkylene, spirocycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged hetero heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, -spiroheterocyclylene-(alkylene)-, or 11- to 13-membered spiroheterocyclylene, where each ring, by itself or as part of another group, is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. m and R n is replaced by; Z 4 represents a bond, alkylene, alkynylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -C(O)-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, has an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. o and R p is replaced by; Z 5 is a bond, -alkylene, -NR″-, -O—, -C(O)—, -S(O)2-, -NR′(CO)—, -C(O)NR—, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring contains an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. q and R r is replaced by; Z 6 is a bond, alkylene, —NR″—, —O—, —(alkylene-O)—, —C(O)—, —S(O)2—, —NR′(CO)—, or —C(O)NR—; wherein each R, R', and R'' is independently hydrogen or alkyl; each a, b, c, and d is independently an integer selected from 1 to 6; -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 5 - and -Z 6 Each alkylene of -, by itself or as part of another group, can be R s and R twhere R s is hydrogen or deuterium, and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl is substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; with the proviso that -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -at least one of which is not a bond); or a pharmaceutically acceptable salt thereof.

[0023] In a fifth aspect, there is provided a method of treating a disease mediated by CDK2 in a patient, preferably a patient in need of such treatment, the method comprising administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of any of the first, second, and third aspects, or a compound of Formula (Ia) of the fourth aspect (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. (For clarity, the phrase "any of the embodiments thereof described herein" includes the first, second, and third aspects and embodiments of Formula (Ia) disclosed herein below, unless otherwise specified.) In a first embodiment of the fifth aspect, the disease is cancer. In a second embodiment of the fifth aspect, the disease is a cancer selected from lung cancer (e.g., adenocarcinoma, small cell and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma, and / or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's 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., cancer of the larynx, hypopharynx, nasopharynx, oropharynx, lip, and / or oral cavity), liver cancer (e.g., hepatocellular carcinoma and / or cholangiocarcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), stomach cancer, thyroid cancer, and parathyroid cancer. In a third embodiment of the fifth aspect, the cancer is a cancer that exhibits resistance to CDK4 / 6 inhibitors via a CDK2-mediated mechanism, e.g., breast cancer. In a fourth embodiment of the fifth aspect, the disease is an autoimmune disease or a condition associated with an autoimmune disease, and the method comprises administering to a patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of any one of the first, second, and third aspects, or a compound of Formula (Ia) (or any of its embodiments described herein), or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease or a condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), Crohn's disease (CD), uveitis, pemphigus vulgaris, and sepsis.In a fifth embodiment of the fifth aspect, the disease is gout. In a sixth embodiment of the fifth aspect, a therapeutically effective amount of a compound of Formula (A1), (A), (I), or (Ia) (or any embodiment thereof disclosed herein including the specified compounds), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.

[0024] In a sixth aspect, methods of treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss are provided, comprising administering to a patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of any one of the first, second, and third aspects, or a compound of Formula (Ia) of the fourth aspect (or any of its embodiments described herein), or a pharmaceutically acceptable salt thereof. In some embodiments of the sixth aspect, the extent of hearing loss is reduced when compared to age-matched controls. In some embodiments, hearing loss is prevented when compared to age-matched controls.

[0025] In a seventh aspect, there is provided a pharmaceutical composition comprising a compound of any one of the first, second, and third aspects, or a compound of formula (Ia) of the fourth aspect (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0026] In an eighth aspect, there is provided a compound of any one of the first, second, and third aspects, or a compound of formula (Ia) of the fourth aspect (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, for use as a medicament. In one embodiment of the eighth aspect, the compound of formula (Ia) of any one of the first, second, and third aspects or the fourth aspect (or any embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, is useful in the treatment of one or more of the diseases disclosed in the fifth and sixth aspects above.

[0027] In a ninth aspect, there is provided the use of a compound of any one of the first, second and third aspects, or a compound of formula (Ia) of the fourth aspect (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 activity of CDK2 contributes to the pathology and / or symptomology of the disease. In one embodiment of the ninth aspect, the disease is one or more of the diseases disclosed in the fourth or fifth aspects above.

[0028] In a tenth aspect, there is provided a method of degrading CDK2 in a cell via the ubiquitin proteasome pathway, the method comprising contacting the cell with a compound comprising a 2,5-disubstituted pyrimidinyl moiety that binds to CDK2, or a pharmaceutically acceptable salt thereof. In one embodiment of the tenth aspect, the 2,5-disubstituted pyrimidinyl moiety is a moiety of Formula (Ia) of the fourth aspect (or embodiments thereof disclosed herein, including specific compounds). In another embodiment of the tenth aspect, CDK2 is degraded in the patient's cells.

[0029] In an embodiment of any one of the above aspects, CDK2 is degraded more selectively than CDK1. In another embodiment of any one of the above aspects, CDK2 is degraded more selectively than CDK1 and CDK4 and / or CDK6.

[0030] In the aforementioned aspects involving the treatment of cancer, further embodiments are provided that include administering a compound of any one of the first, second, third, and Formula (Ia), or a pharmaceutically acceptable salt thereof (or any embodiment thereof disclosed herein), or a pharmaceutical composition of the seventh aspect, in combination with at least one additional anti-cancer agent. When combined therapy is used, the agents can be administered simultaneously or sequentially. DETAILED DESCRIPTION OF THE INVENTION

[0031] Definition: Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this application and have the following meanings:

[0032] "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, etc. It will be recognized by those skilled in the art that the term "alkyl" can include "alkylene" groups.

[0033] "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.

[0034] "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.

[0035] "Alkylene," unless otherwise specified, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0036] "Alkenylene" means a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms containing a double bond, e.g., ethene-diyl, propene-diyl, 2-propene-diyl, butene-diyl, pentene-diyl, and the like.

[0037] "Alkynylene" refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms containing a triple bond, or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms, e.g., [ka] etc.

[0038] "Alkoxy" is R zis alkyl as defined above, -OR z radicals such as methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy.

[0039] "Alkoxyalkyl" means alkyl as defined above substituted with alkoxy as defined above, e.g., methoxymethyl, methoxyethyl, ethoxyethyl, and the like.

[0040] "Alkylthio" is R z is alkyl as defined above, z radicals such as methylthio, ethylthio, n-propylthio, 2-propylthio, n-, iso-, or tert-butylthio.

[0041] "Alkoxycarbonyl" is R Z -C(O)OR is alkyl as defined above Z radicals such as methoxycarbonyl, ethoxycarbonyl, and the like.

[0042] "Alkylcarbonyloxy" is -OR z means a group, where R z is alkylcarbonyl as defined herein.

[0043] "Alkylcarbonylamino" is R Z is alkyl, and R z ' is H or alkyl (as defined above), -NR z 'C(O)R z radicals such as methylcarbonylamino, ethylcarbonylamino, and the like.

[0044] "Acyl" is R z is alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl (as defined herein);z R means a radical such as methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, etc. z When is alkyl, the acyl is also referred to herein as "alkylcarbonyl."

[0045] "Azidocarbonyl" means the -C(O)N2 radical.

[0046] "Amide" is -NR z C(O)- or -C(O)NR z - group, where R z is hydrogen or alkyl as defined above.

[0047] "Sulfonamide" is -NR z S(O)2- or -S(O)2NR z - group, where R z is hydrogen or alkyl as defined above.

[0048] "Amino" means -NH2.

[0049] "Aminoalkyl" means an alkyl as defined above substituted with -NH2, for example, NH2-methyl, NH2-ethyl, and the like.

[0050] "Aminoalkyloxy" and "aminoalkoxy" are R z is aminoalkyl as defined above z radicals such as NH2 methyloxy, NH2 ethyloxy, and the like.

[0051] "Aminocarbonyl" means -C(O)NH2.

[0052] "Alkylaminocarbonyl" is R Z is alkyl as defined above; Z radicals such as ethylaminocarbonyl, propylaminocarbonyl, and the like.

[0053] "Dialkylaminocarbonyl" is R z and R z1 are independently alkyl as defined above, —C(O)NR z1 R z radicals such as dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.

[0054] "Alkylamino" is R z -NHR is alkyl as defined above z radicals such as methylamino, ethylamino, propylamino, and the like.

[0055] "Aminosulfonyl" refers to -S(O)2NH2.

[0056] "Alkylaminosulfonyl" is R Z is alkyl as defined above; z radicals such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.

[0057] "Dialkylaminosulfonyl" is R z and R z1 are independently alkyl as defined above, -S(O)NR z1 R z radicals such as dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.

[0058] "Alkylamino" is R z -NHR is alkyl as defined above z radicals such as methylamino, ethylamino, propylamino, and the like.

[0059] "Alkylaminoalkyl" means an alkyl as defined above substituted with an alkylamino as defined above, for example, methylaminomethyl, methylaminoethyl, ethylaminoethyl, and the like.

[0060] "Alkylaminoalkyloxy" is R z -OR is alkylaminoalkyl as defined above z radicals such as methylaminomethyloxy, methylaminoethyloxy, ethylaminoethyloxy, and the like.

[0061] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

[0062] "Aralkyl" is -(alkylene)-R z means a radical, where R z is aryl as defined above, for example benzyl.

[0063] "Arylene" means a divalent aryl (as defined above) radical, e.g., phenylene or naphthylene.

[0064] "Aryloxy" is R z -OR is aryl as defined above z radicals such as phenyloxy (or phenoxy) or naphthyloxy.

[0065] "Bicyclic heterocyclylene" means a saturated or unsaturated divalent fused bicyclic group of 8 to 12 ring atoms, of which 1, 2, or 3 ring atoms are N, O, and S(O). nwhere n is an integer selected from 0 to 2, and the remaining ring atoms are carbon unless otherwise specified. Furthermore, one or two ring carbon atoms of the bicyclic heterocyclylene ring can be optionally substituted with a -CO- group. More specifically, the term bicyclic heterocyclylene includes, but is not limited to, isoindolinediyl, decahydro-2,6-naphthyridinediyl, octahydrocyclopenta[c]pyrrolediyl, octahydro-1H-pyrrolo[3,4-c]pyridinediyl, 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, as long as the ring is not aromatic.

[0066] "Bridged cycloalkyl" means a saturated monovalent bicyclic ring having five to eight ring carbon atoms, of which two non-adjacent ring atoms are (CR z R z’ ) n group, n is an integer selected from 1 to 3, and R z and R z’ are independently H or methyl (also referred to herein as a "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.

[0067] "Bridged cycloalkylalkyl" is R z -(alkylene)-R is a bridged cycloalkyl as defined above z radicals such as bicyclo[1.1.1]pent-1-ylmethyl, and the like.

[0068] "Bridged cycloalkyloxy" and "bridged cycloalkoxy" are R z -OR is a bridged cycloalkyl as defined above z radicals such as bicyclo[2.2.1]hept-2-yloxy.

[0069] "Bridged cycloalkylene" means a saturated divalent bicyclic ring having from 5 to 8 ring carbon atoms, of which two non-adjacent ring atoms are (CR z R z’ ) n group, n is an integer selected from 1 to 3, and R z and R z’ are independently H or methyl (also referred to herein as a "bridging" group). Bridged cycloalkyls, unless otherwise stated, are optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, bicyclo[2.2.1]heptylene, preferably bicyclo[2.2.1]hept-2,5-ylene.

[0070] A "bridged heterocyclylene" is a saturated divalent bicyclic ring having from 5 to 9 ring carbon atoms, where two non-adjacent ring atoms are (CR z R z ') n group, where n is an integer selected from 1 to 3, and R z and R z ' are independently H or methyl (also referred to herein as a "bridging" group), and further, one or two ring carbon atoms, including atoms in the bridging group, are selected from N, O, and S(O) nwhere n is an integer selected from 0 to 2. Bridged heterocyclylenes are optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless otherwise specified. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octa-3,8-diyl, 7-oxabicyclo[2.2.1]heptanediyl, 2,5-diazabicyclo[2.2.1]heptanediyl, 3,6-diazabicyclo[3.1.1]heptanediyl, 2,5-diazabicyclo[2.2.2]octanediyl, 3,8-diazabicyclo[3.2.1]octanediyl, 6-azabicyclo[3.1.1]heptanediyl, 8-azabicyclo[3.2.1]octanediyl, and the like.

[0071] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon radical of 3 to 10 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0072] "Cycloalkyloxy or cycloalkoxy" refers to R z is cycloalkyl as defined above z Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0073] "Cycloalkylalkyl" is R z -(alkylene)-R is cycloalkyl as defined above z Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0074] "Cycloalkylene," unless otherwise specified, means a divalent saturated hydrocarbon radical of three to six carbon atoms, e.g., 1,1-cyclopropylene, 1,1-cyclobutylene, 1,4-cyclohexylene, and the like.

[0075] "Carbonyl" means -C(O)-.

[0076] "Carboxy" means --COOH.

[0077] "Cycrylaminylene" means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one or two ring atoms are nitrogen and the remaining ring atoms are carbon. More specifically, the term cyclylaminyl includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, piperazinylene, and the like.

[0078] "Cyanoalkyl" means an alkyl as defined above substituted with cyano, for example, cyanomethyl, cyanoethyl, and the like.

[0079] "Cyanoalkoxy" means R z is cyanoalkyl as defined above; z Examples include, but are not limited to, cyanomethoxy, cyanoethoxy, and the like.

[0080] "Deuterium" is 2 It means H or D.

[0081] "Deuteroalkyl" means an alkyl as defined above that is substituted with one, two, or three deuterium atoms.

[0082] "Dialkylamino" is a group consisting of R z -NR is defined above z R z radicals such as dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-, iso-, or tert-butylmethylamino, and the like.

[0083] "Dialkylaminoalkyl" means an alkyl as defined above substituted with a dialkylamino as defined above, for example, dimethylaminomethyl, dimethylaminoethyl, ethylmethylaminoethyl, and the like.

[0084] "Dialkylaminoalkyloxy" is R z -OR is dialkylaminoalkyl as defined above z radicals such as dimethylaminomethyloxy, dimethylaminoethyloxy, ethylmethylaminoethyloxy, and the like.

[0085] "Ether" refers to the group --O--.

[0086] "Fused heterocyclyl" means, unless otherwise specified, a monovalent bicyclic ring in which two adjacent ring atoms of a saturated or partially unsaturated (but not aromatic) monocyclic ring of 4 to 7 ring atoms containing one or two heteroatoms independently selected from N, O, and S(O)n (n is 0, 1, or 2), with the remaining ring atoms being carbon, are fused to two adjacent ring members of phenyl or 5- or 6-membered heteroaryl, respectively, as defined herein. The nitrogen atom is optionally oxidized or quaternized. The fused heterocyclylene can be bonded to any atom of the ring. 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.

[0087] "Fused heterocyclylene" means, unless otherwise specified, a divalent bicyclic ring in which two adjacent ring atoms of a saturated or partially unsaturated (but not aromatic) monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, O, and S(O)n (n is 0, 1, or 2), with the remaining ring atoms being carbon, are fused to two adjacent ring members of phenyl or 5- or 6-membered heteroaryl, respectively, as defined herein. The nitrogen atom is optionally oxidized or quaternized. The fused heterocyclylene can be bonded to any two atoms of the ring. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinoline-1,4-diyl, 3,4-dihydro-2H-benzo[b][1,4]oxazine-5,8-diyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-diyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-diyl, and the like.

[0088] "Fused heterocyclylalkyl" refers to R z -(alkylene)-R is a fused heterocyclyl as defined above z radicals such as 1,2,3,4-tetrahydroquinolinylmethyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinylmethyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinylmethyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinylmethyl, and the like.

[0089] "Fused heterocyclyloxy" refers to R z -OR is a fused heterocyclyl as defined above z Radicals such as 1,2,3,4-tetrahydroquinolinyloxy, 3,4-dihydro-2H-benzo[b][1,4]oxazinyloxy, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyloxy, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyloxy, and the like.

[0090] "Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

[0091] "Haloalkyl" means an alkyl radical as defined above substituted with one or more halogen atoms, e.g., 1 to 5 halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When the alkyl is substituted with only fluoro, it may be referred to in this application as fluoroalkyl.

[0092] "Haloalkoxy" is R z -OR is haloalkyl as defined above z R means a radical, e.g., -OCF3, -OCHF2, etc. z When is haloalkyl, where the alkyl is substituted with only fluoro (and in some instances, one or more fluoro), it is referred to in this Application as fluoroalkoxy.

[0093] "Haloalkylthio" is R z is haloalkyl as defined above, -SR z radicals such as -SCF3, -SCHF2, and the like.

[0094] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0095] "Heteroaryl," unless otherwise specified, 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 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, indazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. 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 a 5- or 6-membered monocyclic heteroaryl or monocyclic heteroarylene. When the heteroaryl ring contains 9 or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as a 9- or 10-membered fused bicyclic heteroaryl.

[0096] "Heteroarylene" refers to a divalent heteroaryl radical as defined above, unless otherwise specified. Representative examples include, but are not limited to, benzimidazolediyl, such as benzimidazole-1,5-diyl. When the heteroarylene ring contains 5 or 6 ring atoms and is a monocyclic ring, it is also referred to herein as a monocyclic heteroarylene or a 5- or 6-membered monocyclic heteroarylene, such as pyrazolyl-1,4-diyl. When the heteroarylene ring contains 9 or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as a 9- or 10-membered fused bicyclic heteroarylene.

[0097] "Heteroarylalkyl" or "heteroaralkyl", unless otherwise specified, refers to -(alkylene)-R z means a radical, where R z is heteroaryl, a monocyclic group of 4 to 8 ring atoms, one or two of which are N, O, and S(O) n where n is an integer selected from 0 to 2, and the remaining ring atoms are C. Furthermore, one or two ring carbon atoms of the heterocyclyl ring can be optionally substituted with a -CO- group. More specifically, the term heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and the like. When a heterocyclyl ring is unsaturated, it can contain one or two ring double bonds, as long as the ring is not aromatic. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

[0098] "Heterocyclylalkyl" is R z -(alkylene)-R is heterocyclyl as defined above zRadicals such as piperidinylmethyl and piperazinylmethyl are meant.

[0099] "Heterocyclyloxy" is R z -OR is heterocyclyl as defined above z radicals such as 1-methylpyrrolidin-3-oxy, 1-methylpyrrolidin-2-oxy, piperidin-3-oxy, piperidin-4-oxy, and the like.

[0100] "Heterocyclylene" refers to a heterocyclylene in which one or two ring atoms are N, O, and S(O). n

[0033] The term heterocyclylene refers to a saturated or unsaturated divalent monocyclic group of 4 to 8 ring atoms, wherein n is an integer selected from 0 to 2, and unless otherwise specified, the remaining ring atoms are C. Furthermore, one or two ring carbon atoms of the heterocyclylene ring can be optionally substituted with a -CO- group. More specifically, the term heterocyclylene includes [ka] , piperidine-1,4-diyl, azetidine-1,3-diyl, and the like.

[0101] The term "linker 'L'" refers to a connector having a linear number of non-hydrogen atoms ranging from 1 to 20 (preferably, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; more preferably, 8 to 16, 9 to 14, 9 to 13, 9 to 12; more preferably, 8, 9, 10, 11, 12, or 13; most preferably, 12 or 13). Linker "L" can be one or more independently selected (preferably 2, 3, 4, 5, 6, 7, or 8; more preferably 3 to 6) heterocyclic groups such as, but not limited to, ether, polyether, thioether, -NH-, -N(alkyl)-, amide, sulfonamide, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, sulfinyl, sulfonyl, ureido, thioureido, cycloalkylene, bridged cycloalkylene, spirocycloalkylene, arylene, heteroarylene, heterocyclylene, bridged heterocyclylene, spiroheterocyclylene, bicyclic heterocyclylene, or fused heterocyclylene. or 3, 4, 5, or 6; most preferably 4 or 5) groups, where cycloalkylene, bridged cycloalkylene, spirocycloalkylene, arylene, heteroarylene, heterocyclylene, bridged heterocyclylene, spiroheterocyclylene, bicyclic heterocyclylene, and fused heterocyclylene are optionally substituted with 1, 2, or 3 substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino, and where alkylene is optionally substituted with 1 or 2 halo (preferably fluoro).In some embodiments, the linker L is selected from the group consisting of -O-, -NH-, -N(CH3)-, sulfonyl, phenylene, alkylene (preferably -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH(CH3)CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-), heterocyclylene (preferably azetidinediyl, piperidinediyl, or piperazinediyl), spiroheterocyclylene (preferably 2,6-diazaspiro[3.3]heptanediyl), and monoheterocyclylene. and cyclic heteroarylene (preferably imidazolyl or pyridinyl, more preferably imidazolyl) containing 3 to 5 groups independently selected from: wherein heterocyclylene, spiroheterocyclylene, and monocyclic heteroarylene are optionally substituted with 1, 2, or 3 substituents independently selected from halo (preferably fluoro) and alkyl (preferably methyl), and alkylene is optionally substituted with 1 or 2 halo (preferably the group is —CH(CHF)—).

[0102] "Phenylene" means a divalent phenyl.

[0103] "Polyether" is [ka] group, where d is an integer selected from 2 to 5, and R z is C 2-6 It is alkylene.

[0104] The term "oxo" as used herein, alone or in combination, means =(O).

[0105] As used herein, the phrase "optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, the phrase "alkylene optionally substituted with halo" is intended to encompass unsubstituted alkylene and alkylene substituted with halo.

[0106] "Spirocycloalkylene" means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 ring atoms, where the rings are connected through only one atom, and the connecting atom, also called a spiro atom, is most often a quaternary carbon ("spirocarbon"). Unless otherwise specified, the spirocycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Representative examples include, but are not limited to, benzimidazolediyl, e.g., spiro[3,5]nonanediyl, e.g., spiro[3,5]nonane-2,7-diyl, and the like.

[0107] "Spiroheterocyclylene" refers to a heterocyclylene in which one, two, or three ring atoms are N, O, and S(O). n

[0033] "Spiroheterocyclylene" refers to a saturated bicyclic divalent ring having 6 to 10 ring atoms, the heteroatoms being selected from the group consisting of: n, n = 0, n = 1, n = 2, n = 3, n = 4, n = 5, n = 6, n = 7, n = 8, n = 9, n = 10, n = 11, n = 12, n = 13, n = 14, n = 15, n = 16, n = 17, n = 18, n = 19, n = 20, n = 21, n = 22, n = 23, n = 24, n = 25, n = 26, n = 27, n = 28, n = 29, n = 30, n = 31, n = 32, n = 33, n = 34, n = 35, n = 36, n = 37, n = 38, n = 39, n = 40, n = 41, n = 42, n = 43, n = 44, n = 45, n = 46, n = 47, n = 48, n = 49, n = 50, n = 51, n = 52, n = 53, n = 54, n = 55, n = 56, n = 57, n = 58, n = 59, n = 60, n = 61, n = 62, n = 63, n = 64, n = 65, n = 66, n = 67, n = 68, n = 69, n = 70, n = 71, n = 72, n = 73, n = 74, n = 75, n = 76, n = 77, n = 78

[0108] "11- to 13-membered spiroheterocyclylene" refers to a heterocyclylene in which one, two, or three ring atoms are N, O, and S(O). n

[0039] The term "spiroheterocyclylene" refers to a saturated bicyclic divalent ring having 11 to 13 ring atoms, the heteroatoms being selected from the group consisting of:

[0040] n is an integer selected from 0 to 2, the remaining ring atoms are C, and the rings are connected through only one atom, also referred to as a spiro atom, most often a quaternary carbon ("spirocarbon"). The 11- to 13-membered spiroheterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless otherwise specified. Representative examples include, but are not limited to, diazaspiro[5.5]undecanediyl, 1-oxa-diazaspiro[5.5]undecanediyl, and the like.

[0109] "Pentafluorothio" means -SF5.

[0110] "Sulfinyl" means the group -S(O)-.

[0111] "Substituted sulfinyl" is R z is alkyl as defined above z , for example, methyl or ethylsulfinyl.

[0112] "Sulfonyl" refers to the group -S(O)2.

[0113] "Substituted sulfonyl" is R z is alkyl as defined above, z , for example, methyl or ethylsulfonyl.

[0114] "Thioether" refers to the group --S--.

[0115] "Thioureido" means the group -NHC(S)NH-.

[0116] "Ureido" means the group -NHC(O)NH-.

[0117] "Substituted ureido" is R z is hydrogen or alkyl, and R z’ is alkyl -NHC(O)NR z R z’ , for example, -NHC(O)NHmethyl, -NHC(O)NMe2, etc.

[0118] The present disclosure also includes protected derivatives of the compounds of the first aspect, the second aspect, the third aspect, or Formula (Ia) (or any embodiment thereof disclosed herein), or pharmaceutically acceptable salts thereof. For example, if the compounds of Formula (Ia) contain groups such as hydroxy, carboxy, or any group containing nitrogen atom(s), these groups can be protected with a suitable protecting group. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds of the present disclosure can be prepared by methods well known in the art.

[0119] The present disclosure also includes polymorphic and deuterated forms of the compounds of the first aspect, second aspect, third aspect, or Formula (Ia) (or any embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof.

[0120] The term "prodrug" refers to a compound that is more active in vivo. Certain compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein that includes certain compounds) are also 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 disclosed herein are structurally modified forms of the compounds 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 be bioavailable, for example, 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 is a compound that is administered as an ester but is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity (the "prodrug"). Additional examples include peptidyl derivatives of the compounds.

[0121] "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and 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 with 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, camphorsulfonic acid, glucoheptan-1, 2-hydroxybenzoylbenzoic acid, ... Examples of suitable pharmaceutically acceptable salts include acid addition salts formed with organic acids such as carboxylic 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 is replaced with a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordination compounds with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts are understood to be non-toxic. Additional information regarding 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.

[0122] Compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein, including specific compounds) may have asymmetric centers. Compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein, including specific compounds) containing asymmetrically substituted atoms may be isolated in optically active or racemic forms. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by separation, such as preparation of a mixture of enantiomeric products followed by conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or other suitable methods known in the art. Unless a specific stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure. It will also be understood by those skilled in the art that when a compound is depicted as the (R) stereoisomer, it may be contaminated with the corresponding (S) stereoisomer, and vice versa.

[0123] Certain compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein, including the specific compounds) can exist as tautomers and / or geometric isomers. All possible tautomers, as individual forms and mixtures thereof, and cis and trans isomers are within the scope of this disclosure. Furthermore, as used herein, the term alkyl includes all possible isomeric forms of said alkyl group, although only a few examples are set forth. Furthermore, when a cyclic group, such as aryl, is substituted, this includes all positional isomers, although only a few examples are set forth. Furthermore, all hydrates of compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein, including the specific compounds) are within the scope of this disclosure.

[0124] Compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein, including specific compounds) may also contain unnatural isotopes at one or more of the atoms that make up such compounds. Unnatural isotopes may be defined as a range from the amount found in nature to 100% of the amount of the atom in question, differing 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 compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine (respectively). 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, 125 Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution (or isotopic enrichment) with heavier isotopes, such as H, may afford certain therapeutic advantages (e.g., increased in vivo half-life or reduced required dosage) resulting from greater metabolic stability. In some embodiments, in compounds of Formula (A1), (A), (I), or (Ia) (and any embodiment thereof disclosed herein, including specific compounds), including those in Table 1 below, one or more hydrogen atoms are 2 H or 3 H or one or more carbon atoms are replaced by 13 C or14 Replaced by C-rich carbon. 15 O. 13 N, 11 C, and 15 Positron-emitting isotopes, such as F, are useful in 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 examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0125] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary and human medicines.

[0126] "Pharmaceutically acceptable carrier / excipient" as used in the specification and claims includes both one and more than one such excipient.

[0127] The term "about," as used herein, is intended to specify the numerical value it modifies and indicates such value as variable within a tolerance. When a specific tolerance is not stated, such as a standard deviation from the mean value shown in a chart or table of data, the term "about" should be understood to mean a range that is inclusive of the stated value and range and that will encompass ±10%, preferably ±5%.

[0128] Certain structures provided herein are drawn with one or more variable substituents. Unless otherwise specified or apparent from the context, the substituent(s) may be present on any atom of the ring to which it is attached, where chemically feasible and valence rules permit. For example, the structure: [ka] In R aa Substituents as well as R bb and X 1The substituents replace the hydrogens of any C-H that are part of the benzo portion of the bicyclic ring that are not already substituted with R bb and X 1 In (R aa ), and similarly, R aa and X 1 In (R bb ), and R aa and R bb In (X 1 (In this case) it can be replaced.

[0129] Additionally, as used throughout this application, including embodiments, when a group is depicted as divalent, the bond on the left side of the divalent group is attached to the group to its left in the remainder of the molecule, and the bond on the right side of the divalent group is attached to the group to its right in the remainder of the molecule. For example, in formula (Ia), the following divalent group: [ka] The left side of (a), (b) and (c) [ka] The bond is in the following ring: [ka] is bound to (a), (b), and (c) on the right [ka] (i.e., X 1 , X 2 , and X 3 ) has the following structure: [ka] L Z 1 is bonded to.

[0130] Similarly, L, i.e., -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z6 - about the left side of L (i.e., Z 1 ) is X 1 , X 2 , X 3 , or X 4 or the attachment point shown in the degron of formula (c), (d), (e), or (f), and Z 6 is attached to the atom of Hy. For example, if L has the formula: [ka] and the degron is a group of formula (a), i.e. [ka] When the bond to the left of L (i.e., the -NH- group) is X 1 The bond to the right of L (i.e., -SO2-) is connected to the atom of Hy. [ka] is bonded to.

[0131] The term "disease," as used herein, is generally intended to be synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "condition" (such as a medical condition) in that it reflects any abnormal condition of the human or animal body or one of its parts that impairs normal function, is typically manifested by characteristic signs and symptoms, and results in a decrease in the lifespan or quality of life of the human or animal.

[0132] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a disease or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents substantially simultaneously, for example, in a single capsule having a fixed ratio of active ingredients, or in separate capsules for each active ingredient. In addition, such administration also includes sequential use of each type of therapeutic agent. In either case, the treatment regimen provides the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0133] 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.

[0134] "Treating" a disease or "treatment" of a disease includes: (1) To prevent disease, i.e., to prevent the development of clinical symptoms of disease in a mammal that is exposed to or susceptible to disease but that has not yet experienced or exhibited symptoms of disease; (2) inhibiting the disease, i.e., delaying, preventing, or reducing the onset or severity of the disease or its clinical symptoms; or (3) To alleviate the disease, i.e., to cause regression of the disease or its clinical symptoms.

[0135] In one embodiment, treating a disease or treating a disease includes inhibiting the disease, i.e., delaying, preventing, or reducing the onset or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0136] "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 being treated.

[0137] "Condition associated with an autoimmune disease" means a condition in which a patient with an autoimmune disease is susceptible, for example, to sepsis, or a condition caused by an autoimmune disease, for example, uveitis.

[0138] The compounds of the first, second, and third aspects, and of Formula (Ia), and their embodiments, may also inhibit CDK2. The terms "inhibit" and "reduce," or any variations of these terms related to CDK2, include a measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease or reduction in CDK2 activity compared to normal of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein.

[0139] The terms "degrading" and "degrading," or any variation of these terms, in reference to CDK2 and CDK1, refer to any measurable decrease in the concentration of CDK2 and CDK1, respectively, in a sample over time. For example, the CDK2 concentration in a sample containing CDK2 and a compound disclosed in the Summary of the Invention, embodiments, and Compound Table 1 disclosed herein (including compounds of Formula (A1), (A), (I), or (Ia)) can be reduced by 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, compared to a comparable sample containing CDK2 without the compound present. Percent degradation can be determined as described in Biological Example 2, below. In one embodiment, the reduction in CDK2 concentration is 40% or more. In one embodiment, the reduction in CDK2 concentration is 50% or more. In one embodiment, the reduction in CDK2 concentration is 60% or more. In one embodiment, the reduction in CDK2 concentration is 70% or more. In one embodiment, the reduction in CDK2 concentration is 80% or more.

[0140] "E3 ubiquitin ligase" refers to a family of proteins that act in concert with E1 ubiquitin-activating enzymes and E2 ubiquitin-conjugating enzymes to either assist or directly catalyze the covalent attachment of ubiquitin to lysine residues on substrate proteins. E3 ubiquitin ligases directly bind to substrate proteins, thus conferring substrate specificity to the ubiquitination process. Ubiquitination serves as a versatile signaling mark for substrate proteins targeting them for degradation by the proteasome or other regulation, ranging from translocation to transcription. Cereblon (CRBN) and von Hippel-Lindau (VHL) proteins are substrate-recognition subunits of two ubiquitously expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of Cullins1 (ROC1). VHL is part of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbx1.

[0141] "E3 ubiquitin ligase ligand" means a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons) that can bind to an E3 ubiquitin ligase or a subunit of an E3 ligase, such as cereblon, VHL, IAP, or MDM2.

[0142] Embodiments: In embodiments A1A to A190, the present disclosure includes the following.

[0143] A1A. In embodiment A1A, there is provided a compound of Formula (A1), or a pharmaceutically acceptable salt thereof, for use as described in the first aspect or embodiments thereof described in the Summary.

[0144] A1. In embodiment A1, there is provided a compound of Formula (A), or a pharmaceutically acceptable salt, for use as described in the second aspect of the Summary of the Invention.

[0145] A2. In embodiment A2, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, for use as described in the third aspect of the Summary of the Invention.

[0146] A3-1. In embodiment A3-1, the compound, or pharmaceutically acceptable salt thereof, for use in embodiment A1A, A1, or A2 is that the compound of formula (A1), (A), or (I) is of formula (Ia1): [ka] (In the formula, R 1 is as defined in the first, second, or third aspect, respectively; R 2 and R 2a are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiroheterocyclylene, bridged heterocyclylene, or fused heterocyclylene, wherein each of the foregoing rings in this paragraph is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. a , R b , and R c is replaced by; Degron is (a) a group of formula (i): [ka] (b) a group of formula (ii): [ka] (c) a group of formula (iii): [ka] (d) a group of formula (iv): [ka] (e) a group of formula (v): [ka] (f) a group of formula (vi): [ka] an E3 ubiquitin ligase ligand selected from: R x and R x1 are hydrogen, respectively; Y a is CH or N; Z a is a bond, -CH2-, -NH-, -O-, or -NHC(O)-, where NH of -NHC(O)- is Y a It is bound to; Ring A is represented by formula (a), (b) or (c): [ka] where: R aa , R bb , R cc , and R dd is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R 4 and R 5 are independently hydrogen or alkyl; or R 4 and R 5 form >C=O with the carbon to which they are attached; M is -O- or -NR 6 - and; R 6 is hydrogen or alkyl; Ring B is phenylene, cyclylaminylene, 5- or 6-membered monocyclic heteroarylene, or 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains 1 to 3 nitrogen ring atoms (no additional heteroatoms), and further wherein the phenylene, cyclylaminylene, and each heteroarylene has R independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.ee and R ff are independently substituted with; X 1 , X 2 , X 3 , and X 4 are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NR gg -alkylene)-, -(alkylene-NR hh )-, [ka] , -NH-, -N(alkyl)-, -C(=O)-, NR jj C(=O)- or -C(=O)NR kk -, where R gg , R hh , R jj , and R kk is independently hydrogen, alkyl, or cycloalkyl, wherein each alkylene is optionally substituted with 1 or 2 fluoro; R y , R y1 , and R y2 R is independently alkyl, hydroxyalkyl, cycloalkyl, or heterocyclyl, where cycloalkyl and heterocyclyl are selected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino. d and R f is replaced by; W a is a bond, O, S, or alkylene; L -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -where: Z 1 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -S(O)2NR-, -NR'S(O)2-, -(O-alkylene) a -, -(Alkylene-O) a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino. h and R i is replaced by; Z 2 represents a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR'(CO)-, -(O-alkylene) b -, -(Alkylene-O) b -, -O(CH2)7-, -O(CH2)8-, cycloalkylene, or -heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino. j and R k is replaced by; Z 3 represents a bond, alkylene, alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR''-, -(O-alkylene) c -, -(Alkylene-O) c-, cycloalkylene, spirocycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene- (alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, -spiroheterocyclylene-(alkylene)-, or 11- to 13-membered spiroheterocyclylene, where each ring, by itself or as part of another group, is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino. m and R n is replaced by; Z 4 represents a bond, alkylene, alkynylene, -(alkylene-NR")-, -(NR"-alkylene)-, -O-, -C(O)-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, has an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino. oand R p is replaced by; Z 5 is a bond, -alkylene, -NR″-, -O—, -C(O)—, -S(O)2-, -NR′(CO)—, -C(O)NR—, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring contains an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; q and R r is replaced by; Z 6 is a bond, alkylene, —NR″—, —O—, —(alkylene-O)—, —C(O)—, —S(O)2—, —NR′(CO)—, or —C(O)NR—; wherein each R, R', and R'' is independently hydrogen or alkyl; each a, b, c, and d is independently an integer selected from 1 to 6; -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 5 Each alkylene of - and -Z6-, by itself or as part of another group, is R s and R t where R s is hydrogen or deuterium, and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl is substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; with the proviso that -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - at least one of which is not a bond; or a pharmaceutically acceptable salt thereof.

[0147] A3. In embodiment A3, the compound, or pharmaceutically acceptable salt thereof, for use in embodiment A1A, A1, A2, or A3-1 is that wherein the compound of formula (IA1), (IA), (I), or (Ia1), respectively, is of formula (Ia): [ka] (In the formula, R 1 , R 2 , R 2a , Hy, and L are as defined in embodiment A3-1; Degron is (a) a group of formula (i): [ka] (b) a group of formula (ii): [ka] (c) a group of formula (iii): [ka] (d) a group of formula (iv): [ka] (e) a group of formula (v): [ka] (f) a group of formula (vi): [ka] an E3 ubiquitin ligase ligand selected from: Ring A is represented by formula (a), (b) or (c): [ka] where: M is -NR 6 - and R 6 is hydrogen or alkyl; R x , R x1 , R y , R y1 , R y2 , W a , ring B, Y a , Z a , X 1 , X 2 , X 3 , X 4 , R 4 , R 5 , R aa , R bb , R cc , and R dd is as defined in A3-1).

[0148] A3A. In embodiment A3A, the compound for use in embodiment A3, or a pharmaceutically acceptable salt thereof, is Z 1 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -S(O)2NR-, -NR'S(O)2-, -(O-alkylene) a -, -(Alkylene-O) a -, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. h and R i is replaced by; Z 2 is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR'(CO)-, -(O-alkylene) b -, -(Alkylene-O) b -, -O(CH2)7-, -O(CH2)8-, cycloalkylene, or -heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. j and R k is replaced by; Z3 is a bond, alkylene, alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR''-, -(O-alkylene) c -, -(Alkylene-O) c -, cycloalkylene, spirocycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged hetero heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, -spiroheterocyclylene-(alkylene)-, or 11- to 13-membered spiroheterocyclylene, where each ring, by itself or as part of another group, is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. m and R n is replaced by; Z 4 is a bond, alkylene, alkynylene, -(alkylene-NR")-, -(NR"-alkylene)-, -O-, -C(O)-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, has an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. o and R p is replaced by; Z 5 is a bond, -alkylene, -NR″-, -O—, -C(O)—, -S(O)2-, -NR′(CO)—, -C(O)NR—, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring contains an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. q and R r is replaced by; Z 6 is a bond, alkylene, —NR″—, —O—, —(alkylene-O)—, —C(O)—, —S(O)2—, —NR′(CO)—, or —C(O)NR—; or a pharmaceutically acceptable salt thereof.

[0149] A4-1. In embodiment A4-1, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1alkylthio, pentafluorothio, haloalkylthio, amino, alkylamino, dialkylamino, cycloalkyl, cycloalkoxy, cycloalkylalkyl, bridged cycloalkyl, bridged cycloalkoxy, bridged cycloalkylalkyl, cyanoalkyl, cyanoalkoxy, alkoxyalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkoxy, acyl, azidocarbonyl, alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, substituted sulfonyl, substituted sulfinyl, substituted ureido, aryl, aralkyl, aryloxy, heteroaryl, heteroaralkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl aryl, heterocyclyloxy, fused heterocyclyl, fused heterocyclyloxy, or fused heterocyclylalkyl, wherein cycloalkyl, by itself or as part of cycloalkoxy and cycloalkylalkyl; aryl, by itself or as part of aralkyl and aryloxy; heteroaryl, by itself or as part of heteroaralkyl and heteroaryloxy; heterocyclyl, by itself or as part of heterocyclylalkyl and heterocyclyloxy; bridged cycloalkyl, by itself or as part of bridged cycloalkoxy and bridged cycloalkylalkyl; and fused heterocyclyl, by itself or as part of fused heterocyclylalkyl and fused heterocyclyloxy, are substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0150] A4-2. In embodiment A4-2, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1is aryl, heteroaryl, heterocyclyl, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF3, -SF5, fused heterocyclyl, bridged cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, aminoalkoxy, alkoxycarbonyl, alkylcarbonylamino, acyl, azidocarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylamino and substituted sulfonyl, wherein aryl (alone and with arylalkyl), heteroaryl (alone and with heteroaryloxy), heterocyclyl, fused heterocyclyl, bridged cycloalkyl (alone and with cycloalkylalkyl), and heterocyclyl (alone and with heterocyclylalkyl) are substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0151] In a subembodiment of embodiment A4-2, R 1 is phenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2,3-dihydrobenzofuranyl, benzodihydropyranyl, 1,4-benzodioxanyl, 2,3-dihydrofuro[3,2-c]pyridine, 2,3-dihydrofuro[2,3-c]pyridine, or 1,2,3,4-tetrahydroquinolinyl, where each ring is substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0152] A4-3. In embodiment A4-3, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is aryl, heteroaryl, heterocyclyl, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF3, or -SF5, each ring substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0153] In a subembodiment of embodiment A4 and 3, R 1 is phenyl (substituted with hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, or haloalkoxy), pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl (substituted with hydrogen or alkyl), tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl (substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano), cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl, or dimethylaminomethyl.

[0154] A4-4. In embodiment A4-4, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is alkylthio (such as methylthio).

[0155] A4-5. In embodiment A4-5, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is pentafluorothio.

[0156] A4-6. In embodiment A4-6, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is haloalkylthio (such as trifluoromethylthio).

[0157] A4-7. In embodiment A4-7, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 However, it is an amino acid.

[0158] A4-8. In embodiment A4-8, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is alkylamino (such as methylamino).

[0159] A4-9. In embodiment A4-9, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a dialkylamino (such as dimethylamino).

[0160] A4-10. In embodiment A4-10, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkyl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-10, cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl, each ring substituted with 1 or 2 substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0161] A4-11. In embodiment A4-11, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R1 is cycloalkoxy, wherein the cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-11, the cycloalkyloxy is cyclopropyloxy, cyclobutyloxy, or cyclopentyloxy, wherein each cycloalkyl ring of the cycloalkyloxy is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0162] A4-12. In embodiment A4-12, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkylalkyl, where cycloalkyl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-12, cycloalkylalkyl is cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, where each ring of cycloalkylalkyl is substituted with 1 or 2 substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0163] A4-13. In embodiment A4-13, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a bridged cycloalkyl (such as bicyclo[1.1.1]pent-1-yl or bicyclo[2.2.1]heptyl), wherein the bridged cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-13, the bridged cycloalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0164] A4-14. In embodiment A4-14, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a bridged cycloalkoxy (such as bicyclo[1.1.1]pent-1-yloxy or bicyclo[2.2.1]heptyloxy) wherein the bridged cycloalkyl of the bridged cycloalkoxy is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-14, the bridged cycloalkyloxy is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0165] A4-15. In embodiment A4-15, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a bridged cycloalkylalkyl (such as bicyclo[1.1.1]pent-1-ylmethyl or bicyclo[2.2.1]heptylmethyl), wherein the bridged cycloalkyl of the bridged cycloalkylalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-15, the bridged cycloalkylalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0166] A4-16. In embodiment A4-16, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-16, R 1 is cyanomethyl or cyanoethyl.

[0167] A4-17. In embodiment A4-17, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is cyanoalkoxy (such as cyanomethoxy or cyanoethoxy).

[0168] A4-18. In embodiment A4-18, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-18, R 1 is methoxymethyl.

[0169] A4-19. In embodiment A4-19, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-19, R 1 is aminomethyl.

[0170] A4-20. In embodiment A4-20, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-20, R 1 is aminomethyloxy.

[0171] A4-21. In embodiment A4-21, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-21, R 1 is methylaminomethyl.

[0172] A4-22. In embodiment A4-22, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-22, R 1 is dimethylaminomethyl.

[0173] A4-23. In embodiment A4-23, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-23, R 1 is methylaminomethyloxy.

[0174] A4-24. In embodiments A4-24, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-24, R 1 is dimethylaminomethyloxy.

[0175] A4-25. In embodiments A4-25, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is acyl. In a subembodiment of embodiment A4-25, acyl is alkylcarbonyl (such as methylcarbonyl).

[0176] A4-26. In embodiments A4-26, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is an azidocarbonyl.

[0177] A4-27. In embodiments A4-27, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a subembodiment of embodiment A4-27, R 1 is methoxycarbonyl or ethoxycarbonyl.

[0178] A4-28. In embodiments A4-28, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is alkylcarbonylamino.

[0179] A4-29. In embodiments A4-29, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is an aminocarbonyl.

[0180] A4-30. In embodiment A4-30, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is alkylaminocarbonyl (such as methylaminocarbonyl).

[0181] A4-31. In embodiment A4-31, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a dialkylaminocarbonyl (such as dimethylaminocarbonyl).

[0182] A4-32. In embodiment A4-32, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is aminosulfonyl.

[0183] A4-33. In embodiment A4-33, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is alkylaminosulfonyl (eg, methylaminosulfonyl).

[0184] A4-34. In embodiments A4-34, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a dialkylaminosulfonyl (such as dimethylaminosulfonyl).

[0185] A4-35. In embodiments A4-35, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a substituted sulfonyl.

[0186] A4-36. In embodiments A4-36, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a substituted sulfinyl.

[0187] A4-37. In embodiments A4-37, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a substituted ureido.

[0188] A4-38. In embodiments A4-38, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is aryl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. 1is phenyl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a second subembodiment of embodiment A4-38, R 1 is phenyl substituted with one, two, or three substituents independently selected from hydrogen, methyl, fluoro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0189] A4-39. In embodiments A4-39, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 In a second subembodiment of embodiment A4-39, R is aralkyl (such as benzyl) and the aryl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. 1 is benzyl, wherein the phenyl of the benzyl is substituted with one, two, or three substituents independently selected from hydrogen, methyl, fluoro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0190] A4-40. In embodiments A4-40, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is heteroaryl, wherein the heteroaryl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. 1 In a second subembodiment of embodiment A4-40, R is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.1 is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one substituent selected from hydrogen and alkyl.

[0191] A4-41. In embodiment A4-41, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is heteroaralkyl, wherein the heteroaryl of the heteroaralkyl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-41, R 1 The heteroaryl of the heteroaralkyl is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0192] A4-42. In embodiments A4-42, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is heteroaryloxy, wherein heteroaryl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A4-42, R 1 The heteroaryl of the heteroaryloxy is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0193] A4-43. In embodiments A4-43, the compound for use in embodiments A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is heterocyclyl, wherein the heterocyclyl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. 1 is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0194] A4-44. In embodiments A4-44, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is heterocyclylalkyl, wherein the heterocyclyl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. 1 The heterocyclyl of heterocyclylalkyl is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0195] A4-45. In embodiments A4-45, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1is heterocyclyloxy, wherein the heterocyclyl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. 1 The heterocyclyl of the heterocyclyloxy is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0196] A4-46. In embodiments A4-46, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a fused heterocyclyl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. 1 is 2,3-dihydrobenzofuranyl, benzodihydropyranyl, 1,4-benzodioxanyl, 2,3-dihydrofuro[3,2-c]pyridine, 2,3-dihydrofuro[2,3-c]pyridine, or 1,2,3,4-tetrahydroquinolinyl, each of which is substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0197] A4-47. In embodiments A4-47, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a fused heterocyclyloxy, wherein the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0198] A4-48. In embodiments A4-48, the compound for use in embodiment A1A, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is a fused heterocyclylalkyl, wherein the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0199] A4-49. In embodiment A4-49, the compound for use in embodiment A1A, A2, A3-1, A3, A3A, or A4-1 through A4-48, or a pharmaceutically acceptable salt thereof, is R 1 but, [ka] and isomers thereof (R and / or S isomers, and / or geometric isomers).

[0200] A4-50. In embodiments A4-50, the compound for use in embodiments A1A, A1, A2, A3-1, A3, or A3A, or a pharmaceutically acceptable salt thereof, is R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano, or cycloalkyl, wherein cycloalkyl is substituted with 1 to 3 halo.

[0201] A4. In embodiment A4, the compound for use in embodiment A1A, A1, A2, A3-1, A3, A3A, or A4-50, or a pharmaceutically acceptable salt thereof, is R 1 is halo, haloalkyl, or haloalkoxy.

[0202] A5. In embodiment A5, the compound for use in any one of embodiments A1 through A3A, A4-50, and A4, or a pharmaceutically acceptable salt thereof, is R 1 But it is a halo.

[0203] A6. In embodiment A6, the compound for use in any one of embodiments A1 through A3A, A4-50, and A4, or a pharmaceutically acceptable salt thereof, is R 1 is haloalkyl.

[0204] A7. In embodiment A7, the compound for use in any one of embodiments A1 through A3A, A4-50, and A4, or a pharmaceutically acceptable salt thereof, is R 1 is haloalkoxy.

[0205] A8. In embodiment A8, the compound for use in any one of embodiments A1-A3A, A4-50, and A4-A7, or a pharmaceutically acceptable salt thereof, is R 1 is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

[0206] A9. In embodiment A9, the compound for use in any one of embodiments A1 through A3A, A4-50, and A4 through A8, or a pharmaceutically acceptable salt thereof, is R 1 is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

[0207] A10. In embodiment A10, the compound for use in any one of embodiments A1 to A3A, A4-50, A4, A5, A8, and A9, or a pharmaceutically acceptable salt thereof, is R 1 is chloro or bromo.

[0208] A11. In embodiment A11, the compound for use in any one of embodiments A1 through A3A, A4-50, A4, A6, A8, and A9, or a pharmaceutically acceptable salt thereof, is R 1 is difluoromethyl or trifluoromethyl.

[0209] A12. In embodiment A12, the compound for use in any one of embodiments A1 to A3A, A4-50, A4, A6, A8, A9, and A11, or a pharmaceutically acceptable salt thereof, is R 1 is trifluoromethyl.

[0210] A13. In embodiment A13, the compound for use in embodiment A1, A2, A3-1, A3, A3A, or A4-50, or a pharmaceutically acceptable salt thereof, is R 1 is alkyl, alkenyl, or alkynyl.

[0211] A14. In embodiment A14, the compound for use in embodiment A1, A2, A3-1, A3, A3A, A4-50, or A13, or a pharmaceutically acceptable salt thereof, is R 1 is methyl, ethyl, propyl, vinyl, propenyl, ethynyl, or propynyl.

[0212] A15. In embodiment A15, the compound for use in embodiment A1, A2, A3-1, A3, A3A, A13, A4-50, or A14, or a pharmaceutically acceptable salt thereof, is R 1 is methyl, ethyl, or propyl.

[0213] A16. In embodiment A16, the compound for use in embodiment A1, A2, A3-1, A3, A3A, A13, A4-50, or A14, or a pharmaceutically acceptable salt thereof, is R 1 is vinyl, propenyl, ethynyl, or propynyl.

[0214] A17. In embodiment A17, the compound for use in embodiment A1, A2, A3-1, A3, A3A, or A4-50, or a pharmaceutically acceptable salt thereof, is R 1 is an alkoxy.

[0215] A18. In embodiment A18, the compound for use in embodiment A1, A2, A3-1, A3, A3A, A4-50, or A17, or a pharmaceutically acceptable salt thereof, is R 1 is methoxy, ethoxy, or propoxy.

[0216] A19. In embodiment A19, the compound for use in embodiment A1, A2, A3-1, A3, A3A, or A4-50, or a pharmaceutically acceptable salt thereof, is R 1 is aryloxy (such as phenoxy).

[0217] A20. In embodiment A20, the compound for use in embodiment A1, A2, A3-1, A3, A3A, or A4-50, or a pharmaceutically acceptable salt thereof, is R 1 However, it is cyano.

[0218] A21. In embodiment A21, the compound for use in embodiment A1, A2, A3-1, A3, A3A, or A4-50, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkyl (such as cyclopropyl).

[0219] A22. In embodiment A22, the compound for use in embodiment A1, A2, A3-1, A3, A3A, or A4-50, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkyl substituted with 1 to 3 halo (such as fluorocyclopropyl or difluorocyclopropyl).

[0220] A23. In embodiment A23, the compound for use in any one of embodiments A1A and A1-A22, or a pharmaceutically acceptable salt thereof, is R 2 and R 2a is hydrogen.

[0221] A24. In embodiment A24, the compound for use in any one of embodiments A1A and A1-A22, or a pharmaceutically acceptable salt thereof, is R 2 and R 2a One of the atoms is deuterium, and the other is R 2 and R 2a The other of R is hydrogen, or 2 and R 2a are deuterium.

[0222] A25. In embodiment A25, the compound for use of any one of embodiments A1A and A1 through A24, or a pharmaceutically acceptable salt thereof, is any one of the following: Hy is heterocyclylene, phenylene, spiroheterocyclylene, bridged heterocyclylene, or cycloalkylene; and each of said rings is selected from the group consisting of R a , R b , and R c is substituted with R a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0223] A26. In embodiment A26, the compound for use in any one of embodiments A1A and A1-A25, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: Hy is R a , R b , and R c and R is a heterocyclylene substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0224] A27. In embodiment A27, the compound for use in any one of embodiments A1A and A1 through A26, or a pharmaceutically acceptable salt thereof, is such that the heterocyclylene of Hy is pyrrolidine-1,3-diyl or piperidine-1,4-diyl; and Hy is R a , R b , and Rc is substituted with R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy; R c is hydrogen, and L is bonded to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

[0225] A28. In embodiment A28, the compound for use in any one of embodiments A1A and A1-A27, or a pharmaceutically acceptable salt thereof, is such that the heterocyclylene of Hy is: [ka] and the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is bonded to L.

[0226] A29. In embodiment A29, the compound for use of any one of embodiments A1A and A1-A28, or a pharmaceutically acceptable salt thereof, is such that the heterocyclylene of Hy is: [ka] and the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is bonded to L.

[0227] A29a. In embodiment A29a, the compound for use in any one of embodiments A1A and A1 through A29, or a pharmaceutically acceptable salt thereof, is such that the heterocyclylene of Hy is: [ka] and the N atom of the piperidine-1,4-diyl ring is bonded to L.

[0228] A30. In embodiment A30, the compound for use of any one of embodiments A1A and A1-A25, or a pharmaceutically acceptable salt thereof, is R 1 wherein Hy is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. a , R b , and R c and wherein the heterocyclylene is a bridged heterocyclylene substituted with

[0229] A31. In embodiment A31, the compound for use of any one of embodiments A1A, A1 through A25, and A30, or a pharmaceutically acceptable salt thereof, is any one of the compounds wherein the bridged heterocyclylene of Hy is of the formula: [ka] and each ring is a ring of R a , R b , and R c is substituted with R c is hydrogen and L is attached to the nitrogen atom of each ring.

[0230] A32. In embodiment A32, the compound for use in embodiment A30 or A31, or a pharmaceutically acceptable salt thereof, is R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy.

[0231] A33. In embodiment A33, the compound for use in embodiment A30, A31, or A32, or a pharmaceutically acceptable salt thereof, is R b is hydrogen.

[0232] A34. In embodiment A34, the compound for use in any one of embodiments A1A and A1-A25, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: Hy is R a , R b , and R c is a cycloalkylene substituted with R ais deuterium, methyl, fluoro, methoxy, or hydroxy, and R b and R c is hydrogen.

[0233] A35. In embodiment A35, the compound for use of any one of embodiments A1A, A1 through A25, and A34, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is cyclohexylene.

[0234] A36. In embodiment A36, the compound for use of any one of embodiments A1A, A1 through A25, A34, and A35, or a pharmaceutically acceptable salt thereof, is any one of the above, wherein the cycloalkylene of Hy is: [ka] and [ka] represents a bond to NH, [ka] represents the bond of L.

[0235] A37. In embodiment A37, the compound for use in any one of embodiments A1A and A1 through A25, or a pharmaceutically acceptable salt thereof, is any one of the following: Hy is arylene; and arylene is R a , R b , and R c phenylene substituted with R a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0236] A38. In embodiment A38, the compound for use in any one of embodiments A1A and A1-A25, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: Hy is R a , R b, and R c and R is a spiroheterocyclylene (e.g., 2-azaspiro[3.3]heptan-2-yl) substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0237] A39. In embodiment A39, the compound for use of any one of embodiments A1A, A1 through A25, and A37, or a pharmaceutically acceptable salt thereof, is any one of the above, wherein the phenylene of Hy has the structure: [ka] is a 1,4-phenylene conforming to the formula [ka] represents a bond to NH, [ka] represents the bond of L.

[0238] A39a. In embodiment A39a, the compound for use in any one of embodiments A1A and A1-A24, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: Hy is R a , R b , and R c and R is a fused heterocyclylene substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0239] A39b. In embodiment A39b, the compound for use in any one of embodiments A1A and A1-A24, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: Hy is R a , R b , and R cand R is a bicyclic heterocyclylene substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0240] A40A. In embodiment A40A, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A2 to A39b is one in which the degron is an E3 ubiquitin ligase ligand of formula (i) or (ii) disclosed in embodiment A3-1.

[0241] A40. In embodiment A40, the compound, or pharmaceutically acceptable salt thereof, for use in any one of embodiments A2, A3-1, A3 through A39b, and A40A is one in which the degron has the formula (i): [ka] It is an E3 ubiquitin ligase ligand for .

[0242] A41. In embodiment A41, the compound for use in any one of embodiments A3-1, A3-A40, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is a group represented by the formula (a): [ka] It is based on the

[0243] A42. In embodiment A42, the compound for use in any one of embodiments A3-1, A3-A41, or a pharmaceutically acceptable salt thereof, is R 4 and R 5 are independently hydrogen or alkyl.

[0244] A43. In embodiment A43, the compound for use in any one of embodiments A3-1, A3-A42, or a pharmaceutically acceptable salt thereof, is R 4 and R5 is hydrogen.

[0245] A44. In embodiment A44, the compound for use in any one of embodiments A3-1, A3-A42, or a pharmaceutically acceptable salt thereof, is R 4 is hydrogen and R 5 is methyl.

[0246] A45. In embodiment A45, the compound for use in any one of embodiments A3-1 and A3-A41, or a pharmaceutically acceptable salt thereof, is R 4 and R 5 However, they form >C=O with the carbon to which they are attached.

[0247] A46. In embodiment A46, the compound for use in any one of embodiments A3-1 and A3-A40, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is a group represented by formula (b): [ka] It is based on the

[0248] A47. In embodiment A47, the compound for use in any one of embodiments A3-1, A3-A40, and A46, or a pharmaceutically acceptable salt thereof, is R 6 is hydrogen.

[0249] A48. In embodiment A48, the compound for use in any one of embodiments A3-1, A3-A40, and A46, or a pharmaceutically acceptable salt thereof, is R 6 is alkyl, preferably methyl.

[0250] A49. In embodiment A49, the compound for use in any one of embodiments A3-1 and A3-A40, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is a group represented by formula (c): [ka] It is based on the

[0251] A50A. In embodiment A50A, the compound for use in any one of embodiments A3-1, and A4-1 through A40, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0252] A50. In embodiment A50, the compound for use in any one of embodiments A3 to A40 and A50A, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0253] A51A. In embodiment A51A, the compound for use in any one of embodiments A3-1, A4-1 through A40, and A50A, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0254] A51. In embodiment A51, the compound for use in any one of embodiments A3 to A40 and A50, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0255] A52A. In embodiment A52A, the compound for use in any one of embodiments A3-1, A4-1 through A40, A50A, and A51A, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0256] A52. In embodiment A52, the compound for use in any one of embodiments A3 to A40, A50, and A51, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0257] A52a. In embodiment A52a, the compound for use of any one of embodiments A3-1 to A41, A45, and A50A to A52, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0258] A53. In embodiment A53, the compound for use in any one of embodiments A3-1 to A41, A45, and A50A to A52, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0259] A54. In embodiment A54, the compound for use in any one of embodiments A3-1 to A43, and A50A to A52, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0260] A55. In embodiment A55, the compound for use in any one of embodiments A3-1 to A43, and A50A to A52, or a pharmaceutically acceptable salt thereof, is an E3 ubiquitin ligase ligand of formula (i), wherein ring A is: [ka] It is what it is.

[0261] A56. In embodiment A56, the compound for use in any one of embodiments A3-1 to A40, A46, A48, and A50A to A52, or a pharmaceutically acceptable salt thereof, is such that ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0262] A57. In embodiment A57, the compound for use in any one of embodiments A3-1 to A40, A46, A48, and A50A to A52, or a pharmaceutically acceptable salt thereof, is such that ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0263] A58. In embodiment A58, the compound for use in any one of embodiments A3-1 to A48 and A50A to A54, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. aa , R bb , R cc and / or R ddis hydrogen unless specifically shown in the structures of formulas (i) and (ii), respectively.

[0264] A59. In embodiment A59, the compound for use in any one of embodiments A3-1 to A48 and A50A to A54, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.

[0265] A60. In embodiment A60, the compound for use in any one of embodiments A3-1 through A48, A50A through A54, A58, and A59, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

[0266] A61. In embodiment A61, the compound for use in any one of embodiments A3-1 to A48, A50A to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen and methyl.

[0267] A62. In embodiment A62, the compound for use in any one of embodiments A3-1 to A48, A50A to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen and methoxy.

[0268] A63. In embodiment A63, the compound for use in any one of embodiments A3-1 to A48, A50A to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen and fluoro.

[0269] A64. In embodiment A64, the compound for use in any one of embodiments A3-1 to A48, A50A to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.

[0270] A65. In embodiment A65, the compound for use in any one of embodiments A3-1 to A48, A50A to A54, A58, and A60, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen and trifluoromethoxy.

[0271] A66. In embodiment A66, the compound for use in any one of embodiments A3-1 to A48, A50A to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl.

[0272] A67. In embodiment A67, the compound for use in any one of embodiments A2, A3-1 to A39b, and A40A, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: [ka] It is an E3 ubiquitin ligase ligand for .

[0273] A68. In embodiment A68, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67, or a pharmaceutically acceptable salt thereof, comprises Y a However, it is CH.

[0274] A69. In embodiment A69, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67, or a pharmaceutically acceptable salt thereof, comprises Y a is N.

[0275] A70. In embodiment A70, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A69, or a pharmaceutically acceptable salt thereof, is Z a is a bond, —NH—, —O—, or —NHC(O)—.

[0276] A71. In embodiment A71, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A70, or a pharmaceutically acceptable salt thereof, is Z a is a bond, —NH—, or —NHC(O)—.

[0277] A72. In embodiment A72, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A71, or a pharmaceutically acceptable salt thereof, is Z a is a bond.

[0278] A73. In embodiment A73, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A71, or a pharmaceutically acceptable salt thereof, is Z a is —NH— or —NHC(O)—.

[0279] A74. In embodiment A74, the compound for use in any one of embodiments A3-1 to A39b, A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof, is Z a is -NH-.

[0280] A74a. In embodiment A74a, the compound for use in any one of embodiments A3-1 to A39b, A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof, is Z a is -NHC(O)-.

[0281] A75. In embodiment A75, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof, is any one of the compounds wherein ring B is R ee and R ff and phenylene substituted with .

[0282] A76. In embodiment A76, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof, is any one of the compounds wherein ring B is R ee and R ff and wherein the cyclylaminylene is substituted with

[0283] A77. In embodiment A77, the compound for use of any one of embodiments A3-1 through A39b, A40A, and A67 through A74a, or a pharmaceutically acceptable salt thereof, is any one of the following: Ring B is a 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, each heteroarylene ring containing 1 to 3 nitrogen ring atoms, and each ring is selected from the group consisting of R ee and R ff is replaced by

[0284] A78. In embodiment A78, the compound for use in any one of embodiments A3-1 to A39b, A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof, is any one of the compounds wherein ring B is R eeand R ff and R is a 5- or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with R.

[0285] A79. In embodiment A79, the compound for use of any one of embodiments A3-1 to A39b, A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof, is one in which ring B contains 1 to 3 nitrogen ring atoms (and no additional heteroatoms), and R ee and R ff and 9- or 10-membered fused bicyclic heteroarylene substituted with

[0286] A80. In embodiment A80, the compound for use of any one of embodiments A3-1 to A39b, A40A, A67 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof, is any one of the compounds wherein ring B is R ee and R ff and wherein the heteroaryl group is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms substituted with:

[0287] A81. In embodiment A81, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A80, or a pharmaceutically acceptable salt thereof, is such that the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0288] A82-1. In embodiment A82-1, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A81, or a pharmaceutically acceptable salt thereof, is such that the E3 ubiquitin ligase ligand of formula (ii) is: [ka] and ring B is a cyclylaminylene.

[0289] A82. In embodiment A82, the compound for use in any one of embodiments A3 to A39b, A40A, and A67 to A82-1, or a pharmaceutically acceptable salt thereof, is such that the E3 ubiquitin ligase ligand of formula (ii) is: [ka] and ring B is a cyclylaminylene.

[0290] A82A. In embodiment A82A, the compound for use in any one of embodiments A3-A39b, A40A, A67, A68, A70-A72, A77, and A79-A82-1, or a pharmaceutically acceptable salt thereof, is such that the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0291] A83. In embodiment A83, the compound for use in any one of embodiments A3 to A39b, A40A, and A67 to A82, or a pharmaceutically acceptable salt thereof, is such that the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0292] A83A. In embodiment A83A, the compound for use in any one of embodiments A3 through A39b, A40A, and A67, A69 through A72, A77, A79 through A82, and A83, or a pharmaceutically acceptable salt thereof, is such that the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0293] A84. In embodiment A84, the compound for use in any one of embodiments A3-1 through A39b, A40A, and A67 through A83A, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: ee and R ff are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy.

[0294] A85. In embodiment A85, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A83A, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.

[0295] A86. In embodiment A86, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A85, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.

[0296] A87. In embodiment A87, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, methyl, ethyl, and isopropyl.

[0297] A88. In embodiment A88, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen and methoxy.

[0298] A89. In embodiment A89, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.

[0299] A90. In embodiment A90, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff is hydrogen or fluoro, and R ee and R ff and the other is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl.

[0300] A91. In embodiment A91, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.

[0301] A92. In embodiment A92, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl.

[0302] A93. In embodiment A93, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff is hydrogen.

[0303] A94. In embodiment A94, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff However, it is Chloro.

[0304] A95. In embodiment A95, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff However, it is fluoro.

[0305] A96. In embodiment A96, the compound for use in any one of embodiments A3-1 to A39b, A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.

[0306] A96a. In embodiment A96a, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A2 to A39b is one in which the degron is an E3 ubiquitin ligase ligand of formula (iii), (iv), (v), or (vi).

[0307] A96b. In embodiment A96b, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A2 through A39b, and A96a, is one in which the degron is an E3 ubiquitin ligase ligand of formula (iv) or (v).

[0308] A96c. In embodiment A96c, the compound for use in any one of embodiments A2 through A39b, A96a, and A96b, or a pharmaceutically acceptable salt thereof, is R y , R y1 , and R y2 is 1-fluorocycloprop-1-yl, and W ais a bond, S, or methylene.

[0309] A96d. In embodiment A96d, the compound for use in any one of embodiments A3-1 through A39b and A96a through A96c, or a pharmaceutically acceptable salt thereof, is W a But it is S.

[0310] A97. In embodiment A97, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are bonds.

[0311] A98. In embodiment A98, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each independently selected from alkylene. In a subembodiment of embodiment A98, X 1 , X 2 , X 3 , and X 4 are methylene groups.

[0312] A99. In embodiment A99, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are -O-, respectively.

[0313] A100. In embodiment A100, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4are each independently selected from -(O-alkylene)-.

[0314] A101. In embodiment A101, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are each independently selected from -(alkylene-O)-.

[0315] A102. In embodiment A102, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are independently -(NR gg -alkylene)-.

[0316] A103. In embodiment A103, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 each independently represents -(alkylene-NR hh )-.

[0317] A104. In embodiment A104, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 However, [ka] It is what it is.

[0318] A105. In embodiment A105, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are each -NH-.

[0319] A106. In embodiment A106, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are each independently selected from -N(alkyl)-. In a subembodiment of embodiment A106, X 1 , X 2 , X 3 , and X 4 are each independently -N(methyl)- or -N(ethyl)-.

[0320] A107. In embodiment A107, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are each -C(=O)-.

[0321] A108. In embodiment A108, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X 4 are independently -NR jj C(=O)-.

[0322] A109. In embodiment A109, the compound for use in any one of embodiments A3-1 to A96, or a pharmaceutically acceptable salt thereof, comprises X 1 , X 2 , X 3 , and X4 are each independently -C(=O)NR kk - is what it is.

[0323] A110. In embodiment A110, the compound for use in any one of embodiments A3-1 to A96, A102, A103, A108, and A109, or a pharmaceutically acceptable salt thereof, is R gg , R hh , R jj and R kk are each independently hydrogen or alkyl.

[0324] A110a. In embodiment A110a, the compound for use in any one of embodiments A3-1 to A110 is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 In a subembodiment of A110a, the compound for use is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 In a subembodiment of A110a, the compound is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - at least four of which are not bonds.

[0325] A111. In embodiment A111, the compound for use in any one of embodiments A3-1 to A110a, or a pharmaceutically acceptable salt thereof, is Z 6 is -S(O)2-.

[0326] A112. In embodiment A112, the compound for use in any one of embodiments A3-1 to A111, or a pharmaceutically acceptable salt thereof, is Z 5is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by

[0327] A113. In embodiment A113, the compound for use in any one of embodiments A3-1 to A112, or a pharmaceutically acceptable salt thereof, is Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is substituted with Z 1 and X 1 Only one of the is a bond, and Z 1 and X 2 Only one of the is a bond, and Z 1 and X 3 Only one of the is a bond, and Z 1 and X 4 where only one of the is a bond (for clarity, X 1 , X 2 , X 3 , and X 4 If is not a bond, then X 1 , X 2 , X 3 , and X 4 as described in any one of embodiments A3-1 and A98 to A109).

[0328] A114. In embodiment A114, the compound for use in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are independently a bond, -(O-alkylene)-, -(NR gg -alkylene)-, [ka] , —NH—, or —N(alkyl)-, and R ggis hydrogen or alkyl, and each alkylene is independently optionally substituted with one or two fluoro (or X in ligands (iii)-(vi) 1 , X 2 , X 3 , and X 4 does not exist); Z 1 is a bond, alkylene, -(CO)NR-, -(O-alkylene) a -, -(Alkylene-O) a -, phenylene or heterocyclylene, each ring being R h and R i is replaced by; Z 2 is a bond, alkylene, -(O-alkylene) b -, -(Alkylene-O) b -, cycloalkylene, or heterocyclylene, each ring being R j and R k is replaced by; Z 3 is a bond, alkylene, —C(O)NR—, —NR′(CO)—, —O—, —NR″-, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, -spiroheterocyclylene-(alkylene)-, or monocyclic heteroarylene, and each ring, by itself or as part of another group, is R m and R n is replaced by; Z 4is a bond, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, and each ring, by itself or as part of another group, is selected from the group consisting of R o and R p is replaced by; Z 5 is a bond; Z 6 is -S(O)2-; Z 1 , Z 2 , Z 3 , and Z 4 Each alkylene in the group may be, by itself or as part of another group, R s and R t are independently substituted with

[0329] A115. In embodiment A115, the compound for use in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 is a bond, alkylene, cycloalkylene, or heterocyclylene, and each ring is j and R k is replaced by; Z 3 is a bond, alkylene, —C(O)NR—, —NR′(CO)—, —O—, —NR″—, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring ism and R n is replaced by; Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2-; Z 2 , Z 3 , and Z 4 Each alkylene in the s and R t is replaced by

[0330] A116. In embodiment A116, the compound for use in any one of embodiments A3-1 to A96d and A115, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is selected from R m and R n is replaced by; Z 4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0331] A117. In embodiment A117, the compound for use in any one of embodiments A3-1 to A96d, A115, and A116, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is alkylene, -O-, cycloalkylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0332] A118. In embodiment A118, the compound for use in any one of embodiments A3-1 to A96d and A115 to A117, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is alkylene, —O—, cycloalkylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy; o and R p is replaced by; Z 5is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0333] A119. In embodiment A119, the compound for use in any one of embodiments A3-1 to A96d and A115 to A118, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is alkylene, —O—, cycloalkylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy, preferably hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; o and R p (In a subembodiment, Z 4 is alkylene or -O-); Z 5is phenylene or monocyclic heteroarylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0334] A120. In embodiment A120, the compound for use in any one of embodiments A3-1 to A96d and A115, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 is cycloalkylene or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; j and R k is replaced by; Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is a bond, alkylene, or -O-; Z 5is phenylene, monocyclic heteroarylene (e.g., pyridinediyl), or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0335] A121. In embodiment A121, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A3-1 to A96d, A111, and A115 is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; j and R k is a heterocyclylene substituted with; Z 3 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is a heterocyclylene substituted with; Z 4 is a bond, alkylene, or -O-; Z 5 is phenylene or monocyclic heteroarylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0336] A122. In embodiment A122, the compound for use in any one of embodiments A3-1 to A96d, A97, A111, and A112, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 But R j and R k and preferably R j and R k are independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z 3 is a bond, alkylene, or -O-; Z 4 is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is R O and R p and preferably R O and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z 5 is phenylene or monocyclic heteroarylene, and each ring is R q and R r and preferably R q and R r are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z 6 is -S(O)2-; Z 3 The alkylene in the s and Rt is replaced by

[0337] A123. In embodiment A123, the compound for use in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, is Z 4 is heterocyclylene or spiroheterocyclylene, and each ring is R o and R p and preferably R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy.

[0338] A124. In embodiment A124, the compound for use in any one of embodiments A3-1 to A96d, A115, and A116, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 are bonds respectively; Z 3 is heterocyclylene and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 R is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; o and R p is a cycloalkylene substituted with; Z 5 is phenylene or monocyclic heteroarylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6is -S(O)2-.

[0339] A125. In embodiment A125, the compound for use in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, is X 1 and Z 1 Only one of or X 2 and Z 1 Only one of or X 3 and Z 1 Only one of or X 4 and Z 1 Only one of the is a bond.

[0340] A126. In embodiment A126, the compound for use in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds.

[0341] A127. In embodiment A127, the compound for use in any one of embodiments A3-1 to A96d, A125, and A126, or a pharmaceutically acceptable salt thereof, is Z 2 is heterocyclylene or bridged heterocyclylene, and each ring is R j and R k is replaced by

[0342] A128. In embodiment A128, the compound for use in any one of embodiments A3-1 to A96d, A125, and A126, or a pharmaceutically acceptable salt thereof, is Z 2 is a bond.

[0343] A129. In embodiment A129, the compound for use in any one of embodiments A3-1 to A96d and A125 to A128, or a pharmaceutically acceptable salt thereof, is Z 3is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is a bond, -alkylene, -NR''-, -O-, -C(O)-, -S(O)2-, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is selected from the group consisting of R q and R r is replaced by; Z 6is a bond, alkylene, —NR″—, —O—, —(alkylene-O)—, —C(O)—, —S(O)2—, —NR′(CO)—, or —C(O)NR—; Z 3 , Z 4 , Z 5 , and Z 6 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0344] A130. In embodiment A130, the compound for use in any one of embodiments A3-1 to A96d and A125 to A129, or a pharmaceutically acceptable salt thereof, is Z 3 is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is a bond, -alkylene, -NR''-, -O-, -C(O)-, -S(O)2-, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is selected from the group consisting of R q and R r is replaced by; Z 6 is -S(O)2-; Z 3 , Z 4 , and Z 5 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0345] A130A. In embodiment A130A, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A3-1, A3A-A97, A111-A113, A126, and A128-A130 is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is -heterocyclylene-(alkylene)-, and heterocyclylene is R m and R nand the alkylene is substituted with R s and R t is replaced by; Z 4 is phenylene or monocyclic heteroarylene, and each ring is R o and R p is replaced by; Z 5 But R q and R r phenylene substituted with; Z 6 is -S(O)2-.

[0346] A131. In embodiment A131, the compound for use in any one of embodiments A3-1 to A96d and A125 to A130, or a pharmaceutically acceptable salt thereof, is Z 3 is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2-; Z 3 and Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0347] A131a. In embodiment A131a, the compound for use in any one of embodiments A3-1 to A96d and A125 to A130, or a pharmaceutically acceptable salt thereof, is Z 3 is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, and each ring, alone or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O)d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2; Z 3 and Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0348] A132. In embodiment A132, the compound for use in any one of embodiments A3-1 to A96d and A125 to A131, or a pharmaceutically acceptable salt thereof, is Z 3 is heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, and each ring, alone or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d -, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, by itself or as part of another group, is independently selected from R o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2; Z 3 and Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0349] A132A. In embodiment A132A, the compound for use in A132, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is -heterocyclylene-(alkylene)-, and heterocyclylene is R m and R n and the alkylene is substituted with R s and R t are independently substituted with; Z 4is phenylene or monocyclic heteroarylene, and each ring is R o and R p is replaced by; Z 5 But R q and R r phenylene substituted with; Z 6 is -S(O)2.

[0350] A133. In embodiment A133, the compound for use in any one of embodiments A3-1 to A96d, A125 to A131, and A132, or a pharmaceutically acceptable salt thereof, is Z 3 is heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, and each ring, alone or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 is alkylene, —O—, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, has an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; o and R p is replaced by; Z 5is phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring has an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; q and R r is replaced by; Z 6 is -S(O)2; Z 3 and Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0351] A134. In embodiment A134, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A3-1 to A96d, A125 to A131, and A132 to A133 is Z 3 is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is R m and R n is replaced by; Z 4 is alkylene, -O-, heterocyclylene, -(alkylene)-heterocyclylene-, -(alkylene)-bridged heterocyclylene-, and each ring, by itself or as part of another group, is R o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2; Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t is replaced by

[0352] A135. In embodiment A135, the compound for use in any one of embodiments A3-1 to A113 and A115 to A134, or a pharmaceutically acceptable salt thereof, is -Z 5 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. q and R r replaced with [ka] (i.e., Z 5 is phenylene, where Z 4 and Z 6 is attached to the meta position of the phenylene ring).

[0353] A136. In embodiment A136, the compound for use in any one of embodiments A3-1 to A113 and A115 to A135, or a pharmaceutically acceptable salt thereof, is -Z 5 R is independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy. q and R r replaced with [ka] It is what it is.

[0354] A137. In embodiment A137, the compound for use in any one of embodiments A3-1 to A113 and A115 to A136, or a pharmaceutically acceptable salt thereof, is -Z 5 R is independently selected from hydrogen, deuterium, or fluoro. q and R r replaced with [ka] It is what it is.

[0355] A137a. In embodiment A137a, the compound for use in any one of embodiments A3-1 to A113 and A115 to A137, or a pharmaceutically acceptable salt thereof, is -Z 5 -but, [ka] (In a subembodiment, -Z 5 -but, [ka] (It is).

[0356] A137b. In embodiment A137b, the compound for use in any one of embodiments A3-1 to A113 and A115 to A136, or a pharmaceutically acceptable salt thereof, is -Z 5 -but, [ka] It is what it is.

[0357] A138. In embodiment A138, the compound for use in any one of embodiments A3-1 to A113, A115 to A132, A133, and A134, or a pharmaceutically acceptable salt thereof, is -Z 5 R is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. q and R r and monocyclic heteroarylene substituted with (such as imidazole-1,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, or pyridine-3,5-diyl).

[0358] A139. In embodiment A139, the compound for use in any one of embodiments A3-1 to A113, A115 to A132, A133, A134, and A138, or a pharmaceutically acceptable salt thereof, is -Z 5is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, or pyridine-3,5-diyl, and each ring is independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy. q and R r is replaced by

[0359] A140. In embodiment A140, the compound for use in any one of embodiments A3-1 to A113, A115 to A132, A133, A134, A138, and A139, or a pharmaceutically acceptable salt thereof, is -Z 5 is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, or pyridine-3,5-diyl, and each ring is independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy. q and R r is replaced by

[0360] A141. In embodiment A141, the compound for use in any one of embodiments A3-1 to A113, A115 to A118, A120, A123, and A125 to A132, A133, and A134, or a pharmaceutically acceptable salt thereof, is -Z 5 R is independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy. q and R r and heterocyclylene substituted with:

[0361] A142. In embodiment A142, the compound for use in any one of embodiments A3-1 to A113, A115 to A118, A120, A123, A125 to A132, A133, A134, and A141, or a pharmaceutically acceptable salt thereof, is -Z5 - is azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl.

[0362] A143. In embodiment A143, the compound for use in any one of embodiments A3-1 to A134, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 Each alkylene by itself, when present, is s and R t and methylene, ethylene, or propylene substituted with .

[0363] A144. In embodiment A144, the compound for use in any one of embodiments A3-1 to A134 and A143, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 Each alkylene by itself, when present, s and R t and methylene substituted with .

[0364] A145. In embodiment A145, the compound for use in any one of embodiments A3-1 to A134, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 alone or Z 1 -(O-alkylene) a -, Z 1 In the -(alkylene-O) a -, Z 2 -(O-alkylene) b -, Z 2 In the -(alkylene-O) b -, Z 3 -(O-alkylene)c -, Z 3 In the -(alkylene-O) c -, Z 4 -(O-alkylene) d -, Z 4 In the -(alkylene-O) d - and Z 6 as part of -(alkylene-O)- in which, when present, is ethylene or propylene; as part of -(alkylene-NR'')- and -(NR''-alkylene)-, when present, is methylene, ethylene or propylene; -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, -(alkylene)-phenylene-, -phenylene-(alkylene)-, -(alkylene)-monocyclic heteroaryl methylene, ethylene, propylene, or butylene as part of the alkylene-, -monocyclic heteroarylene-(alkylene)-, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiroheterocyclylene-, and -spiroheterocyclylene-(alkylene)-, each alkylene group being s and R t is replaced by

[0365] A146. In embodiment A146, the compound for use in any one of embodiments A3-1 to A134 and A145, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 alone or Z 1 -(O-alkylene) a -, Z 1 In the -(alkylene-O) a -, Z 2 -(O-alkylene) b -, Z 2 In the -(alkylene-O) b -, Z 3 -(O-alkylene) c -, Z3 In the -(alkylene-O) c -, Z 4 -(O-alkylene) d -, Z 4 In the -(alkylene-O) d - and Z 6 in which, as part of -(alkylene-O)-, when present, it is ethylene; as part of -(alkylene-NR'')- and -(NR''-alkylene)-, when present, it is methylene; and as part of -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, -(alkylene)-phenylene-, -phenylene-(alkylene)-, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiroheterocyclylene-, and -spiroheterocyclylene-(alkylene)-, when present, it is methylene.

[0366] A147. In embodiment A147, the compound for use in any one of embodiments A3-1 to A146, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 where each R, R', and R'', if present, is independently hydrogen or methyl.

[0367] A148. In embodiment A148, the compound for use in any one of embodiments A3-1 to A147, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 wherein each R, R', and R'', if present, is hydrogen.

[0368] A149. In embodiment A149, the compound for use in any one of embodiments A1 to A147, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 wherein each R, R', and R'', if present, is methyl.

[0369] A150. In embodiment A150, the compound for use in any one of embodiments A3-1 to A149, or a pharmaceutically acceptable salt thereof, is Z 2 , Z 3 , and Z 4 Each cycloalkylene, if present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0370] A151. In embodiment A151, the compound for use in any one of embodiments A3-1 to A150, or a pharmaceutically acceptable salt thereof, is Z 2 , Z 3 , and Z 4 where each cycloalkylene, if present, is independently selected from 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene.

[0371] A152. In embodiment A152, the compound for use of any one of embodiments A3-1 to A151, or a pharmaceutically acceptable salt thereof, is such that heteroarylene is monocyclic heteroarylene and Z 1 , Z 3 , Z 4 , and Z 5 and each monocyclic heteroarylene, if present, is independently selected from imidazoldiyl, pyridinediyl, and pyrimidinediyl, unless otherwise stated in any of the above embodiments.

[0372] A153. In embodiment A153, the compound for use of any one of embodiments A3-1 to A152, or a pharmaceutically acceptable salt thereof, is such that heteroarylene is monocyclic heteroarylene and Z 1 , Z 3 , Z 4 , and Z 5 and each monocyclic heteroarylene, if present, is independently selected from imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, and pyridine-3,5-diyl, unless otherwise stated in any of the above embodiments.

[0373] A154. In embodiment A154, the compound for use in any one of embodiments A3-1 to A153, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 3 , Z 4 , and Z 5 where each phenylene, if present, is independently selected from 1,3-phenylene and 1,4-phenylene, unless otherwise stated in any of the above embodiments.

[0374] A155. In embodiment A155, the compound for use in any one of embodiments A3-1 to A154, or a pharmaceutically acceptable salt thereof, is Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 Each heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, when present, is [ka] and each ring is optionally substituted with 1, 2, or 3 fluoro unless otherwise stated in any of the above embodiments.

[0375] A156. In embodiment A156, the compound for use in any one of embodiments A3-1 to A155, or a pharmaceutically acceptable salt thereof, is Z 1 , Z2 , Z 3 , Z 4 , and Z 5 Each heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, when present, is [ka] and each ring is optionally substituted with 1 or 2 fluoro unless otherwise stated in any of the above embodiments.

[0376] A157. In embodiment A157, the compound for use in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, may comprise any one of L (when degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when degron is a group of formula (i) or (ii)) is independently [ka] [ka] It is what it is.

[0377] A158. In embodiment A158, the compound for use in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, may comprise any one of L (when degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when degron is a group of formula (i) or (ii)) is independently [ka] It is what it is.

[0378] A159. In embodiment A159, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, and A132 to A134, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] and each R m , R n , and R q is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano. q and R m are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl.

[0379] A160. In embodiment A160, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A159, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] and each R m , R n , and R q are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, and cyano (i.e., R r is hydrogen).

[0380] A161. In embodiment A161, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0381] A162. In embodiment A162, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0382] A164. In embodiment A164, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0383] A165. In embodiment A165, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z5 -Z 6 -but, [ka] It is what it is.

[0384] A166. In embodiment A166, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0385] A167. In embodiment A167, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0386] A168A. In embodiment A168A, the compound for use in any one of embodiments A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0387] A168. In embodiment A168, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A159 to A168A is [ka] but, [ka] It is what it is.

[0388] A160A. In embodiment A160A, the compound for use in any one of embodiments A3-1, A3A-A97, A111-A113, A126, and A128-A130A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] and each R m , R n , and R q are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, and cyano (i.e., R r is hydrogen).

[0389] A161A. In embodiment A161A, the compound for use in any one of embodiments A3-1, A3A-A97, A111-A113, A126, A128-A130A, and A160A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0390] A162A. In embodiment A162A, the compound for use in any one of embodiments A3-1, A3A-A97, A111-A113, A126, A128-A130A, and A160A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0391] A163A. In embodiment A163A, the compound for use in any one of embodiments A3-1, A3A-A97, A111-A113, A126, A128-A130A, and A160A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0392] A164A. In embodiment A164A, the compound for use in any one of embodiments A3-1, A3A through A97, A111 through A113, A126, and A128 through A130A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0393] A165A. In embodiment A165A, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments A160A-165A is [ka] but, [ka] It is what it is.

[0394] A169. In embodiment A169, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, and A159 to A168, or a pharmaceutically acceptable salt thereof, is Z 4 But R s and R t is alkylene substituted with R s and R t is hydrogen.

[0395] A170. In embodiment A170, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, and A169, or a pharmaceutically acceptable salt thereof, is Z 4 wherein the alkylene is —CH—, —(CH)—, —(CH)—, —CH(CH)—, —CH—CH(CH)—CH—, or —CH—C(CH)—CH—.

[0396] A171. In embodiment A171, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, A169, and A170, or a pharmaceutically acceptable salt thereof, is Z 4 The alkylene is -CH2-.

[0397] A172. In embodiment A172, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, and A159 to A168, or a pharmaceutically acceptable salt thereof, is Z 4 is -O-.

[0398] A173. In embodiment A173, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, and A159 to A168, or a pharmaceutically acceptable salt thereof, is Z 4 But R s and R t is alkylene substituted with R s is hydrogen or deuterium, and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, or cyano.

[0399] A174. In embodiment A174, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, and A173, or a pharmaceutically acceptable salt thereof, is Z 4 But R s and R t is alkylene substituted with R s is hydrogen or deuterium, and R t are hydrogen and deuterium.

[0400] A175. In embodiment A175, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, and A173, or a pharmaceutically acceptable salt thereof, is Z 4 But R s and R t is alkylene substituted with R s is hydrogen and R t is haloalkyl.

[0401] A176. In embodiment A176, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, and A173, or a pharmaceutically acceptable salt thereof, is Z 4 But R s and R t is alkylene substituted with Rs is hydrogen and R t is a hydroxy group.

[0402] A177. In embodiment A177, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, and A173, or a pharmaceutically acceptable salt thereof, is Z 4 But R s and R t is alkylene substituted with R s is hydrogen and R t is an alkoxy.

[0403] A178. In embodiment A178, the compound for use in any one of embodiments A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, A173, and A175 to A177, or a pharmaceutically acceptable salt thereof, is Z 4 is —CH(CHF2)—, —CH(CF3)—, —C(CH3)(CF3)—, —CH(CH2CF3)—, —CH(CH2CH2CF3)—, —CH(CH(CF3)2)—, —CH(CH2OH)—, —CH(CHOCH3)—, —CH(CHO-ethyl)-, or —CH(CH2CN)—, —CH2-CH(CF3)—CH2—, —CH2-CH(OH)—CH2—, or —CH2-CH(OCH3)—CH2—.

[0404] A179. In embodiment A179, the compound for use in any one of A3-1 to A114, A125 to A130, A131 to A132, A133 to A146, and A159 to A168, or a pharmaceutically acceptable salt thereof, is Z 4 is -(alkylene)-heterocyclylene-, and heterocyclylene is R o and R p is replaced by

[0405] A180. In embodiment A180, the compound for use of any one of A3-1 to A114, A125 to A130, A131 to A132, A133 to A146, A159 to A168, and A179, or a pharmaceutically acceptable salt thereof, is Z 4 is -(CH2)-heterocyclylene-, and heterocyclylene is R o and R p is replaced by

[0406] A181. In embodiment A181, the compound for use in any one of A3-1 to A114, A125 to A130, A131 to A132, A133 to A146, A159 to A168, A179, and A180, or a pharmaceutically acceptable salt thereof, is Z 4 but, [ka] It is what it is.

[0407] A182A. In embodiment A182A, the compound for use in any one of A3-1 to A121, A125 to A130, A131, A132, A133 to A137b, A159 to A168, A160A to A165A, and A179 to A181, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0408] A182. In embodiment A182, the compound for use in any one of A3-1 to A121, A125 to A130, A131, A132, A133 to A137b, A159 to A168, A160A to A165A, and A179 to A182A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0409] A183A. In embodiment A183A, the compound for use in any one of A3-1 to A121, A125 to A130, A131, A132, A133 to A137b, A159 to A168, A160A to A165A, and A179 to A182A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0410] A183. In embodiment A183, the compound for use in any one of A3-1 to A121, A125 to A130, A131, A132, A133 to A137b, A159 to A168, A160A to A165A, and A179 to A183A, or a pharmaceutically acceptable salt thereof, is -Z 3 -Z 4 -Z 5 -Z 6 -but, [ka] It is what it is.

[0411] A184. In embodiment A184, the compound for use in any one of A3-1 to A96d, or a pharmaceutically acceptable salt thereof, comprises L (when degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when degron is a group of formula (i) or (ii)) is independently [ka] It is what it is.

[0412] A185. In embodiment A185, the compound for use in any one of A3-1 to A96d and A184, or a pharmaceutically acceptable salt thereof, comprises L (when degron is a group of formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when degron is a group of formula (i) or (ii)) is independently [ka] It is what it is.

[0413] A186A. In embodiment A186A, the compound for use in any one of embodiments A3-1 to A96 and A97 to A185, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: [ka] an E3 ubiquitin ligase ligand selected from R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, and R ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0414] A186. In embodiment A186, the compound, or pharmaceutically acceptable salt thereof, for use in any one of embodiments A3-1 to A96, and A97 to A186A is selected from the group consisting of: [ka] an E3 ubiquitin ligase ligand selected from R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, and R ffis hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0415] A187. In embodiment A187, the compound, or pharmaceutically acceptable salt thereof, for use in any one of embodiments A3-1 to A96, and A97 to A186 is selected from the group consisting of: [ka] The E3 ligase ligand is selected from the group consisting of:

[0416] A188. In embodiment A188, the compound for use in any one of embodiments A3-1 to A96, and A97 to A186, or a pharmaceutically acceptable salt thereof, is such that the degron is: [ka] E3 ubiquitin ligase ligands of each R ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, preferably methyl; and each R ff When present, is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0417] A189. In embodiment A189, the compound, or pharmaceutically acceptable salt thereof, for use in any one of embodiments A3-1 to A96, and A97 to A186 is selected from the group consisting of: [ka] It is an E3 ubiquitin ligase ligand for .

[0418] A190. In embodiment A190, the compound for use in any one of embodiments A3-1 to A185, or a pharmaceutically acceptable salt thereof, is R x and R x1is hydrogen.

[0419] For clarity, embodiment A includes combinations of embodiment A and any sub-embodiments thereof.

[0420] For clarity, when an embodiment refers to multiple preceding embodiments of varying scope, the scope of the preceding embodiment is controlling. That is, only groups falling within the scope of a group recited in a preceding embodiment should be selected from the embodiment to which it refers. For example, of the groups recited in embodiment A8, all groups recited in A8 should be selected for embodiment A1, but R in embodiment A5 should be selected for embodiment A6. 1 Since the scope of R is limited to halo, only fluoro, chloro, and bromo should be selected for A5; 1 Since the scope is limited to haloalkyl, only difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl should be selected for A6.

[0421] Additional embodiments B1 to B157 are as follows:

[0422] B1A. In embodiment B1A, the compound for use of the first aspect, or a pharmaceutically acceptable salt thereof, wherein the compound (or any one of the embodiments thereof disclosed in the Summary of the Invention) further comprises a linker attached to Hy of the CDK2-binding moiety of Formula (A1).

[0423] B1. In embodiment B1, the compound for use of the second aspect, or a pharmaceutically acceptable salt thereof, is such that the compound further comprises a linker attached to Hy of the CDK2-binding moiety of Formula (A).

[0424] B2-1 to B2-40. In embodiments B2-1 to B2-40, compounds for use in embodiment B1 are those in which the moiety of formula (A) is as disclosed in embodiments A4-50 and A4 to A39b, respectively, or a pharmaceutically acceptable salt thereof.

[0425] B2-41 to B2-112. In embodiments B2-41 to B2-110, compounds for use in embodiment B1A are those in which the moiety of formula (A1) is as disclosed in embodiments A4-1 to A4-50, A4, and A23 to A39b, respectively, or a pharmaceutically acceptable salt thereof.

[0426] B3. In embodiment B3, the compound for use of any one of embodiments B1A, B1, and B2-1 through B2-112, or a pharmaceutically acceptable salt thereof, further comprises an E3 ubiquitin ligase ligand, wherein the ligand is attached to a linker, and the compound has formula (II): [ka] is a compound of degron 1 are E3 ubiquitin ligase ligands.

[0427] B4. In embodiment B4, the compound for use of any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is one wherein the linker comprises one or more -SO2-.

[0428] B5. In embodiment B5, the compound for use in any one of embodiments B1A-B4, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one or more -SO2-, wherein one of the one or more -SO2- is attached to Hy of formula (A1), (A), and (II). In a subembodiment of embodiment B5, the linker comprises one or more -SO2-, wherein one of the one or more -SO2- is attached to a nitrogen in Hy of formula (A1), (A), and (II).

[0429] B6. In embodiment B6, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of the embodiments and B1A-B5 is one in which the linker contains one or two -SO2-.

[0430] B7. In embodiment B7, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of the embodiments and B1A-B6 is one in which the linker comprises one -SO2-.

[0431] B8. In embodiment B8, the compound for use of any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one or more rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0432] B8a. In embodiment B8a, the compound for use in any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one or more rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0433] B9. In embodiment B9, the compound for use in any one of embodiments B1A-B3 and B8, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises 1 to 4 rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with 1 or 2 substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0434] B9a. In embodiment B9a, the compound for use in any one of embodiments B1A-B3 and B8a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises 1 to 4 rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with 1 or 2 substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0435] B10. In embodiment B10, the compound for use of any one of embodiments B1A through B3, B8, and B9, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one or two rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. In a subembodiment of B10, the linker comprises one ring. In a second subembodiment of B10, the linker comprises two rings.

[0436] B10a. In embodiment B10a, the compound for use in any one of embodiments B1A-B3, B8a, and B9a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one or two rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino. In a subembodiment of B10a, the linker comprises one ring. In a second subembodiment of B10a, the linker comprises two rings.

[0437] B11. In embodiment B11, the compound for use of any one of embodiments B1A through B3, B8, and B9, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0438] B11a. In embodiment B11a, the compound for use in any one of embodiments B1A-B3, B8a, and B9a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0439] B12. In embodiment B12, the compound for use of any one of embodiments B4-B7, or a pharmaceutically acceptable salt thereof, is one wherein the linker further comprises one or more rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0440] B12a. In embodiment B12a, the compound for use in any one of embodiments B4-B7, or a pharmaceutically acceptable salt thereof, is one in which the linker further comprises one or more rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0441] B13. In embodiment B13, the compound for use of any one of embodiments B4 through B7 and B12, or a pharmaceutically acceptable salt thereof, is one wherein the linker further comprises 1 to 4 rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with 1 or 2 substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0442] B13a. In embodiment B13a, the compound for use in any one of embodiments B4 through B7 and B12a, or a pharmaceutically acceptable salt thereof, is one in which the linker further comprises 1 to 4 rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with 1 or 2 substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0443] B14. In embodiment B14, the compound for use of any one of embodiments B4 through B7 and B12, or a pharmaceutically acceptable salt thereof, is one wherein the linker further comprises one or two rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0444] B14a. In embodiment B14a, the compound for use in any one of embodiments B4 through B7 and B12a, or a pharmaceutically acceptable salt thereof, is one in which the linker further comprises one or two rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0445] B15. In embodiment B15, the compound for use of any one of embodiments B4 through B7 and B12, or a pharmaceutically acceptable salt thereof, is one wherein the linker further comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0446] B15a. In embodiment B15a, the compound for use in any one of embodiments B4 through B7 and B12a, or a pharmaceutically acceptable salt thereof, is one in which the linker further comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0447] B16. In embodiment B16, the compound for use in any one of embodiments B8 through B15a, or a pharmaceutically acceptable salt thereof, is one in which the rings are independently selected from phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, and each ring is optionally substituted as described therein.

[0448] B17. In embodiment B17, the compound for use in any one of embodiments B12-B16, or a pharmaceutically acceptable salt thereof, is one in which one of the rings is bonded to -SO2- which is bonded to Hy of formula A or A1. In a subembodiment of embodiment B17, one of the rings is bonded to -SO2-, Hy includes a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0449] B18. In embodiment B18, the compound for use of any one of embodiments B12-B17, or a pharmaceutically acceptable salt thereof, is one in which phenylene is bonded to —SO— which is bonded to Hy of formula A or A1, and is optionally substituted as described therein. In a subembodiment of embodiment B18, phenylene is bonded to —SO—, Hy includes a substitutable nitrogen atom, and —SO— is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0450] B19. In embodiment B19, the compound for use in any one of embodiments B12-B17, or a pharmaceutically acceptable salt thereof, is one in which the heteroarylene is bonded to —SO— which is bonded to Hy of formula A or A1, and is optionally substituted as described therein. In a subembodiment of embodiment B19, the heteroarylene is bonded to —SO—, Hy includes a substitutable nitrogen atom, and —SO— is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0451] B20. In embodiment B20, the compound for use of any one of embodiments B12-B17, or a pharmaceutically acceptable salt thereof, is one in which the heterocyclylene is bonded to —SO—, which is bonded to Hy of formula A or A1, and is optionally substituted as described therein. In a subembodiment of embodiment B20, the heterocyclylene is bonded to —SO—, Hy includes a substitutable nitrogen atom, and —SO— is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0452] B21. In embodiment B21, the compound for use in any one of embodiments B12-B17, or a pharmaceutically acceptable salt thereof, is one in which the bridged heterocyclylene is bonded to -SO2- which is bonded to Hy of formula A or A1, and is optionally substituted as described therein. In a subembodiment of embodiment B21, the bridged heterocyclylene is bonded to -SO2-, Hy includes a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0453] B22. In embodiment B22, the compound for use in any one of embodiments B12-B17, or a pharmaceutically acceptable salt thereof, is one in which the spiroheterocyclylene is bonded to —SO—, which is bonded to Hy of formula A or A1, and is optionally substituted as described therein. In a subembodiment of embodiment B22, the spiroheterocyclylene is bonded to —SO—, Hy includes a substitutable nitrogen atom, and —SO— is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0454] B23. In embodiment B23, the compound for use in any one of embodiments B8 through B22, or a pharmaceutically acceptable salt thereof, is one wherein two of said rings are adjacent to one another.

[0455] B23a. In embodiment B23a, the compound for use in embodiment B23, or a pharmaceutically acceptable salt thereof, is one in which the second ring is adjacent to the ring bonded to -SO2-.

[0456] B23b. In embodiment B23b, the compound for use in embodiment B23a, or a pharmaceutically acceptable salt thereof, is one in which the ring adjacent to the ring bonded to -SO2- is selected from heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, each ring being optionally substituted as described therein.

[0457] B24. In embodiment B24, the compound for use in any one of embodiments B8 to B23b, or a pharmaceutically acceptable salt thereof, is any one of the following: [ka] and each ring is substituted as defined therein.

[0458] B25. In embodiment B25, the compound for use in any one of embodiments B8 through B24, or a pharmaceutically acceptable salt thereof, is any one of the compounds described therein, wherein the rings described therein are independently selected from phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, wherein phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene are, respectively: [ka] and each ring is substituted as defined therein.

[0459] B26. In embodiment B26, the compound for use in any one of embodiments B8 to B25, or a pharmaceutically acceptable salt thereof, is such that phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene are each: [ka] and each ring is substituted as defined therein.

[0460] B27. In embodiment B27, the compound for use in any one of embodiments B8 through B26, or a pharmaceutically acceptable salt thereof, is such that phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene are each: [ka] and each ring is substituted as defined therein.

[0461] B28. In embodiment B28, the compound for use in any one of embodiments B8-B27, or a pharmaceutically acceptable salt thereof, is such that phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene are each: [ka] and each ring is substituted as defined therein.

[0462] B29. In embodiment B29, the compound for use in any one of embodiments B17-B28, or a pharmaceutically acceptable salt thereof, is a compound in which a phenylene, heteroarylene, or heterocyclylene is attached to —SO 2 — which is attached to Hy of formula A, each of which is: [ka] wherein each ring is substituted as defined therein. (For clarity, the bond on the right side of the ring is attached to -SO2-). In a subembodiment of embodiment B29, [ka] is bonded to -SO2-, Hy contains a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0463] B30. In embodiment B30, the compound for use in any one of embodiments B17 to B29, or a pharmaceutically acceptable salt thereof, is [ka] is attached to -SO2- which is attached to Hy of formula A or A1 and is substituted as defined therein. [ka] is bonded to -SO2-, Hy contains a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0464] B31. In embodiment B31, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments B17 to B29 is [ka] is attached to -SO2- which is attached to Hy of formula A or A1 and is substituted as defined therein. [ka] is bonded to -SO2-, Hy contains a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0465] B32. In embodiment B32, the compound for use in any one of embodiments B17 to B29, or a pharmaceutically acceptable salt thereof, is [ka] is attached to -SO2- which is attached to Hy of formula A or A1 and is substituted as defined therein. [ka] is bonded to -SO2-, Hy contains a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0466] B33. In embodiment B33, the compound for use in any one of embodiments B23b to B29, or a pharmaceutically acceptable salt thereof, is [ka] is attached to the ring attached to SO2 attached to Hy of formula A or A1. [ka] is bonded to -SO2-, Hy contains a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1.

[0467] B34. In embodiment B34, the compound for use in any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is any one of the compounds wherein the linker comprises one or more groups independently selected from ether, polyether, thioether, amide, sulfonamide, alkylene, alkenylene, alkynylene, carbonyl, —C(O)O—, —OC(O)—, —NH—, —N(alkyl)-, sulfinyl, ureido, thioureido, bicyclic heterocyclylene, and fused heterocyclylene, wherein the bicyclic heterocyclylene and fused heterocyclylene are selected from the group consisting of deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, amino, aryl, arylsulfonyl ... In one embodiment, the linker comprises five or six independently selected groups.

[0468] B35. In embodiment B35, the compound for use of any one of embodiments B1A-B3 and B34, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises 1 to 4 groups independently selected from those described in embodiment B34. In one embodiment, the linker comprises 4 independently selected groups.

[0469] B36. In embodiment B36, the compound for use of any one of embodiments B1A-B3 and B34, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises 1 to 3 groups independently selected from those described in embodiment B34. In one embodiment, the linker comprises 3 independently selected groups.

[0470] B37. In embodiment B37, the compound for use of any one of embodiments B1A-B3 and B34, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one or two groups independently selected from those described in embodiment B34. In one embodiment, the linker comprises two independently selected groups. In one embodiment, the linker comprises one group.

[0471] B38. In embodiment B38, the compound for use in any one of embodiments B4 to B33, or a pharmaceutically acceptable salt thereof, further comprises one or more groups independently selected from ether, polyether, thioether, -NH-, -N(alkyl)-, amide, sulfonamide, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, sulfinyl, ureido, thioureido, bicyclic heterocyclylene, and fused heterocyclylene, wherein bicyclic heterocyclylene and fused heterocyclylene are selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, amino, , alkylamino, and dialkylamino, wherein each alkylene is optionally substituted with one or two substituents, one of which is deuterium and the other of which is deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are optionally substituted with one or two substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0472] B39. In embodiment B39, the compound for use of any one of embodiments B38, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises 1 to 4 groups independently selected from those described in embodiment B38. In one embodiment, the linker comprises 4 independently selected groups.

[0473] B40. In embodiment B40, the compound for use in any one of embodiments B38 and B39, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises 1 to 3 groups independently selected from those described in embodiment B38. In one embodiment, the linker comprises 3 independently selected groups.

[0474] B41. In embodiment B41, the compound for use of any one of embodiments B38-B40, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one or two groups independently selected from those described in embodiment B38. In one embodiment, the linker comprises two independently selected groups.

[0475] B42. In embodiment B42, the compound for use of any one of embodiments B38 to B41, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises one group selected from those described in embodiment B38.

[0476] B43. In embodiment B43, the compound for use in any one of embodiments B34-B42, or a pharmaceutically acceptable salt thereof, is such that each alkylene is unsubstituted.

[0477] B44. In embodiment B44, the compound for use in any one of embodiments B34 to B42, or a pharmaceutically acceptable salt thereof, is one in which one or two, preferably one, alkylenes are substituted as defined therein.

[0478] B45. In embodiment B45, the compound for use in any one of embodiments B34-B44, or a pharmaceutically acceptable salt thereof, is one in which the groups described therein are independently selected from ether, polyether, —NH—, —N(alkyl)-, amide, sulfonamide, alkylene, alkenylene, alkynylene, carbonyl, —C(O)O—, —OC(O)—, ureido, thioureido, bicyclic heterocyclylene, and fused heterocyclylene, and wherein bicyclic heterocyclylene and fused heterocyclylene are bicyclic heterocyclylene and fused heterocyclylene.

[0479] B46. In embodiment B46, the compound for use in any one of embodiments B34-B45, or a pharmaceutically acceptable salt thereof, is one in which the groups described therein are independently selected from ether, polyether, —NH—, —N(alkyl)-, amide, sulfonamide, alkylene, alkenylene, alkynylene, carbonyl, —C(O)O, —OC(O), bicyclic heterocyclylene, and fused heterocyclylene, and wherein bicyclic heterocyclylene and fused heterocyclylene are bicyclic heterocyclylene and fused heterocyclylene.

[0480] B47. In embodiment B47, the compound for use in any one of embodiments B34-B46, or a pharmaceutically acceptable salt thereof, is one in which the groups described therein are independently selected from ether, polyether, -NH-, -N(alkyl)-, amide, sulfonamide, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O, -OC(O), and each alkylene is substituted or unsubstituted as described therein.

[0481] B48. In embodiment B48, the compound for use in any one of embodiments B34 through B47, or a pharmaceutically acceptable salt thereof, is one in which one or more of the groups described therein are independently selected from ether, polyether, —NH—, —N(methyl)-, —NHC(O)—, —C(O)NH—N(methyl)C(O), —C(O)N(methyl)-, —NHSO—, —SONH—, —N(methyl)SO, —SON(methyl)-, —NHC(O)NH—, —NHSONH—, methylene, ethylene, propylene, butylene, pentylene, ethenylene, propenylene, acetylene, propynylene, carbonyl, —C(O)O—, and —OC(O)—.

[0482] B49. In embodiment B49, the compound for use in any one of embodiments B34-B48, or a pharmaceutically acceptable salt thereof, is one in which one or more of the groups described therein are independently selected from ether, -NH-, -N(methyl)-, methylene, ethylene, propylene, butylene, pentylene, ethenylene, propenylene, acetylene, propynylene, and carbonyl.

[0483] B50. In embodiment B50, the compound for use in any one of embodiments B34-B49, or a pharmaceutically acceptable salt thereof, is one in which one or more of the groups described therein are independently selected from ether, —NH—, —N(methyl)-, methylene, ethylene, propylene, butylene, pentylene, ethenylene, propenylene, acetylene, and propynylene.

[0484] B51. In embodiment B51, the compound for use of any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of aryl, ... [ka] and the isomers thereof; each ring is optionally substituted with one, two, or three substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino, each alkylene is optionally substituted with one or two substituents, one of which is deuterium and the other of which is deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; Isomers of the groups in Table A, where applicable, may be cis and / or trans isomers, and / or R and / or S isomers, and / or other geometric isomers; The left side of the group in Table A is ultimately attached to an E3 ubiquitin ligase ligand, and the right side of the group in Table A is ultimately attached to Hy; or alternatively, the left side of the group in Table A is ultimately attached to Hy, and the right side of the group in Table A is ultimately attached to an E3 ubiquitin ligase ligand.

[0485] B51a. In embodiment B51a, the compound for use of any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of aryl, ... [ka] and the isomers thereof; each ring is optionally substituted with one, two, or three substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino, each alkylene is optionally substituted with one or two substituents, one of which is deuterium and the other of which is deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; Isomers of the groups in Table A, where applicable, may be cis and / or trans isomers, and / or R and / or S isomers, and / or other geometric isomers; The left side of the group in Table A is ultimately attached to an E3 ubiquitin ligase ligand, and the right side of the group in Table A is ultimately attached to Hy; or alternatively, the left side of the group in Table A is ultimately attached to Hy, and the right side of the group in Table A is ultimately attached to an E3 ubiquitin ligase ligand.

[0486] B52. In embodiment B52, the compound for use in embodiment B51, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of one group selected from those disclosed in Table A.

[0487] B52-1. In embodiment B52-1, the compound for use in embodiment B51a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of one group selected from those disclosed in Table A.

[0488] B52a. In embodiment B52a, the compound for use in embodiment B51, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of two groups independently selected from those disclosed in Table A.

[0489] B52a-1. In embodiment B52a-1, the compound for use in embodiment B51a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of two groups independently selected from those disclosed in Table A.

[0490] B53. In embodiment B53, the compound for use in embodiment B51, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of three groups independently selected from those disclosed in Table A.

[0491] B53a. In embodiment B53a, the compound for use in embodiment B51a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of three groups independently selected from those disclosed in Table A.

[0492] B54. In embodiment B54, the compound for use in embodiment B51, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of four groups independently selected from those disclosed in Table A.

[0493] B54a. In embodiment B54a, the compound for use in embodiment B51a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of four groups independently selected from those disclosed in Table A.

[0494] B55. In embodiment B55, the compound for use in embodiment B51, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of five groups independently selected from those disclosed in Table A.

[0495] B55a. In embodiment B55a, the compound for use in embodiment B51a, or a pharmaceutically acceptable salt thereof, is one in which the linker comprises or consists of five groups independently selected from those disclosed in Table A.

[0496] B56. In embodiment B56, the compound for use in any one of embodiments B51 through B55a, or a pharmaceutically acceptable salt thereof, is one in which at least one of the groups is -SO2-.

[0497] B57. In embodiment B57, the compound for use in any one of embodiments B51-B56, or a pharmaceutically acceptable salt thereof, is one in which one of the groups is -SO2-.

[0498] B58. In embodiment B58, the compound for use in embodiment B56 or B57, or a pharmaceutically acceptable salt thereof, is one in which -SO2- is attached to Hy of any one of embodiments B1A-B3. In a subembodiment, Hy includes a substitutable nitrogen and -SO2- is attached to the substitutable nitrogen of Hy of any one of embodiments B1A-B3.

[0499] B59. In embodiment B59, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments B51 through B58 is one in which one, two, or three of the groups, preferably two or three of the groups, are rings independently selected from those disclosed in Table A.

[0500] B60. In embodiment B60, the compound for use in embodiment B59, or a pharmaceutically acceptable salt thereof, has one of the rings (designated ring (ia)) bonded to —SO 2 — which is bonded to Hy, preferably ring (ia) is [ka] and more preferably, [ka] wherein ring (ia) is optionally substituted as defined, preferably ring (ia) is [ka] In a subembodiment, ring (ia) is bonded to -SO2- and Hy contains a substitutable nitrogen atom, and -SO2- is bonded to the substitutable nitrogen of Hy of formula A or A1, preferably ring (ia) is [ka] and more preferably, [ka] wherein ring (ia) is optionally substituted as defined, preferably ring (ia) is [ka] It is what it is.

[0501] B61. In embodiment B61, the compounds for use in embodiment B60, and embodiments thereof, or pharmaceutically acceptable salts thereof, are those in which a second ring (referred to herein as ring (ib)) (if the linker has more than one ring) is attached to a ring attached to -SO2- which is attached to Hy. In a subembodiment, ring (ib) is attached to a ring attached to -SO2-, wherein Hy contains a substitutable nitrogen atom, and -SO2- is attached to the substitutable nitrogen of Hy of formula A or A1.

[0502] B62. In embodiment B62, the compound for use in embodiment B61, or a pharmaceutically acceptable salt thereof, is any of the compounds wherein the second ring (ib) is: [ka] wherein each ring (ib) is substituted as described therein.

[0503] B63. In embodiment B63, the compound, or a pharmaceutically acceptable salt thereof, for use in embodiments B51-B62 is one in which one of the groups is [ka] It is what it is.

[0504] B64. In embodiment B64, the compound for use of any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is such that the linker is [ka] [ka] [ka] wherein the right side of the linker is attached to Hy. In a subembodiment, Hy includes a substitutable nitrogen and the right side of the linker is attached to the substitutable nitrogen of Hy.

[0505] B65. In embodiment B65, the compound for use of any one of embodiments B1A-B3, or a pharmaceutically acceptable salt thereof, is any one of the compounds wherein the linker is: [ka] [ka] [ka] wherein the right side of the linker is attached to Hy and the left side is attached to an E3 ubiquitin ligase ligand. In a subembodiment, Hy includes a substitutable nitrogen and the right side of the linker is attached to the substitutable nitrogen of Hy.

[0506] B66. In embodiment B66, the compound for use of any one of embodiments B1A-B3 and B65, or a pharmaceutically acceptable salt thereof, is such that the linker is: [ka] In a first subembodiment, in the above structure, the right side of the linker is attached to Hy. In a second subembodiment, Hy includes a substitutable nitrogen and the right side of the linker is attached to the substitutable nitrogen of Hy.

[0507] B67. In embodiment B67, the compound, or a pharmaceutically acceptable salt thereof, for use in any one of embodiments B3 to B66 is such that the E3 ubiquitin ligase ligand is a CBRN or VHL ligase ligand.

[0508] B68-B138. In embodiments B68-B138, the compound for use in embodiment B67 is one in which the E3 ubiquitin ligase ligand is as disclosed in embodiments A40-A110, respectively, or a pharmaceutically acceptable salt thereof. B139. In embodiment B139, the compound for use in any of embodiments B1A-B138 is one in which Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiroheterocyclylene, bridged heterocyclylene, or fused heterocyclylene, and each of the foregoing rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. a , R b , and R c or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof.

[0509] B140-B157. In embodiments B140-B157, the compound for use in embodiment B139 is one in which Hy is as disclosed in embodiments A25-A39b, respectively, or a pharmaceutically acceptable salt thereof.

[0510] Embodiment C: In embodiments C1 to C279, the present disclosure includes the following.

[0511] C1. In Embodiment C1, there is provided a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, as defined in the fourth embodiment of the Summary of the Invention.

[0512] C2. In embodiment C2, the compound of embodiment C1, or a pharmaceutically acceptable salt thereof, is R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano, or cycloalkyl, wherein cycloalkyl is substituted with 1 to 3 halo.

[0513] C3. In embodiment C3, the compound of embodiment C1 or C2, or a pharmaceutically acceptable salt thereof, is R 1 is halo, haloalkyl, or haloalkoxy.

[0514] C4. In embodiment C4, the compound of any one of embodiments C1-C3, or a pharmaceutically acceptable salt thereof, is R 1 But it is a halo.

[0515] C5. In embodiment C5, the compound of any one of embodiments C1-C3, or a pharmaceutically acceptable salt thereof, is R 1 is haloalkyl.

[0516] C6. In embodiment C6, the compound of any one of embodiments C1-C3, or a pharmaceutically acceptable salt thereof, is R 1 is haloalkoxy.

[0517] C7. In embodiment C7, the compound of any one of embodiments C1-C6, or a pharmaceutically acceptable salt thereof, is R 1 is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

[0518] C8. In embodiment C8, the compound of any one of embodiments C1-C7, or a pharmaceutically acceptable salt thereof, is R 1 is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

[0519] C9. In embodiment C9, the compound of any one of embodiments C1 through C4, C7, and C8, or a pharmaceutically acceptable salt thereof, comprises R 1 is chloro or bromo.

[0520] C10. In embodiment C10, the compound of any one of embodiments C1 through C3, C5, C7, and C8, or a pharmaceutically acceptable salt thereof, comprises R 1 is difluoromethyl or trifluoromethyl.

[0521] C11. In embodiment C11, the compound of any one of embodiments C1-C3, C5, C7, C8, and C10, or a pharmaceutically acceptable salt thereof, comprises R 1 is trifluoromethyl.

[0522] C12. In embodiment C12, the compound of embodiment C1 or C2, or a pharmaceutically acceptable salt thereof, is R 1 is alkyl, alkenyl, or alkynyl.

[0523] C13. In embodiment C13, the compound of embodiment C1, C2, or C12, or a pharmaceutically acceptable salt thereof, comprises R 1 is methyl, ethyl, propyl, vinyl, propenyl, ethynyl, or propynyl.

[0524] C14. In embodiment C14, the compound of embodiment C1, C2, C12, or C13, or a pharmaceutically acceptable salt thereof, is R 1 is methyl, ethyl, or propyl.

[0525] C15. In embodiment C15, the compound of embodiment C1, C2, C12, or C13, or a pharmaceutically acceptable salt thereof, is R 1 is vinyl, propenyl, ethynyl, or propynyl.

[0526] C16. In embodiment C16, the compound of embodiment C1 or C2, or a pharmaceutically acceptable salt thereof, is R 1 is an alkoxy.

[0527] C17. In embodiment 17, the compound of embodiment C1, C2, or C16, or a pharmaceutically acceptable salt thereof, comprises R 1 is methoxy, ethoxy, or propoxy.

[0528] C18. In embodiment C18, the compound of embodiment C1 or C2, or a pharmaceutically acceptable salt thereof, is R 1 is an aryloxy, such as phenoxy.

[0529] C19. In embodiment C19, the compound of embodiment C1 or C2, or a pharmaceutically acceptable salt thereof, is R 1 However, it is cyano.

[0530] C20. In embodiment C20, the compound of embodiment C1 or C2, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkyl.

[0531] C21. In embodiment C21, the compound of embodiment C1, C2, or C20, or a pharmaceutically acceptable salt thereof, comprises R 1 is cyclopropyl.

[0532] C22. In embodiment C22, the compound of embodiment C1 or C2, or a pharmaceutically acceptable salt thereof, is R 1is cycloalkyl substituted with 1 to 3 independently selected halo (eg, fluorocyclopropyl or difluorocyclopropyl).

[0533] C23. In embodiment C23, the compound of embodiment C1, or a pharmaceutically acceptable salt thereof, is R 1 alkylthio, pentafluorothio, haloalkylthio, amino, alkylamino, dialkylamino, cycloalkyl, cycloalkoxy, cycloalkylalkyl, bridged cycloalkyl, bridged cycloalkoxy, bridged cycloalkylalkyl, cyanoalkyl, cyanoalkoxy, alkoxyalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkoxy, acyl, azidocarbonyl, alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, substituted sulfonyl, substituted sulfinyl, substituted ureido, aryl, aralkyl, aryloxy, heteroaryl, heteroaralkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl aryl, heterocyclyloxy, fused heterocyclyl, fused heterocyclyloxy, or fused heterocyclylalkyl, wherein cycloalkyl, by itself or as part of cycloalkoxy and cycloalkylalkyl; aryl, by itself or as part of aralkyl and aryloxy; heteroaryl, by itself or as part of heteroaralkyl and heteroaryloxy; heterocyclyl, by itself or as part of heterocyclylalkyl and heterocyclyloxy; bridged cycloalkyl, by itself or as part of bridged cycloalkoxy and bridged cycloalkylalkyl; and fused heterocyclyl, by itself or as part of fused heterocyclylalkyl and fused heterocyclyloxy, are substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0534] C24. In embodiment C24, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is aryl, heteroaryl, heterocyclyl, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF3, -SF5, fused heterocyclyl, bridged cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, aminoalkoxy, alkoxycarbonyl, alkylcarbonylamino, acyl, azidocarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylamino and substituted sulfonyl, wherein aryl (alone and with arylalkyl), heteroaryl (alone and with heteroaryloxy), heterocyclyl, fused heterocyclyl, bridged cycloalkyl (alone and with cycloalkylalkyl), and heterocyclyl (alone and with heterocyclylalkyl) are substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0535] C25. In embodiment C25, the compound of embodiment C1, C23, or C24, or a pharmaceutically acceptable salt thereof, comprises R 1is phenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2,3-dihydrobenzofuranyl, benzodihydropyranyl, 1,4-benzodioxanyl, 2,3-dihydrofuro[3,2-c]pyridine, 2,3-dihydrofuro[2,3-c]pyridine, or 1,2,3,4-tetrahydroquinolinyl, each ring substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0536] C26. In embodiment C26, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is aryl, heteroaryl, heterocyclyl, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF3, or -SF5, each ring substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0537] C27. In embodiment C27, the compound of embodiment C1, C23, or C26, or a pharmaceutically acceptable salt thereof, comprises R 1 is phenyl (substituted with hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, or haloalkoxy), pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl (substituted with hydrogen or alkyl), tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl (substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano), cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl, or dimethylaminomethyl.

[0538] C28. In embodiment C28, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is alkylthio (eg, methylthio).

[0539] C29. In embodiment C29, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is pentafluorothio.

[0540] C30. In embodiment C30, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is haloalkylthio (eg, trifluoromethylthio).

[0541] C31. In embodiment C31, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 However, it is an amino acid.

[0542] C32. In embodiment C32, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is alkylamino (eg, methylamino).

[0543] C33. In embodiment C33, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is dialkylamino (e.g., dimethylamino).

[0544] C34. In embodiment C34, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkyl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0545] C35. In embodiment C35, the compound of embodiment C1, C23, or C34, or a pharmaceutically acceptable salt thereof, comprises R 1 is cyclopropyl, cyclobutyl, or cyclopentyl, each ring being substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0546] C36. In embodiment C36, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkoxy, wherein the cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0547] C37. In embodiment C37, the compound of embodiment C1, C23, or C36, or a pharmaceutically acceptable salt thereof, comprises R 1 is cyclopropyloxy, cyclobutyloxy, or cyclopentyloxy, wherein each cycloalkyl ring of the cycloalkyloxy is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0548] C38. In embodiment C38, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is cycloalkylalkyl, wherein the cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0549] C39. In embodiment C39, the compound of embodiment C1, C23, or C38, or a pharmaceutically acceptable salt thereof, comprises R 1 is cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, wherein the ring of the cycloalkylalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0550] C40. In embodiment C40, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a bridged cycloalkyl (such as bicyclo[1.1.1]pent-1-yl or bicyclo[2.2.1]heptyl), wherein the bridged cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0551] C41. In embodiment C41, the compound of embodiment C1, C23, or C40, or a pharmaceutically acceptable salt thereof, comprises R 1 is a bridged cycloalkyl (such as bicyclo[1.1.1]pent-1-yl or bicyclo[2.2.1]heptyl), wherein the bridged cycloalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0552] C42. In embodiment C42, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a bridged cycloalkoxy (such as bicyclo[1.1.1]pent-1-yloxy or bicyclo[2.2.1]heptyloxy), wherein the bridged cycloalkyl of the bridged cycloalkoxy is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0553] C43. In embodiment C43, the compound of embodiment C1, C23, or C42, or a pharmaceutically acceptable salt thereof, comprises R 1 is a bridged cycloalkoxy (such as bicyclo[1.1.1]pent-1-yloxy or bicyclo[2.2.1]heptyloxy), wherein the bridged cycloalkyl of the bridged cycloalkoxy is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0554] C44. In embodiment C44, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a bridged cycloalkylalkyl (such as bicyclo[1.1.1]pent-1-ylmethyl or bicyclo[2.2.1]heptylmethyl), wherein the bridged cycloalkyl of the bridged cycloalkylalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0555] C45. In embodiment C45, the compound of embodiment C1, C23, or C44, or a pharmaceutically acceptable salt thereof, is R 1 is a bridged cycloalkylalkyl (such as bicyclo[1.1.1]pent-1-ylmethyl or bicyclo[2.2.1]heptylmethyl), wherein the bridged cycloalkyl of the bridged cycloalkylalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0556] C46. In embodiment C46, ​​the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a cyanoalkyl (such as cyanomethyl or cyanoethyl).

[0557] C47. In embodiment C47, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is cyanoalkoxy (such as cyanomethoxy or cyanoethoxy).

[0558] C48. In embodiment C48, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is alkoxyalkyl (eg, methoxymethyl).

[0559] C49. In embodiment C49, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R1 is aminoalkyl (eg, aminomethyl).

[0560] C50. In embodiment C50, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is aminoalkoxy, for example, R 1 is aminomethyloxy.

[0561] C51. In embodiment C51, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is alkylaminoalkyl (e.g., R 1 (but is methylaminomethyl).

[0562] C52. In embodiment C52, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a dialkylaminoalkyl (e.g., R 1 (but is dimethylaminomethyl).

[0563] C53. In embodiment C53, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is alkylaminoalkoxy (e.g., R 1 is methylaminomethyloxy).

[0564] C54. In embodiment C54, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, comprises R 1 is dialkylaminoalkoxy (e.g., R 1 is dimethylaminomethyloxy).

[0565] C55. In embodiment C55, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 However, it is an acyl.

[0566] C55a. In embodiment C55a, the compound of embodiment C1, C23, or C55, or a pharmaceutically acceptable salt thereof, comprises R 1 is an alkylcarbonyl (such as methylcarbonyl).

[0567] C56. In embodiment C56, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is an azidocarbonyl.

[0568] C57. In embodiment C57, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is an alkoxycarbonyl (for example, methoxycarbonyl or ethoxycarbonyl).

[0569] C58. In embodiment C58, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is alkylcarbonylamino.

[0570] C59. In embodiment C59, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is an aminocarbonyl.

[0571] C60. In embodiment C60, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is alkylaminocarbonyl (such as methylaminocarbonyl).

[0572] C61. In embodiment C61, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a dialkylaminocarbonyl (such as dimethylaminocarbonyl).

[0573] C62. In embodiment C62, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R1 is aminosulfonyl.

[0574] C63. In embodiment C63, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, comprises R 1 is alkylaminosulfonyl (such as methylaminosulfonyl).

[0575] C64. In embodiment C64, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a dialkylaminosulfonyl (such as dimethylaminosulfonyl).

[0576] C65. In embodiment C65, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a substituted sulfonyl (eg, methylsulfonyl).

[0577] C66. In embodiment C66, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a substituted sulfinyl.

[0578] C67. In embodiment C67, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a substituted ureido.

[0579] C68. In embodiment C68, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is aryl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0580] C69. In embodiment C69, the compound of embodiment C1, C23, or C68, or a pharmaceutically acceptable salt thereof, comprises R 1is phenyl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0581] C69a. In embodiment C69a, the compound of embodiment C1, C23, C68, or C69, or a pharmaceutically acceptable salt thereof, comprises R 1 is phenyl substituted with one, two, or three substituents independently selected from hydrogen, methyl, fluoro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0582] C70. In embodiment C70, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is aralkyl (such as benzyl), where the aryl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0583] C71. In embodiment C71, the compound of embodiment C1, C23, or C70, or a pharmaceutically acceptable salt thereof, comprises R 1 is benzyl, wherein the phenyl of the benzyl is substituted with one, two, or three substituents independently selected from hydrogen, methyl, fluoro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0584] C72. In embodiment C72, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is heteroaryl, wherein the heteroaryl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0585] C73. In embodiment C73, the compound of embodiment C1, C23, or C72, or a pharmaceutically acceptable salt thereof, comprises R 1 is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0586] C73a. In embodiment C73a, the compound of embodiment C1, C23, or C72, or a pharmaceutically acceptable salt thereof, comprises R 1 is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one substituent selected from hydrogen and alkyl.

[0587] C74. In embodiment C74, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is heteroaralkyl, wherein the heteroaryl of the heteroaralkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0588] C74a. In embodiment C74a, the compound of embodiment C1, C23, or C74, or a pharmaceutically acceptable salt thereof, comprises R 1 wherein the heteroaryl of the heteroaralkyl is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0589] C75. In embodiment C75, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1is heteroaryloxy, wherein the heteroaryl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0590] C76. In embodiment C76, the compound of embodiment C1, C23, or C75, or a pharmaceutically acceptable salt thereof, comprises R 1 wherein the heteroaryl of the heteroaryloxy is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0591] C77. In embodiment C77, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is heterocyclyl, wherein the heterocyclyl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0592] C78. In embodiment C78, ​​the compound of embodiment C1, C23, or C77, or a pharmaceutically acceptable salt thereof, comprises R 1 is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0593] C79. In embodiment C79, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is heterocyclylalkyl, wherein the heterocyclyl is substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0594] C80. In embodiment C80, the compound of embodiment C1, C23, or C79, or a pharmaceutically acceptable salt thereof, comprises R 1 wherein the heterocyclyl of the heterocyclylalkyl is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0595] C81. In embodiment C81, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is heterocyclyloxy, wherein the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0596] C82. In embodiment C82, the compound of embodiment C1, C23, or C81, or a pharmaceutically acceptable salt thereof, comprises R 1 wherein the heterocyclyl of the heterocyclyloxy is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, wherein the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0597] C83. In embodiment C83, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a fused heterocyclyl substituted with 1, 2, or 3 substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0598] C84. In embodiment C84, the compound of embodiment C1, C23, or C83, or a pharmaceutically acceptable salt thereof, comprises R1 is a fused heterocyclyl selected from 2,3-dihydrobenzofuranyl, benzodihydropyranyl, 1,4-benzodioxanyl, 2,3-dihydrofuro[3,2-c]pyridine, 2,3-dihydrofuro[2,3-c]pyridine, and 1,2,3,4-tetrahydroquinolinyl, each of which is substituted with one, two, or three substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0599] C85. In embodiment C85, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a fused heterocyclyloxy, wherein the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0600] C86. In embodiment C86, the compound of embodiment C1 or C23, or a pharmaceutically acceptable salt thereof, is R 1 is a fused heterocyclylalkyl, wherein the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0601] C87. In embodiment C87, the compounds of embodiments C1 and C23-C86, or pharmaceutically acceptable salts thereof, are those in which R 1 but, [ka] and isomers thereof (R and / or S isomers, and / or geometric isomers).

[0602] C88. In embodiment C88, the compound of any one of embodiments C1 to C87, or a pharmaceutically acceptable salt thereof, is R 2 and R 2a is hydrogen.

[0603] C89. In embodiment C89, the compound of any one of embodiments C1 to C87, or a pharmaceutically acceptable salt thereof, is R 2 and R 2a One of the atoms is deuterium, and the other is R 2 and R 2a The other of R is hydrogen, or 2 and R 2a are deuterium.

[0604] C90. In embodiment C90, the compound of any one of embodiments C1 through C89, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 through C89, wherein Hy is heterocyclylene, phenylene, spiroheterocyclylene, bridged heterocyclylene, or cycloalkylene, and each of said rings is selected from the group consisting of R a , R b , and R c is substituted with R a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0605] C91. In embodiment C91, the compound of any one of embodiments C1 to C90, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C90, wherein Hy is R a , R b , and R c and R is a heterocyclylene substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0606] C92. In embodiment C92, the compound of any one of embodiments C1-C91, or a pharmaceutically acceptable salt thereof, is any one of the following: the heterocyclylene of Hy is pyrrolidine-1,3-diyl or piperidine-1,4-diyl; and Hy is R a , R b , and R c is substituted with Ra and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy; R c is hydrogen, and L is bonded to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

[0607] C93. In embodiment C93, the compound of any one of embodiments C1 to C92, or a pharmaceutically acceptable salt thereof, is any one of the following embodiments wherein the heterocyclylene of Hy is: [ka] and the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is bonded to L.

[0608] C94. In embodiment C94, compounds of any one of C1 to C93, or pharmaceutically acceptable salts thereof, are those in which the heterocyclylene of Hy is: [ka] and the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is bonded to L.

[0609] C95. In embodiment C95, the compound of any one of embodiments C1 to C94, or a pharmaceutically acceptable salt thereof, is any one of the above, wherein the heterocyclylene of Hy is: [ka] and the N atom of the piperidine-1,4-diyl ring is bonded to L.

[0610] C96. In embodiment C96, the compound of any one of embodiments C1 through C90, or a pharmaceutically acceptable salt thereof, is any one of R 1 to R 2 , wherein Hy is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. a , R b , and R cand wherein the heterocyclylene is a bridged heterocyclylene substituted with

[0611] C97. In embodiment C97, the compound of any one of embodiments C1 through C90, and C96, or a pharmaceutically acceptable salt thereof, is any one of the above, wherein the bridged heterocyclylene of Hy is of the formula: [ka] and each ring is a ring of R a , R b , and R c is substituted with R c is hydrogen and L is attached to the nitrogen atom of each ring.

[0612] C98. In embodiment C98, the compound of embodiment C96 or C97, or a pharmaceutically acceptable salt thereof, comprises R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy.

[0613] C99. In embodiment C99, the compound of embodiment C96, C97, or C98, or a pharmaceutically acceptable salt thereof, comprises R b is hydrogen.

[0614] C100. In embodiment C100, the compound of any one of embodiments C1 to C90, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C90, wherein Hy is R a , R b , and R c is a cycloalkylene substituted with R a is deuterium, methyl, fluoro, methoxy, or hydroxy, and R b and R c is hydrogen.

[0615] C101. In embodiment C101, the compound of any one of embodiments C1 through C90, and C100, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is cyclohexylene.

[0616] C102. In embodiment C102, the compound of any one of embodiments C1 to C90, C100, and C101, or a pharmaceutically acceptable salt thereof, is any one of the following: [ka] and [ka] represents a bond to NH, [ka] represents the bond of L.

[0617] C103. In embodiment C103, the compound of any one of embodiments C1 through C90, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 through C90, wherein Hy is arylene and arylene is R a , R b , and R c phenylene substituted with R a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0618] C104. In embodiment C104, the compound of any one of embodiments C1 to C90, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C90, wherein Hy is R a , R b , and R c and R is a spiroheterocyclylene (e.g., 2-azaspiro[3.3]heptan-2-yl) substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0619] C105. In embodiment C105, the compound of any one of embodiments C1 through C90, and C103, or a pharmaceutically acceptable salt thereof, is any one of the foregoing, wherein the phenylene of Hy has the structure [ka] is a 1,4-phenylene conforming to the formula [ka] represents a bond to NH, [ka] represents the bond of L.

[0620] C106. In embodiment C106, the compound of any one of embodiments C1 to C89, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C89, wherein Hy is R a , R b , and R c and R is a fused heterocyclylene substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0621] C107. In embodiment C107, the compound of any one of embodiments C1 to C89, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C89, wherein Hy is R a , R b , and R c and R is a bicyclic heterocyclylene substituted with a and R b is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; R c is hydrogen.

[0622] C108. In embodiment C108, the compound of any one of embodiments C1 to C107, or a pharmaceutically acceptable salt thereof, is one wherein the degron is an E3 ubiquitin ligase ligand of formula (i) or (ii).

[0623] C109. In embodiment C109, the compound of any one of embodiments C1 to C108, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C108, wherein the degron has the formula (i): [ka] It is an E3 ubiquitin ligase ligand for .

[0624] C110. In embodiment C110, the compound of any one of embodiments C1 to C109, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C109, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is a group represented by the formula (a): [ka] It is based on the

[0625] C111. In embodiment C111, the compound of any one of embodiments C1 to C110, or a pharmaceutically acceptable salt thereof, is R 4 and R 5 are independently hydrogen or alkyl.

[0626] C112. In embodiment C112, the compound of any one of embodiments C1 to C111, or a pharmaceutically acceptable salt thereof, is R 4 and R 5 is hydrogen.

[0627] C113. In embodiment C113, the compound of any one of embodiments C1 to C111, or a pharmaceutically acceptable salt thereof, is R 4 is hydrogen and R 5 is methyl.

[0628] C114. In embodiment C114, the compound of any one of embodiments C1 to C110, or a pharmaceutically acceptable salt thereof, is R 4 and R 5 However, they form >C=O with the carbon to which they are attached.

[0629] C115. In embodiment C115, the compound of any one of embodiments C1 to C109, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C109, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is a group represented by formula (b): [ka] It is based on the

[0630] C116. In embodiment C116, the compound of any one of embodiments C1 to C109, and C115, or a pharmaceutically acceptable salt thereof, is R 6 is hydrogen.

[0631] C117. In embodiment C117, the compound of any one of embodiments C1 to C109, and C115, or a pharmaceutically acceptable salt thereof, is R 6 is alkyl, for example, methyl.

[0632] C118. In embodiment C118, the compound of any one of embodiments C1 to C109, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C109, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is a group represented by formula (c): [ka] It is based on the

[0633] C119. In embodiment C119, the compound of any one of embodiments C1 to C117, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C117, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0634] C120. In embodiment C120, the compound of any one of embodiments C1 to C117, and C119, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C117, and C119, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0635] C121. In embodiment C121, the compound of any one of embodiments C1 to C117, and C119, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C117, and C119, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0636] C122. In embodiment C122, the compound of any one of embodiments C1 to C117 and C119 to C121, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C117 and C119 to C121, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0637] C123. In embodiment C123, the compound of any one of embodiments C1 to C117, C119, and C121, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C117, C119, and C121, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0638] C124. In embodiment C124, the compound of any one of embodiments C1 to C117 and C119 to C122, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C117 and C119 to C122, or a pharmaceutically acceptable salt thereof, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0639] C125. In embodiment C125, the compound of any one of embodiments C1 to C110, C114, and C119 to C124, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C110, C114, and C119 to C124, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0640] C126. In embodiment C126, the compound of any one of embodiments C1 to C110, C114, and C119 to C124, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C110, C114, and C119 to C124, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0641] C127. In embodiment C127, the compound of any one of embodiments C1 to C112 and C119 to C124, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C112 and C119 to C124, or a pharmaceutically acceptable salt thereof, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0642] C128. In embodiment C128, the compound of any one of embodiments C1 to C112 and C119 to C124, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C112 and C119 to C124, or a pharmaceutically acceptable salt thereof, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0643] C129. In embodiment C129, the compound of any one of embodiments C1 to C109, C115, C117, and C119 to C124, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C109, C115, C117, and C119 to C124, or a pharmaceutically acceptable salt thereof, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0644] C130. In embodiment C130, the compound of any one of embodiments C1 to C109, C115, C117, and C119 to C124, or a pharmaceutically acceptable salt thereof, is any one of the compounds of embodiments C1 to C109, C115, C117, and C119 to C124, or a pharmaceutically acceptable salt thereof, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: [ka] It is what it is.

[0645] C131. In embodiment C131, the compound of any one of embodiments C1 to C117 and C119 to C127, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. aa , R bb , R cc and / or R dd is hydrogen unless specifically shown in the structures of formulas (i) and (ii), respectively.

[0646] C132. In embodiment C132, the compound of any one of embodiments C1 to C117 and C119 to C127, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.

[0647] C133. In embodiment C133, the compound of any one of embodiments C1 to C117, C119 to C127, C131, and C132, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

[0648] C134. In embodiment C134, any one of compounds C1 to C117, C119 to C127, and C131 to C133, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of R aa , R bb , R cc , and R dd are independently selected from hydrogen and methyl.

[0649] C135. In embodiment C135, the compound of any one of embodiments C1 to C117, C119 to C127, and C131 to C133, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen and methoxy.

[0650] C136. In embodiment C136, the compound of any one of embodiments C1 to C117, C119 to C127, and C131 to C133, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen and fluoro.

[0651] C137. In embodiment C137, the compound of any one of embodiments C1 to C117, C119 to C127, and C131 to C133, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and Rdd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.

[0652] C138. In embodiment C138, the compound of any one of embodiments C1 to C117, C119 to C127, C131, and C133, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen and trifluoromethoxy.

[0653] C139. In embodiment C139, the compound of any one of embodiments C1 to C117, C119 to C127, and C131 to C133, or a pharmaceutically acceptable salt thereof, is R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl.

[0654] C140. In embodiment C140, the compound of any one of embodiments C1 to C108, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C108, wherein the degron is a compound of formula (ii): [ka] It is an E3 ubiquitin ligase ligand for .

[0655] C141. In embodiment C141, the compound of any one of embodiments C1 to C108, and C140, or a pharmaceutically acceptable salt thereof, comprises Y a However, it is CH.

[0656] C142. In embodiment C142, the compound of any one of embodiments C1 to C108, and C140, or a pharmaceutically acceptable salt thereof, comprises Y a is N.

[0657] C143. In embodiment C143, the compound of any one of embodiments C1 to C108, and C140 to C142, or a pharmaceutically acceptable salt thereof, is Z a But the bond, -NH-, -O-, or -NHC(O)-.

[0658] C144. In embodiment C144, the compound of any one of embodiments C1 to C108, and C140 to C143, or a pharmaceutically acceptable salt thereof, is Z a But the bond, It is —NH— or —NHC(O)—.

[0659] C145. In embodiment C145, the compound of any one of embodiments C1 to C108, and C140 to C144, or a pharmaceutically acceptable salt thereof, is Z a is a bond.

[0660] C146. In embodiment C146, the compound of any one of embodiments C1 to C108, and C140 to C144, or a pharmaceutically acceptable salt thereof, is Z a is —NH— or —NHC(O)—.

[0661] C147. In embodiment C147, the compound of any one of embodiments C1 to C108, C140 to C144, and C146, or a pharmaceutically acceptable salt thereof, is Z a is -NH-.

[0662] C148. In embodiment C148, the compound of any one of embodiments C1 to C108, C140 to C144, and C146, or a pharmaceutically acceptable salt thereof, is Z a is -NHC(O)-.

[0663] C149. In embodiment C149, the compound of any one of embodiments C1 to C108 and C140 to C148, or a pharmaceutically acceptable salt thereof, is any one of the above, wherein ring B is R ee and Rff and phenylene substituted with .

[0664] C150. In embodiment C150, the compound of any one of embodiments C1 to C108 and C140 to C148, or a pharmaceutically acceptable salt thereof, is any one of the above, wherein ring B is R ee and R ff and wherein the cyclylaminylene is substituted with

[0665] C151. In embodiment C151, the compound of any one of embodiments C1 through C108 and C140 through C148, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 through C148, wherein ring B is a 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, each heteroarylene ring containing 1 to 3 nitrogen ring atoms, and each ring is selected from the group consisting of R ee and R ff is replaced by

[0666] C152. In embodiment C152, the compound of any one of embodiments C1 to C108, C140 to C148, and C151, or a pharmaceutically acceptable salt thereof, is any one of the foregoing, wherein ring B is selected from the group consisting of R ee and R ff and R is a 5- or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with R.

[0667] C153. In embodiment C153, the compound of any one of embodiments C1-C108, C140-C148, and C151, or a pharmaceutically acceptable salt thereof, is any compound wherein ring B contains 1 to 3 nitrogen ring atoms (and no additional heteroatoms), and R ee and R ff and 9- or 10-membered fused bicyclic heteroarylene substituted with

[0668] C154. In embodiment C154, the compound of any one of embodiments C1 to C108, C140 to C148, C151, and C153, or a pharmaceutically acceptable salt thereof, is any one of the foregoing, wherein ring B is selected from the group consisting of R ee and R ffand wherein the heteroaryl group is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms substituted with:

[0669] C155. In embodiment C155, the compound of any one of embodiments C1 to C108 and C140 to C154, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C108 and C140 to C154, wherein the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0670] C156. In embodiment C156, the compound of any one of embodiments C1 to C108 and C140 to C155, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C108 and C140 to C155, wherein the E3 ubiquitin ligase ligand of formula (ii) is: [ka] and ring B is a cyclylaminylene.

[0671] C157. In embodiment C157, the compound of any one of embodiments C1 to C108 and C140 to C156, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C108 and C140 to C156, wherein the E3 ubiquitin ligase ligand of formula (ii) is: [ka] and ring B is cyclylaminylene, [ka] It is what it is.

[0672] C158. In embodiment C158, the compound of any one of embodiments C1 to C108 and C140 to C157, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C108 and C140 to C157, wherein the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0673] C159. In embodiment C159, the compound of any one of embodiments C1-C108 and C140-C157, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1-C108 and C140-C157, wherein the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0674] C160. In embodiment C160, the compound of any one of embodiments C1 to C108, C140 to C157, and C159, or a pharmaceutically acceptable salt thereof, is any one of embodiments C1 to C108, C140 to C157, and C159, wherein the E3 ubiquitin ligase ligand of formula (ii) is: [ka] It is what it is.

[0675] C161. In embodiment C161, the compound of any one of embodiments C1 to C108 and C140 to C160, or a pharmaceutically acceptable salt thereof, is any one of the following: ee and R ff are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy.

[0676] C162. In embodiment C162, the compound of any one of embodiments C1 to C108 and C140 to C160, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.

[0677] C163. In embodiment C163, the compound of any one of embodiments C1 to C108 and C140 to C162, or a pharmaceutically acceptable salt thereof, is R ee and R ffare independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.

[0678] C164. In embodiment C164, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, methyl, ethyl, and isopropyl.

[0679] C165. In embodiment C165, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen and methoxy.

[0680] C166. In embodiment C166, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.

[0681] C167. In embodiment C167, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff is hydrogen or fluoro, and R ee and R ff and the other is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl.

[0682] C168. In embodiment C168, the compound of any one of embodiments C1 to C108, C140 to C161, and C163, or a pharmaceutically acceptable salt thereof, is Ree and R ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.

[0683] C169. In embodiment C169, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl.

[0684] C170. In embodiment C170, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff is hydrogen.

[0685] C171. In embodiment C171, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff However, it is Chloro.

[0686] C172. In embodiment C172, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff However, it is fluoro.

[0687] C173. In embodiment C173, the compound of any one of embodiments C1 to C108 and C140 to C163, or a pharmaceutically acceptable salt thereof, is R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.

[0688] C174. In embodiment C174, the compound of any one of embodiments C1 to C107, or a pharmaceutically acceptable salt thereof, is one wherein the degron is an E3 ubiquitin ligase ligand of formula (iii), (iv), (v), or (vi).

[0689] C175. In embodiment C175, the compound of any one of embodiments C1 through C107, and C174, or a pharmaceutically acceptable salt thereof, is one wherein the degron is an E3 ubiquitin ligase ligand of formula (iv) or (v).

[0690] C176. In embodiment C176, the compound of any one of embodiments C1 to C107, C174, and C175, or a pharmaceutically acceptable salt thereof, is R y , R y1 , and R y2 is 1-fluorocycloprop-1-yl, and W a is a bond, S, or methylene.

[0691] C177. In embodiment C177, the compound of any one of embodiments C1 to C107 and C174 to C176, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of W a But it is S.

[0692] C178. In embodiment C178, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are bonds.

[0693] C179. In embodiment C179, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each independently selected from alkylene. In a subembodiment of C179, each alkylene is methylene.

[0694] C180. In embodiment C180, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are -O-, respectively.

[0695] C181. In embodiment C181, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each independently selected from -(O-alkylene)-.

[0696] C181a. In embodiment C181a, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each independently selected from -(alkylene-O)-.

[0697] C182. In embodiment C182, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are independently -(NR gg -alkylene)-.

[0698] C183. In embodiment C183, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 each independently represents -(alkylene-NR hh )-.

[0699] C184. In embodiment C184, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 However, [ka] It is what it is.

[0700] C185. In embodiment C185, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each -NH-.

[0701] C186. In embodiment C186, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each independently selected from -N(alkyl)-. In a subembodiment of C186, each -N(alkyl)- is independently -N(methyl)- or -N(ethyl)-.

[0702] C187. In embodiment C187, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each -C(=O)-.

[0703] C188. In embodiment C188, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are independently -NR jjC(=O)-.

[0704] C189. In embodiment C189, the compound of any one of embodiments C1 to C173, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are each independently -C(=O)NR kk - is what it is.

[0705] C190. In embodiment C190, the compound of any one of embodiments C1 to C173, C182, C183, C188, and C189, or a pharmaceutically acceptable salt thereof, is R gg , R hh , R jj and R kk are each independently hydrogen or alkyl.

[0706] C190a. In embodiment C190a, the compound of any one of embodiments C1 through C190 is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 In a subembodiment of C190a, the compound is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 In a subembodiment of C190a, the compound is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - at least four of which are not bonds.

[0707] C191. In embodiment C191, the compound of any one of embodiments C1 through C190a, or a pharmaceutically acceptable salt thereof, is Z 6is -S(O)2-.

[0708] C192. In embodiment C192, the compound of any one of embodiments C1 to C191, or a pharmaceutically acceptable salt thereof, is Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by

[0709] C193. In embodiment C193, the compound of any one of embodiments C1 to C192, or a pharmaceutically acceptable salt thereof, is Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is substituted with Z 1 and X 1 Only one of the is a bond, and Z 1 and X 2 Only one of the is a bond, and Z 1 and X 3 Only one of the is a bond, and Z 1 and X 4 where only one of the is a bond (for clarity, X 1 , X 2 , X 3 , and X 4 If is not a bond, then X 1 , X 2 , X 3 , and X 4 is as described in any one of embodiments C1 and C179 to C189).

[0710] C194. In embodiment C194, the compound of any one of embodiments C1 to C177, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 are independently a bond, -(O-alkylene)-, -(NR gg -alkylene)-, [ka] , —NH—, or —N(alkyl)-, and R gg is hydrogen or alkyl, and each alkylene is independently optionally substituted with one or two fluoro (or when the E3 ubiquitin ligase ligand is (iii)-(vi), X 1 , X 2 , X 3 , and X 4 is a join); Z 1 is a bond, alkylene, -(CO)NR-, -(O-alkylene) a -, -(Alkylene-O) a -, phenylene or heterocyclylene, each ring being R h and R i is replaced by; Z 2 is a bond, alkylene, -(O-alkylene) b -, -(Alkylene-O) b -, cycloalkylene, or heterocyclylene, each ring being R j and R k is replaced by; Z 3 is a bond, alkylene, —C(O)NR—, —NR′(CO)—, —O—, —NR″-, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, -spiroheterocyclylene-(alkylene)-, or monocyclic heteroarylene, and each ring, by itself or as part of another group, is R m and R n is replaced by; Z 4is a bond, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, and each ring, by itself or as part of another group, is selected from the group consisting of R o and R p is replaced by; Z 5 is a bond; Z 6 is -S(O)2-; Z 1 , Z 2 , Z 3 , and Z 4 Each alkylene in the group may be, by itself or as part of another group, R s and R t are independently substituted with

[0711] C195. In embodiment C195, the compound of any one of embodiments C1 to C177, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 is a bond, alkylene, cycloalkylene, or heterocyclylene, and each ring is j and R k is replaced by; Z 3 is a bond, alkylene, —C(O)NR—, —NR′(CO)—, —O—, —NR″—, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is mand R n is replaced by; Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2-; Z 2 , Z 3 , and Z 4 Each alkylene in the s and R t is replaced by

[0712] C196. In embodiment C196, the compound of any one of embodiments C1 to C177, and C195, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is selected from R m and R n is replaced by; Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0713] C197. In embodiment C197, the compound of any one of embodiments C1 to C177, C195, and C196, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is alkylene, -O-, cycloalkylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; o and R p is replaced by; Z 5is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0714] C198. In embodiment C198, the compound of any one of embodiments C1 to C177 and C195 to C197, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , and X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is alkylene, —O—, cycloalkylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy, preferably hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; o and R p is replaced by; Z 5is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0715] C199. In embodiment C119, the compound of any one of embodiments C1 to C177 and C195 to C198, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is alkylene, —O—, cycloalkylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy, preferably hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; o and R p and preferably Z 4 is alkylene or -O-; Z 5is phenylene or monocyclic heteroarylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0716] C200. In embodiment C200, the compound of any one of embodiments C1 to C177, and C195, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 is cycloalkylene or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; j and R k is replaced by; Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 is a bond, alkylene, or -O-; Z 5is phenylene, monocyclic heteroarylene (e.g., pyridinediyl), or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0717] C201. In embodiment C201, the compound of any one of embodiments C1 to C177, C191, and C195, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; j and R k is a heterocyclylene substituted with; Z 3 R is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is a heterocyclylene substituted with; Z 4 is a bond, alkylene, or -O-; Z 5 is phenylene or monocyclic heteroarylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-; Z 4 The alkylene in the s and R t is replaced by

[0718] C202. In embodiment C202, the compound of any one of embodiments C1 to C177, C178, C191, and C192, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds respectively; Z 2 But R j and R k and preferably R j and R k is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z 3 is a bond, alkylene, or -O-; Z 4 is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is R O and R p and preferably R O and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z 5 is phenylene or monocyclic heteroarylene, and each ring is R q and R r and preferably R q and R r are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z 6 is -S(O)2-; Z 3 The alkylene in the s and Rt is replaced by

[0719] C203. In embodiment C203, the compound of any one of embodiments C1 to C177, or a pharmaceutically acceptable salt thereof, is Z 4 is heterocyclylene or spiroheterocyclylene, and each ring is R o and R p and preferably R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy.

[0720] C204. In embodiment C204, the compound of any one of embodiments C1 to C177, C195, and C196, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 are bonds respectively; Z 3 is heterocyclylene and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; m and R n is replaced by; Z 4 R is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; o and R p is a cycloalkylene substituted with; Z 5 is phenylene or monocyclic heteroarylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; q and R r is replaced by; Z 6 is -S(O)2-.

[0721] C205. In embodiment C205, the compound of any one of embodiments C1 to C177, or a pharmaceutically acceptable salt thereof, is X 1 and Z 1 Only one of or X 2 and Z 1 Only one of or X 3 and Z 1 Only one of or X 4 and Z 1 Only one of the is a bond.

[0722] C206. In embodiment C206, the compound of any one of embodiments C1 to C177, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , and Z 1 are bonds.

[0723] C207. In embodiment C207, the compound of any one of embodiments C1 to C177, C205, and C206, or a pharmaceutically acceptable salt thereof, comprises Z 2 is heterocyclylene or bridged heterocyclylene, and each ring is R j and R k is replaced by

[0724] C208. In embodiment C208, the compound of any one of embodiments C1 to C177, C205, and C206, or a pharmaceutically acceptable salt thereof, comprises Z 2 is a bond.

[0725] C209. In embodiment C209, the compound of any one of embodiments C1 to C177, and C205 to C208, or a pharmaceutically acceptable salt thereof, is Z 3is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is a bond, -alkylene, -NR''-, -O-, -C(O)-, -S(O)2-, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is selected from the group consisting of R q and R r is replaced by; Z 6is a bond, alkylene, -NR''-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR'(CO)-, or -C(O)NR-; Z 3 , Z 4 , Z 5 , and Z 6 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0726] C210. ​​In embodiment C210, the compound of any one of embodiments C1 to C177, and C205 to C209, or a pharmaceutically acceptable salt thereof, is Z 3 is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is a bond, -alkylene, -NR''-, -O-, -C(O)-, -S(O)2-, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is selected from the group consisting of R q and R r is replaced by; Z 6 is -S(O)2-; Z 3 , Z 4 , and Z 5 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0727] C211. In embodiment C211, the compound of any one of embodiments C1 to C178, C191 to C193, C206, and C208 to C210, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is -heterocyclylene-(alkylene)-, and heterocyclylene is R m and R n and the alkylene is substituted with Rs and R t is replaced by; Z 4 is phenylene or monocyclic heteroarylene, and each ring is R o and R p is replaced by; Z 5 But R q and R r phenylene substituted with; Z 6 is -S(O)2-.

[0728] C212. In embodiment C212, the compound of any one of embodiments C1 to C177, and C205 to C210, or a pharmaceutically acceptable salt thereof, is Z 3 is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2-; Z 3 and Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0729] C212a. In embodiment C212a, the compound of any one of embodiments C1 to C177, and C205 to C210, or a pharmaceutically acceptable salt thereof, is Z 3 is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, and each ring, alone or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4 alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O)d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is independently selected from the group consisting of -, ... o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2; Z 3 and Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0730] C213. In embodiment C213, the compound of any one of embodiments C1 to C177, and C205 to C212, or a pharmaceutically acceptable salt thereof, is Z 3 is heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, and each ring, alone or as part of another group, is selected from the group consisting of R m and R n is replaced by; Z 4alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) d -, -(Alkylene-O) d -, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, by itself or as part of another group, is independently selected from R o and R p is replaced by; Z 5 is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is q and R r is replaced by; Z 6 is -S(O)2; Z 3 and Z 4 Each alkylene in the group, by itself or as part of another group, can be R s and R t are independently substituted with

[0731] C213a. In embodiment C213a, the compound of C213, or a pharmaceutically acceptable salt thereof, is X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are bonds respectively; Z 3 is -heterocyclylene-(alkylene)-, and heterocyclylene is R m and R n and the alkylene is substituted with R s and R t are independently substituted with; Z 4is phenylene or monocyclic heteroarylene, and each ring is R o and R p is replaced by; Z 5 But R q and R r phenylene substituted with; Z 6 is -S(O)2.

[0732] C214. In embodiment C214, the compound of any one of embodiments C1 to C177, C205 to C210, and C213, or a pharmaceutically acceptable salt thereof, is Z 3 is heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, and each ring, alone or as part of another group,...

Claims

1. Compounds of formula (Ia): 【Chemical 588】 (In the formula, R １ is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano, cycloalkyl, wherein said cycloalkyl is substituted with 1 to 3 halo; R ２ and R ２ａ are independently hydrogen or deuterium; Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiroheterocyclylene, bridged heterocyclylene, or fused heterocyclylene, wherein each of the foregoing rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano. ａ , R ｂ , and R ｃ is substituted with; Degron is (a) a group of formula (i): 【Chemical 589】 (b) a group of formula (ii): 【Chemical 590】 (c) a group of formula (iii): 【Chemistry 591】 (d) a group of formula (iv): 【Chemical 592】 (e) a group of formula (v): 【Chem.593】 and (f) a group of formula (vi): 【Chem.594】 an E3 ubiquitin ligase ligand selected from: R ｘ and R ｘ１ are each hydrogen; Y ａ is CH, or N; Z ａ is a bond, -CH ２ -, -NH-, -O-, or -NHC(O)-, wherein NH of -NHC(O)- is Y ａ is bound to; Ring A is represented by formula (a), (b) or (c): 【Chemical 595】 and where: R ａａ , R ｂｂ , R ｃｃ , and R ｄｄ is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; R ４ and R ５ are independently hydrogen or alkyl; or R ４ and R ５ form >C=O with the carbon to which they are attached; R ６ is hydrogen or alkyl; Ring B is phenylene, cyclylaminylene, 5- or 6-membered monocyclic heteroarylene, or 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains 1 to 3 nitrogen ring atoms, and further wherein said phenylene, cyclylaminylene, and each heteroarylene has R independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. ｅｅ and R ｆｆ are independently substituted with; X １ , X ２ , X ３ , and X ４ are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NR ｇｇ -alkylene)-, -(alkylene-NR ｈｈ ) -, 【Chemical 596】 , —NH—, —N(alkyl)-, —C(═O)—, NR ｊｊ C(=O)- or -C(=O)NR ｋｋ -, where R ｇｇ , R ｈｈ , R ｊｊ , and R ｋｋ is independently hydrogen, alkyl, or cycloalkyl, each alkylene by itself or as part of another group optionally substituted with 1 or 2 fluoro; R ｙ , R ｙ１ , and R ｙ２ is independently alkyl, hydroxyalkyl, cycloalkyl, or heterocyclyl, where cycloalkyl and heterocyclyl are selected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino; ｄ and R ｆ is substituted with; W ａ is a bond, O, S, or alkylene; L is -Z １ -Z ２ -Z ３ -Z ４ -Z ５ -Z ６ -, where: Z １ represents a bond, alkylene, —C(O)NR—, —NR′(CO)—, —S(O) ２ NR-, -NR'S(O) ２ -, -(O-alkylene) ａ -, -(alkylene-O) ａ -, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. ｈ and R ｉ is substituted with; Z ２ represents a bond, alkylene, alkynylene, —C(O)—, —C(O)N(R)—, —NR′(CO)—, —(O-alkylene) ｂ -, -(alkylene-O) ｂ -, -O(CH ２ ) ７ -, -O(CH ２ ) ８ -, cycloalkylene, or -heterocyclylene, where each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. ｊ and R ｋ is substituted with; Z ３ represents a bond, alkylene, alkynylene, —C(O)NR—, —NR′(CO)—, —O—, —NR″—, —(O-alkylene) ｃ -, -(alkylene-O) ｃ -, cycloalkylene, spirocycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, -spiroheterocyclylene-(alkylene)-, or 11- to 13-membered spiroheterocyclylene, where each ring, by itself or as part of another group, is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. ｍ and R ｎ is substituted with; Z ４ represents a bond, alkylene, alkynylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -C(O)-, -NR''-, or -(O-alkylene) ｄ -, -(alkylene-O) ｄ -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, has an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. ｏ and R ｐ is substituted with; Z ５ represents a bond, -alkylene, -NR″-, -O-, -C(O)-, -S(O) ２ -, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring has an R independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. ｑ and R ｒ is substituted with; Z ６ represents a bond, alkylene, —NR″—, —O—, —(alkylene-O)—, —C(O)—, —S(O) ２ -, -NR'(CO)-, or -C(O)NR-; wherein each R, R', and R'' is independently hydrogen or alkyl; each a, b, c, and d is independently an integer selected from 1 to 6; -Z １ -, -Z ２ -, -Z ３ -, -Z ４ -, -Z ５ - and -Z ６ Each alkylene of -, by itself or as part of another group, can be R ｓ and R ｔ and independently substituted with, where R ｓ is hydrogen or deuterium, R ｔ is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl is substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; with the proviso that -Z １ -Z ２ -Z ３ -Z ４ -Z ５ -Z ６ - at least one of which is not a bond; or and pharmaceutically acceptable salts thereof.

2. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is halo, haloalkyl, or haloalkoxy.

3. R １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is halo.

4. R １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: is haloalkyl.

5. R １ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: is haloalkoxy.

6. R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

7. R １ The compound according to any one of claims 1 to 3 and 6, or a pharmaceutically acceptable salt thereof, wherein is chloro or bromo.

8. R １ 7. The compound of any one of claims 1, 2, 4, and 6, or a pharmaceutically acceptable salt thereof, wherein is difluoromethyl or trifluoromethyl.

9. R ２ and R ２ａ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein both of are hydrogen.

10. R ２ and R ２ａ is deuterium, and R ２ and R ２ａ The other of R is hydrogen, or ２ and R ２ａ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein both of are deuterium.

11. Hy is heterocyclylene, phenylene, spiroheterocyclylene, bridged heterocyclylene, or cycloalkylene, and each of the aforementioned rings is R ａ , R ｂ , and R ｃ and R ａ and R ｂ is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, and hydroxy; R ｃ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12. Hy is R ａ , R ｂ , and R ｃ and R ａ and R ｂ is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, and hydroxy; R ｃ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

13. The heterocyclylene of Hy is pyrrolidine-1,3-diyl or piperidine-1,4-diyl, and Hy is R ａ , R ｂ , and R ｃ and R ａ and R ｂ are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy; R ｃ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein is hydrogen and L is bonded to a nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

14. The heterocyclylene of Hy is 【Chem.597】 and the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is bonded to L, or a pharmaceutically acceptable salt thereof.

15. The heterocyclylene of Hy is 【Chemical 598】 and the N atom of the piperidine-1,4-diyl ring is bonded to L, or a pharmaceutically acceptable salt thereof.

16. The degron has the formula (i): 【Chemical 599】 The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, which is an E3 ubiquitin ligase ligand of

17. Ring A of the E3 ubiquitin ligase ligand of formula (i) is a group represented by the formula (a): 【Chemical 600】 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein:

18. Ring A of the E3 ubiquitin ligase ligand of formula (i) is a group represented by formula (b): 【Chemical 601】 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein:

19. Ring A of the E3 ubiquitin ligase ligand of formula (i) is 【Chemical 602】 19. The compound according to any one of claims 1 to 18, wherein:

20. Ring A of the E3 ubiquitin ligase ligand of formula (i) is 【Chemical 603】 20. The compound according to any one of claims 1 to 19, wherein:

21. Ring A of the E3 ubiquitin ligase ligand of formula (i) is 【Chemical 604】 21. The compound according to any one of claims 1 to 20, wherein:

22. R ａａ , R ｂｂ , R ｃｃ , and R ｄｄ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

23. R ａａ , R ｂｂ , R ｃｃ , and R ｄｄ is independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy, or a pharmaceutically acceptable salt thereof.

24. The degron has the formula (ii): 【Chemical 605】 The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, which is an E3 ubiquitin ligase ligand of

25. The E3 ubiquitin ligase ligand of formula (ii) 【Chemical 606】 25. The compound according to any one of claims 1 to 15 and 24, wherein:

26. The E3 ubiquitin ligase ligand of formula (ii) 【Chemical 607】 and ring B is cyclylaminylene, or a pharmaceutically acceptable salt thereof.

27. X １ , X ２ , X ３ , and X ４ and each represent a bond, or a pharmaceutically acceptable salt thereof.

28. Z ６ Ga-S(O) ２ 28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein

29. Z ５ is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is ｑ and R ｒ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, substituted with:

30. X １ , X ２ , X ３ , X ４ , and Z １ are bonds respectively; Z ２ is a bond, alkylene, cycloalkylene, or heterocyclylene, and each ring is ｊ and R ｋ is substituted with; Z ３ is a bond, alkylene, —C(O)NR—, —NR′(CO)—, —O—, —NR″—, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is ｍ and R ｎ is substituted with; Z ４ is a bond, alkylene, —O—, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is ｏ and R ｐ is substituted with; Z ５ is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ２ , Z ３ , and Z ４ Each alkylene in the ｓ and R ｔ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, substituted with:

31. X １ , X ２ , X ３ , X ４ , Z １ , and Z ２ are bonds respectively; Z ３ is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is ｍ and R ｎ is substituted with; Z ４ is a bond, alkylene, —O—, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｏ and R ｐ is substituted with; Z ５ is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ４ The alkylene in the ｓ and R ｔ 31. The compound of any one of claims 1 to 26 and 30, or a pharmaceutically acceptable salt thereof, substituted with:

32. X １ , X ２ , X ３ , X ４ , Z １ , and Z ２ are bonds respectively; Z ３ is heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｍ and R ｎ is substituted with; Z ４ is alkylene, —O—, cycloalkylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｏ and R ｐ is substituted with; Z ５ is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ４ The alkylene in the ｓ and R ｔ 32. The compound of any one of claims 1 to 26, 30, and 31, or a pharmaceutically acceptable salt thereof, substituted with:

33. X １ , X ２ , X ３ , and X ４ , Z １ , and Z ２ are bonds respectively; Z ３ is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｍ and R ｎ is substituted with; Z ４ is alkylene, —O—, cycloalkylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy, preferably hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｏ and R ｐ is substituted with; Z ５ is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ４ The alkylene in the ｓ and R ｔ 33. The compound of any one of claims 1 to 26 and 30 to 32, or a pharmaceutically acceptable salt thereof, substituted with:

34. X １ , X ２ , X ３ , X ４ , Z １ , and Z ２ are bonds respectively; Z ３ is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｍ and R ｎ is substituted with; Z ４ is alkylene or —O—; Z ５ is phenylene or monocyclic heteroarylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ４ The alkylene in the ｓ and R ｔ 34. The compound of any one of claims 1 to 26 and 30 to 33, or a pharmaceutically acceptable salt thereof, substituted with:

35. X １ , X ２ , X ３ , X ４ , and Z １ are bonds respectively; Z ２ is cycloalkylene or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; ｊ and R ｋ is substituted with; Z ３ is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiroheterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｍ and R ｎ is substituted with; Z ４ is a bond, alkylene, or —O—; Z ５ is phenylene, monocyclic heteroarylene (e.g., pyridinediyl), or heterocyclylene, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ４ The alkylene in the ｓ and R ｔ 31. The compound of any one of claims 1 to 26 and 30, or a pharmaceutically acceptable salt thereof, substituted with:

36. X １ , X ２ , X ３ , X ４ , and Z １ are bonds respectively; Z ２ But, R ｊ and R ｋ and preferably R ｊ and R ｋ is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z ３ is a bond, alkylene, or —O—; Z ４ is heterocyclylene, bridged heterocyclylene, or spiroheterocyclylene, and each ring is ｏ and R ｐ and preferably R ｏ and R ｐ are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z ５ is phenylene or monocyclic heteroarylene, and each ring is ｑ and R ｒ and preferably R ｑ and R ｒ are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z ６ But -S(O) ２ - and; Z ３ The alkylene in the ｓ and R ｔ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, substituted with:

37. X １ , X ２ , X ３ , X ４ , Z １ and Z ２ are bonds respectively; Z ３ is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R ｍ and R ｎ is substituted with; Z ４ is alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) ｄ -, -(alkylene-O) ｄ -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is selected from the group consisting of -, ... ｏ and R ｐ is substituted with; Z ５ is a bond, -alkylene, -NR″-, -O-, -C(O)-, -S(O) ２ -, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, each ring being ｑ and R ｒ is substituted with; Z ６ represents a bond, alkylene, —NR″—, —O—, —(alkylene-O)—, —C(O)—, —S(O) ２ -, -NR'(CO)-, or -C(O)NR-; Z ３ , Z ４ , Z ５ , and Z ６ Each alkylene in the group, by itself or as part of another group, can be R ｓ and R ｔ 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, independently substituted with:

38. Z ３ is alkylene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from the group consisting of R ｍ and R ｎ is substituted with; Z ４ is alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) ｄ -, -(alkylene-O) ｄ -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is selected from the group consisting of -, ... ｏ and R ｐ is substituted with; Z ５ is a bond, -alkylene, -NR″-, -O-, -C(O)-, -S(O) ２ -, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, each ring being ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ３ , Z ４ , and Z ５ Each alkylene in the group, by itself or as part of another group, can be R ｓ and R ｔ 40. The compound of any one of claims 1 to 26 and 37, or a pharmaceutically acceptable salt thereof, independently substituted with:

39. Z ３ is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene-, or -spiroheterocyclylene-(alkylene), and each ring, by itself or as part of another group, is selected from R ｍ and R ｎ is substituted with; Z ４ is alkylene, -(alkylene-NR'')-, -(NR''-alkylene)-, -O-, -NR''-, -(O-alkylene) ｄ -, -(alkylene-O) ｄ -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiroheterocyclylene, -(alkylene)-spiroheterocyclylene, or -spiroheterocyclylene-(alkylene)-, wherein each ring, alone or as part of another group, is selected from the group consisting of -, ... ｏ and R ｐ is substituted with; Z ５ is phenylene, monocyclic heteroarylene, or heterocyclylene, and each ring is ｑ and R ｒ is substituted with; Z ６ But -S(O) ２ - and; Z ３ and Z ４ Each alkylene in the group, by itself or as part of another group, can be R ｓ and R ｔ 40. The compound of any one of claims 1 to 26, 37, and 38, or a pharmaceutically acceptable salt thereof, independently substituted with:

40. -Z ５ - is independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; ｑ and R ｒ replaced with 【Chemical 608】 (i.e., Z ５ is phenylene, where Z ４ and Z ６ is bonded to the meta position of the phenylene ring), or a pharmaceutically acceptable salt thereof.

41. -Z ５ -but, 【Chemical 609】 41. The compound according to any one of claims 1 to 40, wherein:

42. -Z ５ - is independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; ｑ and R ｒ 40. The compound of any one of claims 1 to 39, which is a monocyclic heteroarylene substituted with: or a pharmaceutically acceptable salt thereof.

43. Z １ , Z ２ , Z ３ , Z ４ , and Z ５ Each heterocyclylene, bridged heterocyclylene, and spiroheterocyclylene, when present, is 【Chemical 610】 and each ring is optionally substituted with 1, 2, or 3 fluoro unless otherwise stated in any of claims 1-42, or a pharmaceutically acceptable salt thereof.

44. -Z ３ -Z ４ -Z ５ -Z ６ -が、 【Chemical 611】 and each R ｍ , R ｎ , and R ｑ 40. The compound of any one of claims 1 to 35 and 37 to 39, or a pharmaceutically acceptable salt thereof, wherein is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano.

45. Z ４ But, R ｓ and R ｔ is alkylene substituted with R ｓ and R ｔ 45. The compound according to any one of claims 1 to 35, 37 to 42 and 44, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

46. Z ４ The compound according to any one of claims 1 to 35, 37 to 42, and 44, or a pharmaceutically acceptable salt thereof, wherein is -O-.

47. Z ４ But, R ｓ and R ｔ is alkylene substituted with R ｓ is hydrogen or deuterium, and R ｔ 45. The compound of any one of claims 1 to 35, 37 to 42 and 44, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, or cyano.

48. Z ４ is -(alkylene)-heterocyclylene-, and heterocyclylene is R ｏ and R ｐ 45. The compound of any one of claims 1 to 29, 37 to 42 and 44, or a pharmaceutically acceptable salt thereof, substituted with:

49. Z ４ But -(CH ２ )-heterocyclylene-, wherein heterocyclylene is R ｏ and R ｐ 49. The compound of any one of claims 1 to 29, 37 to 42, 44, and 48, or a pharmaceutically acceptable salt thereof, substituted with:

50. Z ４ but, 【Chemical 612】 50. The compound according to any one of claims 1 to 29, 37 to 42, 44, 48, and 49, or a pharmaceutically acceptable salt thereof, wherein:

51. -Z ３ -Z ４ -Z ５ -Z ６ -が、 【Chemical Formula 613】 51. The compound according to any one of claims 1 to 29, 37 to 42, 44, and 48 to 50, or a pharmaceutically acceptable salt thereof, wherein:

52. Degron, 【Chemical 614】 and each R is an E3 ubiquitin ligase ligand selected from ｅｅ is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, and each R ｆｆ 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

53. The compound is 1-(1-methyl-6-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-1-methyl-6-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(3,3-difluoro-1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(6-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-(2,2,2-trifluoroethyl)-6-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenethyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; N-((R)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidine-4-carboxamide; (2S,4R)-1-((R)-2-(1-fluorocyclopropane-1-carboxamide)-3-methyl-3-(((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)methyl)thio)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)acetamido)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; 1-(1-methyl-6-(1-(3-(((1r,4r)-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)sulfonyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(4-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-(difluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-(((3R,4S)-3-fluoro-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-1-methyl-6-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-(1,1-difluoroethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-((3-fluoro-4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(((1r,4r)-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)sulfonyl)piperidin-3-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(((1r,4r)-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)sulfonyl)piperidin-4-yl)methyl)-piperidin-4-yl)-1H-indazol-3-yl)-dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 5-(4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 1-(6-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-bromopyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-fluoropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-(((3R,4S)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2,2-difluoroethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(2-(1-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)piperidin-3-yl)ethyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(5-(4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 1-(6-(1-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-(1-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(1-oxo-5-(4-(3-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(6-fluoro-1-oxo-5-(4-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(4-(3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 1-(6-(6-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-methyl-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)-1H-imidazol-2-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(1-oxo-5-(1-(3-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)azetidin-3-yl)isoindolin-2-yl)piperidine-2,6-dione; 1-(1-methyl-6-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)azetidin-3-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(5-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-azetidin-3-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 1-(1-methyl-6-(4-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(2,2-dimethyl-3-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-azetidin-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-methoxypyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-((4-((5-vinylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-(((1r,4r)-4-((5-chloropyrimidin-2-yl)amino)cyclohexyl)sulfonyl)-benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-((4-((5-methyl-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-ethylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-((4-((5-phenoxypyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(3-(((1r,4r)-4-((5-chloropyrimidin-2-yl)amino)cyclohexyl)sulfonyl)benzyl)-piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-(dimethylamino)-pyrimidin-2-yl)amino)piperidin-1-yl)-sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-chloro-6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-piperazin-1-yl)isoindoline-1,3-dione; 1-(1-methyl-6-(1-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)azetidin-3-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(5-(4-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 1-(6-(1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(1-oxo-5-(4-(3-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 1-(6-(1-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(4-(3-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 5-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione; 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(4-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione; 1-(6-(1-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)azetidin-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(4-(4-(3-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(3-methyl-2-oxo-4-(1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(6-(4-((3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)-amino)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(4-((3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)amino)piperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)propyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(4-((methyl(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)amino)-methyl)piperidin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-chloro-1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(3,3-difluoro-1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-(2,2,2-trifluoroethyl)-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(1-oxo-5-(4-(3-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)azetidin-1-yl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 1-(6-(1-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-fluoro-1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-fluoro-5-(4-(2-methyl-3-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)propyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-fluoro-1-oxo-5-(4-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)-piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 1-(6-(3-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(5-(4-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)-azetidin-1-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(5-(4-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)-piperazin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(3-methyl-2-oxo-4-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)azetidin-3-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(4-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(5-fluoro-1-methyl-6-(4-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(4-(4-((1-(3-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(8-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoro-methoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (R)-1-(6-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (S)-1-(6-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-2-methylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)-azetidin-3-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-fluoro-1-oxo-5-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione; 3-(5-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(4-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(6-(1-((3'-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-[1,1'-biphenyl]-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(2-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)ethyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(2-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenoxy)-ethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(6-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-3,6-diazabicyclo-[3.1.1]heptan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(6-((1-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-((2S,6R)-4-((1-(3-((4-((5-chloro-pyrimidin-2-yl)amino)piperidin-1-yl)-sulfonyl)phenyl)piperidin-4-yl)methyl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(4-(1-(3-((4-((5-(difluoromethoxy)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-azetidin-3-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((5-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)pyridin-3-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((2-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-azaspiro[3.3]heptan-6-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-(4-((1-(3-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)amino)piperidine-2,6-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (S)-1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-pyrrolidin-3-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-azepan-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-5-(1-((1-(3-((4-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperazin-1-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(4-(1-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(5-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)piperidin-4-yl)methyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; Ethyl 1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidine-4-carboxylate; 1-(6-(1-((1-(2-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(5-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-2,5-diazabicyclo-[4.1.0]heptan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (R)-1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-pyrrolidin-3-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-7-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-((6-((5-(trifluoro-methyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]-heptan-2-yl)sulfonyl)benzyl)-piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-piperidin-1-yl)benzonitrile; 1-(6-(1-((1-(3-fluoro-5-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 1-(1-methyl-6-(1-(3-((3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)azetidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate; 1-(6-(1-(4-(1-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-3-yl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)-2,2-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile 2,2,2-trifluoroacetate; 2-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-4-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(1-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-piperidine-4-carbonitrile; 1-(1-methyl-6-(1-((1-(4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(3-methyl-2-oxo-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-(7-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-2-oxobenzo[d]oxazole-3(2H)-yl)piperidine-2,6-dione; 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(2-oxo-3-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(1-methyl-6-(1-((1-(3-((6-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(4-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-(4-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(6-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(4-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 3-(3-methyl-2-oxo-5-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(1-methyl-6-(1-((1-(3-((3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)azetidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-((4-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)methyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(4-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)piperidin-1-yl)methyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile; 1-(3-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((2-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)pyridin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(4-(1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-5-fluorobenzyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzonitrile; 3-(2-oxo-3-((1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-4-fluorophenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(3-methyl-4-(1-(3-(methyl(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)amino)propyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione; 1-(6-(4-((8-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-fluoropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-(difluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)methyl)benzonitrile; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)piperidin-1-yl)methyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-bromopyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzonitrile; 3-(2-oxo-7-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)benzo[d]oxazole-3(2H)-yl)piperidine-2,6-dione; rac-1-(6-(1-((1-(3-(((3R,4S)-4-((5-chloropyrimidin-2-yl)amino)-3-fluoropiperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzonitrile; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)-pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-4-methylpiperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 1-(1-methyl-6-(1-((1-(3-((4-((5-vinylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)pyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)pyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(8-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)imidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)-4-hydroxypiperidin-1-yl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzonitrile; 1-(6-(1-((1-(3-(((3R,4S)-4-((5-chloropyrimidin-2-yl)amino)-3-methoxypiperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; rac-1-(6-(1-((1-(3-(((3R,4R)-4-((5-chloropyrimidin-2-yl)amino)-3-methoxypiperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 4-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)methyl)piperidin-1-yl)benzonitrile; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)benzo[d]isoxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; rac-1-(6-(1-((1-(3-(((3R,4S)-3-fluoro-4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperazin-1-yl)methyl)cyclohexyl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; N-(2,6-dioxopiperidin-3-yl)-5-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)picolinamide; 1-(6-(1-(3-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)prop-2-yn-1-yl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-(((1R,5S)-3-((5-chloropyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; rac-1-(6-(1-((1-(3-(((1R,5S,8s)-8-((5-chloropyrimidin-2-yl)amino)-3-azabicyclo-[3.2.1]octan-3-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(3-(4-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)prop-1-yn-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(3-(4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenyl)piperazin-1-yl)prop-1-yn-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(4-((3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)ethynyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(4-((3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-ethynyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-oxopiperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(3-(4-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)propyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)benzamide; 4-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide; 1-(1-methyl-6-(4-((4-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-1-yl)methyl)cyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)-4-thioxotetrahydropyrimidin-2(1H)-one; 1-(6-(1-((1-(3-(((1r,4r)-4-((5-chloropyrimidin-2-yl)amino)cyclohexyl)sulfonyl)-phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-7-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(2,2,2-trifluoroethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-isopropylpyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; 3-(5-(4-((4-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(1-oxo-5-(4-((4-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione; 1-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)azetidin-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenyl)piperidin-4-yl)methyl)piperidin-4-yl)benzo[b]thiophen-3-yl)piperidine-2,6-dione; 3-(1-methyl-6-(1-((1-(3-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione; 1-(6-(1-((1-(3-((4-((5-cyclopropoxypyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)-dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-((1-(3-((4-((5-isopropoxypyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 3-(6-(1-((1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-1-methyl-1H-indol-3-yl)piperidine-2,6-dione; (R)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzonitrile; (S)-4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)benzonitrile; (S)-1-(6-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-3-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (R)-1-(6-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-3-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (S)-1-(6-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)pyrrolidin-2-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (R)-1-(6-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-2-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; (S)-1-(6-(1-((1-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperidin-2-yl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-(((3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)amino)methyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(4-((3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(3-((4-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(1-methyl-6-(1-(1-(1-((4-((5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-3-yl)propan-2-yl)piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(6-(1-(3-((4-((5-(chlorodifluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; 1-(7-chloro-6-(1-(3-((4-((5-chloropyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)benzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; and 1-(6-(1-(3-(3-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

54. 54. A pharmaceutical composition comprising a compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

55. 54. A method of treating a disease mediated by CDK2 in a patient, comprising administering to said patient identified as in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutical composition of claim 53.

56. 55. A method of treating cancer in a patient, comprising administering to said patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 54.

57. 57. The method of claim 56, wherein the compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 54, is administered in combination with at least one other anticancer agent.

58. 58. The method of claim 56 or 57, wherein the cancer is lung cancer, skin cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer, head and neck cancer, liver cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, or parathyroid cancer.

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