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

Abstract

The present disclosure provides certain bifunctional compounds that elicit degradation of cyclin dependent kinase 2 (CDK2) via the ubiquitin proteasome pathway, and thus are useful in the treatment of diseases mediated by CDK2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

[0001] Cross - Reference to Related Applications

[0002] This PCT international patent application claims the benefit of U.S. Provisional Application No. 63 / 424,871, filed on November 11, 2022; U.S. Provisional Application No. 63 / 485,255, filed on February 15, 2023; U.S. Provisional Application No. 63 / 512,594, filed on July 7, 2023; and U.S. Provisional Application No. 63 / 528,596, filed on July 24, 2023; the entire contents of each of these applications are hereby incorporated by reference. Technical Field

[0003] This disclosure provides certain bifunctional compounds containing 2,5 - substituted pyrimidine derivatives, which cause the degradation of cyclin - dependent kinase 2 (CDK2) via the ubiquitin - proteasome pathway and thus can be used to treat CDK2 - mediated diseases. Also provided are pharmaceutical compositions containing such compounds and methods for preparing such compounds. Background Art

[0004] Cyclin - dependent kinases (CDKs) are cell kinases that are crucial for orchestrating signaling events such as DNA replication and protein synthesis to ensure reliable eukaryotic cell division and proliferation. To date, at least twenty - one mammalian CDKs have been identified (Malumbres M. Genome Biol. (2014) 15:122). Among these CDKs, at least the CDK1 / cyclin B, CDK2 / cyclin E, CDK2 / cyclin A, CDK4 / cyclin D, CDK6 / cyclin D complexes are considered important regulators of the cell cycle progression; while other CDKs are important in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D.O. Annu. Rev. Cell. Dev. Biol. (1997) 13:261 - 291).

[0005] Due to their role in regulating the cell cycle and other essential cellular processes, it has been shown that increased or transiently abnormal activation of CDKs leads to the development of various cancer types. The development of human tumors is often associated with alterations in the CDK proteins themselves or their 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, amplifications of regulatory subunits of CDKs and cyclins have been reported, as well as mutations, gene deletions, or transcriptional silencing of endogenous CDK inhibitory regulators (Smalley et al. Cancer Res. (2008) 68:5743-52). A large number of studies have established the role of these alterations in promoting tumorigenesis and development. Thus, in the past two decades, there has been great interest in developing cyclin-dependent kinase (CDK) inhibitors for therapeutic purposes.

[0006] Selective CDK4 / 6 inhibitors have changed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (MBC). Palbociclib, ribociclib, and abemaciclib are selective reversible inhibitors of CDK4 and CDK6, which are approved for use in hormone receptor-positive (HR+) metastatic breast cancer in combination with endocrine therapy. Other clinical trials using these CDK4 / 6 inhibitors are ongoing in breast cancer and other cancers, either as single agents or in combination with other therapeutic agents. (O'Leary et al. Nature Reviews (2016) 13:417-430). Although CDK4 / 6 inhibitors have shown significant clinical efficacy in ER-positive metastatic breast cancer, the clinical benefit may be limited over time due to the development of primary or acquired resistance.

[0007] An important mechanism of CDK4 / 6 inhibitor resistance is the abnormal activation of CDK2. It has been reported that the high expression of cyclin E results in an over-activated CDK2 / cyclin E complex, bypassing the requirement for CDK4 / 6 to re-enter the cell cycle (Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561). In addition, it has been found that when CDK4 / 6 is inhibited, there is the formation of a non-canonical CDK2 / cyclin D1 complex that promotes the restoration of pRb phosphorylation and drives cell cycle progression (Herrera-Abreu MT et al., Cancer Res. (2006) 15:2301).

[0008] The CDK2 / cyclin E complex plays an important role in regulating the G1 / S transition, histone biosynthesis, and centrosome duplication. After Rb is initially phosphorylated by CDK4 / 6 / cyclin D, CDK2 / cyclin E further hyperphosphorylates p-RB, releasing E2F to transcribe genes required to enter the S phase. During the S phase, cyclin E is degraded, and CDK2 forms a complex with cyclin A to promote phosphorylation of substrates, allowing DNA replication and inactivation of E2F to complete the S phase (Asghar et al. Nat. Rev. Drug. Discov. (2015) 14:130-146). In addition to cyclin binding, the activity of CDK2 is tightly regulated by its interaction with negative regulators such as p21 and p27. In response to mitogenic stimuli that signal an optimal environment for the cell cycle, p21 and p27 are phosphorylated and degraded, relieving the interruption of CDK2 / cyclin activation.

[0009] Cyclin E (the regulatory cyclin of CDK2) is often overexpressed in cancers, and its overexpression is associated with poor prognosis. For example, it has been shown that amplification or overexpression of cyclin E is associated with poor outcomes in breast cancer (Keyomarsi et al., N Engl J Med. [The New England Journal of Medicine] (2002) 347:1566 - 75). Overexpression of cyclin E2 (CCNE2) is associated with endocrine resistance in breast cancer cells, and it has been reported that CDK2 inhibition restores sensitivity to tamoxifen or CDK4 / 6 inhibitors in tamoxifen - resistant and CCNE2 - overexpressing cells. (Caldon et al., Mol Cancer Ther. [Molecular Cancer Therapeutics] (2012) 11:1488 - 99; Herrera - Abreu et al., Cancer Res. [Cancer Research] (2016) 76:2301 - 2313). It has been reported that cyclin E amplification also contributes to trastuzumab resistance in HER2 + breast cancer. (Scaltriti et al Proc Natl Acad Sci. [Proceedings of the National Academy of Sciences of the United States of America] (2011) 108:3761 - 6). It has also been reported that cyclin E overexpression plays a role in basal - like and triple - negative breast cancer (TNBC) and inflammatory breast cancer (Elsawaf Z. et al Breast Care [Breast Care] (2011) 6:273 - 278; Alexander A. et al Oncotarget [Oncotarget] (2017) 8:14897 - 14911).

[0010] Amplification or overexpression of cyclin E1 (CCNE1) is also frequently found in ovarian cancer, gastric cancer, endometrial cancer, uterine cancer, bladder cancer, esophageal cancer, prostate cancer, lung cancer, and other types of cancers (Nakayama et al Cancer [Cancer] (2010) 116:2621 - 34; Etemadmoghadam et al Clin Cancer Res [Clinical Cancer Research] (2013) 19:5960 - 71; Au - Yeung et al Clin.Cancer Res. [Clinical Cancer Research] (2017) 23:1862 - 1874; Ayhan et al Modern Pathology [Modern Pathology] (2017) 30:297 - 303; Ooi et al Hum Pathol. [Human Pathology] (2017) 61:58 - 67; Noske et al Oncotarget [Oncotarget] (2017) 8:14794 - 14805), and is generally associated with poor clinical outcomes.

[0011] In some cancers, FBXW7 (the SCF responsible for cyclin E degradationFbw7 Loss-of-function mutations in components of the ubiquitin E3 ligase also lead to cyclin E overexpression and CDK2 activation. Alternatively, certain cancer cells express a truncated, overactive form of cyclin E. In addition, amplification and overexpression of cyclin A have been reported in various cancers such as hepatocellular carcinoma, colorectal cancer, and breast cancer.

[0012] In contrast to the frequent upregulation of cyclin E, inhibitory regulators of CDK2, p21, and p27 are often abnormally downregulated in cancers. It is hypothesized that the loss or reduction of these key endogenous inhibitors leads to hyperactivation and / or transient abnormal activation of CDK2, thus promoting tumor growth.

[0013] In addition, CDC25A and CDC25B (protein phosphatases responsible for activating dephosphorylation of CDK2) are overexpressed in various tumors. These different mechanisms of CDK2 activation have been validated using mouse cancer models. In addition, 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 with myc overexpression.

[0014] Recently, it has also been shown that pharmacological inhibition or genetic deletion of CDK2 preserves hearing function in animal models treated with cisplatin or noise (Teitz T et al. J Exp Med. [Journal of Experimental Medicine] April 2, 2018; 215(4):1187-1203). Mechanistically, inhibition of CDK2 kinase activity reduces cisplatin-induced production of mitochondrial reactive oxygen species, thus improving the survival of inner ear cells. Therefore, in addition to anti-tumor therapies, CDK2 inhibition can also be used as a promising prophylactic treatment against noise-, cisplatin- or antibiotic-induced, or age-related hearing loss, for which there are currently no Food and Drug Administration-approved drugs available.

[0015] Targeted protein degradation is emerging as a potential therapeutic modality that uses endogenous protein degradation systems (such as the ubiquitin-proteasome pathway or lysosomes) to eliminate specific proteins (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 subsequently proteolyzed by the large enzyme complex proteasome. The ubiquitination process is a complex post-translational modification cascade in which three enzymes (ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin-protein ligase E3) act sequentially to attach ubiquitin to the substrate protein. Since 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.

[0016] A proteolysis targeting chimera (PROTAC) is a bifunctional molecule consisting of a target protein recruitment moiety and a ligand for an E3 ligase, which are connected by a biocompatible linker. PROTACs can bring the target protein and the E3 ligase into close proximity and induce ubiquitination of the target protein and subsequent degradation of the target protein by the proteasome. Compared with traditional small molecule drugs that typically bind to disease-related proteins and inhibit their functions, PROTACs exhibit several unique and attractive features, making them ideal drug candidates. PROTACs have the ability to target previously undruggable proteins because they are not limited to binding catalytic domains. PROTACs have been shown to be more selective than their inhibitor counterparts, which may reduce off-target toxicity. In addition, PROTACs can undergo multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can act at sub-stoichiometric receptor occupancy. The E3 ligases used in PROTACs mainly include cereblon (CRBN), von Hippel-Lindau-containing complex (VHL), inhibitor of apoptosis protein (IAP), and murine double minute 2 (MDM2).

[0017] Compared with inhibition, removing the CDK2 protein will eliminate CDK2 activity as well as any protein interaction or scaffolding function of CDK2. Therefore, a bifunctional molecule that can recruit CDK2 to a ubiquitin ligase and thus lead to ubiquitination and proteasomal degradation of CDK2 is needed. This disclosure meets this need and related needs. SUMMARY OF THE INVENTION

[0018] In a first aspect, there is provided a compound for degrading and / or inhibiting CDK2, wherein the compound comprises a CDK2-binding moiety having formula (A1):

[0019]

[0020] Wherein:

[0021] 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, heteroaryloxy, heterocyclic, heterocyclicalkyl, heterocyclicoxy, fused heterocyclic, fused heterocyclicoxy or fused heterocyclicalkyl, wherein the cycloalkyl itself or as part of cycloalkoxy and cycloalkylalkyl, the aryl itself or as part of aralkyl and aryloxy, the heteroaryl itself or as part of heteroaralkyl and heteroaryloxy, the heterocyclic itself or as part of heterocyclicalkyl and heterocyclicoxy, the bridged cycloalkyl alone or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and the fused heterocyclic itself or as part of fused heterocyclicalkyl and fused heterocyclicoxy are substituted by one, two or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano;

[0022] R 2 and R 2a are independently hydrogen or deuterium; and

[0023] Hy is cycloalkylene, arylene, heteroarylene, heterocycloalkylene, bicyclic heteroalkylene, spiro heteroalkylene, bridged heteroalkylene or fused heteroalkylene, wherein each of the above rings is independently substituted by R a 、R b and R c selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano; or

[0024] its pharmaceutically acceptable salts;

[0025] wherein the compound having formula (A1) degrades and / or inhibits CDK2, and the degradation of CDK2 proceeds via the ubiquitin proteasome pathway.

[0026] In a first embodiment of the first aspect, the compound having formula (A1) degrades CDK2 via the ubiquitin proteasome pathway.

[0027] In a second embodiment of the first aspect, the compound having formula (A1) inhibits CDK2.

[0028] In a second aspect, there is provided a compound for degrading CDK2, wherein the compound comprises a CDK2 binding moiety having formula (A):

[0029]

[0030] Wherein:

[0031] R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano or cycloalkyl, wherein the cycloalkyl is substituted with one to three halo;

[0032] R 2 and R 2a are independently hydrogen or deuterium; and

[0033] Hy is cycloalkylene, arylene, heteroarylene, heterocycloalkylene, bicyclic heterocycloalkylene, spiroheterocycloalkylene, bridged heterocycloalkylene or fused heterocycloalkylene, wherein each of the above rings is independently substituted with R a 、R b and R c selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano; or

[0034] its pharmaceutically acceptable salts;

[0035] wherein the degradation of CDK2 proceeds via the ubiquitin proteasome pathway.

[0036] In a third aspect, the compounds of formula (A1) and (A) for degrading CDK2 as described in the first and / or second aspects are according to formula (I):

[0037]

[0038] Wherein:

[0039] R 1 as defined herein;

[0040] R 2 and R 2a are independently hydrogen or deuterium;

[0041] Hy is cycloalkylene, arylene, heteroarylene, heterocycloalkylene, bicyclic heterocycloalkylene, spiroheterocycloalkylene, bridged heterocycloalkylene or fused heterocycloalkylene, wherein each of the above rings is independently substituted with R a 、R b and R c substituted;

[0042] L is a linker; and

[0043] The degron is an E3 ubiquitin ligase ligand; or

[0044] a pharmaceutically acceptable salt thereof.

[0045] In a fourth aspect, there is provided a compound having the formula (Ia):

[0046]

[0047] wherein

[0048] R 1 is 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, heteroaryloxy, heterocyclic, heterocyclicalkyl, heterocyclicoxy, fused heterocyclic, fused heterocyclicoxy or fused heterocyclicalkyl, wherein the cycloalkyl itself or as part of cycloalkoxy and cycloalkylalkyl, aryl itself or as part of aralkyl and aryloxy, heteroaryl itself or as part of heteroaralkyl and heteroaryloxy, heterocyclic itself or as part of heterocyclicalkyl and heterocyclicoxy, bridged cycloalkyl alone or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and fused heterocyclic itself or as part of fused heterocyclicalkyl and fused heterocyclicoxy is substituted by one, two or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano;

[0049] R 2 and R 2a are independently hydrogen or deuterium; and

[0050] Hy is cycloalkylene, arylene, heteroarylene, heterocycloalkylene, bicyclic heteroalkylene, spiroheteroalkylene, bridged heteroalkylene or fused heteroalkylene, wherein each of the above rings is independently substituted by R a , R b and R c independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano;

[0051] The degradation-resolving stator is an E3 ubiquitin ligase ligand selected from the following:

[0052] (a) A group having formula (i):

[0053]

[0054] (b) A group having formula (ii):

[0055]

[0056] (c) A group having formula (iii):

[0057]

[0058] (d) A group having formula (iv):

[0059]

[0060] (e) A group having formula (v):

[0061]

[0062] (f) A group having formula (vi):

[0063]

[0064] Wherein:

[0065] R x And R x1 Are each hydrogen;

[0066] Y a Is CH or N;

[0067] Z a Is a bond, -CH 2 -, -NH-, -O- or -NHC(O)-, where the NH of -NHC(O)- is attached to Y a Attached;

[0068] Ring A is a group having formula (a), (b) or (c):

[0069]

[0070] Wherein:

[0071] R aa 、R bb 、R cc And R dd Are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano;

[0072] R4 and R 5 is independently hydrogen or alkyl; or R 4 and R 5 together with the carbon to which they are attached form >C=O; and

[0073] R 6 is hydrogen or alkyl;

[0074] Ring B is phenylene, cycloimino, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, each heteroarylene ring containing one to three nitrogen ring atoms and further wherein the phenylene, cycloimino and each heteroarylene are independently substituted by R ee and R ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano; and

[0075] 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 )-, -NH-, -N(alkyl)-, -C(=O)-, -NR jj C(=O)- or -C(=O)NR kk -, where R gg 、R hh 、R jj and R kk are independently hydrogen, alkyl or cycloalkyl, and each alkylene is optionally substituted by one or two fluorines, either alone or as part of another group;

[0076] R y 、R y1 and R y2 are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic group are substituted by R d and R f independently selected from hydrogen, halo, cyano, alkylcarbonyl and alkylcarbonylamino; and

[0077] W a is a bond, O, S or alkylene; and

[0078] L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6-, wherein:

[0079] Z 1 is a bond, an alkylene group, -C(O)NR-, -NR'(CO)-, -S(O) 2 NR-, -NR'S(O) 2 -, -(O-alkylene) a -, -(alkylene-O) a -, a phenylene group, a monocyclic heteroarylene group or a heteroalkylenyl group, wherein each ring is independently substituted by R h and R i selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino;

[0080] Z 2 is a bond, an alkylene group, an alkynylene group, -C(O)-, -C(O)N(R)-, -NR'(CO)-, -(O-alkylene) b -, -(alkylene-O) b -, -O(CH 2 ) 7 -, -O(CH 2 ) 8 -, a cycloalkylene group or a heteroalkylenyl group, wherein each ring is independently substituted by R j and R k selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino;

[0081] Z 3 is a bond, an alkylene group, an alkynylene group, -C(O)NR-, -NR'(CO)-, -O-, -NR”-,-(O-alkylene) c -, -(alkylene-O) c -, a cycloalkylene group, a spiroalkylene group, a phenylene group, -(alkylene)-phenylene-, -phenylene-(alkylene)-, a monocyclic heteroarylene group, -(alkylene)-monocyclic heteroarylene-,-monocyclic heteroarylene-(alkylene)-, a heteroalkylenyl group, -(alkylene)-heteroalkylenyl-,-heteroalkylenyl-(alkylene)-, a bicyclic heteroalkylenyl group, a bridged heteroalkylenyl group,-(alkylene)-bridged heteroalkylenyl-,-bridged heteroalkylenyl-(alkylene)-, a fused heteroalkylenyl group, a spiroheteroalkylenyl group,-(alkylene)-spiroheteroalkylenyl-,-spiroheteroalkylenyl-(alkylene)- or an 11- to 13-membered spiroheteroalkylenyl group, wherein each ring, either by itself or as part of another group, is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino;

[0082] Z 4 is a bond, an alkylene, an alkynylene, -(alkylene-NR"), -(NR"-alkylene)-, -O-, -C(O)-, -NR"-, -(O-alkylene) d -, -(alkylene-O) d -, a cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, a spirocycloalkylene, a phenylene, a heteroarylene, a heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, a fused heterocyclylene, a bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, a spiroheterocyclylene, -(alkylene)-spiroheterocyclylene or -spiroheterocyclylene-(alkylene)-, wherein each ring is independently substituted by R o and R p selected from hydrogen, deuterium, an alkyl, an alkoxy, a halogen, a haloalkyl, a haloalkoxy, a cyano, a hydroxy, an amino, an alkylamino and a dialkylamino;

[0083] Z 5 is a bond, -alkylene, -NR", -O-, -C(O)-, -S(O) 2 -, -NR'(CO)-, -C(O)NR-, a phenylene, a monocyclic heteroarylene or a heterocyclylene, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, an alkyl, an alkoxy, a halogen, a haloalkyl, a haloalkoxy, a cyano, a hydroxy, an amino, an alkylamino and a dialkylamino; and

[0084] Z 6 is a bond, an alkylene, -NR", -O-, -(alkylene-O)-, -C(O)-, -S(O) 2 -, -NR'(CO)- or -C(O)NR-;

[0085] wherein each R, R' and R" is independently hydrogen or an alkyl, each a, b, c and d is independently an integer selected from 1 to 6, and each -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 5 -, - and -Z 6 - in each alkylene is independently substituted by R s and R t wherein R s is hydrogen or deuterium and R tis hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocycloalkyl, aryl or monocyclic heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy or cyano; provided that -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 at least one of - is not a bond;

[0086] or a pharmaceutically acceptable salt thereof.

[0087] In a fifth aspect, there is provided a method of treating a CDK2-mediated disease in a patient (preferably a patient in need thereof), the method comprising administering to the patient (preferably a patient in need thereof) a therapeutically effective amount of a compound as described in any one of the first, second, and third aspects or a compound of formula (Ia) as described in the fourth aspect (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof. (For clarity, the phrase "any embodiment thereof described herein" includes embodiments of the first, second, and third aspects and formula (Ia) disclosed 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 cancer is selected from: lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchial cancer, 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, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer, head and neck cancer (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer and / or oral cancer), 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., pancreatic exocrine cancer), gastric cancer, thyroid cancer, and parathyroid cancer. In a third embodiment of the fifth aspect, the cancer is a cancer that is resistant to CDK4 / 6 inhibitors through a CDK2-mediated mechanism, such as breast cancer. In a fourth embodiment of the fifth aspect, the disease is an autoimmune disease or a condition associated with an autoimmune disease, the method comprising administering to the patient (preferably a patient in need thereof) a therapeutically effective amount of a compound as described in any one of the first, second, and third aspects or a compound of formula (Ia) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary 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 specific compounds) or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.

[0088] In a sixth aspect, there is provided a method for treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced or age-related hearing loss, the method comprising administering to a patient (preferably a patient in need of such treatment) a therapeutically effective amount of a compound as described in any one of the first, second and third aspects or a compound having formula (Ia) as described in the fourth aspect (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof. In some embodiments of the sixth aspect, the amount of hearing loss is reduced when compared to an age-matched control. In some embodiments, the hearing loss is prevented when compared to an age-matched control.

[0089] In a seventh aspect, there is provided a pharmaceutical composition comprising a compound as described in any one of the first, second and third aspects or a compound having formula (Ia) as described in the fourth aspect (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0090] In an eighth aspect, there is provided a compound as described in any one of the first, second and third aspects or a compound having formula (Ia) as described in the fourth aspect (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment of the eighth aspect, a compound as described in any one of the first, second and third aspects or a compound having formula (Ia) as described in the fourth aspect (or any embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof can be used to treat one or more of the diseases disclosed in the fifth and sixth aspects above.

[0091] In a ninth aspect, there is provided the use of a compound as described in any one of the first, second and third aspects or a compound having formula (Ia) as described in the fourth aspect (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease in a patient, wherein the activity of CDK2 contributes to the pathology and / or symptoms 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.

[0092] In a tenth aspect, there is provided a method for 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 or a pharmaceutically acceptable salt thereof, wherein the moiety binds to CDK2. In one embodiment of the tenth aspect, the 2,5-disubstituted pyrimidinyl moiety is a moiety having formula (Ia) as described in the fourth aspect (or an embodiment thereof disclosed herein, including specific compounds). In another embodiment of the tenth aspect, CDK2 is degraded in the cells of a patient.

[0093] In an embodiment of any of the above aspects, CDK2 is selectively degraded relative to CDK1. In another embodiment of any of the above aspects, CDK2 is selectively degraded relative to CDK1 and CDK4 and / or CDK6.

[0094] In the above aspects related to cancer treatment, additional embodiments are provided, which include administering in combination a compound as described in any of the first, second, third aspects and a compound having the formula (Ia) or a pharmaceutically acceptable salt thereof (or any embodiment disclosed herein) or a pharmaceutical composition as described in the seventh aspect with at least one additional anti-cancer agent. When using combination therapy, these agents can be administered simultaneously or sequentially. Detailed Description

[0095] Definitions:

[0096] Unless otherwise specified, the following terms used in this specification and claims are defined for the purposes of this application and have the following meanings:

[0097] "Alkyl" means a straight-chain or branched-chain saturated monovalent hydrocarbon group having one to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.

[0098] "Alkenyl" means a straight-chain or branched-chain monovalent hydrocarbon group having two to six carbon atoms containing a double bond, e.g., vinyl, propenyl, 2-propenyl, butenyl, pentenyl, etc.

[0099] "Alkynyl" means a straight-chain or branched-chain monovalent hydrocarbon group having two to six carbon atoms containing a triple bond, e.g., ethynyl, propynyl, 2-propynyl, butynyl, etc.

[0100] Unless otherwise specified, "alkylene" means a straight-chain saturated divalent hydrocarbon group having one to six carbon atoms or a branched-chain saturated divalent hydrocarbon group having three to six carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

[0101] "Alkenylene" means a straight-chain unsaturated divalent hydrocarbon group having two to six carbon atoms containing a double bond or a branched-chain unsaturated divalent hydrocarbon group having three to six carbon atoms, e.g., ethene-diyl, propene-diyl, 2-propene-diyl, butene-diyl, pentene-diyl, etc.

[0102] "Alkynylene" means a straight-chain unsaturated divalent hydrocarbon group having two to six carbon atoms containing a triple bond or a branched-chain unsaturated divalent hydrocarbon group having three to six carbon atoms, e.g., etc.

[0103] "Alkoxy" means -OR z group (wherein R z is an alkyl group as defined above), for example, methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy or tert-butoxy, etc.

[0104] "Alkoxyalkyl" means an alkyl group as defined above substituted by an alkoxy group as defined above, for example, methoxymethyl, methoxyethyl, ethoxyethyl, etc.

[0105] "Alkylthio" means -SR z group (wherein R z is an alkyl group as defined above), for example, methylthio, ethylthio, n-propylthio, 2-propylthio, n-butylthio, isobutylthio or tert-butylthio, etc.

[0106] "Alkoxycarbonyl" means -C(O)OR z group (wherein R z is an alkyl group as defined above), for example, methoxycarbonyl, ethoxycarbonyl, etc.

[0107] "Alkylcarbonyloxy" means -OR z group, wherein R z is an alkylcarbonyl as defined herein.

[0108] "Alkylcarbonylamino" means -NR z 'C(O)R z group (wherein R z is an alkyl group as defined above, and R z ' is H or an alkyl group as defined above), for example, methylcarbonylamino, ethylcarbonylamino, etc.

[0109] "Acyl" means -C(O)R z group (wherein R z is an alkyl group, haloalkyl group, cycloalkyl group, optionally substituted phenyl group, optionally substituted heteroaryl group or optionally substituted heterocyclic group as defined herein), for example, methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, etc. When R z is an alkyl group, the acyl group is also referred to as "alkylcarbonyl" herein.

[0110] "Azidocarbonyl" means -C(O)N 2 group.

[0111] "Amido" means -NR z C(O)- or -C(O)NR z - group, wherein R z is hydrogen or an alkyl group as defined above.

[0112] "Sulfamoyl" means -NR z S(O) 2 - or -S(O) 2 NR z - group, where R z is hydrogen or an alkyl group as defined above.

[0113] "Amino" means -NH 2 .

[0114] "Aminoalkyl" means an alkyl group as defined above substituted by -NH 2 , for example, NH 2 methyl, NH 2 ethyl, etc.

[0115] "Aminoalkyloxy" and "aminoalkoxy" mean -OR z group (where R z is an aminoalkyl group as defined above), for example, NH 2 methyloxy, NH 2 ethyloxy, etc.

[0116] "Aminocarbonyl" means -C(O)NH 2 .

[0117] "Alkylaminocarbonyl" means -C(O)NHR z group (where R z is an alkyl group as defined above), for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, etc.

[0118] "Dialkylaminocarbonyl" means -C(O)NR z1 R z group (where R z and R z1 are independently an alkyl group as defined above), for example, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, etc.

[0119] "Alkylamino" means -NHR z group (where R z is an alkyl group as defined above), for example, methylamino, ethylamino, propylamino, etc.

[0120] "Aminosulfonyl" means -S(O) 2 NH 2 .

[0121] "Alkylaminosulfonyl" means -S(O) 2 NHR z group (where R z(which is an alkyl group as defined above), for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, etc.

[0122] “Dialkylaminosulfonyl” means -S(O) 2 NR z1 R z group (where R z and R z1 are independently alkyl groups as defined above), for example, dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, etc.

[0123] “Alkylamino” means -NHR z group (where R z is an alkyl group as defined above), for example, methylamino, ethylamino, propylamino, etc.

[0124] “Alkylaminoalkyl” means an alkyl group as defined above substituted with an alkylamino as defined above, for example, methylaminomethyl, methylaminoethyl, ethylaminoethyl, etc.

[0125] “Alkylaminoalkyloxy” means -OR z group (where R z is an alkylaminoalkyl as defined above), for example, methylaminomethyloxy, methylaminoethyloxy, ethylaminoethyloxy, etc.

[0126] “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, phenyl or naphthyl.

[0127] “Aralkyl” means -(alkylene)-R z group (where R z is an aryl group as defined above), for example, benzyl.

[0128] “Arylene” means a divalent aryl group (as defined above), for example, phenylene or naphthylene.

[0129] “Aryloxy” means -OR z group (where R z is an aryl group as defined above), for example, phenyloxy (phenyloxy / phenoxy) or naphthyloxy.

[0130] “Bicyclic heteroarylene” means a saturated or unsaturated divalent fused bicyclic group having 8 to 12 ring atoms, wherein one, two or three ring atoms are independently selected from N, O and S(O) na heteroatom (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are carbon, unless otherwise specified. Additionally, one or two ring carbon atoms of the bicyclic heteroarylene group may optionally be replaced by a -CO- group. More specifically, the term bicyclic heteroarylene includes, but is not limited to, isoindoline-diyl, decahydro-2,6-naphthyridine-diyl, octahydrocyclopenta[c]pyrrole-diyl, octahydro-1H-pyrrolo[3,4-c]pyridine-diyl, hexahydrofuro[3,2-b]furan-3,6-diyl, and the like. When the heteroarylene ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic.

[0131] "Bridged cycloalkyl" means a saturated monovalent bicyclic having 5 to 8 ring carbon atoms, wherein two non-adjacent ring atoms are connected by a (CR z R z ') n group (which may also be referred to herein as a "bridging" group), where n is an integer selected from 1 to 3, and R z and R z ' are independently H or methyl. 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.

[0132] "Bridged cycloalkylalkyl" means a -(alkylene)-R z group (where R z is a bridged cycloalkyl as defined above), for example, bicyclo[1.1.1]pent-1-ylmethyl, and the like.

[0133] "Bridged cycloalkyloxy" and "bridged cycloalkoxy" mean an -OR z group (where R z is a bridged cycloalkyl as defined above), for example, bicyclo[2.2.1]hept-2-yloxy.

[0134] "Bridged cycloalkylene" means a saturated divalent bicyclic having 5 to 8 ring carbon atoms, wherein two non-adjacent ring atoms are connected by a (CR z R z ') n group (which may also be referred to herein as a "bridging" group), where n is an integer selected from 1 to 3, and R z and R z ' are independently H or methyl. Unless otherwise specified, the bridged cycloalkylene is optionally substituted by 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.

[0135] "Bridged heterocyclylene" means a saturated divalent bicyclic having 5 to 9 ring carbon atoms, wherein two non-adjacent ring atoms are joined by a (CR z R z ’) n group (which may also be referred to herein as a "bridging" group), where n is an integer selected from 1 to 3 and R z and R z ’ are independently H or methyl, and further wherein one or two of the ring carbon atoms (including the atoms in the bridging group) are replaced by a heteroatom selected from N, O, and S(O) n (where n is an integer selected from 0 to 2). Unless otherwise specified, the bridged heterocyclylene is optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octane-3,8-diyl, 7-oxabicyclo[2.2.1]heptane-diyl, 2,5-diazabicyclo[2.2.1]heptane-diyl, 3,6-diazabicyclo[3.1.1]heptane-diyl, 2,5-diazabicyclo[2.2.2]octane-diyl, 3,8-diazabicyclo[3.2.1]octane-diyl, 6-azabicyclo[3.1.1]heptane-diyl, 8-azabicyclo[3.2.1]octane-diyl, etc.

[0136] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon group having three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0137] "Cycloalkyloxy or cycloalkoxy" means an -OR z group, where R z is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0138] "Cycloalkylalkyl" means a -(alkylene)-R z group, where R z is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

[0139] Unless otherwise specified, "cycloalkylene" means a divalent saturated hydrocarbon group having three to six carbon atoms, e.g., 1,1-cyclopropylene, 1,1-cyclobutylene, 1,4-cyclohexylene, etc.

[0140] "Carbonyl" means -C(O)-.

[0141] "Carboxyl" means -COOH.

[0142] "Cycloimino" means a saturated divalent monocyclic ring having 4 to 8 ring atoms, where one or two of the ring atoms are nitrogen and the remaining ring atoms are carbon. More specifically, the term cycloamino includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, etc.

[0143] "Cyanoalkyl" means an alkyl group as defined above substituted with a cyano group, e.g., cyanomethyl, cyanoethyl, etc.

[0144] "Cyanoalkoxy" means an -OR z group, where R z is a cyanoalkyl group as defined above. Examples include, but are not limited to, cyanomethoxy, cyanoethoxy, etc.

[0145] "Deuterium" means 2 H or D.

[0146] "Deuterated alkyl" means an alkyl group as defined above substituted with one, two, or three deuteriums.

[0147] "Dialkylamino" means an -NR z R z group (where each R z is an alkyl group as defined above), e.g., dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-butylmethylamino, isobutylmethylamino, or tert-butylmethylamino, etc.

[0148] "Dialkylaminoalkyl" means an alkyl group as defined above substituted with a dialkylamino group as defined above, e.g., dimethylaminomethyl, dimethylaminoethyl, ethylmethylaminoethyl, etc.

[0149] "Dialkylaminoalkyloxy" and "dialkylaminoalkoxy" mean an -OR z group (where R z is a dialkylaminoalkyl group as defined above), e.g., dimethylaminomethyloxy, dimethylaminoethyloxy, ethylmethylaminoethyloxy, etc.

[0150] "Ether" means an -O- group.

[0151] "Fused heterocyclic group" means a monovalent bicyclic group in which two adjacent ring atoms of a saturated or partially unsaturated (but non-aromatic) monocyclic ring having 4 to 7 ring atoms, having one or two heteroatoms independently selected from N, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl group or a five- or six-membered heteroaryl group (each as defined herein), unless otherwise specified. The nitrogen atom is optionally oxidized or quaternized. The fused heterocyclic moiety can be attached 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.

[0152] "Fused heterocyclic moiety" means a divalent bicyclic group in which two adjacent ring atoms of a saturated or partially unsaturated (but non-aromatic) monocyclic ring having 4 to 7 ring atoms, having one or two heteroatoms independently selected from N, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl group or a five- or six-membered heteroaryl group (each as defined herein), unless otherwise specified. The nitrogen atom is optionally oxidized or quaternized. The fused heterocyclic moiety can be attached 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.

[0153] "Fused heterocyclic group alkyl" means -(alkylene)-R z group (where R z is a fused heterocyclic group as defined above), for example, 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.

[0154] "Fused heterocyclic group oxy" means -OR z group (where R z is a fused heterocyclic group as defined above), for example, 1,2,3,4-tetrahydroquinolinyl oxy, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl oxy, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl oxy, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl oxy, and the like.

[0155] "Halogenated" means fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0156] "Haloalkyl" means an alkyl group as defined above that is substituted with one or more halogen atoms (e.g., one to five halogen atoms, such as fluorine or chlorine), including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 2 , etc. When the alkyl is substituted only with fluorine, it may be referred to as fluoroalkyl in this application.

[0157] "Haloalkoxy" means an -OR z group (where R z is a haloalkyl as defined above), e.g., -OCF 3 , -OCHF 2 , etc. When R z is a haloalkyl (where the alkyl is substituted only with fluorine (in some instances, one or more fluorines)), it is referred to as fluoroalkoxy in this application.

[0158] "Haloalkylthio" means an -SR z group (where R z is a haloalkyl as defined above), e.g., -SCF 3 , -SCHF 2 , etc.

[0159] "Hydroxyalkyl" means a straight-chain monovalent hydrocarbon group having one to six carbon atoms or a branched-chain monovalent hydrocarbon group having three to six carbons that is substituted with one or two hydroxy groups, provided that if there are two hydroxy groups, they are not both on the same carbon atom simultaneously. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0160] Unless otherwise specified, "heteroaryl" means a monovalent monocyclic or fused bicyclic aromatic group having 5 to 10 ring atoms, wherein 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, furyl, indolyl, isoindolyl, indazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When the heteroaryl ring contains 5 or 6 ring atoms and is monocyclic, it is also referred to herein as a 5-membered or 6-membered monocyclic heteroaryl or monocyclic heteroarylene. When the heteroaryl ring contains 9 or 10 ring atoms and is a fused bicyclic, it is also referred to herein as a 9-membered or 10-membered fused bicyclic heteroaryl.

[0161] "Heteroarylene" means a divalent heteroaryl group as defined above, unless otherwise specified. Representative examples include, but are not limited to, benzimidazolylene, e.g., benzimidazole-1,5-diyl, etc. When the heteroarylene ring contains 5 or 6 ring atoms and is monocyclic, it is also referred to herein as a monocyclic heteroarylene or 5-membered or 6-membered monocyclic heteroarylene, e.g., pyrazole-1,4-diyl. When the heteroarylene ring contains 9 or 10 ring atoms and is a fused bicyclic, it is also referred to herein as a 9-membered or 10-membered fused bicyclic heteroarylene.

[0162] "Heteroarylalkyl" or "heteroalkyl" means a -(alkylene)-R z group, wherein R z is a heteroaryl as a monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are independently heteroatoms selected from N, O and S(O) n (wherein n is an integer selected from 0 to 2), and the remaining ring atoms are C, unless otherwise specified. Additionally, one or two ring carbon atoms in the heterocyclic group can optionally be replaced by a -CO- group. More specifically, the term heterocyclic group includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro-furyl, tetrahydro-pyranyl, thiomorpholinyl, etc. When the heterocyclic ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic. When the heterocyclic group contains at least one nitrogen atom, it is also referred to herein as a heterocyclic amino and is a subset of the heterocyclic group.

[0163] "Heterocyclicalkyl" means a -(alkylene)-R z group (wherein R zis a heterocyclic group as defined above), for example, piperidinylmethyl and piperazinylmethyl.

[0164] "Heterocyclic group oxy" means -OR z group (wherein R z is a heterocyclic group as defined above), for example, 1-methylpyrrolidin-3-oxy, 1-methylpyrrolidin-2-oxy, piperidin-3-oxy, piperidin-4-oxy, etc.

[0165] "Heterocyclic group" means a saturated or unsaturated divalent monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are independently selected from N, O, and S(O) n (where n is an integer selected from 0 to 2) of heteroatoms, and the remaining ring atoms are C, unless otherwise specified. In addition, one or two ring carbon atoms in the heterocyclic group ring may optionally be replaced by a -CO- group. More specifically, the term heterocyclic group includes, but is not limited to piperidine-1,4-diyl, azetidine-1,3-diyl, etc.

[0166] The term "linker 'L'" is a linker having a number of linear non-hydrogen atoms in the range of 1 to 20 (preferably 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; more preferably 8 to 16, 9 to 14, 9 to 13, 9 to 12; more preferably 8, 9, 10, 11, 12 or 13; most preferably 12 or 13). The linker "L" may contain one or more (preferably 2, 3, 4, 5, 6, 7 or 8; more preferably 3 to 6 or 3, 4, 5 or 6; most preferably 4 or 5) groups independently selected from, for example, but not limited to the following: ether, polyether, thioether, -NH-, -N(alkyl)-, amide group, sulfonamide group, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, sulfinyl, sulfonyl, ureido, thioureido, cycloalkylene, bridged cycloalkylene, spirocycloalkylene, arylene, heteroarylene, heterocyclic group, bridged heterocyclic group, spiroheterocyclic group, bicyclic heterocyclic group or fused heterocyclic group, and wherein the cycloalkylene, bridged cycloalkylene, spirocycloalkylene, arylene, heteroarylene, heterocyclic group, bridged heterocyclic group, spiroheterocyclic group, bicyclic heterocyclic group and fused heterocyclic group are optionally substituted by one, two or three substituents independently selected from the following: deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, amino, alkylamino and dialkylamino, and wherein the alkylene is optionally substituted by one or two halogen (preferably fluorine). In some or any embodiments, the linker L contains 3 to 5 groups independently selected from the following: -O-, -NH-, -N(CH 3 )-, sulfonyl, phenylene, alkylene (preferably -CH 2 -, -CH2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 3 )-, -CH 2 C(CH 3 ) 2 CH 2 -), heteroalkylene groups (preferably azetidine-diyl, piperidine-diyl or piperazine-diyl), spiroheteroalkylene groups (preferably 2,6-diazaspiro[3.3]heptane-diyl), and monocyclic heteroarylene groups (preferably imidazolyl or pyridyl; more preferably imidazolyl), wherein the heteroalkylene groups, spiroheteroalkylene groups and monocyclic heteroarylene groups are optionally substituted by one, two or three substituents independently selected from halo (preferably fluoro) and alkyl (preferably methyl), and wherein the alkylene group is optionally substituted by one or two halo groups, preferably the group is -CH(CHF 2 ).

[0167] "Phenylene" means a divalent phenyl group.

[0168] "Polyether" means a group wherein d is an integer selected from 2 to 5 and R z is C 2-6 alkylene.

[0169] As used herein, the term "oxo" alone or in combination means =(O).

[0170] As used herein, the phrase "optionally" or "optional" means that the subsequent described event or circumstance may but need not occur, and the description includes both the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, the phrase "alkylene group optionally substituted by a halo group" is intended to encompass both an alkylene group not substituted by a halo group and an alkylene group substituted by a halo group.

[0171] "Spiroalkylene" means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 ring atoms, wherein the rings are connected only by one atom, which connecting atom is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise specified, the spiroalkylene group is optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy and cyano. Representative examples include, but are not limited to, spiro[3,5]nonanediyl, for example, spiro[3.5]nonane-2,7-diyl, etc.

[0172] "Spiroheterocyclylene" means a saturated divalent bicyclic group having 6 to 10 ring atoms, where one, two or three ring atoms are heteroatoms selected from N, O and S(O) n (where n is an integer selected from 0 to 2), the remaining ring atoms are C, and the rings are connected only through one atom, which is also called the spiro atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise specified, spiroheterocyclylene is optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy and cyano. Representative examples include, but are not limited to, 2-azaspiro[3.3]heptane-diyl, 2,6-diazaspiro[3.3]heptane-diyl, 1,7-diazaspiro[3.5]nonane-diyl, 2,7-diazaspiro[3.5]nonane-diyl, 3,9-diazaspiro[5.5]undecane-diyl, etc.

[0173] "11- to 13-membered spiroheterocyclylene" means a saturated divalent bicyclic group having 11 to 13 ring atoms, where one, two or three ring atoms are one or more heteroatoms selected from N, O and S(O) n (where n is an integer selected from 0 to 2), the remaining ring atoms are C, and the rings are connected only through one atom, which is also called the spiro atom, most commonly a quaternary carbon ("spiro carbon"). Unless otherwise specified, 11- to 13-membered spiroheterocyclylene is optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy and cyano. Representative examples include, but are not limited to, diazaspiro[5.5]undecane-diyl, 1-oxa-diazaspiro[5.5]undecane-diyl, etc.

[0174] "Pentafluorothio" means -SF 5 .

[0175] "Sulfinyl" means the -S(O)- group.

[0176] "Substituted sulfinyl" means -S(O)R z (where R z is alkyl as defined above), for example, methylsulfinyl or ethylsulfinyl.

[0177] "Sulfonyl" means -S(O) 2 - group.

[0178] "Substituted sulfonyl" means -S(O) 2 R z (where R z is alkyl as defined above), for example, methylsulfonyl or ethylsulfonyl.

[0179] "Sulfide" means the -S- group.

[0180] "Thioureido" means the -NHC(S)NH- group.

[0181] "Ureido" means the -NHC(O)NH- group.

[0182] "Substituted ureido" means -NHC(O)NR z R z’ (wherein R z is hydrogen or an alkyl group as defined above and R z’ is an alkyl group as defined above), for example, -NHC(O)NHmethyl, -NHC(O)NMe 2 and the like.

[0183] This disclosure also includes protected derivatives of the compounds described in the first, second, and third aspects, or the compounds of formula (Ia) (or any of its embodiments disclosed herein), or their pharmaceutically acceptable salts. For example, when the compound of formula (Ia) contains groups (such as hydroxyl, carboxyl, or any group containing one or more nitrogen atoms), these groups can be protected by appropriate protecting groups. A complete list of suitable protecting groups can be found in: T.W. Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of the compounds of this disclosure can be prepared by methods well known in the art.

[0184] This disclosure also includes polymorphic forms and deuterated forms of the compounds described in the first, second, and third aspects, or the compounds of formula (Ia) (or any of its embodiments disclosed herein), or their pharmaceutically acceptable salts.

[0185] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds having the formula (A1), (A), (I) or (Ia) (and any embodiments thereof disclosed herein, including specific compounds) may also exist as prodrugs, as described in the following literature: Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). A prodrug of a compound described herein is a structurally modified form of a compound that readily undergoes chemical change under physiological conditions to provide the active compound. They are often useful because in some cases prodrugs are more readily administered than the compound or the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. Examples (but not limited to) of prodrugs will be compounds administered as esters ("prodrugs") but then metabolically hydrolyzed to carboxylic acids (the active entity). Additional examples include peptidyl derivatives of the compounds.

[0186] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include:

[0187] acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed with organic acids (such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid, muconic acid, etc.); or

[0188] When the acidic protons present in the parent compound are replaced by metal ions (e.g., alkali metal ions, alkaline earth ions, or aluminum ions); or salts formed by coordination with organic bases (such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in the following literature: Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference in its entirety.

[0189] Compounds having the formula (A1), (A), (I), or (Ia) (and any embodiments thereof disclosed herein, including specific compounds) can have asymmetric centers. Compounds having the formula (A1), (A), (I), or (Ia) that contain asymmetrically substituted atoms (and any embodiments thereof disclosed herein, including specific compounds) can be isolated in optically active or racemic forms. The individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation (e.g., conversion into a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral column, or any other suitable method known in the art). Unless a specific stereochemical form or isomeric form is specifically indicated, all chiral forms, diastereomeric forms, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure. Those of ordinary skill in the art should also understand that when a compound is represented as an (R) stereoisomer, it can contain the corresponding (S) stereoisomer as an impurity, and vice versa.

[0190] Certain compounds having the formula (A1), (A), (I), or (Ia) (and any embodiments thereof disclosed herein, including specific compounds) can exist as tautomers and / or geometric isomers. All possible tautomers and cis- and trans-isomers (as individual forms and mixtures thereof) are within the scope of this disclosure. Additionally, as used herein, although only a few examples are listed, the term alkyl includes all possible isomeric forms of the alkyl group. Furthermore, when these cyclic groups (such as aryl) are substituted, although only a few examples are listed, it includes all positional isomers. Additionally, all hydrates of compounds having the formula (A1), (A), (I), or (Ia) (and any embodiments thereof disclosed herein, including specific compounds) are within the scope of this disclosure.

[0191] Compounds having the formula (A1), (A), (I), or (Ia) (and any embodiments thereof disclosed herein, including specific compounds) may also contain unnatural amounts of isotopes on one or more atoms that make up such compounds. Unnatural amounts of isotopes can be defined as ranging from the amounts found in nature to 100% of the amount of the atom in question, differing only in the presence of one or more isotope-enriched atoms. Exemplary isotopes that can be incorporated into the compounds disclosed herein, such as compounds having the formula (A1), (A), (I), or (Ia) (and any embodiments thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 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, and 125 1. Isotope-labeled compounds (e.g., compounds labeled with 3 H and 14 C) can be used in compound or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful because of their ease of preparation and detectability. In addition, substitution (or isotope enrichment) with heavier isotopes such as deuterium (i.e., 2 H) may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In some embodiments, in compounds having the formula (A1), (A), (I), or (Ia) (and any embodiments thereof disclosed herein, including specific compounds, including those in Table 1 below), one or more hydrogen atoms are replaced with 2 H or 3 H, or one or more carbon atoms are replaced with carbon enriched with 13 C or 14 C. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 15F) It can be used in positron emission tomography (PET) studies to examine the occupancy of substrate receptors. Isotopically labeled compounds can generally be prepared by procedures similar to those disclosed in the protocols or examples herein, by replacing non-isotopically labeled reagents with isotopically labeled reagents.

[0192] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in the preparation of pharmaceutical compositions, which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes carriers or excipients acceptable for veterinary as well as human pharmaceutical use.

[0193] As used in this specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0194] As used herein, the term "about" is intended to qualify the value it modifies, indicating that this value is a variable within the error bounds. When no specific error range is listed (e.g., the standard deviation of the mean given in a data graph or table), the term "about" should be understood to mean encompassing a range of ±10%, preferably ±5%, including the recited value and range.

[0195] Certain structures provided herein are drawn with one or more floating substituents. Unless otherwise provided or otherwise clear from the context, one or more substituents may be present on any atom of the ring to which they are attached, provided that it is chemically feasible and the valence rules permit. For example, in the structure: in which R aa substituents and similarly R bb and X 1 substituents may replace the hydrogen of any CH that is not already replaced by R bb and X 1 (in the case of R aa ), similarly R aa and X 1 (in the case of R bb ), and R aa and R bb (in the case of X 1 ) of a part of the bicyclic benzodiazepine moiety.

[0196] In addition, as used throughout the application (including in the examples), when a group is introduced as divalent, the left hand of the divalent group is attached to the group on the left side in the rest of the molecule, and the right hand of the divalent group is attached to the group on the right side in the rest of the molecule. For example, in formula (Ia), in the following divalent groups:

[0197]

[0198] (a), (b) and on the left side of (c) The key is attached to the following ring:

[0199]

[0200] And on the right side of (a), (b) and (c) (i.e., X 1 , X 2 and X 3 ) is attached to the Z of L having the following structure 1 :

[0201]

[0202] Similarly, for L, i.e., -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, the left side of L (i.e., Z 1 ) is attached to X 1 , X 2 , X 3 or X 4 or the attachment point shown by the degradation resolvent of formula (c), (d), (e) or (f), and Z 6 is attached to the atom of Hy. For example, when L is a group having the following formula:

[0203]

[0204] and the degradation resolvent is a group having formula (a), i.e., when, the left key of L (i.e., the -NH- group) is attached to X 1 and the right key of L (i.e., -SO 2 -) is attached to the atom of Hy .

[0205] As used herein, the term "disease" is intended to be generally synonymous and may be used interchangeably with the terms "disorder", "syndrome" and "condition" (as in medical conditions), all of which reflect an abnormal condition of a human or animal body or one of its parts that impairs its normal function, typically manifested by distinct signs and symptoms, and causing a reduced life expectancy or quality of life for the human or animal.

[0206] The term "combination therapy" means the administration of two or more therapeutic agents to treat the diseases or disorders described in this disclosure. Such administration encompasses co-administering these therapeutic agents in a substantially simultaneous manner, such as in a single capsule with active ingredients in a fixed ratio or in multiple separate capsules for each active ingredient. Additionally, such administration also encompasses using each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0207] 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.

[0208] "Treating or treatment" of a disease includes:

[0209] (1) Preventing the disease, i.e., preventing the clinical symptoms of the disease from developing in a mammal that may be exposed to or is susceptible to the disease but has not yet experienced or shown symptoms of the disease;

[0210] (2) Inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or

[0211] (3) Alleviating the disease, i.e., causing the disease or its clinical symptoms to subside.

[0212] In one embodiment, "treating or treatment" of a disease includes inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or alleviating the disease, i.e., causing the disease or its clinical symptoms to subside.

[0213] "Therapeutically effective amount" means an amount of the compounds of this disclosure and / or their pharmaceutically acceptable salts that is sufficient to effect such treatment of a disease when administered to a patient for treating the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

[0214] "Conditions associated with autoimmune diseases" means conditions to which a patient with an autoimmune disease is susceptible (such as sepsis) or conditions caused by an autoimmune disease (such as uveitis).

[0215] The compounds described in the first, second, and third aspects, as well as the compounds having formula (Ia) and their examples, can also inhibit CDK2. The terms "inhibit" and "reduce" related to CDK2, or any variants of these terms, include any measurable decrease or complete inhibition to achieve the desired result. For example, the decrease can be 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 in CDK2 activity compared to the normal activity, or any range derivable therefrom.

[0216] The terms "degrading" and "degrade" related to CDK2 and CDK1, or any variants of these terms, mean a measurable decrease in the concentration of CDK2 and CDK1 in the sample over time, respectively. For example, compared to an equivalent sample containing CDK2, the decrease can be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more in the concentration of CDK2 in the sample containing CDK2 in the presence of the compounds disclosed in the present disclosure, embodiments, and compound Table 1 herein (including compounds having formula (A1), (A), (I), or (Ia)), or any range derivable therefrom. The degradation % can be determined as described in Biological Example 2 below. In one embodiment, the decrease in the concentration of CDK2 ≥ 40%. In one embodiment, the decrease in the concentration of CDK2 ≥ 50%. In one embodiment, the decrease in the concentration of CDK2 ≥ 60%. In one embodiment, the decrease in the concentration of CDK2 ≥ 70%. In one embodiment, the decrease in the concentration of CDK2 ≥ 80%.

[0217] "E3 ubiquitin ligase" refers to a family of proteins that act in conjunction with E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzyme, and assist or directly catalyze the covalent attachment of ubiquitin to the lysine residue of the substrate protein. The E3 ubiquitin ligase directly binds to the substrate protein, thereby conferring substrate specificity to the ubiquitination process. Ubiquitination can serve as a general signal tag for the substrate protein, which is targeted for degradation by the proteasome or other regulation from translocation to transcription. Cereblon (CRBN) and von Hippel-Lindau (VHL) proteins are the substrate recognition subunits of two ubiquitously expressed and biologically important Cullin RING E3 ubiquitin ligase complexes. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). VHL is part of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2, and Rbx1.

[0218] "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 is capable of binding to an E3 ubiquitin ligase or a subunit of an E3 ligase, such as Cereblon, VHL, IAP, or MDM2.

[0219] Examples:

[0220] In Examples A1A to A190, this disclosure includes:

[0221] A1A. In Example A1A, a compound of formula (A1) or a pharmaceutically acceptable salt thereof is provided for use as described in the first aspect or its embodiments in the Summary of the Invention.

[0222] A1. In Example A1, a compound of formula (A) or a pharmaceutically acceptable salt thereof is provided for use as described in the second aspect in the Summary of the Invention.

[0223] A2. In Example A2, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use as described in the third aspect in the Summary of the Invention.

[0224] A3-1. In Example A3-1, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A1, or A2 is a compound of formula (A1), (A), or (I) according to formula (Ia1):

[0225]

[0226] Wherein:

[0227] R 1 as defined in the first, second or third aspect, respectively;

[0228] R 2 and R 2a are each independently hydrogen or deuterium;

[0229] Hy is a cycloalkylene, arylene, heteroarylene, heterocycloalkylene, bicyclic heterocycloalkylene, spiro heterocycloalkylene, bridged heterocycloalkylene or fused heterocycloalkylene, wherein each of the above rings in the segment is independently substituted by R a 、R b and R c selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano;

[0230] The downregulator is an E3 ubiquitin ligase ligand selected from:

[0231] (a) a group having formula (i):

[0232]

[0233] (b) a group having formula (ii):

[0234]

[0235] (c) a group having formula (iii):

[0236]

[0237] (d) a group having formula (iv):

[0238]

[0239] (e) a group having formula (v):

[0240]

[0241] (f) a group having formula (vi):

[0242]

[0243] wherein:

[0244] R x and R x1 are each hydrogen;

[0245] Y a is CH or N;

[0246] Z a is a bond, -CH 2-, -NH-, -O- or -NHC(O)-, wherein the NH of -NHC(O)- is attached to Y a attached;

[0247] Ring A is a group having formula (a), (b) or (c):

[0248]

[0249] wherein:

[0250] R aa 、R bb 、R cc and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano;

[0251] R 4 and R 5 are independently hydrogen or alkyl; or R 4 and R 5 together with the carbon to which they are attached form >C=O;

[0252] M is -O- or -NR 6 -; and

[0253] R 6 is hydrogen or alkyl;

[0254] Ring B is phenylene, cycloimino, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms (and no additional heteroatoms) and further wherein the phenylene, cycloimino and each heteroarylene are independently substituted by R ee and R ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano; and

[0255] 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 )-, -NH-, -N(alkyl)-, -C(=O)-, -NR jj C(=O)- or -C(=O)NR kk -, wherein R gg 、R hh 、R jj and R kkis independently hydrogen, alkyl or cycloalkyl, and each alkylene is optionally substituted with one or two fluorines;

[0256] R y 、R y1 and R y2 are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic group are substituted with R d and R f selected from hydrogen, halo, cyano, alkylcarbonyl and alkylcarbonylamino; and

[0257] W a is a bond, O, S or alkylene; and

[0258] L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, where:

[0259] Z 1 is 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 heterocycloalkylene, wherein each ring is independently substituted with R h and R i selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino and dialkylamino;

[0260] Z 2 is 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 heterocycloalkylene, wherein each ring is independently substituted with R j and R k selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino and dialkylamino;

[0261] Z 3is a bond, alkylene, alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR'-, -(O-alkylene) c -, -(alkylene-O) c -, cycloalkylene, spiroalkylene, 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 an 11- to 13-membered spiroheterocyclylene, where each ring is independently substituted by R m and R n substituted;

[0262] 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)-, spiroalkylene, 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 is independently substituted by R o and R p substituted;

[0263] 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 is independently substituted by Rq and R r is substituted; and

[0264] Z 6 is a bond, alkylene, -NR”-, -O-, -(alkylene - O)-, -C(O)-, -S(O) 2 -, -NR'(CO)- or -C(O)NR-;

[0265] 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, and -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 5 -, -Z 6 - and -Z s and R t substituted, wherein R s is hydrogen or deuterium and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocycloalkyl, aryl or monocyclic heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, monocyclic heteroaryl is substituted by one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy or cyano; provided that at least one of -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - is not a bond; or

[0266] its pharmaceutically acceptable salts.

[0267] A3. In Example A3, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A1, A2 or A3 - 1 is a compound having formula (IA1), (IA), (I) or (Ia1) respectively according to formula (Ia):

[0268]

[0269] wherein R 1 , R 2 , R 2a , Hy and L are as defined in Example A3 - 1; and

[0270] The degrader is an E3 ubiquitin ligase ligand selected from:

[0271] (a) a group having formula (i):

[0272]

[0273] (b) A group having the formula (ii):

[0274]

[0275] (c) A group having the formula (iii):

[0276]

[0277] (d) A group having the formula (iv):

[0278]

[0279] (e) A group having the formula (v):

[0280]

[0281] (f) A group having the formula (vi):

[0282]

[0283] Wherein:

[0284] Ring A is a group having the formula (a), (b) or (c):

[0285]

[0286] Wherein:

[0287] M is -NR 6 -, wherein R 6 is hydrogen or alkyl; and

[0288] 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 are as defined in A3-1.

[0289] In Example A3A, a compound or a pharmaceutically acceptable salt thereof for use as described in Example A3, wherein:

[0290] Z 1 is 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, wherein each ring is independently substituted by R h and R i selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino;

[0291] Z 2 is 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, wherein each ring is independently substituted by R j and R k selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino;

[0292] Z 3 is a bond, alkylene, alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR”-, -(O-alkylene) c -, -(alkylene-O) c-, a cycloalkylene, spirocycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, a monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, a heteroannylene, -(alkylene)-heteroannylene-, -heteroannylene-(alkylene)-, a bicyclic heteroannylene, a bridged heteroannylene, -(alkylene)-bridged heteroannylene-, -bridged heteroannylene-(alkylene)-, a fused heteroannylene, a spiroheteroannylene, -(alkylene)-spiroheteroannylene-, -spiroheteroannylene-(alkylene)- or an 11- to 13-membered spiroheteroannylene, wherein each ring is independently substituted, either by itself or as part of another group, with an R selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino m and R n substituted;

[0293] Z 4 is a bond, alkylene, alkynylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -C(O)-, -NR”-, -(O-alkylene) d -, -(alkylene-O) d -, a cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heteroannylene, -(alkylene)-heteroannylene-, -heteroannylene-(alkylene)-, a fused heteroannylene, a bridged heteroannylene, -(alkylene)-bridged heteroannylene-, -bridged heteroannylene-(alkylene)-, a spiroheteroannylene, -(alkylene)-spiroheteroannylene or -spiroheteroannylene-(alkylene)-, wherein each ring is independently substituted, either by itself or as part of another group, with an R selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino o and R p substituted;

[0294] Z 5 is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O) 2 -, -NR’(CO)-, -C(O)NR-, phenylene, a monocyclic heteroarylene or heteroannylene, wherein each ring is independently substituted with an R selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino q and R r substituted; and

[0295] Z 6 is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2 -, -NR'(CO)- or -C(O)NR-; or

[0296] its pharmaceutically acceptable salts.

[0297] A4-1. In Example A4-1, the compound or its pharmaceutically acceptable salt for use as described in Examples A1A, A2, A3-1, A3 or A3A is one in which R 1 is 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, heterocyclic, heterocyclicalkyl, heterocyclicoxy, fused heterocyclic, fused heterocyclicoxy or fused heterocyclicalkyl, wherein the cycloalkyl itself or as part of cycloalkoxy and cycloalkylalkyl, the aryl itself or as part of aralkyl and aryloxy, the heteroaryl itself or as part of heteroaralkyl and heteroaryloxy, the heterocyclic itself or as part of heterocyclicalkyl and heterocyclicoxy, the bridged cycloalkyl alone or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and the fused heterocyclic itself or as part of fused heterocyclicalkyl and fused heterocyclicoxy are substituted by one, two or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0298] A4-2. In Example A4-2, the compound or its pharmaceutically acceptable salt for use as described in Examples A1A, A2, A3-1, A3 or A3A is one in which R 1 is aryl, heteroaryl, heterocyclic, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF 3 -, -SF 5, fused heterocyclic group, bridged cycloalkyl group, cycloalkylalkyl group, heterocyclicalkyl group, aralkyl group, aminoalkoxy group, alkoxycarbonyl group, alkylcarbonylamino group, acyl group, azidocarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, substituted ureido group, aminosulfonyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group and substituted sulfonyl group; wherein the aryl group alone and in the aralkyl group, the heteroaryl group alone and in the heteroaryloxy group, the heterocyclic group, fused heterocyclic group, bridged cycloalkyl group alone and in the cycloalkylalkyl group, and the heterocyclic group alone and in the heterocyclicalkyl group are each substituted by one, two or three substituents independently selected from hydrogen, alkyl group, alkoxy group, halogen group, haloalkyl group, haloalkoxy group and cyano group.

[0299] In the sub - example of Example 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, chromanyl, 1,4 - benzodioxanyl, 2,3 - dihydrofuro[3,2 - c]pyridine, 2,3 - dihydrofuro[2,3 - c]pyridine or 1,2,3,4 - tetrahydroquinolinyl; wherein each of these rings is substituted by hydrogen, alkyl group, alkoxy group, halogen group, haloalkyl group, haloalkoxy group or cyano group.

[0300] A4 - 3. In Example A4 - 3, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is aryl group, heterocyclic group, cyanoalkyl group, alkoxyalkyl group, aminoalkyl group, alkylaminoalkyl group, dialkylaminoalkyl group, heteroaryloxy group, cyanoalkoxy group, alkylthio group, amino group, alkylamino group, dialkylamino group, -SCF 3 or -SF 5 ; wherein each of these rings is substituted by hydrogen, alkyl group, alkoxy group, halogen group, haloalkyl group, haloalkoxy group or cyano group.

[0301] In the sub - example of Example A4 - 3, R 1 is phenyl (substituted by hydrogen, alkyl group, alkoxy group, halogen group, cyano group, haloalkyl group or haloalkoxy group), pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl (substituted by hydrogen or alkyl group), tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl (substituted by hydrogen, alkyl group, alkoxy group, halogen group, haloalkyl group, haloalkoxy group or cyano group), cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl or dimethylaminomethyl.

[0302] A4-4. In Example A4-4, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is alkylthio (such as methylthio).

[0303] A4-5. In Example A4-5, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is pentafluorothio.

[0304] A4-6. In Example A4-6, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is haloalkylthio (such as trifluoromethylthio).

[0305] A4-7. In Example A4-7, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is amino.

[0306] A4-8. In Example A4-8, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is alkylamino (such as methylamino).

[0307] A4-9. In Example A4-9, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is dialkylamino (such as dimethylamino).

[0308] A4-10. In Example A4-10, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is a cycloalkyl group substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In a sub-example of Example A4-10, the cycloalkyl group is cyclopropyl, cyclobutyl or cyclopentyl, each ring being substituted by one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0309] A4-11. In Example A4-11, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1is a cycloalkyloxy group, wherein the cycloalkyl group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the sub - embodiments of Example A4 - 11, the cycloalkyloxy group is cyclopropyloxy, cyclobutyloxy or cyclopentyloxy, and each cycloalkyl ring of the cycloalkyloxy group is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0310] A4 - 12. In Example A4 - 12, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a cycloalkylalkyl group, wherein the cycloalkyl group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the sub - embodiments of Example A4 - 12, the cycloalkylalkyl group is cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, and each cycloalkyl ring of the cycloalkylalkyl group is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0311] A4 - 13. In Example A4 - 13, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a bridged cycloalkyl group (such as bicyclo[1.1.1]pent - 1 - yl or bicyclo[2.2.1]heptyl), wherein the bridged cycloalkyl group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the sub - embodiments of Example A4 - 13, the bridged cycloalkyl group is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0312] A4 - 14. In Example A4 - 14, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a bridged cycloalkyloxy group (such as bicyclo[1.1.1]pent - 1 - yloxy or bicyclo[2.2.1]heptyloxy), wherein the bridged cycloalkyl group in the bridged cycloalkyloxy group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the sub - embodiments of Example A4 - 14, the bridged cycloalkyloxy group is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0313] A4 - 15. In Example A4 - 15, the compound or its pharmaceutically acceptable salt for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1is a bridged cycloalkylalkyl (such as bicyclo[1.1.1]pentan-1-ylmethyl or bicyclo[2.2.1]heptylmethyl), wherein the bridged cycloalkyl in the bridged cycloalkylalkyl is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the sub-embodiments of Example A4-15, the bridged cycloalkylalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0314] A4-16. In Example A4-16, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one wherein R 1 is cyanoalkyl. In the sub-embodiments of Example A4-16, R 1 is cyanomethyl or cyanoethyl.

[0315] A4-17. In Example A4-17, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one wherein R 1 is cyanoalkoxy (such as cyanomethoxy or cyanoethoxy).

[0316] A4-18. In Example A4-18, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one wherein R 1 is alkoxyalkyl. In the sub-embodiments of Example A4-18, R 1 is methoxymethyl.

[0317] A4-19. In Example A4-19, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one wherein R 1 is aminoalkyl. In the sub-embodiments of Example A4-19, R 1 is aminomethyl.

[0318] A4-20. In Example A4-20, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one wherein R 1 is aminoalkoxy. In the sub-embodiments of Example A4-20, R 1 is aminomethyloxy.

[0319] A4-21. In Example A4-21, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one wherein R 1 is alkylaminoalkyl. In the sub-embodiments of Example A4-21, R1 is methylaminomethyl.

[0320] A4-22. In Example A4-22, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is dialkylaminoalkyl. In a sub-example of Example A4-22, R 1 is dimethylaminomethyl.

[0321] A4-23. In Example A4-23, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is alkylaminoalkoxy. In a sub-example of Example A4-23, R 1 is methylaminomethoxy.

[0322] A4-24. In Example A4-24, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is dialkylaminoalkoxy. In a sub-example of Example A4-24, R 1 is dimethylaminomethoxy.

[0323] A4-25. In Example A4-25, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is acyl. In a sub-example of Example A4-25, the acyl is alkylcarbonyl (such as methylcarbonyl).

[0324] A4-26. In Example A4-26, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is azidocarbonyl.

[0325] A4-27. In Example A4-27, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is alkoxycarbonyl. In a sub-example of Example A4-27, R 1 is methoxycarbonyl or ethoxycarbonyl.

[0326] A4-28. In Example A4-28, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is alkylcarbonylamino.

[0327] A4 - 29. In Example A4 - 29, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is aminocarbonyl.

[0328] A4 - 30. In Example A4 - 30, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is alkylaminocarbonyl (such as methylaminocarbonyl).

[0329] A4 - 31. In Example A4 - 31, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is dialkylaminocarbonyl (such as dimethylaminocarbonyl).

[0330] A4 - 32. In Example A4 - 32, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is aminosulfonyl.

[0331] A4 - 33. In Example A4 - 33, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is alkylaminosulfonyl (such as methylaminosulfonyl).

[0332] A4 - 34. In Example A4 - 34, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is dialkylaminosulfonyl (such as dimethylaminosulfonyl).

[0333] A4 - 35. In Example A4 - 35, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a substituted sulfonyl.

[0334] A4 - 36. In Example A4 - 36, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a substituted sulfinyl.

[0335] A4-37. In Example A4-37, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is a substituted ureido group.

[0336] A4-38. In Example A4-38, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is an aryl group substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the first sub-example of Example A4-38, R 1 is a phenyl group substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the second sub-example of Example A4-38, R 1 is a phenyl group substituted by one, two or three substituents independently selected from: hydrogen, methyl, fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0337] A4-39. In Example A4-39, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is an aralkyl group (such as benzyl), in which the aryl group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the sub-example of Example A4-39, R 1 is benzyl, in which the phenyl group in benzyl is substituted by one, two or three substituents independently selected from: hydrogen, methyl, fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0338] A4-40. In Example A4-40, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3 or A3A is one in which R 1 is a heteroaryl group, in which the heteroaryl group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the first sub-example of Example A4-40, R 1 is pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl, each of which is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In the second sub-example of Example A4-40, R 1is a pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl group, each of which is substituted by a substituent selected from hydrogen and alkyl.

[0339] A4-41. In Example A4-41, the compound or a pharmaceutically acceptable salt thereof for use as described in Examples A1A, A2, A3-1, A3 or A3A is one in which R 1 is a heteroarylalkyl group, wherein the heteroaryl in the heteroarylalkyl group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In a sub-example of Example A4-41, R 1 in the heteroarylalkyl group is a pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl group, each of which is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0340] A4-42. In Example A4-42, the compound or a pharmaceutically acceptable salt thereof for use as described in Examples A1A, A2, A3-1, A3 or A3A is one in which R 1 is a heteroaryloxy group, wherein the heteroaryl is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In a sub-example of Example A4-42, R 1 in the heteroaryloxy group is a pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl group, each of which is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0341] A4-43. In Example A4-43, the compound or a pharmaceutically acceptable salt thereof for use as described in Examples A1A, A2, A3-1, A3 or A3A is one in which R 1 is a heterocyclic group, wherein the heterocyclic group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In a sub-example of Example A4-43, R 1 is a tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl group, wherein the piperazinyl group is optionally substituted by alkyl, alkoxy, halo, haloalkyl, haloalkoxy or cyano.

[0342] A4-44. In Example A4-44, the compound or a pharmaceutically acceptable salt thereof for use as described in Examples A1A, A2, A3-1, A3 or A3A is one in which R 1is a heterocyclic alkyl group, wherein the heterocyclic group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. In the sub - embodiment of Example A4 - 44, R 1 the heterocyclic group in the heterocyclic alkyl group of is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the piperazinyl is optionally substituted by alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0343] A4 - 45. In Example A4 - 45, the compound or its pharmaceutically acceptable salt for use as described in Examples A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a heterocyclic oxy group, wherein the heterocyclic group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. In the sub - embodiment of Example A4 - 45, R 1 the heterocyclic group in the heterocyclic oxy group of is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the piperazinyl is optionally substituted by alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0344] A4 - 46. In Example A4 - 46, the compound or its pharmaceutically acceptable salt for use as described in Examples A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a fused heterocyclic group substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano. In the sub - embodiment of Example A4 - 6, R 1 is 2,3 - dihydrobenzofuranyl, chromanyl, 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 by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0345] A4 - 47. In Example A4 - 47, the compound or its pharmaceutically acceptable salt for use as described in Examples A1A, A2, A3 - 1, A3 or A3A is one in which R 1 is a fused heterocyclic oxy group, wherein the heterocyclic group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0346] A4-48. In Example A4-48, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3, A3A is one in which R 1 is a fused heterocyclic alkyl group, wherein the heterocyclic group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0347] A4-49. In Example A4-49, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A2, A3-1, A3, A3A, A4-1 to A4-48 is one in which R 1 is selected from:

[0348]

[0349]

[0350] and its isomers (R and / or S isomers, and / or geometric isomers).

[0351] A4-50. In Example A4-50, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A1, A2, A3-1, A3, A3A is one in which R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano or cycloalkyl, wherein the cycloalkyl is substituted with one to three halo groups.

[0352] A4. In Example A4, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A, A1, A2, A3-1, A3, A3A, A4-50 is one in which R 1 is halo, haloalkyl or haloalkoxy.

[0353] A5. In Example A5, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1 to A3A, A4-50 and A4 is one in which R 1 is halo.

[0354] A6. In Example A6, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1 to A3A, A4-50 and A4 is one in which R 1 is haloalkyl.

[0355] A7. In Example A7, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1 to A3A, A4-50 and A4 is one in which R 1 is haloalkoxy.

[0356] A8. In Example A8, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1 to A3A, A4-50, and A4 to A7 is one in which R 1 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

[0357] A9. In Example A9, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1 to A3A, A4-50, and A4 to A8 is one in which R 1 is chlorine, bromine, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

[0358] A10. In Example A10, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1 to A3A, A4-50, A4, A5, A8, and A9 is one in which R 1 is chlorine or bromine.

[0359] A11. In Example A11, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1 to A3A, A4-50, A4, A6, A8, and A9 is one in which R 1 is difluoromethyl or trifluoromethyl.

[0360] A12. In Example A12, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1 to A3A, A4-50, A4, A6, A8, A9, and A11 is one in which R 1 is trifluoromethyl.

[0361] A13. In Example A13, the compound or its pharmaceutically acceptable salt for use as described in Example A1, A2, A3-1, A3, A3A, or A4-50 is one in which R 1 is alkyl, alkenyl, or alkynyl.

[0362] A14. In Example A14, the compound or its pharmaceutically acceptable salt for use as described in Example A1, A2, A3-1, A3, A3A, A4-50, or A13 is one in which R 1 is methyl, ethyl, propyl, vinyl, propenyl, ethynyl, or propynyl.

[0363] A15. In Example A15, the compound or its pharmaceutically acceptable salt for use as described in Example A1, A2, A3-1, A3, A3A, A13, A4-50, or A14 is one in which R 1 is methyl, ethyl, or propyl.

[0364] A16. In Example A16, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1, A2, A3-1, A3, A3A, A13, A4-50 or A14 is one in which R 1 is vinyl, propenyl, ethynyl or propargyl.

[0365] A17. In Example A17, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1, A2, A3-1, A3, A3A or A4-50 is one in which R 1 is an alkoxy group.

[0366] A18. In Example A18, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1, A2, A3-1, A3, A3A, A4-50 or A17 is one in which R 1 is methoxy, ethoxy or propoxy.

[0367] A19. In Example A19, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1, A2, A3-1, A3, A3A or A4-50 is one in which R 1 is an aryloxy group (such as phenoxy).

[0368] A20. In Example A20, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1, A2, A3-1, A3, A3A or A4-50 is one in which R 1 is cyano.

[0369] A21. In Example A21, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1, A2, A3-1, A3, A3A or A4-50 is one in which R 1 is a cycloalkyl group (such as cyclopropyl).

[0370] A22. In Example A22, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1, A2, A3-1, A3, A3A or A4-50 is one in which R 1 is a cycloalkyl group substituted with one to three halogen groups (such as fluorocyclopropyl or difluorocyclopropyl).

[0371] A23. In Example A23, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A1A and any one of Examples A1 to A22 is one in which R 2 and R 2a are hydrogen.

[0372] A24. In Example A24, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A22 is one in which R 2 and R 2a one of which is deuterium and R 2 and R 2a the other of which is hydrogen, or R 2 and R 2a both are deuterium.

[0373] A25. In Example A25, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A24 is one in which Hy is a heteroalicyclic group, a phenylene group, a spiroheteroalicyclic group, a bridged heteroalicyclic group or a cycloalkyl group, each of the above rings being substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[0374] A26. In Example A26, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A25 is one in which Hy is a heteroalicyclic group substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[0375] A27. In Example A27, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A26 is one in which the heteroalicyclic group of Hy is pyrrolidine-1,3-diyl or piperidine-1,4-diyl, where Hy is substituted by R a , R b and R c , where R a and R b are independently hydrogen, deuterium, methyl, fluorine, methoxy or hydroxy, R c is hydrogen, and L is attached to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

[0376] A28. In Example A28, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A27 is one in which the heteroalicyclic group of Hy is:

[0377]

[0378] wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0379] A29. In Example A29, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A28 is one wherein the hetero-subcyclic group of Hy is:

[0380]

[0381] wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0382] A29a. In Example A29a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A29 is one wherein the hetero-subcyclic group of Hy is:

[0383]

[0384] wherein the N atom of the piperidine-1,4-diyl ring is attached to L.

[0385] A30. In Example A30, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A25 is one wherein Hy is a bridged hetero-subcyclic group independently substituted by R a , R b and R c : hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano.

[0386] A31. In Example A31, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A, A1 to A25 and A30 is one wherein the bridged hetero-subcyclic group of Hy is a ring having the formula:

[0387]

[0388] and each ring is substituted by R a , R b and R c , wherein R c is hydrogen, and L is attached to the nitrogen atom of each ring.

[0389] A32. In Example A32, the compound or a pharmaceutically acceptable salt thereof for use as described in Example A30 or A31 is one wherein R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy or hydroxy.

[0390] A33. In Example A33, the compound or its pharmaceutically acceptable salt for use as described in Example A30, A31 or A32 is one in which R b is hydrogen.

[0391] A34. In Example A34, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1A and A1 to A25 is one in which Hy is a cycloalkylene group substituted by R a , R b and R c , where R a is deuterium, methyl, fluorine, methoxy or hydroxy, and R b and R c are hydrogen.

[0392] A35. In Example A35, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1A, A1 to A25 and A34 is one in which the cycloalkylene group of Hy is cyclohexylene.

[0393] A36. In Example A36, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1A, A1 to A25, A34 and A35 is one in which the cycloalkylene group of Hy is where represents the bond to NH, and represents the bond to L.

[0394] A37. In Example A37, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1A and A1 to A25 is one in which Hy is an arylene group, where the arylene group is a phenylene group substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[0395] A38. In Example A38, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1A and A1 to A25 is one in which Hy is a spiroheterocyclic group (such as 2-azaspiro[3.3]heptan-2-yl) substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano, and Rc is hydrogen.

[0396] A39. In Example A39, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A, A1 to A25, and A37 is one in which the phenylene of Hy is a 1,4-phenylene according to the structure where represents a bond to NH, and represents a bond to L.

[0397] A39a. In Example A39a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A24 is one in which Hy is a fused hetero-subcyclic group substituted by R a , R b , and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.

[0398] A39b. In Example A39b, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A1A and A1 to A24 is one in which Hy is a bicyclic hetero-subcyclic group substituted by R a , R b , and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy, and cyano, and R c is hydrogen.

[0399] A40A. In Example A40A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A2 to A39b is one in which the degron is an E3 ubiquitin ligase ligand having formula (i) or (ii) as disclosed in Example A3-1.

[0400] A40. In Example A40, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A2, A3-1, A3 to A39b, and A40A is one in which the degron is an E3 ubiquitin ligase ligand having formula (i):

[0401]

[0402] A41. In Example A41, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3 to A40 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is a group having formula (a):

[0403]

[0404] A42. In Example A42, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3 to A41 is one in which R 4 and R 5 are independently hydrogen or alkyl.

[0405] A43. In Example A43, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3 to A42 is one in which R 4 and R 5 are hydrogen.

[0406] A44. In Example A44, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3 to A42 is one in which R 4 is hydrogen and R 5 is methyl.

[0407] A45. In Example A45, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 and A3 to A41 is one in which R 4 and R 5 together with the carbon to which they are attached form >C=O.

[0408] A46. In Example A46, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 and A3 to A40 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is a group having formula (b):

[0409]

[0410] A47. In Example A47, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3 to A40 and A46 is one in which R 6 is hydrogen.

[0411] A48. In Example A48, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3 to A40 and A46, wherein R 6 is alkyl, preferably methyl.

[0412] A49. In Example A49, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 and A3 to A40 is one in which Ring A of the E3 ubiquitin ligase ligand having Formula (i) is a group having Formula (c):

[0413]

[0414] A50A. In Example A50A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 and A4-1 to A40 is one in which Ring A of the E3 ubiquitin ligase ligand having Formula (i) is:

[0415]

[0416] A50. In Example A50, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3 to A40 and A50A is one in which Ring A of the E3 ubiquitin ligase ligand having Formula (i) is:

[0417]

[0418] A51A. In Example A51A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A4-1 to A40 and A50A is one in which Ring A of the E3 ubiquitin ligase ligand having Formula (i) is:

[0419]

[0420] A51. In Example A51, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3 to A40 and A50 is one in which Ring A of the E3 ubiquitin ligase ligand having Formula (i) is:

[0421]

[0422] A52A. In Example A52A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A4-1 to A40, A50A and A51A is one in which Ring A of the E3 ubiquitin ligase ligand having Formula (i) is:

[0423]

[0424] A52. In Example A52, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3 to A40, A50 and A51 is one in which Ring A of the E3 ubiquitin ligase ligand having Formula (i) is:

[0425]

[0426] A52a. In Example A52a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A41, A45, and A50A to A52 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0427]

[0428] A53. In Example A53, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A41, A45, and A50A to A52 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0429]

[0430] A54. In Example A54, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A43 and A50A to A52 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0431]

[0432] A55. In Example A55, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A43 and A50A to A52 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0433]

[0434] A56. In Example A56, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A40, A46, A48, and A50A to A52 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0435]

[0436] A57. In Example A57, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A40, A46, A48, and A50A to A52 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0437]

[0438] A58. In Example A58, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A48 and A50A to A54 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. For clarity, when R aa 、R bb 、R cc and / or R dd are not specifically shown in the structures of formulas (i) and (ii), respectively, they are hydrogen.

[0439] A59. In Example A59, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A48 and A50A to A54 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.

[0440] A60. In Example A60, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A48, A50A to A54, A58, and A59 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

[0441] A61. In Example A61, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A48, A50A to A54, and A58 to A60 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen and methyl.

[0442] A62. In Example A62, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A48, A50A to A54, and A58 to A60 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen and methoxy.

[0443] A63. In Example A63, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A48, A50A to A54, and A58 to A60 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen and fluorine.

[0444] A64. In Example A64, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A48, A50A to A54, and A58 to A60 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.

[0445] A65. In Example A65, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A48, A50A to A54, A58, and A60 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen and trifluoromethoxy.

[0446] A66. In Example A66, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A48, A50A to A54, and A58 to A60 is one in which R aa 、R bb 、R cc and R dd are independently selected from hydrogen, fluorine, and trifluoromethyl.

[0447] A67. In Example A67, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A2, A3-1 to A39b, and A40A is one in which the degron is an E3 ubiquitin ligase ligand having formula (ii):

[0448]

[0449] A68. In Example A68, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 is one in which Y a is CH.

[0450] A69. In Example A69, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 is one in which Ya It is N.

[0451] A70. In Example A70, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A69 is one in which Z a is a bond, -NH-, -O-, or -NHC(O)-.

[0452] A71. In Example A71, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A70 is one in which Z a is a bond, -NH-, or -NHC(O)-.

[0453] A72. In Example A72, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A71 is one in which Z a is a bond.

[0454] A73. In Example A73, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A71 is one in which Z a is -NH- or -NHC(O)-.

[0455] A74. In Example A74, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, A67 to A71, and A73 is one in which Z a is -NH-.

[0456] A74a. In Example A74a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, A67 to A71, and A73 is one in which Z a is -NHC(O)-.

[0457] A75. In Example A75, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A74a is one in which ring B is a phenylene group substituted by R ee and R ff substituted phenylene.

[0458] A76. In Example A76, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A74a is one in which ring B is a phenylene group substituted by R ee and R ffSubstituted cyclic imino group.

[0459] A77. In Example A77, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A74a is one in which ring B is a 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, each heteroarylene ring containing one to three nitrogen ring atoms, and each ring is substituted by R ee and R ff Substituted.

[0460] A78. In Example A78, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A39b, A40A, A67 to A74a, and A77 is one in which ring B is a 5- or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted by R ee and R ff Substituted.

[0461] A79. In Example A79, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A39b, A40A, A67 to A74a, and A77 is one in which ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms (and no other heteroatoms) and substituted by R ee and R ff Substituted.

[0462] A80. In Example A80, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A39b, A40A, A67 to A74a, A77, and A79 is one in which ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted by R ee and R ff Substituted.

[0463] A81. In Example A81, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A80 is one in which the E3 ubiquitin ligase ligand having formula (ii) is:

[0464]

[0465] A82-1. In Example A82-1, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A81 is one in which the E3 ubiquitin ligase ligand having formula (ii) is:

[0466]

[0467]

[0468] wherein ring B is a cyclic imino group.

[0469] A82. In Example A82, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3 to A39b, A40A, and A67 to A82-1, wherein the E3 ubiquitin ligase ligand having formula (ii) is:

[0470]

[0471]

[0472] wherein ring B is a cyclic imino group.

[0473] A82A. In Example A82A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3 to A39b, A40A, A67, A68, A70 to A72, A77, and A79 to A82-1, wherein the E3 ubiquitin ligase ligand having formula (ii) is

[0474] A83. In Example A83, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3 to A39b, A40A, and A67 to A82, wherein the E3 ubiquitin ligase ligand having formula (ii) is:

[0475]

[0476]

[0477] A83A. In Example A83A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3 to A39b, A40A, and A67, A69 to A72, A77, A79 to A82, and A83, wherein the E3 ubiquitin ligase ligand having formula (ii) is

[0478] A84. In Example A84, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A83A, wherein each R ee and R ff is independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy.

[0479] A85. In Example A85, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A83A is one in which R ee and R ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.

[0480] A86. In Example A86, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A85 is one in which 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.

[0481] A87. In Example A87, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff are independently selected from hydrogen, methyl, ethyl, and isopropyl.

[0482] A88. In Example A88, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff are independently selected from hydrogen and methoxy.

[0483] A89. In Example A89, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.

[0484] A90. In Example A90, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which one of R ee and R ff is hydrogen or fluoro, and the other of R ee and R ff is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl.

[0485] A91. In Example A91, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.

[0486] A92. In Example A92, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff are independently selected from hydrogen, chlorine, fluorine, and trifluoromethyl.

[0487] A93. In Example A93, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff is hydrogen.

[0488] A94. In Example A94, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff is chlorine.

[0489] A95. In Example A95, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff is fluorine.

[0490] A96. In Example A96, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b, A40A, and A67 to A86 is one in which R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.

[0491] A96a. In Example A96a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A2 to A39b is one in which the degron is an E3 ubiquitin ligase ligand having formula (iii), (iv), (v), or (vi).

[0492] A96b. In Example A96b, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A2 to A39b and A96a is one in which the degron is an E3 ubiquitin ligase ligand having formula (iv) or (v).

[0493] A96c. In Example A96c, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A2 to A39b, A96a, and A96b is one in which R y , R y1 and R y2 are 1-fluorocyclopropan-1-yl and W a is a bond, S or methylene.

[0494] A96d. In Example A96d, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A39b and A96a to A96c is one in which W a is S.

[0495] A97. In Example A97, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 are each a bond.

[0496] A98. In Example A98, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 are each independently selected from alkylene. In a sub-example of Example A98, X 1 , X 2 , X 3 and X 4 are each methylene.

[0497] A99. In Example A99, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 are each -O-.

[0498] A100. In Example A100, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X3 and X 4 each independently selected from -(O-alkylene)-.

[0499] A101. In Example A101, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 each independently selected from -(alkylene-O)-.

[0500] A102. In Example A102, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 each independently selected from -(NR gg -alkylene)-.

[0501] A103. In Example A103, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 each independently selected from -(alkylene-NR hh )-.

[0502] A104. In Example A104, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 each is

[0503] A105. In Example A105, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4 each is -NH-.

[0504] A106. In Example A106, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96 is one in which X 1 , X 2 , X 3 and X 4Each independently selected from -N(alkyl)-. In a sub - embodiment of Example A106, X 1 , X 2 , X 3 and X 4 are each independently -N(methyl)- or -N(ethyl)-.

[0505] A107. In Example A107, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3 - 1 to A96 is one in which X 1 , X 2 , X 3 and X 4 are each -C(=O)-.

[0506] A108. In Example A108, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3 - 1 to A96 is one in which X 1 , X 2 , X 3 and X 4 are each independently -NR jj C(=O)-.

[0507] A109. In Example A109, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3 - 1 to A96 is one in which X 1 , X 2 , X 3 and X 4 are each independently -C(=O)NR kk -.

[0508] A110. In Example A110, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3 - 1 to A96, A102, A103, A108 and A109 is one in which R gg , R hh , R jj and R kk are each independently hydrogen or alkyl.

[0509] A110a. In Example A110a, the compound for use as described in any one of Examples A3 - 1 to A110 is one in which -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - in which at least two are not bonds. In a sub - embodiment of A110a, the compound for said use is one in which -Z 1 -Z 2-Z 3 -Z 4 -Z 5 -Z 6 At least three of the - are not bonds. In a sub - embodiment of A110a, the compound is one in which -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - at least four of which are not bonds.

[0510] A111. In embodiment A111, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of embodiments A3 - 1 to A110a is one in which Z 6 is -S(O) 2 -.

[0511] A112. In embodiment A112, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of embodiments A3 - 1 to A111 is one in which Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, each ring of which is substituted by R q and R r substituted.

[0512] A113. In embodiment A113, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of embodiments A3 - 1 to A112 is one in which Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, each ring of which is substituted by R q and R r substituted, and one and only one of Z 1 and X 1 is a bond, one and only one of Z 1 and X 2 is a bond, one and only one of Z 1 and X 3 is a bond, and one and only one of Z 1 and X 4 is a bond (for clarity, when X 1 、X 2 、X 3 and X 4 are not bonds, then X 1 、X 2 、X 3 and X 4 are as described in any one of embodiments A3 - 1 and A98 to A109).

[0513] A114. In embodiment A114, the compound for use as described in any one of embodiments A3-1 to A96d, or a pharmaceutically acceptable salt thereof, is wherein:

[0514] X 1 , X 2 , X 3 and X 4 are independently a bond, -(O-alkylene)-, -(NR gg -alkylene)-, -NH- or -N(alkyl)-, where R gg is hydrogen or alkyl, and each alkylene group is independently optionally substituted with one or two fluorine groups (or X 1 , X 2 , X 3 and X 4 not present in ligands (iii) to (vi));

[0515] Z 1 is a bond, alkylene, -(CO)NR-, -(O-alkylene) a -, -(alkylene-O) a -, phenylene or heterocyclic group, wherein each ring is R h and R i replace;

[0516] Z 2 is a bond, alkylene, -(O-alkylene) b -, -(alkylene-O) b -, cycloalkylene or heterocyclylene, wherein each ring is R j and R k replace;

[0517] 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, wherein each ring, by itself or as part of another group, is replaced by R m and R n replace;

[0518] Z 4is a bond, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, -(alkylene)-heterocycloalkylene-, -heterocycloalkylene-(alkylene)-, fused heterocycloalkylene, bridged heterocycloalkylene, -(alkylene)-bridged heterocycloalkylene-, -bridged heterocycloalkylene-(alkylene)-, spiroheterocycloalkylene, -(alkylene)-spiroheterocycloalkylene or -spiroheterocycloalkylene-(alkylene)-, wherein each ring is itself or as part of another group substituted by R o and R p substituted;

[0519] Z 5 is a bond; and

[0520] Z 6 is -S(O) 2 -; and

[0521] wherein Z 1 , Z 2 , Z 3 and Z 4 each alkylene in is itself or as part of another group independently substituted by R s and R t substituted.

[0522] A115. In Example A115, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d is wherein:

[0523] X 1 , X 2 , X 3 , X 4 and Z 1 are each a bond;

[0524] Z 2 is a bond, alkylene, cycloalkylene or heterocycloalkylene, wherein each ring is substituted by R j and R k substituted;

[0525] Z 3 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -O-, -NR”-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, bicyclic heteroarylene, bridged heterocycloalkylene, fused heterocycloalkylene or spiroheterocycloalkylene, wherein each ring is substituted by R m and R n substituted;

[0526] Z 4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, fused heterocycloalkylene or spiro heterocycloalkylene, wherein each ring is substituted by R o and R p ;

[0527] Z 5 is phenylene, monocyclic heteroarylene or heterocycloalkylene, wherein each ring is substituted by R q and R r ; and

[0528] Z 6 is -S(O) 2 -; and

[0529] wherein each alkylene in Z 2 , Z 3 and Z 4 is independently substituted by R s and R t .

[0530] A116. In Example A116, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d and A115 is one in which:

[0531] X 1 、X 2 、X 3 、X 4 、Z 1 and Z 2 are each a bond;

[0532] Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, bicyclic heteroalkylene, bridged heteroalkylene, fused heteroalkylene or spiro heteroalkylene, wherein each ring is substituted by R m and R n ;

[0533] Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, fused heteroalkylene or spiro heteroalkylene, wherein each ring is independently substituted by R o and R p selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[0534] Z 5 is phenylene, monocyclic heteroarylene or heterocycloalkylene, wherein each ring is substituted by R q and R r ; and

[0535] Z 6 is -S(O)2 -; and

[0536] wherein Z 4 the alkylene in is replaced by R s and R t .

[0537] A117. In Example A117, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d, A115, and A116 is wherein:

[0538] X 1 , X 2 , X 3 , X 4 , Z 1 , and Z 2 are each a bond;

[0539] Z 3 is a heteroalkylene group, bicyclic heteroalkylene group, bridged heteroalkylene group, fused heteroalkylene group, or spiro heteroalkylene group, wherein each ring is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[0540] Z 4 is an alkylene group, -O-, cycloalkylene group, monocyclic heteroaryl group, heteroalkylene group, fused heteroalkylene group, or spiro heteroalkylene group, wherein each ring is independently substituted by R o and R p selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[0541] Z 5 is a phenylene group, monocyclic heteroaryl group, or heteroalkylene group, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

[0542] Z 6 is -S(O) 2 -; and

[0543] wherein the alkylene in Z 4 is replaced by R s and R t .

[0544] A118. In Example A118, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d and A115 to A117 is wherein:

[0545] X 1 、X 2 、X 3 and X 4 、Z 1 and Z 2 each is a bond;

[0546] Z 3 is a heteroalkylene, bridged heteroalkylene or spiroheteroalkylene, wherein each ring is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[0547] Z 4 is an alkylene, -O-, cycloalkylene or heteroalkylene, wherein each ring is independently substituted by R o and R p selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano and hydroxy;

[0548] Z 5 is a phenylene, monocyclic heteroarylene or heteroalkylene, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and

[0549] Z 6 is -S(O) 2 -; and

[0550] wherein the alkylene in Z 4 is substituted by R s and R t selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl and haloalkoxy.

[0551] A119. In Example A119, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d and A115 to A118 is one in which:

[0552] X 1 、X 2 、X 3 、X 4 、Z 1 and Z 2 each is a bond;

[0553] Z 3 is a heteroalkylene, bridged heteroalkylene or spiroheteroalkylene, wherein each ring is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[0554] Z 4 is an alkylene group, -O-, cycloalkylene group or hetero-cycloalkylene group, wherein each ring is independently selected from hydrogen, deuterium, alkyl group, alkoxy group, halogen group, haloalkyl group, haloalkoxy group, cyano group and hydroxyl group, preferably R selected from hydrogen, deuterium, alkyl group, alkoxy group, halogen group, haloalkyl group and haloalkoxy group o and R p substituted (in the sub-embodiment, Z 4 is an alkylene group or -O-);

[0555] Z 5 is a phenylene group or a monocyclic hetero-arylene group, each ring being independently substituted by R q and R r selected from hydrogen, deuterium, alkyl group, alkoxy group, hydroxyl group, cyano group, halogen group, haloalkyl group and haloalkoxy group; and

[0556] Z 6 is -S(O) 2 -; and

[0557] wherein the alkylene group in Z 4 is substituted by R s and R t substituted.

[0558] A120. In Example A120, the compound or its pharmaceutically acceptable salt for use in any one of Examples A3-1 to A96d and A115 is one in which:

[0559] X 1 、X 2 、X 3 、X 4 and Z 1 are each a bond;

[0560] Z 2 is a cycloalkylene group or a hetero-cycloalkylene group, each ring being independently substituted by R j and R k selected from hydrogen, deuterium, alkyl group, alkoxy group, halogen group, haloalkyl group and haloalkoxy group;

[0561] Z 3 is a cycloalkylene group, phenylene group, monocyclic hetero-arylene group, hetero-cycloalkylene group, bicyclic hetero-cycloalkylene group, bridged hetero-cycloalkylene group, fused hetero-cycloalkylene group or spiro hetero-cycloalkylene group, each ring being independently substituted by R m and R n selected from hydrogen, deuterium, alkyl group, alkoxy group, hydroxyl group, cyano group, halogen group, haloalkyl group and haloalkoxy group;

[0562] Z 4 is a bond, alkylene group or -O-;

[0563] Z 5 is a phenylene, a monocyclic heteroarylene (such as pyridinediyl) or a heteroalkylene, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and

[0564] Z 6 is -S(O) 2 -; and

[0565] wherein the alkylene in Z 4 is substituted by R s and R t .

[0566] A121. In Example A121, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d, A111 and A115 is one in which:

[0567] X 1 、X 2 、X 3 、X 4 and Z 1 are each a bond;

[0568] Z 2 is a heteroalkylene substituted by R j and R k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl and haloalkoxy;

[0569] Z 3 is a heteroalkylene substituted by R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[0570] Z 4 is a bond, an alkylene or -O-;

[0571] Z 5 is a phenylene or a monocyclic heteroarylene, each ring being independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and

[0572] Z 6 is -S(O) 2 -; and

[0573] wherein the alkylene in Z 4 is substituted by R s and Rt Substituted.

[0574] A122. In Example A122, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96d, A97, A111, and A112 is one in which:

[0575] X 1 , X 2 , X 3 , X 4 and Z 1 each is a bond;

[0576] Z 2 is a hetero-subcyclic group substituted by R j and R k , preferably R j and R k are independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

[0577] Z 3 is a bond, alkylene, or -O-;

[0578] Z 4 is a hetero-subcyclic group, bridged hetero-subcyclic group, or spiro hetero-subcyclic group, each ring of which is substituted by R o and R p , preferably R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[0579] Z 5 is a phenylene or monocyclic hetero-arylene, each ring of which is substituted by R q and R r , preferably R q and R r are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

[0580] Z 6 is -S(O) 2 -; and

[0581] wherein the alkylene in Z 3 is substituted by R s and R t .

[0582] A123. In Example A123, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96d is one in which Z 4 is a hetero-subcyclic group or spiro hetero-subcyclic group, each ring of which is substituted by R oand R p is replaced, preferably by R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy.

[0583] A124. In Example A124, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d, A115 and A116 is one in which:

[0584] X 1 、X 2 、X 3 、X 4 、Z 1 and Z 2 each is a bond;

[0585] Z 3 is a hetero-subcyclic group, in which each ring is independently replaced by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[0586] Z 4 is a cycloalkylidene group replaced by R o and R p independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl and haloalkoxy;

[0587] Z 5 is a phenylene or monocyclic hetero-subaryl group, each ring of which is independently replaced by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and

[0588] Z 6 is -S(O) 2 -.

[0589] A125. In Example A125, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d is one in which one and only one of X 1 and Z 1 、or one and only one of X 2 and Z 1 、or one and only one of X 3 and Z 1 、or one and only one of X 4 and Z 1 is a bond.

[0590] A126. In Example A126, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d is one in which X 1 、X 2 、X 3 、X 4 and Z 1 are each a bond.

[0591] A127. In Example A127, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d, A125 and A126 is one in which Z 2 is a hetero-subcyclic group or a bridged hetero-subcyclic group, each ring being substituted by R j and R k .

[0592] A128. In Example A128, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d, A125 and A126 is one in which Z 2 is a bond.

[0593] A129. In Example A129, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d and A125 to A128 is one in which:

[0594] Z 3 is an alkylene group, a cycloalkylene group, a phenylene group, -(alkylene)-phenylene-, -phenylene-(alkylene)-, a monocyclic heteroaryl group, -(alkylene)-monocyclic heteroaryl-, -monocyclic heteroaryl-(alkylene)-, a hetero-subcyclic group, -(alkylene)-hetero-subcyclic-, -hetero-subcyclic-(alkylene)-, a bicyclic hetero-subcyclic group, a bridged hetero-subcyclic group, -(alkylene)-bridged hetero-subcyclic-, -bridged hetero-subcyclic-(alkylene)-, a fused hetero-subcyclic group, a spiro hetero-subcyclic group, -(alkylene)-spiro hetero-subcyclic- or -spiro hetero-subcyclic-(alkylene), where each ring is itself or as part of another group substituted by R m and R n ;

[0595] Z 4 is an alkylene group, -(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 is itself or as part of another group substituted by R o and R p substituted;

[0596] Z 5 is a bond, -alkylene, -NR”-,-O-,-C(O)-,-S(O) 2 -, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is substituted by R q and R r substituted; and

[0597] Z 6 is a bond, alkylene, -NR”-,-O-,-(alkylene-O)-,-C(O)-,-S(O) 2 -, -NR'(CO)- or -C(O)NR-; and

[0598] and Z 3 、Z 4 、Z 5 and Z 6 each alkylene in and is itself or as part of another group independently substituted by R s and R t substituted.

[0599] A130. In Example A130, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96d and A125 to A129 is one in which:

[0600] 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), wherein each ring is itself or as part of another group substituted by R m and R nSubstituted;

[0601] Z 4 is an alkylene group, -(alkylene-NR")-, -(NR"-alkylene)-, -O-, -NR"-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocycloalkylene, -(alkylene)-heterocycloalkylene-, -heterocycloalkylene-(alkylene)-, fused heterocycloalkylene, bridged heterocycloalkylene, -(alkylene)-bridged heterocycloalkylene-, -bridged heterocycloalkylene-(alkylene)-, spiroheterocycloalkylene, -(alkylene)-spiroheterocycloalkylene-, or -spiroheterocycloalkylene-(alkylene)-, wherein each ring is itself or as part of another group substituted by R o and R p substituted;

[0602] Z 5 is a bond, -alkylene, -NR"-, -O-, -C(O)-, -S(O) 2 -, -NR'(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene or heterocycloalkylene, wherein each ring is substituted by R q and R r substituted; and

[0603] Z 6 is -S(O) 2 -; and

[0604] And Z 3 , Z 4 and Z 5 each alkylene group in is itself or as part of another group independently substituted by R s and R t substituted.

[0605] A130A. In Example A130A, the compound or its pharmaceutically acceptable salt for use in any one of Examples A3-1, A3A to A97, A111-A113, A126 and A128-A130 is one in which:

[0606] X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 are each a bond;

[0607] Z 3 is -heterocycloalkylene-(alkylene)-, wherein the heterocycloalkylene is substituted by R m and Rn is replaced, and the alkylene group is replaced by R s and R t ;

[0608] Z 4 is phenylene or monocyclic heteroarylene, wherein each ring is replaced by R o and R p ;

[0609] Z 5 is phenylene replaced by R q and R r ; and

[0610] Z 6 is -S(O) 2 -.

[0611] A131. In Example A131, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d and A125 to A130 is one in which:

[0612] Z 3 is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heteroalicyclic group, -(alkylene)-heteroalicyclic group-, -heteroalicyclic group-(alkylene)-, bridged heteroalicyclic group, -(alkylene)-bridged heteroalicyclic group-, -bridged heteroalicyclic group-(alkylene)-, spiroheteroalicyclic group, -(alkylene)-spiroheteroalicyclic group- or -spiroheteroalicyclic group-(alkylene), wherein each ring is itself or as part of another group replaced by R m and R n ;

[0613] Z 4 is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heteroalicyclic group, -(alkylene)-heteroalicyclic group-, -heteroalicyclic group-(alkylene)-, fused heteroalicyclic group, bridged heteroalicyclic group, -(alkylene)-bridged heteroalicyclic group-, -bridged heteroalicyclic group-(alkylene)-, spiroheteroalicyclic group, -(alkylene)-spiroheteroalicyclic, or -spiroheteroalicyclic group-(alkylene)-, wherein each ring is itself or as part of another group replaced by R o and R p ;

[0614] Z5 is a phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is substituted by R q and R r ; and

[0615] Z 6 is -S(O) 2 -; and

[0616] and Z 3 and Z 4 each alkylene group in itself or as part of another group is independently substituted by R s and R t substituted.

[0617] A131a. In Example A131a, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96d and A125 to A130 is wherein:

[0618] Z 3 is alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, wherein each ring in itself or as part of another group is substituted by R m and R n substituted;

[0619] Z 4 is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiroalkylene, 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 in itself or as part of another group is substituted by R o and R p substituted;

[0620] Z 5 is phenylene, monocyclic heteroarylene or heterocyclylene, wherein each ring is substituted by R q and R r substituted; and

[0621] Z 6 is -S(O) 2 ; and

[0622] and Z 3 and Z 4 each alkylene in is independently substituted by R s and R t substituted.

[0623] A132. In Example A132, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d and A125 to A131 is one in which:

[0624] Z 3 is a hetero-subcyclic group, -(alkylene)-hetero-subcyclic group-, -hetero-subcyclic group-(alkylene)-, bridged hetero-subcyclic group, -(alkylene)-bridged hetero-subcyclic group-, -bridged hetero-subcyclic group-(alkylene)-, spiro hetero-subcyclic group, -(alkylene)-spiro hetero-subcyclic group- or -spiro hetero-subcyclic group-(alkylene), where each ring is independently substituted by R m and R n substituted;

[0625] Z 4 is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene) d -, -(alkylene-O) d -, phenylene, heteroaryl, hetero-subcyclic group, -(alkylene)-hetero-subcyclic group-, -hetero-subcyclic group-(alkylene)-, bridged hetero-subcyclic group, -(alkylene)-bridged hetero-subcyclic group-, -bridged hetero-subcyclic group-(alkylene)-, spiro hetero-subcyclic group, -(alkylene)-spiro hetero-subcyclic group or -spiro hetero-subcyclic group-(alkylene)-, where each ring is independently substituted by R o and R p substituted;

[0626] Z 5 is phenylene, monocyclic heteroaryl or hetero-subcyclic group, where each ring is substituted by R q and R r substituted; and

[0627] Z 6 is -S(O) 2 ; and

[0628] and Z 3 and Z 4 each alkylene in is independently substituted by R s and R t substituted.

[0629] In Example A132A, the compound or a pharmaceutically acceptable salt thereof for use as described in A132 is one in which:

[0630] X 1 、X 2 、X 3 、X 4 、Z 1 and Z 2 each is a bond;

[0631] Z 3 is -heterocyclylene-(alkylene)-, wherein the heterocyclylene is substituted by R m and R n and wherein the alkylene is independently substituted by R s and R t ;

[0632] Z 4 is phenylene or monocyclic heteroarylene, wherein each ring is substituted by R o and R p ;

[0633] Z 5 is phenylene substituted by R q and R r ; and

[0634] Z 6 is -S(O) 2 .

[0635] In Example A133, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d, A125 to A131 and A132 is one in which:

[0636] Z 3 is heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene- or -spiro heterocyclylene-(alkylene), wherein each ring by itself or as part of another group is substituted by R m and R n ;

[0637] Z 4is an alkylene group, -O-, a hetero-subcyclic group, -(alkylene)-hetero-subcyclic group-, -hetero-subcyclic group-(alkylene)-, a bridged hetero-subcyclic group, -(alkylene)-bridged hetero-subcyclic group-, -bridged hetero-subcyclic group-(alkylene)-, a spiro hetero-subcyclic group, -(alkylene)-spiro hetero-subcyclic group or -spiro hetero-subcyclic group-(alkylene)-, wherein each ring is independently substituted by R selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino o and R p substituted;

[0638] Z 5 is a phenylene group, a monocyclic heteroaryl group or a hetero-subcyclic group, wherein each ring is independently substituted by R selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino q and R r substituted; and

[0639] Z 6 is -S(O) 2 ; and

[0640] and Z 3 and Z 4 each alkylene group in is independently substituted by R s and R t substituted.

[0641] A134. In Example A134, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96d, A125 to A131 and A132 to A133 is wherein:

[0642] Z 3 is a hetero-subcyclic group, a bridged hetero-subcyclic group or a spiro hetero-subcyclic group, wherein each ring is substituted by R m and R n substituted;

[0643] Z 4 is an alkylene group, -O-, a hetero-subcyclic group, -(alkylene)-hetero-subcyclic group-, -(alkylene)-bridged hetero-subcyclic group-, wherein each ring is independently substituted by R o and R p substituted;

[0644] Z 5 is a phenylene group, a monocyclic heteroaryl group or a hetero-subcyclic group, wherein each ring is substituted by R q and R r substituted; and

[0645] Z6 is -S(O) 2 ; and

[0646] and Z 4 each alkylene group in s and R t is substituted by R

[0647] A135. In Example A135, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113 and A115 to A134 is one in which -Z 5 - is R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy (i.e., Z 5 is phenylene, where Z 4 and Z 6 are attached at the meta positions of the phenylene ring).

[0648] A136. In Example A136, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113 and A115 to A135 is one in which -Z 5 - is R q and R r independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy

[0649] A137. In Example A137, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113 and A115 to A136 is one in which -Z 5 - is R q and R r independently selected from hydrogen, deuterium, or fluoro

[0650] A137a. In Example A137a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113 and A115 to A137 is one in which -Z 5 - is (in the sub-example -Z 5 - is ).

[0651] A137b. In Example A137b, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113 and A115 to A136 is wherein -Z 5 - is

[0652] A138. In Example A138, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113, A115 to A132, A133 and A134 is wherein -Z 5 - is R independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl and haloalkoxy q and R r substituted monocyclic heteroarylene (such as imidazole-1,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl).

[0653] A139. In Example A139, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113, A115 to A132, A133, A134 and A138 is wherein -Z 5 - is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl, each ring being independently substituted by R q and R r selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy and trifluoromethoxy.

[0654] A140. In Example A140, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113, A115 to A132, A133, A134, A138 and A139 is wherein -Z 5 - is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl, each ring being independently substituted by R q and R r selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0655] A141. In Example A141, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A113, A115 to A118, A120, A123 and A125 to A132, A133 and A134 is wherein -Z 5-R is independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy and trifluoromethoxy q and R r substituted heteroalkylene group.

[0656] A142. In Example A142, the compound or its pharmaceutically acceptable salt for use in any one of Examples A3-1 to A113, A115 to A118, A120, A123, A125 to A132, A133, A134 and A141 is wherein -Z 5 - is azetidinyl, pyrrolidinyl, piperazinyl or piperidinyl.

[0657] A143. In Example A143, the compound or its pharmaceutically acceptable salt for use in any one of Examples A3-1 to A134 is wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 each alkylene group itself and when present is methylene, ethylene or propylene each substituted by R s and R t .

[0658] A144. In Example A144, the compound or its pharmaceutically acceptable salt for use in any one of Examples A3-1 to A134 and A143 is wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 each alkylene group itself and when present is methylene substituted by R s and R t .

[0659] A145. In Example A145, the compound or its pharmaceutically acceptable salt for use in any one of Examples A3-1 to A134 is wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 each alkylene group itself or as -(O-alkylene) 1 - in Z a , -(alkylene-O) 1 - in Z a , Z 2-(O-alkylene) in b -, Z 2 -(alkylene-O) in b -, Z 3 -(O-alkylene) in c -, Z 3 -(alkylene-O) in c -, Z 4 -(O-alkylene) in d -, and Z 4 -(alkylene-O) in d -, and Z 6 a part of -(alkylene-O)- and when present is ethylene or propylene; as a part of –(alkylene-NR”)- and –(NR”-alkylene)- and when present is methylene, ethylene or propylene; and as a part of -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, -(alkylene)-phenyl-, -phenyl-(alkylene)-, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiroheterocyclylene- and -spiroheterocyclylene-(alkylene)- is methylene, ethylene, propylene or butylene, wherein each of the above alkylene groups is substituted by R s and R t substituted.

[0660] A146. In Example A146, the compound or its pharmaceutically acceptable salt for use in any one of Examples A3-1 to A134 and A145 is wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 each alkylene in itself or as -(O-alkylene) in Z 1 -, Z a -(alkylene-O) in 1 -, Z a -(O-alkylene) in 2 -, Z b -(alkylene-O) in 2 -, Z b -(O-alkylene) in 3 -, Z c -(alkylene-O) in 3 -, Z c -(O-alkylene) in 4 -, Zd - and Z 4 in -(alkylene-O) of d -, and Z 6 part of -(alkylene-NR”)- and -(NR”-alkylene)- and is ethylene when present; 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)- and is methylene when present.

[0661] A147. In Example A147, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A146 is one in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 each R, R' and R” when present is independently hydrogen or methyl.

[0662] A148. In Example A148, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A147 is one in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 each R, R' and R” when present is hydrogen.

[0663] A149. In Example A149, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A1 to A147 is one in which Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 each R, R' and R” when present is methyl.

[0664] A150. In Example A150, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A149 is one in which Z 2 , Z 3 and Z4 Each cycloalkylene group, when present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0665] A151. In Example A151, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A150 is one in which Z 2 、Z 3 and Z 4 Each cycloalkylene group, when present, is independently selected from 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene.

[0666] A152. In Example A152, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A151 is one in which the heteroarylene is a monocyclic heteroarylene, and Z 1 、Z 3 、Z 4 and Z 5 Each monocyclic heteroarylene group, when present, is independently selected from imidazolediyl, pyridinediyl, and pyrimidinediyl, unless otherwise specified in any of the above examples.

[0667] A153. In Example A153, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A152 is one in which the heteroarylene is a monocyclic heteroarylene, and Z 1 、Z 3 、Z 4 and Z 5 Each monocyclic heteroarylene group, when present, is independently selected from imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, and pyridine-3,5-diyl, unless otherwise specified in any of the above examples.

[0668] A154. In Example A154, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A153 is one in which Z 1 、Z 3 、Z 4 and Z 5 Each phenylene group, when present, is independently selected from 1,3-phenylene and 1,4-phenylene, unless otherwise specified in any of the above examples.

[0669] A155. In Example A155, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A154 is one in which Z 1 、Z 2 、Z 3 、Z 4 and Z 5Each hetero-subcyclic group, bridged hetero-subcyclic group, and spiro hetero-subcyclic group, when present, is independently selected from:

[0670]

[0671] wherein each ring is optionally substituted with 1, 2, or 3 fluorines, unless otherwise specified in any of the above embodiments.

[0672] A156. In Example A156, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A155 is one in which each hetero-subcyclic group, bridged hetero-subcyclic group, and spiro hetero-subcyclic group in Z 1 、Z 2 、Z 3 、Z 4 and Z 5 is independently selected from:

[0673]

[0674] wherein each ring is optionally substituted with 1 or 2 fluorines, unless otherwise specified in any of the above embodiments.

[0675] A157. In Example A157, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96d is one in which L (when the degron is a group having formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L-, and -X 4 -L- (when the degron is a group having formula (i) or (ii)) is independently:

[0676]

[0677]

[0678]

[0679] A158. In Example A158, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A96d is one in which L (when the degron is a group having formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L-, and -X 4 -L- (when the degron is a group having formula (i) or (ii)) is independently:

[0680]

[0681] A159. In Example A159, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, and A132 to A134 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0682]

[0683] where each R m , R n and R q is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano. In a sub-example, each R q and R m is independently selected from hydrogen, methyl, fluorine, chlorine, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl.

[0684] A160. In Example A160, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A159 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0685]

[0686]

[0687] where each R m , R n and R q is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, and cyano (i.e., R r is hydrogen).

[0688] A161. In Example A161, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0689]

[0690] A162. In Example A162, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0691]

[0692] A164. In Example A164, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0693]

[0694] A165. In Example A165, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0695]

[0696] A166. In Example A166, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0697]

[0698] In Example A167, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160 is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0699]

[0700] In Example A168A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A110, A113, A115 to A122, A124 to A131, A132 to A134, and A160 is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0701]

[0702] In Example A168, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A159 to 168A is wherein is:

[0703]

[0704] In Example A160A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3A to A97, A111 to A113, A126, and A128 to A130A is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0705]

[0706] wherein each R m 、R n and R q is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, and cyano (i.e., R r is hydrogen).

[0707] A161A. In Example A161A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3A to A97, A111 to A113, A126, A128 to A130A and A160A is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0708]

[0709] A162A. In Example A162A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3A to A97, A111 to A113, A126, A128 to A130A and A160A is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0710]

[0711] A163A. In Example A163A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3A to A97, A111 to A113, A126, A128 to A130A and A160A is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0712]

[0713] A164A. In Example A164A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1, A3A to A97, A111 to A113, A126 and A128 to A130A is wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0714]

[0715] A165A. In Example A165A, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A160A to 165A is wherein is:

[0716] A169. In Example A169, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, and A159 to A168 is one in which Z 4 is an alkylene group substituted by R s and R t , wherein R s and R t are hydrogen.

[0717] A170. In Example A170, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, and A169 is one in which the alkylene group in Z 4 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH(CH 3 )-, -CH 2 -CH(CH 3 )-CH 2 -, or -CH 2 -C(CH 3 ) 2 -CH 2 -.

[0718] A171. In Example A171, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, A169, and A170 is one in which the alkylene group in Z 4 is -CH 2 -.

[0719] A172. In Example A172, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, and A159 to A168 is one in which Z 4 is -O-.

[0720] A173. In Example A173, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, and A159 to A168 is one in which Z4 is an alkylene group substituted by R s and R t wherein R s is hydrogen or deuterium, and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy or cyano.

[0721] A174. In Example A174, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168 and A173 is one wherein Z 4 is an alkylene group substituted by R s and R t wherein R s is hydrogen or deuterium, and R t is hydrogen and deuterium.

[0722] A175. In Example A175, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168 and A173 is one wherein Z 4 is an alkylene group substituted by R s and R t wherein R s is hydrogen, and R t is haloalkyl.

[0723] A176. In Example A176, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168 and A173 is one wherein Z 4 is an alkylene group substituted by R s and R t wherein R s is hydrogen, and R t is hydroxy.

[0724] A177. In Example A177, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168 and A173 is one wherein Z 4 is an alkylene group substituted by R s and R t wherein R s is hydrogen, and R t is alkoxy.

[0725] A178. In Example A178, the compound or a pharmaceutically acceptable salt thereof for use in any one of A3-1 to A121, A125 to A130, A131 to A132, A133 to A142, A159 to A168, A173, and A175 to A177 is one in which Z 4 is -CH(CHF 2 )-, -CH(CF 3 )-, -C(CH 3 )(CF 3 )-, -CH(CH 2 CF 3 )-, -CH(CH 2 CH 2 CF 3 )-, -CH(CH(CF 3 )) 2 )-, -CH(CH 2 OH)-, -CH(CH 2 OCH 3 )-, -CH(CH 2 O-ethyl)- or -CH(CH 2 CN)-, -CH 2 -CH(CF 3 )-CH 2 -, -CH 2 -CH(OH)-CH 2 - or -CH 2 -CH(OCH 3 )-CH 2 -.

[0726] A179. In Example A179, the compound or a pharmaceutically acceptable salt thereof for use in any one of A3-1 to A114, A125 to A130, A131 to A132, A133 to A146, and A159 to A168 is one in which Z 4 is -(alkylene)-heterocyclylene-, where the heterocyclylene is substituted by R o and R p .

[0727] A180. In Example A180, the compound or a pharmaceutically acceptable salt thereof for use in any one of A3-1 to A114, A125 to A130, A131 to A132, A133 to A146, A159 to A168, and A179 is one in which Z 4 is -(CH 2 )-heterocyclylene-, where the heterocyclylene is substituted by R o and R p .

[0728] A181. In Example A181, the compound or a pharmaceutically acceptable salt thereof 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 is one in which Z 4 is:

[0729]

[0730] A182A. In Example A182A, the compound or a pharmaceutically acceptable salt thereof 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 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0731]

[0732]

[0733] A182. In Example A182, the compound or a pharmaceutically acceptable salt thereof 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 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0734]

[0735]

[0736] A183A. In Example A183A, the compound or a pharmaceutically acceptable salt thereof 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 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0737]

[0738] A183. In Example A183, the compound or a pharmaceutically acceptable salt thereof 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 is one in which -Z 3 -Z 4 -Z 5 -Z 6 - is:

[0739]

[0740] A184. In Example A184, the compound or a pharmaceutically acceptable salt thereof for use in any one of A3-1 to A96d is one in which L (when the degron is a group having formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the degron is a group having formula (i) or (ii)) is independently:

[0741]

[0742] A185. In Example A185, the compound or a pharmaceutically acceptable salt thereof for use in any one of A3-1 to A96d and A184 is one in which L (when the degron is a group having formula (iii) to (vi)), -X 1 -L-, -X 2 -L-, -X 3 -L- and -X 4 -L- (when the degron is a group having formula (i) or (ii)) is independently:

[0743]

[0744] A186A. In Example A186A, the compound or a pharmaceutically acceptable salt thereof for use in any one of Examples A3-1 to A96 and A97 to A185 is one in which the degron is an E3 ubiquitin ligase ligand selected from:

[0745]

[0746] wherein 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.

[0747] A186. In Example A186, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 and A97 to A186A is one in which the degron is an E3 ubiquitin ligase ligand selected from the following:

[0748]

[0749] wherein 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.

[0750] A187. In Example A187, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 and A97 to A186 is one in which the degron is an E3 ligase ligand selected from the following:

[0751]

[0752] A188. In Example A188, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 and A97 to A186 is one in which the degron is the E3 ubiquitin ligase ligand where 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.

[0753] A189. In Example A189, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A96 and A97 to A186 is one in which the degron is the E3 ubiquitin ligase ligand

[0754] A190. In Example A190, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples A3-1 to A185 is one in which R x and R x1 are hydrogen.

[0755] For clarity, Example A includes combinations of Example A and its sub-examples.

[0756] For the sake of clarity, when an embodiment involves more than one of the foregoing embodiments in a range of variations, the scope of the foregoing embodiments is controlled, that is, only those groups that fall within the scope of one or more groups listed in one or more of the foregoing embodiments should be selected from the relevant embodiments. For example, among the groups listed in Embodiment A8, although all the groups listed in A8 should be selected for Embodiment A1, only fluorine, chlorine, and bromine should be selected for Embodiment A5 because the range of R 1 in A5 is limited to halogen; and only difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl should be selected for Embodiment A6 because the range of R 1 in A6 is limited to haloalkyl.

[0757] Additional embodiments B1-157 are:

[0758] B1A. In Embodiment B1A, the compound or its pharmaceutically acceptable salt for use in the use as described in the first aspect is one in which the compound (or any of its embodiments disclosed in the disclosure of the invention) further comprises a linker attached to Hy of a CDK2 binding moiety having formula (A1).

[0759] B1. In Embodiment B1, the compound or its pharmaceutically acceptable salt for use in the use as described in the second aspect is one in which the compound further comprises a linker attached to Hy of a CDK2 binding moiety having formula (A).

[0760] B2-1 to B2-40. In Embodiments B2-1 to B2-40, the compound or its pharmaceutically acceptable salt for use in the use as described in Embodiment B1 is one in which the moiety having formula (A) is as disclosed in Embodiments A4-50 and A4 to A39b, respectively.

[0761] B2-41 to B2-112. In Embodiments B2-41 to B2-110, the compound or its pharmaceutically acceptable salt for use in the use as described in Embodiment B1A is one in which the moiety of formula (A1) is as disclosed in Embodiments A4-1 to A4-50, A4, and A23 to A39b, respectively.

[0762] B3. In Embodiment B3, the compound or its pharmaceutically acceptable salt for use in the use as described in any one of Embodiments B1A, B1, and B2-1 to B2-112 is one in which the compound further comprises an E3 ubiquitin ligase ligand, and in which the ligand is attached to the linker, and the compound is a compound having formula (II):

[0763]

[0764] wherein the degron 1 is an E3 ubiquitin ligase ligand.

[0765] B4. In Example B4, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 is one in which the linker contains one or more -SO 2 -.

[0766] B5. In Example B5, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B4 is one in which the linker contains one or more -SO 2 -, and one of the one or more -SO 2 - is attached to Hy having formula (A1), (A) and (II). In a sub - example of Example B5, the linker contains one or more -SO 2 -, and one of the one or more -SO 2 - is attached to the nitrogen in Hy having formula (A1), (A) and (II).

[0767] B6. In Example B6, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B5 is one in which the linker contains one or two -SO 2 -.

[0768] B7. In Example B7, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B6 is one in which the linker contains one -SO 2 -.

[0769] B8. In Example B8, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 is one in which the linker contains one or more rings, the one or more rings being independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene and spiroheterocycloalkylene, where each ring is optionally substituted by one or two substituents independently selected from: deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino.

[0770] B8a. In Example B8a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 is one in which the linker contains one or more rings, the one or more rings being independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene and spiroheterocycloalkylene, where each ring is optionally substituted by one or two substituents independently selected from: deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino and dialkylamino.

[0771] B9. In Example B9, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 and B8 is one in which the linker comprises one to four rings, the one to four rings being independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0772] B9a. In Example B9a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 and B8a is one in which the linker comprises one to four rings, the one to four rings being independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0773] B10. In Example B10, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3, B8, and B9 is one in which the linker comprises one or two rings, the one or two rings being independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino. In a sub - example of B10, the linker comprises one ring. In a second sub - example of B10, the linker comprises two rings.

[0774] B10a. In Example B10a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3, B8a, and B9a is one in which the linker comprises one or two rings, the one or two rings being independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is 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 sub - example of B10a, the linker comprises one ring. In a second sub - example of B10a, the linker comprises two rings.

[0775] B11. In Example B11, the compound or its pharmaceutically acceptable salt for use in any one of Examples B1A to B3, B8, and B9 is one in which the linker comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0776] B11a. In Example B11a, the compound or its pharmaceutically acceptable salt for use in any one of Examples B1A to B3, B8a, and B9a is one in which the linker comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0777] B12. In Example B12, the compound or its pharmaceutically acceptable salt for use in any one of Examples B4 to B7 is one in which the linker further comprises one or more rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0778] B12a. In Example B12a, the compound or its pharmaceutically acceptable salt for use in any one of Examples B4 to B7 is one in which the linker further comprises one or more rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0779] B13. In Example B13, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B4 to B7 and B12 is one in which the linker further comprises one to four rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino.

[0780] B13a. In Example B13a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B4 to B7 and B12a is one in which the linker further comprises one to four rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino and dialkylamino.

[0781] B14. In Example B14, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B4 to B7 and B12 is one in which the linker further comprises one or two rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino and dialkylamino.

[0782] B14a. In Example B14a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B4 to B7 and B12a is one in which the linker further comprises one or two rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, carboxyl, alkoxycarbonyl, amino, alkylamino and dialkylamino.

[0783] B15. In Example B15, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B4 to B7 and B12 is one in which the linker further comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino.

[0784] B15a. In Example B15a, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B4 to B7 and B12a is one in which the linker further comprises three rings independently selected from cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted with one or two substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino.

[0785] B16. In Example B16, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B8 to B15a is one in which the rings are independently selected from phenylene, heteroarylene, heterocycloalkylene, bridged heterocycloalkylene, and spiroheterocycloalkylene, wherein each ring is optionally substituted as described therein.

[0786] B17. In Example B17, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B12 to B16 is one in which one of the rings is attached to -SO attached to Hy having formula A or A1. 2 -. In a sub - example of Example B17, one of the rings is attached to -SO 2 -, Hy contains a replaceable nitrogen atom, and -SO 2 - is attached to the replaceable nitrogen of Hy having formula A or A1.

[0787] B18. In Example B18, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B12 to B17 is one in which phenylene is attached to -SO attached to Hy having formula A or A1 and is optionally substituted as described therein. In a sub - example of Example B18, phenylene is attached to -SO 2 -, Hy contains a replaceable nitrogen atom, and -SO 2 - is attached to the replaceable nitrogen of Hy having formula A or A1. 2

[0788] ​B19. In Example B19, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B12 to B17 is one in which the heteroarylene is attached to -SO attached to Hy having formula A or A1 2 - and is optionally substituted as described therein. In a sub - example of Example B19, the heteroarylene is attached to -SO 2 -, Hy contains a substitutable nitrogen atom, -SO 2 - is attached to the substitutable nitrogen of Hy having formula A or A1. B20. In Example B20, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B12 to B17 is one in which the heteroannulene is attached to -SO attached to Hy having formula A or A1 2 - and is optionally substituted as described therein. In a sub - example of Example B20, the heteroannulene is attached to -SO 2 -, Hy contains a substitutable nitrogen atom, -SO 2 - is attached to the substitutable nitrogen of Hy having formula A or A1.

[0789] B21. In Example B21, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B12 to B17 is one in which the bridged heteroannulene is attached to -SO2 - attached to Hy having formula A or A1 and is optionally substituted as described therein. In a sub - example of Example B21, the bridged heteroannulene is attached to -SO 2 -, Hy contains a substitutable nitrogen atom, -SO 2 - is attached to the substitutable nitrogen of Hy having formula A or A1.

[0790] B22. In Example B22, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B12 to B17 is one in which the spiroheteroannulene is attached to -SO attached to Hy having formula A or A1 and is optionally substituted as described therein. In a sub - example of Example B22, the spiroheteroannulene is attached to -SO 2 -, Hy contains a substitutable nitrogen atom, -SO 2 -, -SO 2 - is attached to the substitutable nitrogen of Hy having formula A or A1.

[0791] B23. In Example B23, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B8 to B22 is one in which two of the rings are adjacent to each other.

[0792] B23a. In Example B23a, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B23 is one in which the second ring is attached to -SO 2-adjacent to the ring.

[0793] B23b. In Example B23b, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B23a is one in which the ring adjacent to the ring attached to -SO 2 -is selected from heterosubylene, bridged heterosubylene, and spiroheterosubylene, where each ring is optionally substituted as described therein.

[0794] B24. In Example B24, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B8 to B23b is one in which each of cycloalkylene, bridged cycloalkylene, phenylene, heteroarylene, heterosubylene, bridged heterosubylene, and spiroheterosubylene is independently selected from:

[0795]

[0796] where each ring is substituted as defined therein.

[0797] B25. In Example B25, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B8 to B24 is one in which the rings described are independently selected from phenylene, heteroarylene, heterosubylene, bridged heterosubylene, and spiroheterosubylene, and each of phenylene, heteroarylene, heterosubylene, bridged heterosubylene, and spiroheterosubylene is independently selected from:

[0798]

[0799] where each ring is substituted as defined therein.

[0800] B26. In Example B26, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B8 to B25 is one in which each of phenylene, heteroarylene, heterosubylene, bridged heterosubylene, and spiroheterosubylene is independently selected from:

[0801]

[0802]

[0803] where each ring is substituted as defined therein.

[0804] B27. In Example B27, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B8 to B26 is one in which each of phenylene, heteroarylene, heterosubylene, bridged heterosubylene, and spiroheterosubylene is independently selected from:

[0805]

[0806] Each ring is substituted as defined therein.

[0807] B28. In Example B28, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B8 to B27 is one in which each of the phenylenes, heteroarylenes, heterocyclenes, bridged heterocyclenes and spiroheterocyclenes is independently selected from:

[0808]

[0809] Each ring is substituted as defined therein.

[0810] B29. In Example B29, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B17 to B28 is one in which the phenylene, heteroarylene or heterocyclene is attached to -SO 2 - and are respectively: Each ring is substituted as defined therein. (For clarity, the bond on the right side of the ring is attached to -SO 2 -). In a sub-example of Example B29, attached to -SO 2 -, Hy contains a substitutable nitrogen atom, and -SO 2 - is attached to the substitutable nitrogen of Hy having formula A or A1.

[0811] B30. In Example B30, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B17 to B29 is one in which is attached to -SO 2 - attached to Hy having formula A or A1 and is substituted as defined therein. In a sub-example of Example B30, is attached to -SO 2 -, Hy contains a substitutable nitrogen atom, and -SO 2 - is attached to the substitutable nitrogen of Hy having formula A or A1.

[0812] B31. In Example B31, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B17 to B29 is one in which is attached to -SO 2 - attached to Hy having formula A or A1 and is substituted as defined therein. In a sub-example of Example B31, is attached to -SO 2 -, Hy contains a substitutable nitrogen atom, and -SO 2 - is attached to the substitutable nitrogen of Hy having formula A or A1.

[0813] B32. In Example B32, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B17 to B29 is one in which attached to -SO attached to Hy having formula A or A1 2 - and substituted as defined therein. In a sub - example of Example B29, attached to -SO 2 -, Hy contains a replaceable nitrogen atom, and -SO 2 - is attached to the replaceable nitrogen of Hy having formula A or A1.

[0814] B33. In Example B33, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B23b to B29 is one in which attached to SO attached to Hy having formula A or A1 2 . In a sub - example of Example B33, attached to -SO 2 -, Hy contains a replaceable nitrogen atom, and -SO 2 - is attached to the replaceable nitrogen of Hy having formula A or A1.

[0815] B34. In Example B34, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 is one in which the linker comprises one or more groups independently selected from the following: ether, polyether, thioether, amido, sulfonamido, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, -NH-, -N(alkyl)-, sulfinyl, ureido, thioureido, bicyclic hetero - sub - ring and fused hetero - sub - ring; wherein the bicyclic hetero - sub - ring and the fused hetero - sub - ring are optionally substituted with one, two or three substituents independently selected from the following: deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, amino, alkylamino and dialkylamino, and each alkylene is optionally substituted with one or two substituents, one of these substituents being deuterium and the other of these two substituents being deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclic, aryl or monocyclic heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and monocyclic heteroaryl are optionally substituted with one or two substituents independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano. In one embodiment, the linker comprises five or six independently selected groups.

[0816] B35. In Example B35, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 and B34 is one in which the linker contains one to four groups independently selected from those groups described in Example B34. In one embodiment, the linker contains four independently selected groups.

[0817] B36. In Example B36, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 and B34 is one in which the linker contains one to three groups independently selected from those groups described in Example B34. In one embodiment, the linker contains three independently selected groups.

[0818] B37. In Example B37, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 and B34 is one in which the linker contains one or two groups independently selected from those groups described in Example B34. In one embodiment, the linker contains two independently selected groups. In one embodiment, the linker contains one group.

[0819] B38. In Example B38, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B4 to B33 is one in which the linker further contains one or more groups independently selected from the following: ether, polyether, thioether, -NH-, -N(alkyl)-, amido, sulfonamido, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, sulfinyl, ureido, thioureido, bicyclic hetero-subcyclic group, and fused hetero-subcyclic group; wherein the bicyclic hetero-subcyclic group and the fused hetero-subcyclic group are optionally substituted by one, two or three substituents independently selected from the following: deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxy, cyano, amino, alkylamino and dialkylamino, and each alkylene is optionally substituted by one or two substituents, wherein one of these substituents is deuterium and the other of the two substituents is deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclic group, aryl or monocyclic heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl and monocyclic heteroaryl are optionally substituted by one or two substituents independently selected from alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0820] B39. In Example B39, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B38 is one in which the linker contains one to four groups independently selected from those groups described in Example B38. In one embodiment, the linker contains four independently selected groups.

[0821] B40. In Example B40, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B38 and B39 is one in which the linker comprises one to three groups independently selected from those groups described in Example B38. In one embodiment, the linker comprises three independently selected groups.

[0822] B41. In Example B41, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B38 to B40 is one in which the linker comprises one or two groups independently selected from those groups described in Example B38. In one embodiment, the linker comprises two independently selected groups.

[0823] B42. In Example B42, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B38 to B41 is one in which the linker comprises one group selected from those groups described in Example B38.

[0824] B43. In Example B43, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B34 to B42 is one in which each alkylene group is unsubstituted.

[0825] B44. In Example B44, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B34 to B42 is one in which the one or two, preferably one, alkylene group as defined therein is substituted.

[0826] B45. In Example B45, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B34 to B44 is one in which the one or more groups are independently selected from ether, polyether, -NH-, -N(alkyl)-, amido, sulfonamido, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-, ureido, thioureido, bicyclic hetero-subcyclic group, and fused hetero-subcyclic group, where the bicyclic hetero-subcyclic group and the fused hetero-subcyclic group.

[0827] B46. In Example B46, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B34 to B45 is one in which the one or more groups are independently selected from: ether, polyether, -NH-, -N(alkyl)-, amido, sulfonamido, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O, -OC(O), bicyclic hetero-subcyclic group, and fused hetero-subcyclic group, where the bicyclic hetero-subcyclic group and the fused hetero-subcyclic group.

[0828] B47. In Example B47, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B34 to B46 is one or more of the groups therein independently selected from ether, polyether, -NH-, -N(alkyl)-, amido, sulfonamido, alkylene, alkenylene, alkynylene, carbonyl, -C(O)O, -OC(O), and each alkylene is substituted or unsubstituted as described therein.

[0829] B48. In Example B48, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B34 to B47 is one or more of the groups therein independently selected from ether, polyether, -NH-, -N(methyl)-, -NHC(O)-, -C(O)NH-, -N(methyl)C(O)-, -C(O)N(methyl)-, -NHSO 2 -, -SO 2 NH-, -N(methyl)SO 2 -, -SO 2 N(methyl)-, -NHC(O)NH-, -NHSO 2 NH-, methylene, ethylene, propylene, butylene, pentylene, vinyl, propenyl, acetylene, propynyl, carbonyl, -C(O)O- and -OC(O)-.

[0830] B49. In Example B49, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B34 to B48 is one or more of the groups therein independently selected from ether, -NH-, -N(methyl)-, methylene, ethylene, propylene, butylene, pentylene, vinyl, propenyl, acetylene, propynyl and carbonyl.

[0831] B50. In Example B50, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B34 to B49 is one or more of the groups therein independently selected from ether, -NH-, -N(methyl)-, methylene, ethylene, propylene, butylene, pentylene, vinyl, propenyl, acetylene and propynyl.

[0832] B51. In Example B51, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B1A to B3 is one in which the linker comprises one or more of the groups or consists of one or more of the groups, preferably comprises one to seven groups or consists of one to seven groups, which are independently selected from those groups disclosed in Table A:

[0833]

[0834]

[0835] and its isomers;

[0836] wherein 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, and each alkylene is optionally substituted with one or two substituents, wherein one of these substituents is deuterium and the other of these two substituents is deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocycloalkyl, aryl or monocyclic heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano;

[0837] wherein the isomers of the groups in Table A can be cis and / or trans isomers, and / or R and / or S isomers, and / or other geometric isomers where applicable;

[0838] wherein the left side of the group in Table A is ultimately attached to the 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 the E3 ubiquitin ligase ligand.

[0839] B51a. In Example B51a, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 is one in which the linker comprises one or more groups or consists of one or more groups, preferably one to seven groups or consists of one to seven groups, which groups are independently selected from those disclosed in Table A:

[0840]

[0841]

[0842] and its isomers;

[0843] wherein 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, and each alkylene is optionally substituted with one or two substituents, wherein one of these substituents is deuterium and the other of these two substituents is deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocycloalkyl, aryl or monocyclic heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano;

[0844] The isomers of the groups in Table A can be cis- and / or trans-isomers, and / or R- and / or S-isomers, and / or other geometric isomers where applicable;

[0845] where the left side of the group in Table A is finally attached to the E3 ubiquitin ligase ligand, and the right side of the group in Table A is finally attached to Hy; or alternatively, the left side of the group in Table A is finally attached to Hy, and the right side of the group in Table A is finally attached to the E3 ubiquitin ligase ligand.

[0846] B52. In Example B52, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51 is one in which the linker comprises or consists of a group selected from those disclosed in Table A.

[0847] B52-1. In Example B52-1, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51a is one in which the linker comprises or consists of a group selected from those disclosed in Table A.

[0848] B52a. In Example B52a, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51 is one in which the linker comprises or consists of two groups independently selected from those disclosed in Table A.

[0849] B52a-1. In Example B52a-1, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51a is one in which the linker comprises or consists of two groups independently selected from those disclosed in Table A.

[0850] B53. In Example B53, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51 is one in which the linker comprises or consists of three groups independently selected from those disclosed in Table A.

[0851] B53a. In Example B53a, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51a is one in which the linker comprises or consists of three groups independently selected from those disclosed in Table A.

[0852] B54. In Example B54, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51 is one in which the linker comprises or consists of four groups independently selected from those disclosed in Table A.

[0853] B54a. In Example B54a, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51a is one in which the linker comprises or consists of four groups independently selected from those disclosed in Table A.

[0854] B55. In Example B55, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51 is one in which the linker comprises or consists of five groups independently selected from those groups disclosed in Table A.

[0855] B55a. In Example B55a, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B51a is one in which the linker comprises or consists of five groups independently selected from those groups disclosed in Table A.

[0856] B56. In Example B56, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B51 to B55a is one in which at least one of these groups is -SO 2 -.

[0857] B57. In Example B57, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B51 to B56 is one in which one of these groups is -SO 2 -.

[0858] B58. In Example B58, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B56 or B57 is one in which -SO 2 - is attached to Hy as described in any one of Examples B1A to B3. In a sub - example, Hy contains a replaceable nitrogen, and -SO 2 - is attached to the replaceable nitrogen of Hy as described in any one of Examples B1A to B3.

[0859] B59. In Example B59, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B51 to B58 is one in which one, two or three of these groups, preferably two or three of these groups, are rings independently selected from those rings disclosed in Table A.

[0860] B60. In Example B60, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B59 is one in which one of these rings (referred to as ring (ia)) is attached to -SO 2 -, preferably ring (ia) is: More preferably wherein ring (ia) is optionally substituted as defined, preferably ring (ia) is: In a sub - example, ring (ia) is attached to -SO 2 -, Hy contains a replaceable nitrogen atom, and -SO 2- Attached to the replaceable nitrogen of Hy having formula A or A1, preferably the ring (ia) is: More preferably Wherein the ring (ia) is optionally substituted as defined, preferably the ring (ia) is:

[0861] B61. In Example B61, the compound or its pharmaceutically acceptable salt for use as described in Example B60 and the examples therein is one in which the second ring (referred to herein as ring (ib)) (when the linker has two or more rings) is attached to the ring attached to -SO 2 - (Attached to Hy) attached ring. In a sub - embodiment, the ring (ib) is attached to the ring attached to -SO 2 - attached ring, Hy contains a replaceable nitrogen atom, and -SO 2 - is attached to the replaceable nitrogen of Hy having formula A or A1.

[0862] B62. In Example B62, the compound or its pharmaceutically acceptable salt for use as described in Example B61 is one in which the second ring (ib) is selected from the group consisting of:

[0863] Where each ring (ib) is substituted as described therein.

[0864] B63. In Example B63, the compound or its pharmaceutically acceptable salt for use as described in Examples B51 to B62 is one in which one of these groups is:

[0865]

[0866] B64. In Example B64, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B1A to B3 is one in which the linker contains a group selected from:

[0867]

[0868]

[0869]

[0870] Wherein, in the above structures, the right - hand side of the linker is attached to Hy. In a sub - embodiment, Hy contains a replaceable nitrogen, and the right - hand side of the linker is attached to the replaceable nitrogen of Hy.

[0871] B65. In Example B65, the compound or its pharmaceutically acceptable salt for use as described in any one of Examples B1A to B3 is one in which the linker is selected from:

[0872]

[0873]

[0874]

[0875] Among them, in the above structure, the right side of the linker is attached to Hy and the left side is attached to the E3 ubiquitin ligase ligand. In a sub - embodiment, Hy contains a replaceable nitrogen, and the right side of the linker is attached to the replaceable nitrogen of Hy.

[0876] B66. In Example B66, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B1A to B3 and B65 is one in which the linker is selected from:

[0877]

[0878] In a first sub - embodiment, in the above structure, the right side of the linker is attached to Hy.

[0879] In a second sub - embodiment, Hy contains a replaceable nitrogen, and the right side of the linker is attached to the replaceable nitrogen of Hy.

[0880] B67. In Example B67, the compound or a pharmaceutically acceptable salt thereof for use as described in any one of Examples B3 to B66 is one in which the E3 ubiquitin ligase ligand is a CBRN or VHL ligase ligand.

[0881] B68 to B138. In Examples B68 to B138, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B67 is one in which the E3 ubiquitin ligase ligand is as disclosed in Examples A40 to A110 respectively. B139. In Example B139, the compound for use as described in any one of Examples B1A to B138 is one in which Hy is a cycloalkylene, arylene, heteroarylene, heterocycloalkylene, bicyclic heterocycloalkylene, spiroheterocycloalkylene, bridged heterocycloalkylene or fused heterocycloalkylene, where each of the above rings is independently substituted by R a 、R b and R c ; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt thereof.

[0882] B140 to B157. In Examples B140 to B157, the compound or a pharmaceutically acceptable salt thereof for use as described in Example B139 is one in which Hy is as disclosed in Examples A25 - A39b respectively.

[0883] Example C:

[0884] In Examples C1 to C279, the present disclosure includes:

[0885] C1. In Example C1, there is provided a compound having formula (Ia) or a pharmaceutically acceptable salt thereof as defined in the fourth embodiment of the Summary of the Invention.

[0886] C2. In Example C2, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 is one in which R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano or cycloalkyl, wherein the cycloalkyl is substituted with one to three halo groups.

[0887] C3. In Example C3, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C2 is one in which R 1 is halo, haloalkyl or haloalkoxy.

[0888] C4. In Example C4, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C3 is one in which R 1 is halo.

[0889] C5. In Example C5, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C3 is one in which R 1 is haloalkyl.

[0890] C6. In Example C6, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C3 is one in which R 1 is haloalkoxy.

[0891] C7. In Example C7, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C6 is one in which R 1 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.

[0892] C8. In Example C8, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C7 is one in which R 1 is chlorine, bromine, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.

[0893] C9. In Example C9, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C4, C7 and C8 is one in which R 1 is chlorine or bromine.

[0894] C10. In Example C10, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C3, C5, C7, and C8 is one in which R 1 is difluoromethyl or trifluoromethyl.

[0895] C11. In Example C11, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C3, C5, C7, C8, and C10 is one in which R 1 is trifluoromethyl.

[0896] C12. In Example C12, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C2 is one in which R 1 is alkyl, alkenyl or alkynyl.

[0897] C13. In Example C13, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C2 or C12 is one in which R 1 is methyl, ethyl, propyl, vinyl, propenyl, ethynyl or propynyl.

[0898] C14. In Example C14, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C2, C12 or C13 is one in which R 1 is methyl, ethyl or propyl.

[0899] C15. In Example C15, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C2, C12 or C13 is one in which R 1 is vinyl, propenyl, ethynyl or propynyl.

[0900] C16. In Example C16, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C2 is one in which R 1 is alkoxy.

[0901] C17. In Example 17, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C2 or C16 is one in which R 1 is methoxy, ethoxy or propoxy.

[0902] C18. In Example C18, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C2 is one in which R 1 is aryloxy, such as phenoxy.

[0903] C19. In Example C19, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C2 is one in which R 1 is cyano.

[0904] C20. In Example C20, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C2 is one in which R 1 is cycloalkyl.

[0905] C21. In Example C21, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C2 or C20 is one in which R 1 is cyclopropyl.

[0906] C22. In Example C22, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C2 is one in which R 1 is cycloalkyl substituted with one to three independently selected halogen substituents (such as fluorocyclopropyl or difluorocyclopropyl).

[0907] C23. In Example C23, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 is one in which R 1 is 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, heterocyclic group, heterocyclic group alkyl, heterocyclic group oxy, fused heterocyclic group, fused heterocyclic group oxy or fused heterocyclic group alkyl, wherein the cycloalkyl itself or as part of cycloalkoxy and cycloalkylalkyl, the aryl itself or as part of aralkyl and aryloxy, the heteroaryl itself or as part of heteroaralkyl and heteroaryloxy, the heterocyclic group itself or as part of heterocyclic group alkyl and heterocyclic group oxy, the bridged cycloalkyl alone or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and the fused heterocyclic group itself or as part of fused heterocyclic group alkyl and fused heterocyclic group oxy are substituted by one, two or three substituents independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0908] C24. In Example C24, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is aryl, heteroaryl, heterocyclic group, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF 3 、-SF5 , fused heterocyclic group, bridged cycloalkyl group, cycloalkylalkyl group, heterocyclicalkyl group, aralkyl group, aminoalkoxy group, alkoxycarbonyl group, alkylcarbonylamino group, acyl group, azidocarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, substituted ureido group, aminosulfonyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group and substituted sulfonyl group; wherein the aryl group alone and in the aralkyl group, the heteroaryl group alone and in the heteroaryloxy group, the heterocyclic group, fused heterocyclic group, bridged cycloalkyl group alone and in the cycloalkylalkyl group, and the heterocyclic group alone and in the heterocyclicalkyl group are substituted by one, two or three substituents independently selected from hydrogen, alkyl group, alkoxy group, halogenated group, haloalkyl group, haloalkoxy group and cyano group.

[0909] C25. In Example C25, the compound as described in Example C1, C23 or C24 or a pharmaceutically acceptable salt thereof is one in which R 1 is phenyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, triazolyl group, tetrahydrofuranyl group, tetrahydropyranyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, piperazinyl group, cyanomethyl group, cyanoethyl group, methoxymethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 2,3-dihydrobenzofuranyl group, chromanyl group, 1,4-benzodioxanyl group, 2,3-dihydrofuro[3,2-c]pyridine, 2,3-dihydrofuro[2,3-c]pyridine or 1,2,3,4-tetrahydroquinolinyl group; wherein each of these rings is substituted by hydrogen, alkyl group, alkoxy group, halogenated group, haloalkyl group, haloalkoxy group or cyano group.

[0910] C26. In Example C26, the compound as described in Example C1 or C23 or a pharmaceutically acceptable salt thereof is one in which R 1 is aryl group, heterocyclic group, cyanoalkyl group, alkoxyalkyl group, aminoalkyl group, alkylaminoalkyl group, dialkylaminoalkyl group, heteroaryloxy group, cyanoalkoxy group, alkylthio group, amino group, alkylamino group, dialkylamino group, -SCF 3 or -SF 5 ; wherein each of these rings is substituted by hydrogen, alkyl group, alkoxy group, halogenated group, haloalkyl group, haloalkoxy group or cyano group.

[0911] C27. In Example C27, the compound as described in Example C1, C23 or C26 or a pharmaceutically acceptable salt thereof is one in which R 1is 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.

[0912] C28. In Example C28, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is alkylthio (such as methylthio).

[0913] C29. In Example C29, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is pentafluorothio.

[0914] C30. In Example C30, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is haloalkylthio (such as trifluoromethylthio).

[0915] C31. In Example C31, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is amino.

[0916] C32. In Example C32, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is alkylamino (such as methylamino).

[0917] C33. In Example C33, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is dialkylamino (such as dimethylamino).

[0918] C34. In Example C34, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a cycloalkyl substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0919] C35. In Example C35, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C34 is one in which R 1 is cyclopropyl, cyclobutyl or cyclopentyl, each ring being substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0920] C36. In Example C36, the compound as described in Example C1 or C23 or a pharmaceutically acceptable salt thereof is one in which R 1 is cycloalkyloxy, wherein the cycloalkyl is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0921] C37. In Example C37, the compound as described in Example C1, C23 or C36 or a pharmaceutically acceptable salt thereof is one in which R 1 is cyclopropyloxy, cyclobutyloxy or cyclopentyloxy, and each cycloalkyl ring of the cycloalkyloxy is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0922] C38. In Example C38, the compound as described in Example C1 or C23 or a pharmaceutically acceptable salt thereof is one in which 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.

[0923] C39. In Example C39, the compound as described in Example C1, C23 or C38 or a pharmaceutically acceptable salt thereof is one in which R 1 is cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl, and the ring of the cycloalkylalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0924] C40. In Example C40, the compound as described in Example C1 or C23 or a pharmaceutically acceptable salt thereof is one in which R 1 is 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.

[0925] C41. In Example C41, the compound as described in Example C1, C23 or C40 or a pharmaceutically acceptable salt thereof is one in which R 1 is 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, fluorine and cyano.

[0926] C42. In Example C42, the compound as described in Example C1 or C23 or a pharmaceutically acceptable salt thereof is one in which R 1is a bridged cycloalkyloxy group (such as bicyclo[1.1.1]pentan-1-yloxy or bicyclo[2.2.1]heptyloxy), wherein the bridged cycloalkyl group in the bridged cycloalkyloxy group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0927] C43. In Example C43, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C42 is one wherein R 1 is a bridged cycloalkyloxy group (such as bicyclo[1.1.1]pentan-1-yloxy or bicyclo[2.2.1]heptyloxy), wherein the bridged cycloalkyl group of the bridged cycloalkyloxy group is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0928] C44. In Example C44, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one wherein R 1 is a bridged cycloalkylalkyl group (such as bicyclo[1.1.1]pentan-1-ylmethyl or bicyclo[2.2.1]heptylmethyl), wherein the bridged cycloalkyl group in the bridged cycloalkylalkyl group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0929] C45. In Example C45, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C44 is one wherein R 1 is a bridged cycloalkylalkyl group (such as bicyclo[1.1.1]pentan-1-ylmethyl or bicyclo[2.2.1]heptylmethyl), wherein the bridged cycloalkyl group of the bridged cycloalkylalkyl group is substituted with one or two substituents independently selected from hydrogen, methyl, fluorine and cyano.

[0930] C46. In Example C46, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one wherein R 1 is a cyanoalkyl group, such as cyanomethyl or cyanoethyl.

[0931] C47. In Example C47, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one wherein R 1 is a cyanoalkoxy group (such as cyanomethoxy or cyanoethoxy).

[0932] C48. In Example C48, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one wherein R 1 is an alkoxyalkyl group (such as methoxymethyl).

[0933] C49. In Example C49, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is aminoalkyl (such as aminomethyl).

[0934] C50. In Example C50, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is aminoalkoxy, for example, R 1 is aminomethyloxy.

[0935] C51. In Example C51, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is alkylaminoalkyl (for example, R 1 is methylaminomethyl).

[0936] C52. In Example C52, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is dialkylaminoalkyl (for example, R 1 is dimethylaminomethyl).

[0937] C53. In Example C53, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is alkylaminoalkoxy (for example, R 1 is methylaminomethyloxy).

[0938] C54. In Example C54, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is dialkylaminoalkoxy (for example, R 1 is dimethylaminomethyloxy).

[0939] C55. In Example C55, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is acyl.

[0940] C55a. In Example C55a, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C55 is one in which R 1 is alkylcarbonyl (such as methylcarbonyl).

[0941] C56. In Example C56, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is azidocarbonyl.

[0942] C57. In Example C57, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an alkoxycarbonyl (such as methoxycarbonyl or ethoxycarbonyl).

[0943] C58. In Example C58, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an alkylcarbonylamino.

[0944] C59. In Example C59, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an aminocarbonyl.

[0945] C60. In Example C60, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an alkylaminocarbonyl (such as methylaminocarbonyl).

[0946] C61. In Example C61, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a dialkylaminocarbonyl (such as dimethylaminocarbonyl).

[0947] C62. In Example C62, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an aminosulfonyl.

[0948] C63. In Example C63, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an alkylaminosulfonyl (such as methylaminosulfonyl).

[0949] C64. In Example C64, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a dialkylaminosulfonyl (such as dimethylaminosulfonyl).

[0950] C65. In Example C65, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a substituted sulfonyl (such as methylsulfonyl).

[0951] C66. In Example C66, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a substituted sulfinyl.

[0952] C67. In Example C67, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a substituted ureido group.

[0953] C68. In Example C68, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an aryl group substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0954] C69. In Example C69, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C68 is one in which R 1 is a phenyl group substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0955] C69a. In Example C69a, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23, C68 or C69 is one in which R 1 is a phenyl group substituted with one, two or three substituents independently selected from: hydrogen, methyl, fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0956] C70. In Example C70, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is an aralkyl group (such as benzyl), in which the aryl group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0957] C71. In Example C71, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C70 is one in which R 1 is benzyl, in which the phenyl group in benzyl is substituted with one, two or three substituents independently selected from: hydrogen, methyl, fluorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0958] C72. In Example C72, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a heteroaryl group, in which the heteroaryl group is substituted with one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0959] C73. In Example C73, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C72 is one in which R 1 is pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl, each of which is substituted by one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0960] C73a. In Example C73a, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C72 is one in which R 1 is pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl, each of which is substituted by one substituent selected from hydrogen and alkyl.

[0961] C74. In Example C74, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is heteroarylalkyl, wherein the heteroaryl in the heteroarylalkyl is substituted by one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0962] C74a. In Example C74a, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C74 is one in which R 1 the heteroaryl in the heteroarylalkyl of which is pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl, each of which is substituted by one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0963] C75. In Example C75, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is heteroaryloxy, wherein the heteroaryl is substituted by one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0964] C76. In Example C76, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C75 is one in which R 1 the heteroaryl in the heteroaryloxy of which is pyrazolyl, imidazolyl, oxazolyl, thiazolyl or triazolyl, each of which is substituted by one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0965] C77. In Example C77, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1is a heterocyclic group, wherein the heterocyclic group is substituted with one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0966] C78. In Example C78, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C77 is one wherein R 1 is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the piperazinyl is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0967] C79. In Example C79, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one wherein R 1 is heterocyclic alkyl, wherein the heterocyclic group is substituted with one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0968] C80. In Example C80, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C79 is one wherein R 1 the heterocyclic group in the heterocyclic alkyl of is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the piperazinyl is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0969] C81. In Example C81, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one wherein R 1 is heterocyclic oxy, wherein the heterocyclic group is substituted with one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0970] C82. In Example C82, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C81 is one wherein R 1 the heterocyclic group in the heterocyclic oxy of is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl, wherein the piperazinyl is optionally substituted with alkyl, alkoxy, halogen, haloalkyl, haloalkoxy or cyano.

[0971] C83. In Example C83, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one wherein R 1 is a fused heterocyclic group substituted with one, two or three substituents independently selected from the following: hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano.

[0972] C84. In Example C84, the compound or a pharmaceutically acceptable salt thereof as described in Example C1, C23 or C83 is one in which R 1 is a fused heterocyclic group selected from: 2,3-dihydrobenzofuranyl, chromanyl, 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 by one, two or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0973] C85. In Example C85, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a fused heterocyclic group oxy, in which the heterocyclic group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0974] C86. In Example C86, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 or C23 is one in which R 1 is a fused heterocyclic group alkyl, in which the heterocyclic group is substituted by one, two or three substituents independently selected from: hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy and cyano.

[0975] C87. In Example C87, the compound or a pharmaceutically acceptable salt thereof as described in Example C1 and C23 to C86 is one in which R 1 is selected from:

[0976]

[0977]

[0978] and its isomers (R and / or S isomers, and / or geometric isomers).

[0979] C88. In Example C88, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C87 is one in which R 2 and R 2a are hydrogen.

[0980] C89. In Example C89, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C87 is one in which one of R 2 and R 2a is deuterium and the other of R 2 and R 2a is hydrogen, or R 2 and R2a Both are deuterium.

[0981] C90. In Example C90, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C89 is one in which Hy is a hetero-subcyclic group, a phenylene group, a spiro hetero-subcyclic group, a bridged hetero-subcyclic group or a cycloalkyl group, wherein each of the above rings is substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[0982] C91. In Example C91, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 is one in which Hy is a hetero-subcyclic group substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[0983] C92. In Example C92, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C91 is one in which the hetero-subcyclic group of Hy is pyrrolidine-1,3-diyl or piperidine-1,4-diyl, where Hy is substituted by R a , R b and R c , where R a and R b are independently hydrogen, deuterium, methyl, fluorine, methoxy or hydroxy, R c is hydrogen, and L is attached to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

[0984] C93. In Example C93, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C92 is one in which the hetero-subcyclic group of Hy is:[[]]

[0985]

[0986] where the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0987] C94. In Example C94, the compound or a pharmaceutically acceptable salt thereof as described in any one of C1 to C93 is one in which the hetero-subcyclic group of Hy is:[[]]

[0988]

[0989] wherein the N atom of the pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to L.

[0990] C95. In Example C95, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C94 is one wherein the hetero-subcyclic group of Hy is:

[0991]

[0992] wherein the N atom of the piperidine-1,4-diyl ring is attached to L.

[0993] C96. In Example C96, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 is one wherein Hy is a bridged hetero-subcyclic group independently substituted by R a , R b and R c : hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy and cyano.

[0994] C97. In Example C97, for the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 and C96, the bridged hetero-subcyclic group of Hy is a ring having the formula:

[0995]

[0996] and each ring is substituted by R a , R b and R c , wherein R c is hydrogen, and L is attached to the nitrogen atom of each ring.

[0997] C98. In Example C98, the compound or a pharmaceutically acceptable salt thereof as described in Example C96 or C97 is one wherein R a and R b are independently hydrogen, deuterium, methyl, fluoro, methoxy or hydroxy.

[0998] C99. In Example C99, the compound or a pharmaceutically acceptable salt thereof as described in Example C96, C97 or C98 is one wherein R b is hydrogen.

[0999] C100. In Example C100, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 is one wherein Hy is substituted by R a , R b and R cA substituted cycloalkylene, wherein R a is deuterium, methyl, fluorine, methoxy or hydroxy, and R b and R c are hydrogen.

[1000] C101. In Example C101, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 and C100 is one in which the cycloalkylene of Hy is cyclohexylene.

[1001] C102. In Example C102, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90, C100 and C101 is one in which the cycloalkylene of Hy is wherein represents a bond to NH, and represents a bond to L.

[1002] C103. In Example C103, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 is one in which Hy is an arylene, wherein the arylene is a phenylene substituted by R a , R b and R c , wherein R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[1003] C104. In Example C104, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 is one in which Hy is a spiroheterocycloalkylene (such as 2-azaspiro[3.3]heptan-2-yl) substituted by R a , R b and R c , wherein R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[1004] C105. In Example C105, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C90 and C103 is one in which the phenylene of Hy is 1,4-phenylene according to the structure , wherein represents a bond to NH, and represents a bond to L.

[1005] C106. In Example C106, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C89 is one in which Hy is a fused hetero-subcyclic group substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[1006] C107. In Example C107, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C89 is one in which Hy is a bicyclic hetero-subcyclic group substituted by R a , R b and R c , where R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano, and R c is hydrogen.

[1007] C108. In Example C108, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C107 is one in which the degron is an E3 ubiquitin ligase ligand having formula (i) or (ii).

[1008] C109. In Example C109, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 is one in which the degron is an E3 ubiquitin ligase ligand having formula (i):

[1009]

[1010] C110. In Example C110, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C109 is one in which ring A of the E3 ubiquitin ligase ligand having formula (i) is a group having formula (a):

[1011]

[1012] C111. In Example C111, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C110 is one in which R 4 and R 5 are independently hydrogen or alkyl.

[1013] C112. In Example C112, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C111 is one in which R 4 and R 5is hydrogen.

[1014] C113. In Example C113, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C111 is one in which R 4 is hydrogen and R 5 is methyl.

[1015] C114. In Example C114, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C110 is one in which R 4 and R 5 together with the carbon to which they are attached form >C=O.

[1016] C115. In Example C115, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C109 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is a group having formula (b):

[1017]

[1018] C116. In Example C116, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C109 and C115 is one in which R 6 is hydrogen.

[1019] C117. In Example C117, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C109 and C115, wherein R 6 is an alkyl group, such as methyl.

[1020] C118. In Example C118, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C109 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is a group having formula (c):

[1021]

[1022] C119. In Example C119, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1023]

[1024] C120. In Example C120, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117 and C119 is one in which Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1025]

[1026] C121. In Example C121, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117 and C119 is such that Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1027]

[1028] C122. In Example C122, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117 and C119 to C121 is such that Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1029]

[1030] C123. In Example C123, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117, C119 and C121 is such that Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1031]

[1032] C124. In Example C124, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117 and C119 to C122 is such that Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1033]

[1034] C125. In Example C125, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C110, C114 and C119 to C124 is such that Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1035]

[1036] C126. In Example C126, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C110, C114 and C119 to C124 is such that Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1037]

[1038] C127. In Example C127, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C112 and C119 to C124 is such that Ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[1039]

[1040] 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 wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[1041]

[1042] 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 wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[1043]

[1044] 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 wherein Ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[1045]

[1046] C131. In embodiment C131, the compound as described in any one of embodiments C1 to C117 and C119 to C127 or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl and haloalkoxy. aa , R bb , R cc and / or R dd When not specifically indicated in the structures of formulae (i) and (ii), respectively, they are hydrogen.

[1047] C132. In embodiment C132, the compound or pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C117 and C119 to C127 is wherein R aa , R bb , R cc and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl and cyano.

[1048] C133. In Example C133, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117, C119 to C127, C131, and C132 is one in which R aa , R bb , R cc , and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluorine, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

[1049] C134. In Example C134, the compound or a pharmaceutically acceptable salt thereof as described in any one of C1 to C117, C119 to C127, and C131 to C133 is one in which R aa , R bb , R cc , and R dd are independently selected from hydrogen and methyl.

[1050] C135. In Example C135, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117, C119 to C127, and C131 to C133 is one in which R aa , R bb , R cc , and R dd are independently selected from hydrogen and methoxy.

[1051] C136. In Example C136, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117, C119 to C127, and C131 to C133 is one in which Raa, R bb , R cc , and R dd are independently selected from hydrogen and fluorine.

[1052] C137. In Example C137, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117, C119 to C127, and C131 to C133 is one in which R aa , R bb , R cc , and R dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.

[1053] C138. In Example C138, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117, C119 to C127, C131, and C133 is one in which R aa , R bb , R cc , and R dd are independently selected from hydrogen and trifluoromethoxy.

[1054] C139. In Example C139, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C117, C119 to C127, and C131 to C133 is one in which R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluorine, and trifluoromethyl.

[1055] C140. In Example C140, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 is one in which the degron is an E3 ubiquitin ligase ligand having formula (ii):

[1056]

[1057] C141. In Example C141, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 is one in which Y a is CH.

[1058] C142. In Example C142, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 is one in which Y a is N.

[1059] C143. In Example C143, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C142 is one in which Z a is a bond, -NH-, -O-, or -NHC(O)-.

[1060] C144. In Example C144, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C143 is one in which Z a is a bond, -NH-, or -NHC(O)-.

[1061] C145. In Example C145, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C144 is one in which Z a is a bond.

[1062] C146. In Example C146, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C144 is one in which Z a is -NH- or -NHC(O)-.

[1063] C147. In Example C147, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108, C140 to C144 and C146 is one in which Z a is -NH-.

[1064] C148. In Example C148, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108, C140 to C144 and C146 is one in which Z a is -NHC(O)-.

[1065] C149. In Example C149, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C148 is one in which ring B is a phenylene group substituted by R ee and R ff Substituted phenylene group.

[1066] C150. In Example C150, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C148 is one in which ring B is a cyclic imino group substituted by R ee and R ff Substituted cyclic imino group.

[1067] C151. In Example C151, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C148 is one in which ring B is a 5- or 6-membered monocyclic heteroarylene group or a 9- or 10-membered fused bicyclic heteroarylene group, wherein each heteroarylene ring contains one to three nitrogen ring atoms, and each ring is substituted by R ee and R ff Substituted.

[1068] C152. In Example C152, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108, C140 to C148 and C151 is one in which ring B is a 5- or 6-membered monocyclic heteroarylene group containing one or two nitrogen ring atoms substituted by R ee and R ff Substituted 5- or 6-membered monocyclic heteroarylene group.

[1069] C153. In Example C153, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108, C140 to C148 and C151 is one in which ring B is a 9- or 10-membered fused bicyclic heteroarylene group containing one to three nitrogen ring atoms (and no other heteroatoms) and substituted by R ee and R ff Substituted 9- or 10-membered fused bicyclic heteroarylene group.

[1070] C154. In Example C154, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108, C140 to C148, C151 and C153 is a 9- or 10-membered fused bicyclic heteroarylene in which ring B contains one or two nitrogen ring atoms and is substituted by R ee and R ff .

[1071] C155. In Example C155, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C154 is such that the E3 ubiquitin ligase ligand having formula (ii) is:

[1072]

[1073] C156. In Example C156, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C155 is such that the E3 ubiquitin ligase ligand having formula (ii) is:

[1074]

[1075]

[1076] wherein ring B is a cyclic imino group.

[1077] C157. In Example C157, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C156 is such that the E3 ubiquitin ligase ligand having formula (ii) is:

[1078]

[1079] wherein ring B is a cyclic imino group,

[1080] C158. In Example C158, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C157 is such that the E3 ubiquitin ligase ligand having formula (ii) is

[1081] C159. In Example C159, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C157 is such that the E3 ubiquitin ligase ligand having formula (ii) is:

[1082]

[1083]

[1084] C160. In Example C160, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108, C140 to C157, and C159 is such that the E3 ubiquitin ligase ligand having formula (ii) is

[1085] C161. In Example C161, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C160 is such that each R ee and R ff is independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy.

[1086] C162. In Example C162, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C160 is such that R ee and R ff is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.

[1087] C163. In Example C163, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C162 is such that R ee and R ff is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.

[1088] C164. In Example C164, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is such that R ee and R ff is independently selected from hydrogen, methyl, ethyl, and isopropyl.

[1089] C165. In Example C165, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is such that R ee and R ff is independently selected from hydrogen and methoxy.

[1090] C166. In Example C166, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is such that R ee and R ff is independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.

[1091] C167. In Example C167, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is one in which R ee and R ff one of them is hydrogen or fluorine, and R ee and R ff the other one is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethyl.

[1092] C168. In Example C168, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108, C140 to C161 and C163 is one in which R ee and R ff are independently selected from hydrogen, difluoromethoxy and trifluoromethoxy.

[1093] C169. In Example C169, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is one in which R ee and R ff are independently selected from hydrogen, chlorine, fluorine and trifluoromethyl.

[1094] C170. In Example C170, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is one in which R ee and R ff is hydrogen.

[1095] C171. In Example C171, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is one in which R ee and R ff is chlorine.

[1096] C172. In Example C172, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is one in which R ee and R ff is fluorine.

[1097] C173. In Example C173, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C108 and C140 to C163 is one in which R ee and R ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.

[1098] C174. In Example C174, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C107 is one in which the degron is an E3 ubiquitin ligase ligand having formula (iii), (iv), (v) or (vi).

[1099] C175. In Example C175, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C107 and C174 is one in which the degron is an E3 ubiquitin ligase ligand having formula (iv) or (v).

[1100] C176. In Example C176, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C107, C174 and C175 is one in which R y , R y1 and R y2 are 1-fluorocyclopropan-1-yl and W a is a bond, S or methylene.

[1101] C177. In Example C177, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C107 and C174 to C176 is one in which W a is S.

[1102] C178. In Example C178, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each a bond.

[1103] C179. In Example C179, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each independently selected from alkylene. In a sub-example of C179, each alkylene is methylene.

[1104] C180. In Example C180, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each -O-.

[1105] C181. In Example C181, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1, X 2 , X 3 and X 4 are each independently selected from -(O-alkylene)-.

[1106] C181a. In Example C181a, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each independently selected from -(alkylene-O)-.

[1107] C182. In Example C182, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each independently selected from -(NR gg -alkylene)-.

[1108] C183. In Example C183, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each independently selected from -(alkylene-NR hh )-.

[1109] C184. In Example C184, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each

[1110] C185. In Example C185, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each -NH-.

[1111] C186. In Example C186, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C173 is one in which X 1 , X 2 , X 3 and X 4Each independently selected from -N(alkyl)-. In a sub - embodiment of C186, each -N(alkyl)- is independently -N(methyl)- or -N(ethyl)-.

[1112] C187. In embodiment C187, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each -C(=O)-.

[1113] C188. In embodiment C188, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each independently -NR jj C(=O)-.

[1114] C189. In embodiment C189, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C173 is one in which X 1 , X 2 , X 3 and X 4 are each independently -C(=O)NR kk -.

[1115] C190. In embodiment C190, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C173, C182, C183, C188 and C189 is one in which R gg , R hh , R jj and R kk are each independently hydrogen or alkyl.

[1116] C190a. In embodiment C190a, the compound as described in any one of embodiments C1 to C190 is one in which -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - at least two of which are not bonds. In a sub - embodiment of C190a, the compound is one in which -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6At least three of the - are not bonds. In a sub - embodiment of C190a, the compound is one in which -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 At least four of the - are not bonds.

[1117] C191. In embodiment C191, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C190a is one in which Z 6 is -S(O) 2 -.

[1118] C192. In embodiment C192, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C191 is one in which Z 5 is phenylene, monocyclic heteroarylene or heteroarylene, where each ring is substituted by R q and R r substituted.

[1119] C193. In embodiment C193, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C192 is one in which Z 5 is phenylene, monocyclic heteroarylene or heteroarylene, where each ring is substituted by R q and R r substituted, and one and only one of Z 1 and X 1 is a bond, one and only one of Z 1 and X 2 is a bond, one and only one of Z 1 and X 3 is a bond, and one and only one of Z 1 and X 4 is a bond (for clarity, when X 1 、X 2 、X 3 and X 4 are not bonds, then X 1 、X 2 、X 3 and X 4 are as described in any one of embodiments C1 and C179 to C189).

[1120] C194. In embodiment C194, the compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments C1 to C177 is one in which:

[1121] X 1 、X 2 、X 3 and X4 independently is a bond, -(O-alkylene)-, -(NR gg -alkylene)-, -NH- or -N(alkyl)-, where R gg is hydrogen or alkyl, and each alkylene is independently optionally substituted with one or two fluorines (or when the E3 ubiquitin ligase ligand is (iii) to (vi), X 1 、X 2 、X 3 and X 4 is a bond);

[1122] Z 1 is a bond, alkylene, -(CO)NR-, -(O-alkylene) a -, -(alkylene-O) a -, phenylene or hetero-subcyclic group, where each ring is substituted by R h and R i ;

[1123] Z 2 is a bond, alkylene, -(O-alkylene) b -, -(alkylene-O) b -, cycloalkylene or hetero-subcyclic group, where each ring is substituted by R j and R k ;

[1124] Z 3 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -O-, -NR”, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroaryl, -(alkylene)-monocyclic heteroaryl-, -monocyclic heteroaryl-(alkylene)-, hetero-subcyclic group, -(alkylene)-hetero-subcyclic group-, -hetero-subcyclic group-(alkylene)-, bridged hetero-subcyclic group, -(alkylene)-bridged hetero-subcyclic group-, -bridged hetero-subcyclic group-(alkylene)-, spiro hetero-subcyclic group, -(alkylene)-spiro hetero-subcyclic group-, -spiro hetero-subcyclic group-(alkylene)- or monocyclic heteroaryl, where each ring itself or as part of another group is substituted by R m and R n ;

[1125] Z 4is a bond, -(alkylene-NR")-, -(NR"-alkylene)-, -O-, -NR", cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, -(alkylene)-heterocycloalkylene-, -heterocycloalkylene-(alkylene)-, fused heterocycloalkylene, bridged heterocycloalkylene, -(alkylene)-bridged heterocycloalkylene-, -bridged heterocycloalkylene-(alkylene)-, spiroheterocycloalkylene, -(alkylene)-spiroheterocycloalkylene or -spiroheterocycloalkylene-(alkylene)-, wherein each ring is itself or as part of another group substituted by R o and R p substituted;

[1126] Z 5 is a bond; and

[1127] Z 6 is -S(O) 2 -; and

[1128] wherein Z 1 , Z 2 , Z 3 and Z 4 each alkylene therein is itself or as part of another group independently substituted by R s and R t substituted.

[1129] C195. In Example C195, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177 is wherein:

[1130] X 1 , X 2 , X 3 , X 4 and Z 1 are each a bond;

[1131] Z 2 is a bond, alkylene, cycloalkylene or heterocycloalkylene, wherein each ring is substituted by R j and R k substituted;

[1132] Z 3 is a bond, alkylene, -C(O)NR-, -NR'(CO)-, -O-, -NR", cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, bicyclic heteroarylene, bridged heterocycloalkylene, fused heterocycloalkylene or spiroheterocycloalkylene, wherein each ring is substituted by R m and R n substituted;

[1133] Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, fused heterocycloalkylene or spiroheterocycloalkylene, wherein each ring is substituted by Ro and R p is substituted with;

[1134] Z 5 is a phenylene, monocyclic heteroarylene or heteroalkylene group, wherein each ring is substituted with R q and R r is substituted with; and

[1135] Z 6 is -S(O) 2 -; and

[1136] wherein Z 2 , Z 3 and Z 4 each alkylene group in is independently substituted with R s and R t is substituted with.

[1137] C196. In Example C196, the compound or a pharmaceutically acceptable salt thereof according to any one of Examples C1 to C177 and C195 is one in which:

[1138] X 1 、X 2 、X 3 、X 4 、Z 1 and Z 2 are each a bond;

[1139] Z 3 is a cycloalkylene, phenylene, monocyclic heteroarylene, heteroalkylene, bicyclic heteroalkylene, bridged heteroalkylene, fused heteroalkylene or spiro heteroalkylene group, wherein each ring is substituted with R m and R n is substituted with;

[1140] Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heteroalkylene, fused heteroalkylene or spiro heteroalkylene group, wherein each ring is independently substituted with R selected from hydrogen, deuterium, alkyl, alkoxy, hydroxyl, cyano, halo, haloalkyl and haloalkoxy o and R p is substituted with;

[1141] Z 5 is a phenylene, monocyclic heteroarylene or heteroalkylene group, wherein each ring is substituted with R q and R r is substituted with; and

[1142] Z 6 is -S(O) 2 -; and

[1143] wherein the alkylene group in Z 4 is substituted with Rs and R t is replaced.

[1144] C197. In Example C197, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177, C195 and C196 is one in which:

[1145] X 1 、X 2 、X 3 、X 4 、Z 1 and Z 2 are each a bond;

[1146] Z 3 is a hetero-subcyclic group, bicyclic hetero-subcyclic group, bridged hetero-subcyclic group, fused hetero-subcyclic group or spiro hetero-subcyclic group, wherein each ring is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[1147] Z 4 is an alkylene group, -O-, cycloalkylene group, monocyclic heteroaryl group, hetero-subcyclic group, fused hetero-subcyclic group or spiro hetero-subcyclic group, wherein each ring is independently substituted by R o and R p selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[1148] Z 5 is a phenylene group, monocyclic heteroaryl group or hetero-subcyclic group, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and

[1149] Z 6 is -S(O) 2 -; and

[1150] wherein the alkylene group in Z 4 is substituted by R s and R t selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy.

[1151] C198. In Example C198, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177 and C195 to C197 is one in which:

[1152] X 1 、X 2 、X 3 and X 4 、Z 1and Z 2 are each a bond;

[1153] Z 3 is a heteroalkylene, bridged heteroalkylene or spiroheteroalkylene, wherein each ring is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[1154] Z 4 is an alkylene, -O-, cycloalkylene or heteroalkylene, wherein each ring is independently substituted by R o and R p selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano and hydroxy, preferably hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[1155] Z 5 is a phenylene, monocyclic heteroarylene or heteroalkylene, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and

[1156] Z 6 is -S(O) 2 -; and

[1157] wherein the alkylene in Z 4 is substituted by R s and R t selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy.

[1158] C199. In Example C119, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177 and C195 to C198 is one in which:

[1159] X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 are each a bond;

[1160] Z 3 is a heteroalkylene, bridged heteroalkylene or spiroheteroalkylene, wherein each ring is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[1161] Z 4is an alkylene, -O-, cycloalkylene or hetero cycloalkylene, wherein each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano and hydroxyl, preferably R selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy o and R p substituted, preferably Z 4 is alkylene or -O-;

[1162] Z 5 is a phenylene or monocyclic heteroarylene, each ring being independently substituted by R and R selected from hydrogen, deuterium, alkyl, alkoxy, hydroxyl, cyano, halogen, haloalkyl and haloalkoxy; and q and R r substituted; and

[1163] Z 6 is -S(O) 2 -; and

[1164] wherein the alkylene in Z 4 is substituted by R s and R t substituted.

[1165] C200. In Example C200, the compound or a pharmaceutically acceptable salt thereof according to any one of Examples C1 to C177 and C195 is one in which:

[1166] X 1 、X 2 、X 3 、X 4 and Z 1 are each a bond;

[1167] Z 2 is cycloalkylene or hetero cycloalkylene, wherein each ring is independently substituted by R and R selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy; j and R k substituted;

[1168] Z 3 is cycloalkylene, phenylene, monocyclic heteroarylene, hetero cycloalkylene, bicyclic hetero cycloalkylene, bridged hetero cycloalkylene, fused hetero cycloalkylene or spiro hetero cycloalkylene, wherein each ring is independently substituted by R and R selected from hydrogen, deuterium, alkyl, alkoxy, hydroxyl, cyano, halogen, haloalkyl and haloalkoxy; m and R n substituted;

[1169] Z 4 is a bond, alkylene or -O-;

[1170] Z 5is a phenylene, a monocyclic heteroarylene (e.g., pyridinediyl) or a heteroalkylene, wherein each ring is independently substituted by R selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy q and R r substituted; and

[1171] Z 6 is -S(O) 2 -; and

[1172] wherein the alkylene in Z 4 is substituted by R s and R t substituted.

[1173] C201. In Example C201, the compound or a pharmaceutically acceptable salt thereof according to any one of Examples C1 to C177, C191, and C195 is one in which:

[1174] X 1 、X 2 、X 3 、X 4 and Z 1 are each a bond;

[1175] Z 2 is a heteroalkylene substituted by R j and R k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

[1176] Z 3 is a heteroalkylene substituted by R m and R n independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[1177] Z 4 is a bond, an alkylene, or -O-;

[1178] Z 5 is a phenylene or a monocyclic heteroarylene, each ring of which is independently substituted by R q and R r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

[1179] Z 6 is -S(O) 2 -; and

[1180] wherein the alkylene in Z 4 is substituted by R s and R t substituted.

[1181] C202. In Example C202, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177, C178, C191, and C192 is one in which:

[1182] X 1 、X 2 、X 3 、X 4 and Z 1 each is a bond;

[1183] Z 2 is a hetero-subcyclic group substituted by R j and R k , preferably R j and R k are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy;

[1184] Z 3 is a bond, alkylene, or -O-;

[1185] Z 4 is a hetero-subcyclic group, a bridged hetero-subcyclic group, or a spiro hetero-subcyclic group, wherein each ring is substituted by R o and R p , preferably R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halogen, haloalkyl, and haloalkoxy;

[1186] Z 5 is a phenylene or a monocyclic hetero-subaryl, each ring being substituted by R q and R r , preferably R q and R r are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halogen, haloalkyl, and haloalkoxy; and

[1187] Z 6 is -S(O) 2 -; and

[1188] wherein the alkylene in Z 3 is substituted by R s and R t .

[1189] C203. In Example C203, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177 is one in which Z 4 is a hetero-subcyclic group or a spiro hetero-subcyclic group, wherein each ring is substituted by R o and R p , preferably R o and Rp independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy.

[1190] C204. In Example C204, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177, C195 and C196 is one in which:

[1191] X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 are each a bond;

[1192] Z 3 is a hetero-subcyclic group, wherein each ring is independently substituted by R m and R n selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy;

[1193] Z 4 is a cycloalkylidene group substituted by R o and R p independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl and haloalkoxy;

[1194] Z 5 is a phenylene or monocyclic hetero-subaryl group, each ring being independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and

[1195] Z 6 is -S(O) 2 -.

[1196] C205. In Example C205, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples C1 to C177 is one in which one and only one of X 1 and Z 1 , or one and only one o...

Claims

1. A compound having the formula (Ia): Wherein: R 1 is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, halogenated group, haloalkyl group, haloalkoxy group, alkoxy group, aryloxy group, cyano group, cycloalkyl group, wherein the cycloalkyl group is substituted with one to three halogenated groups; R 2 and R 2a are independently hydrogen or deuterium; Hy is a cycloalkylene, arylene, heteroarylene, heterocycloalkylene, bicyclic heterocycloalkylene, spiro heterocycloalkylene, bridged heterocycloalkylene or fused heterocycloalkylene, wherein each of the above rings is independently substituted by R selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy and cyano a , R b and R c ; The degron is an E3 ubiquitin ligase ligand selected from the following: (a) A group having the formula (i): (b) A group having the formula (ii): (c) A group having the formula (iii): (d) A group having the formula (iv): (e) A group having the formula (v): (f) A group having the formula (vi): Wherein: R x and R x1 each is hydrogen; Y a is CH or N; Z a is a bond, -CH 2 -, -NH-, -O- or -NHC(O)-, wherein the NH of -NHC(O)- is attached to Y a attached; Ring A is a group having the formula (a), (b) or (c): Wherein: R aa 、R bb 、R cc and R dd are independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano; R 4 and R 5 are independently hydrogen or alkyl; or R 4 and R 5 together with the carbon to which they are attached form >C=O; and R 6 is hydrogen or alkyl; Ring B is a phenylene, cycloimino, 5- or 6-membered monocyclic heteroarylene, or 9- or 10-membered fused bicyclic heteroarylene, where each heteroarylene ring contains one to three nitrogen ring atoms and further where the phenylene, cycloimino, and each heteroarylene are independently substituted by R ee and R ff substituents; and 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 ), -NH-, -N(alkyl)-, -C(=O)-, -NR jj C(=O)- or -C(=O)NR kk (-), where R gg , R hh , R jj and R kk are independently hydrogen, alkyl or cycloalkyl, and each alkylene is optionally substituted by one or two fluorines, either alone or as part of another group; R y 、R y1 and R y2 are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic group are substituted by R d and R f selected from hydrogen, halogen, cyano, alkylcarbonyl and alkylcarbonylamino; and W a is a bond, O, S or an alkylene; and L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -, where: Z 1 is a bond, an alkylene group, -C(O)NR-, -NR'(CO)-, -S(O) 2 NR-, -NR'S(O) 2 -, -(O-alkylene) a -, -(alkylene-O) a -, a phenylene group, a monocyclic heteroarylene group or a heteroalkylenyl group, wherein each ring is independently substituted by R h and R i substituted; Z 2 is a bond, an alkylene, an alkynylene, -C(O)-, -C(O)N(R)-, -NR'(CO)-, -(O-alkylene) b -, -(alkylene-O) b -, -O(CH 2 ) 7 -, -O(CH 2 ) 8 -, a cycloalkylene or a hetero-cycloalkylene, wherein each ring is independently substituted by R j and R k selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; Z 3 is a bond, an alkylene, an alkynylene, -C(O)NR-, -NR'(CO)-, -O-, -NR'', -(O-alkylene) c -, -(alkylene-O) c -, cycloalkylene, spiroalkylene, 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 an 11- to 13-membered spiroheterocyclylene, wherein each ring by itself or as part of another group is independently substituted by R m and R n substituted; Z 4 is a bond, an alkylene, an 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)-, wherein each ring is independently substituted, by itself or as part of another group, with R o and R p substituted; Z 5 is a bond, -alkylene, -NR”-,-O-,-C(O)-,-S(O) 2 -, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene or heteroalkylene, wherein each ring is independently substituted by R q and R r substituted; and Z 6 is a bond, an alkylene group, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O) 2 -, -NR'(CO)- or -C(O)NR-; where each R, R', and R" is independently hydrogen or alkyl, each of a, b, c, and d is independently an integer selected from 1 to 6, and -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 5 -, -Z 6 each alkylene in -Z s - and -Z t - and -Z s - and -Z t - and -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - is independently substituted by R s and R t either by itself or as part of another group, where R s is hydrogen or deuterium and R t is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocycloalkyl, aryl, or monocyclic heteroaryl, where the cycloalkyl, heterocycloalkyl, aryl, or monocyclic heteroaryl is substituted by one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano; provided that at least one of -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - is not a bond; or Its pharmaceutically acceptable salts.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is a halogenated group, a haloalkyl group or a haloalkoxy group.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 1 is a halogenated group.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 1 is a haloalkyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 1 is a haloalkoxy group.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy or trifluoroethoxy.

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

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

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

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

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Hy is a hetero-subcyclic group, a phenylene group, a spiro hetero-subcyclic group, a bridged hetero-subcyclic group or a cycloalkyl group, each of the above rings being substituted by R a , R b and R c , wherein R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R c is hydrogen.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Hy is a hetero-subcyclic group substituted by R a , R b and R c , wherein R a and R b are independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy and hydroxy, and R c is hydrogen.

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

14. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein the hetero-subcyclic group of Hy is: Wherein the N atoms of these pyrrolidine-1,3-diyl or piperidine-1,4-diyl rings are attached to L.

15. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 14, wherein the hetero-subcyclic group of Hy is: Wherein the N atom of the piperidine-1,4-diyl ring is attached to L.

16. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein the degron is an E3 ubiquitin ligase ligand having the formula (i):

17. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein ring A of the E3 ubiquitin ligase ligand having the formula (i) is a group having the formula (a):

18. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 16, wherein ring A of the E3 ubiquitin ligase ligand having the formula (i) is a group having the formula (b):

19. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 18, wherein ring A of the E3 ubiquitin ligase ligand having the formula (i) is:

20. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 19, wherein ring A of the E3 ubiquitin ligase ligand having the formula (i) is:

21. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 20, wherein ring A of the E3 ubiquitin ligase ligand having the formula (i) is:

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

23. The compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein R aa , R bb , R cc and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluorine, trifluoromethyl, difluoromethyl and trifluoromethoxy.

24. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 15, wherein the degron is an E3 ubiquitin ligase ligand having the formula (ii):

25. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 15 and 24, wherein the E3 ubiquitin ligase ligand having the formula (ii) is:

26. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 15, 24 and 25, wherein the E3 ubiquitin ligase ligand having the formula (ii) is: Wherein ring B is a cyclic imino group.

27. The compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 and X 4 are each a bond.

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

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

30. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 26, Wherein: X 1 , X 2 , X 3 , X 4 and Z 1 are each a key; Z 2 is a bond, an alkylene, a cycloalkylene or a heteroalkylene, wherein each ring is substituted by R j and R k substituted; Z 3 is a bond, an alkylene group, -C(O)NR-, -NR'(CO)-, -O-, -NR'', a cycloalkylene group, a phenylene group, a monocyclic heteroarylene group, a heterocycloalkylene group, a bicyclic heterocycloalkylene group, a bridged heterocycloalkylene group, a fused heterocycloalkylene group or a spiro heterocycloalkylene group, wherein each ring is substituted by R m and R n substituted; Z 4 is a bond, an alkylene group, -O-, a cycloalkylene group, a phenylene group, a monocyclic heteroarylene group, a heteroalkylene group, a fused heteroalkylene group or a spiro heteroalkylene group, wherein each ring is substituted by R o and R p substituted; Z 5 is a phenylene, monocyclic heteroarylene or heteroarylene group, wherein each ring is substituted by R q and R r ; and Z 6 is -S(O) 2 -; and Wherein Z 2 , Z 3 and Z 4 each of the alkylene groups is independently substituted by R s and R t .

31. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 26 and 30, Wherein: X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 are each a key; Z 3 is a cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, bicyclic heterocycloalkylene, bridged heterocycloalkylene, fused heterocycloalkylene or spiro heterocycloalkylene, wherein each ring is substituted by R m and R n substituted; Z 4 is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, fused heterocycloalkylene or spiroheterocycloalkylene, wherein each ring is independently substituted by R o and R p substituted; Z 5 is a phenylene, monocyclic heteroarylene or heteroarylidene, wherein each ring is substituted by R q and R r ; and Z 6 is -S(O) 2 -; and Wherein Z 4 The alkylene group in s is substituted by R t and R substituted.

32. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 26, 30 and 31, Wherein: X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key; Z 3 is a heteroalicyclic group, bicyclic heteroalicyclic group, bridged heteroalicyclic group, fused heteroalicyclic group or spiro heteroalicyclic group, wherein each ring is independently substituted by R m and R n substituted; Z 4 is an alkylene, -O-, cycloalkylene, monocyclic heteroarylene, heteroalkylene, fused heteroalkylene or spiro heteroalkylene, wherein each ring is independently substituted by R o and R p substituted; Z 5 is a phenylene, monocyclic heteroarylene or heteroarylene group, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and Z 6 is -S(O) 2 -; and wherein Z 4 the alkylene group in s is replaced by R t and R 33. A compound as claimed in any one of claims 1 to 26 and 30 to 32, or a pharmaceutically acceptable salt thereof, wherein: X 1 、X 2 、X 3 and X 4 、Z 1 and Z 2 are each a key; Z 3 is a heteroarylene, bridged heteroarylene or spiro heteroarylene, wherein each ring is independently substituted by R m and R n selected from the group consisting of hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; Z 4 is an alkylene group, -O-, cycloalkylene group or hetero-cycloalkylene group, each ring of which is independently substituted by R selected from hydrogen, deuterium, alkyl group, alkoxy group, halogen group, haloalkyl group, haloalkoxy group, cyano group and hydroxyl group, preferably hydrogen, deuterium, alkyl group, alkoxy group, hydroxyl group, cyano group, halogen group, haloalkyl group and haloalkoxy group o and R p substituted; Z 5 is a phenylene, monocyclic heteroarylene or heteroarylene group, wherein each ring is independently substituted by R q and R r selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and Z 6 is -S(O) 2 -; and wherein Z 4 the alkylene group in s is substituted by R t and R 34. A compound as claimed in any one of claims 1 to 26 and 30 to 33, or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key; Z 3 is a heteroalicyclic group, a bridged heteroalicyclic group or a spiro heteroalicyclic group, wherein each ring is independently substituted by R m and R n substituted; Z 4 is an alkylene group or -O-; Z 5 is a phenylene or monocyclic heteroarylene, each ring independently substituted by R q and R r selected from the group consisting of hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and Z 6 is -S(O) 2 -; and Wherein Z 4 in the alkylene group is replaced by R s and R t substituted.

35. A compound as claimed in any one of claims 1 to 26 and 30, or a pharmaceutically acceptable salt thereof, wherein: X 1 、X 2 、X 3 、X 4 and Z 1 are each a key; Z 2 is a cycloalkylene or heterocycloalkylene, wherein each ring is independently substituted by R j and R k selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy; Z 3 is a cycloalkylene, phenylene, monocyclic heteroarylene, heterocycloalkylene, bicyclic heterocycloalkylene, bridged heterocycloalkylene, fused heterocycloalkylene or spiro heterocycloalkylene, wherein each ring is independently substituted by R m and R n substituted; Z 4 is a bond, an alkylene group or -O-; Z 5 is a phenylene, monocyclic heteroarylene (such as pyridinediyl) or heteroarylidene, wherein each ring is independently substituted by R q and R r substituted; and Z 6 is -S(O) 2 -; and wherein Z 4 the alkylene group in s is substituted by R t and R substituted.

36. A compound as claimed in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein: X 1 、 X 2 、 X 3 、 X 4 and Z 1 are each a key; Z 2 is a hetero-subcyclic group substituted by R j and R k Preferably, R j and R k are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl and haloalkoxy; Z 3 is a bond, an alkylene group or -O-; Z 4 is a heteroalicyclic group, a bridged heteroalicyclic group or a spiro heteroalicyclic group, wherein each ring is substituted by R o and R p preferably, R o and R p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; Z 5 is a phenylene or a monocyclic heteroarylene, each ring being substituted by R q and R r substituted, preferably R q and R r are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl and haloalkoxy; and Z 6 is -S(O) 2 -; and Wherein Z 3 The alkylene group in s is substituted by R t and R substituted.

37. A compound as claimed in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 , X 3 , X 4 , Z 1 and Z 2 Each is a key; Z 3 is an 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, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene- or -spiro heterocyclylene-(alkylene), wherein each ring is itself or as part of another group substituted by R m and R n substituted; Z 4 is an alkylene, -(alkylene-NR")-, -(NR"-alkylene)-, -O-, -NR"-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocycloalkylene, -(alkylene)-heterocycloalkylene-, -heterocycloalkylene-(alkylene)-, fused heterocycloalkylene, bridged heterocycloalkylene, -(alkylene)-bridged heterocycloalkylene-, -bridged heterocycloalkylene-(alkylene)-, spiroheterocycloalkylene, -(alkylene)-spiroheterocycloalkylene, or -spiroheterocycloalkylene-(alkylene)-, where each ring is itself or as part of another group substituted by R o and R p substituted; Z 5 is a bond, -alkylene, -NR″-, -O-, -C(O)-, -S(O) 2 -, -NR′(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene or heteroarylene, wherein each ring is substituted by R q and R r substituted; and Z 6 is a bond, an alkylene group, -NR″-, -O-, -(alkylene-O)-, -C(O)-, -S(O) 2 -, -NR′(CO)- or -C(O)NR-; and Z 3 、Z 4 、Z 5 and Z 6 each alkylene group therein, either by itself or as part of another group, is independently substituted by R s and R t substituted.

38. A compound as claimed in any one of claims 1 to 26 and 37, or a pharmaceutically acceptable salt thereof, wherein: Z 3 is an 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, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene- or -spiro heterocyclylene-(alkylene), wherein each ring is itself or as part of another group substituted by R m and R n substituted; Z 4 is an alkylene group, -(alkylene-NR")-, -(NR"-alkylene)-, -O-, -NR"-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocycloalkylene, -(alkylene)-heterocycloalkylene-, -heterocycloalkylene-(alkylene)-, fused heterocycloalkylene, bridged heterocycloalkylene, -(alkylene)-bridged heterocycloalkylene-, -bridged heterocycloalkylene-(alkylene)-, spiroheterocycloalkylene, -(alkylene)-spiroheterocycloalkylene, or -spiroheterocycloalkylene-(alkylene)-, where each ring is itself or as part of another group is substituted by R o and R p substituted; Z 5 is a bond, -alkylene, -NR″-, -O-, -C(O)-, -S(O) 2 -, -NR′(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene or heteroarylene, wherein each ring is substituted by R q and R r substituted; and Z 6 is -S(O) 2 -; and And Z 3 、Z 4 and Z 5 each alkylene in or as part of another group is independently substituted by R s and R t substituted.

39. A compound as claimed in any one of claims 1 to 26, 37 and 38, or a pharmaceutically acceptable salt thereof, wherein: Z 3 is an alkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene- or -spiro heterocyclylene-(alkylene), wherein each ring is itself or as part of another group substituted by R m and R n substituted; Z 4 is an alkylene group, -(alkylene-NR")-, -(NR"-alkylene)-, -O-, -NR"-, -(O-alkylene) d -, -(alkylene-O) d -, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spirocycloalkylene, phenylene, heteroarylene, heterocycloalkylene, -(alkylene)-heterocycloalkylene-, -heterocycloalkylene-(alkylene)-, fused heterocycloalkylene, bridged heterocycloalkylene, -(alkylene)-bridged heterocycloalkylene-, -bridged heterocycloalkylene-(alkylene)-, spiroheterocycloalkylene, -(alkylene)-spiroheterocycloalkylene, or -spiroheterocycloalkylene-(alkylene)-, wherein each ring is itself or as part of another group substituted by R o and R p substituted; Z 5 is a phenylene, monocyclic heteroarylene or heteroarylidene, wherein each ring is substituted by R q and R r ; and Z 6 is -S(O) 2 -; and Z 3 and Z 4 each alkylene therein, either by itself or as part of another group, is independently substituted by R s and R t substituted.

40. The compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein -Z 5 - is R independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, and haloalkoxy q and R r substituted (i.e., Z 5 is phenylene, wherein Z 4 and Z 6 are attached at the meta positions of the phenylene ring).

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

43. The compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, wherein Z 1 、Z 2 、Z 3 、Z 4 and Z 5 each hetero-subcyclic group, bridged hetero-subcyclic group and spiro hetero-subcyclic group, when present, is independently selected from: each ring is optionally substituted with 1, 2 or 3 fluorines, unless otherwise specified in any of the preceding claims.

44. A compound according to any one of claims 1 to 35 and 37 to 39, or a pharmaceutically acceptable salt thereof, wherein -Z 3 -Z 4 -Z 5 -Z 6 - is: where each R m , R n and R q is independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy and cyano.

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

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

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

48. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, 37 to 42 and 44, wherein Z 4 is -(alkylene)-heterocyclylene-, wherein the heterocyclylene is substituted by R o and R p substituted.

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

50. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, 37 to 42, 44, 48 and 49, wherein Z 4 is:

51. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, 37 to 42, 44 and 48 to 50, wherein -Z 3 -Z 4 -Z 5 -Z 6 - is:

52. A compound as claimed in any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein the degron is an E3 ubiquitin ligase ligand selected from the following: where each R ee is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, and each R ff is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy or trifluoromethyl.

53. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 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-Fluorocyclopropanecarboxamido)-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-(trifluoromethyl)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-(trifluoromethyl)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-(trifluoromethyl)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-(trifluoromethyl)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-methylpyrimidin-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-chloro-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; 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-(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-(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-(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-(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-(trifluoromethoxy)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)dihydro-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)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-(trifluoromethyl)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-(trifluoromethyl)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-chloropyrimidin-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-(trifluoromethyl)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-(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-((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; 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-carboxylic acid ethyl ester; 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-(trifluoromethyl)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)dihydro-pyrimidine-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-oxobenz[d]oxazol-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]oxazol-3(2H)-yl)piperidine-2,6-dione; Racemic-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; racemic-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)-1H-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)picolylamide; 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.

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

55. A method for treating a CDK2-mediated disease in a patient, the method comprising administering to a patient in recognized need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 53 or a pharmaceutical composition as described in claim 53.

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

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

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

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