Bifunctional compounds containing 2,5-substituted pyrimidine derivatives for degrading cyclin-dependent kinase 2 and cyclin-dependent kinase 4 via ubiquitin proteasome pathway

Abstract

The present disclosure provides certain bifunctional compounds containing 2,5-substituted pyrimidine derivatives that cause degradation of Cyclin-dependent kinase 2 (CDK2) and Cyclin-dependent kinase 4 (CDK4) via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by CDK2 and / or CDK4. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

[0001] BIFUNCTIONAL COMPOUNDS CONTAINING 2,5-SUBSTITUTED PYRIMIDINE

[0002] DERIVATIVES FOR DEGRADING CYCLIN-DEPENDENT KINASE 2 AND CYCLIN- DEPENDENT KINASE 4 VIA UBIQUITIN PROTEASOME PATHWAY

[0003] Field of the disclosure

[0004] The present disclosure provides certain bifunctional compounds containing 2, 5 -substituted pyrimidine derivatives that cause degradation of Cyclin-dependent kinase 2 (CDK2) and Cyclin- dependent kinase 4 (CDK4) via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by CDK2 and / or CDK4. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

[0005] Background

[0006] Cyclin-dependent kinases (CDKs) are essential cellular serine / threonine kinases that play an important role in orchestrating signaling events, such as DNA replication and protein synthesis, to ensure faithful eukaryotic cell division and proliferation. The regulation of CDK activity is tightly controlled by the fluctuating levels of various cyclins, which form heterodimeric complexes with CDKs to activate them. Out of the 21 identified CDKs, CDKl / Cyclin B, CDK2 / Cyclin E, CDK2 / Cyclin A, CDK4 / Cyclin D, CDK6 / Cyclin D complexes are well known to be vital regulators of cell cycle progression. Other CDKs are involved in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, D. O. Annu. Rev. Cell. Dev. Biol. (1997) 13: 261-291). In the canonical model of cell cycle, mitogenic signaling upregulates D-type cyclins, which directly bind and activate CDK4 / 6. Active CDK4 / 6-cyclin D complexes partially phosphorylate Rb, disrupting the Rb / E2F interaction and de-repressing E2F activity, leading to upregulation of cyclin E, a CDK2 activator. Cdk2-cyclin E further hyperphosphorylates Rb, releasing E2F to transcribe genes required for S-phase entry. During S-phase, cyclin E is degraded and CDK2 forms a complex with cyclin A to promote phosphorylation of substrates essential for DNA replication and inactivation of E2F, completing S-phase (Asghar et al. Nat. Rev. Drug. Discov. (2015) 14: 130-146). CDKl-Cyclin A and CDKl-Cyclin B complexes are activated in late S and G2 phases to drive the transition into and completion of mitosis, respectively (Katsuno et al., 2009; Lindqvist et al., 2009; Lohka et al., 1988).

[0007] Due to their crucial roles in regulating cell cycle and other essential cellular processes, increased activity or temporally abnormal activation of CDKs has been shown to promote tumorigenesis and disease progression (Cordon-Cardo C. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Nat. Med. (1995) 1 :309-320; Hall M, Peters G. Adv. Cancer Res. (1996) 68:67-108). Genetic changes in CDK-cyclin complexes and the proteins that regulate them are widespread in various cancers and are often associated with poor clinical outcomes. Common alterations include amplifications / overexpression of cyclin D, cyclin E, CDK4 and CDK6; loss of Rb; deficiency in CDK inhibitory regulators such as pl 6, p21, p27, and loss-of-function mutations in FBXW7, a component of SCFFbw7ubiquitin E3 ligase responsible for cyclin E degradation. (Smalley et al. Cancer Res. (2008) 68: 5743-52).

[0008] Over the last two decades, there has been significant interest in developing CDK inhibitors for therapeutic purposes. In combination with endocrine therapies, selective reversible inhibitors of CDK4 and CDK6 e.g., palbociclib, ribociclib, and abemaciclib have revolutionized the therapeutic management for hormone receptor-positive (HR+) metastatic breast cancer (MBC). Ongoing clinical trials are also investigating these CDK4 / 6 inhibitors as single agents or in combination with other therapeutics for various cancers. (O'Leary et al. Nature Reviews (2016) 13:417-430).

[0009] Despite their significant clinical efficacy in ER-positive metastatic breast cancer, CDK4 / 6 inhibitors have some limitations. One major drawback is the development of primary or acquired resistance over time. An important mechanism of resistance involves the abnormal activation of CDK2. This can occur due to an overactivated CDK2 / Cyclin E complex caused by elevated Cyclin E expression (Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561) or formation of the noncanonical CDK2 / cyclin DI complex in response to CDK4 / 6 inhibition (Herrera- Abreu MT et al, Cancer Res. (2006) 15: 2301), which bypasses the need for CDK4 / 6 for cell cycle reentry. Additionally, CDK4 / 6 inhibitors palbociclib and ribociclib exhibit relatively high hematological toxicity, primarily neutropenia. CDK6 is highly expressed in the blood system and plays a role in regulating the growth of hematopoietic cells. Therefore, it is generally believed that the inhibition of CDK6 leads to neutropenia, while breast cancer cells mainly depend on CDK4 for proliferation. Abemaciclib exhibits weaker inhibition of CDK6 than CDK4, resulting in lower hematological toxicity.

[0010] Considering these factors, developing a small molecule inhibitor or a proteolysis-targeting chimeric molecule (PROTAC) that specifically targets CDK4 and / or CDK2 could represent a therapeutic opportunity with reduced toxicity and improved overall therapeutic efficacy.

[0011] PROTACs are bifunctional molecules comprised of target protein-recruitment moiety and a ligand for E3 ligase, connected by a biocompatible linker. PROTACs bring the protein of interest and the E3 ligase into close proximity and induce ubiquitination and subsequent degradation of the target protein by proteasome. Compared to small molecule drugs that typically bind disease-relevant proteins and inhibit their function, PROTACs display several unique and attractive features that make them desirable drug candidates. For example, PROTACs have been shown to be more selective than their inhibitor counterparts, potentially reducing off-target toxicity. Moreover, PROTACs can perform multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can function at sub-stoichiometric receptor occupancies. The E3 ligases used in PROTACs mainly include cereblon (CRBN), Von Hippel-Lindau-containing complex (VHL), inhibitor of apoptosis protein (LAP), and mouse double minute 2 (MDM2).

[0012] Therefore, PROTACs that could recruit CDK2 and CDK4 to a ubiquitin ligase, and thereby causing ubiquitylation and proteasomal degradation of CDK2 and CDK4 are desirable. The present disclosure fulfills this and related needs.

[0013] Summary

[0014] In a first aspect, provided is a compound of Formula (I): wherein: n is 0 or 1;

[0015] R1is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy (wherein cycloalkyl, either alone or as part of cycloalkoxy, is substituted with one to three halo), halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, or cyano;

[0016] R2and R2aare independently hydrogen or deuterium;

[0017] Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the aforementioned rings is substituted with Ra, Rb, and Rcindependently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano; Degron is an E3 ubiquitin ligase ligand selected from:

[0018] (a) a group of formula (i):

[0019] (b) a group of formula (ii):

[0020] (ii); where:

[0021] Yais CH or N;

[0022] Zais a bond, -CH2-, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is attached to Ya; ring A is a group of formula (a) or (b): where:

[0023] Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;

[0024] R4and R5are independently hydrogen or alkyl; or R4and R5together with the carbon to which they are attached form >C=O;

[0025] M is -O- or -NR6-; and

[0026] R6is hydrogen or alkyl; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three ring atoms that are heteroatoms independently selected from nitrogen, oxygen, and sulfur and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with Reeand Rffindependently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and

[0027] Z is -O-, -NR3- (where R3is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene and where each of the aforementioned ring is substituted with Rdand Reindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; alk is alkynylene substituted with Rfand Rgindependently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano; or when Rfand Rgare attached to the same carbon atom of the alkynylene, they can combine with the carbon atom to which they are attached to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R7and R8independently selected from hydrogen, alkyl, and halo; alk1is absent or alkylene optionally substituted with R9and R10independently selected from halo, hydroxy, and cyano;

[0028] Ar is phenylene, monocyclic heteroarylene, heterocyclylene, unsaturated heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each of the aforementioned rings is substituted with Rh, R1, and R1independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and

[0029] Ar1is phenylene, monocyclic heteroarylene, or heterocyclylene where each of the aforementioned rings is substituted with Rk, Rm, and Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; or a pharmaceutically acceptable salt thereof.

[0030] In a second aspect, provided is a compound of Formula (IA): wherein: n, Z, alk, alk1, Ar, Ar1, Hy, R1, R2, and R2aare as defined in Formula (I) above; and Degron is an E3 ubiquitin ligase ligand; or a pharmaceutically acceptable salt thereof. In a third aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0031] In a fourth aspect, provided is a method of treating a disease mediated by CDK2 and / or CDK4 in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein below), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed herein. In a first embodiment of the fourth aspect, the disease is cancer. In a second subembodiment of the fourth aspect the disease is cancer selected from lung cancer (c.g, adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, and / or pleuropulmonary blastoma), skin cancer (c.g, melanoma, squamous cell carcinoma, Kaposi sarcoma, and / or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (c.g, cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, and / or mouth), liver cancer (e.g., hepatocellular carcinoma and / or cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g., exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, bone cancer, biliary tract cancer, vaginal cancer, astrocytoma, liposarcoma, glioblastoma, neuroblastoma and / or kidney cancer. In a third embodiment of the fourth aspect, the cancers are those that are resistant to CDK4 / 6 inhibitors through CDK2 -mediated mechanisms e.g., breast cancer. In a fourth embodiment of the fourth aspect, the disease is an autoimmune disease or a condition associated with an autoimmune disease, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein below), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed herein. In some embodiments, the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), uveitis, pemphigus vulgaris, and sepsis. In a fifth embodiment of the fourth aspect, the disease is gout. In a fifth aspect, provided is a method of treating noise-induced, ch emotherapy -induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss, which method comprises administering to a patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof as disclosed therein. In some embodiments, the amount of hearing loss is reduced when compared to an age-matched control. In some embodiments, the hearing loss is prevented when compared to an age-matched control.

[0032] In a sixth aspect, provided is a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof (or a pharmaceutical composition thereof disclosed herein) for use in therapy. In one embodiment of the sixth aspect, the compound of Formula (I) or (IA) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof is for use in the treatment of one or more of diseases disclosed in the fourth and fifth aspect above.

[0033] In a seventh aspect, provided is the use of a compound of Formula (I) or (IA) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK2 and / or CDK4 contributes to the pathology and / or symptoms of the disease. In one embodiment of the seventh aspect, the disease is one or more of diseases disclosed in the fourth and fifth aspects above.

[0034] In an eighth aspect, provided is a method of degrading CDK2 and / or CDK4 in a cell via ubiquitin proteasome pathway which method comprises contacting the cell with a compound of Formula (I) or (IA) (or embodiments thereof as disclosed herein). In one embodiment of the first and seventh aspects, the CDK2 and / or CDK4 are degraded in vitro. In another embodiment of the first and seventh aspects, the CDK2 and / or CDK4 are degraded in vivo. In yet another embodiment of the first and seventh aspects, the CDK2 and / or CDK4 are degraded in a cell of a patient.

[0035] In the aforementioned aspects involving the treatment of cancer, further embodiments are provided comprising administering the compound of first aspect and of Formula (I) or (IA), or a pharmaceutically acceptable salt thereof (or any embodiments thereof disclosed herein) or the pharmaceutical composition of the third aspect, in combination with at least one additional anticancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially. It has been surprisingly discovered that PROTACs of Formula (I) and (IA) containing -Z- (alk^-Ar^n-alk-Ar- linker can degrade CDK2 and CDK4 selectively over CDK1. The ability of compounds of Formula (I) and (IA) to degrade CDK2 and CDK4 selectively over CDK1 was measure by determining potency of the compounds in inhibiting retinoblastoma protein (Rb) phosphorylation in 0VCAR3 (CDK2 dependent cell line), T47D (CDK4 dependent cell line) and KYSE520 (CDK1 dependent cell line) as described in Biological Example 1 below, and then determining the ratio of Rb IC50 from 0VCAR3 and KYSE520 and T47D and KYSE520, respectively. Additionally, although the compounds of Formula (I) and (IA) degrade both CDK2 and CDK4, they can, however, selectively degrade CDK2 over CDK4 or visa-versa by determining the ratio of Rb IC50 from 0VCAR3 and T47D as described above or as described in Biological Example 2 below. For sake of clarity, selectively degrade as used herein means the compound disclosed herein may cause degradation of one protein to a greater extent than the other.

[0036] Detailed Description

[0037] Definitions:

[0038] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning:

[0039] “Alkyl” means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

[0040] “Alkenyl” means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like.

[0041] “Alkynyl” means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.

[0042] “Alkylene” means a linear or branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise stated. When alkylene contains three to six carbon atoms it is also referred to herein as C3 to C6 alkylene. Examples include, but are not limited to, methylene, ethylene, propylene, 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0043] “Alkynylene” means a linear or branched divalent hydrocarbon radical of two to eight carbon atoms containing a triple bond unless stated otherwise, e.g., , the like.

[0044] “Alkoxy” means a -ORPradical where Rpis alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or / c / V-butoxy, and the like. “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

[0045] “Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene.

[0046] “Aryloxy” means a -O-REradical where Rpis aryl as defined above e.g., phenyloxy (or phenoxy), or naphthyl oxy.

[0047] “Bridged heterocyclylene” means a saturated divalent bicyclic radical having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRpRp’)n2 group where n2 is an integer selected from 1 to 3 and Rpand Rp’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, NH, O, and S(O)ni, where nl is an integer selected from 0 to 2. Bridged heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to, 3,8- diazabicyclo[3.2.1]octa-3,8-diyl, 7-oxabicyclo[2.2.1]heptan-diyl, 2,5-diazabicyclo[2.2.1]heptan- diyl, 3,6-diazabicyclo-[3.1.1]heptan-diyl, 2,5-diazabicyclo[2.2.2]octan-diyl, 3,8- diazabicyclo[3.2.1]octan-diyl, 6-azabicyclo[3.1.1]heptan-diyl, 8-azabicyclo[3.2.1]octan-diyl, and the like.

[0048] “Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0049] “Cycloalkyloxy or cycloalkoxy” means a -ORPradical where Rpis cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0050] “Cycloalkylene” means a divalent saturated hydrocarbon radical of three to six carbon atoms, otherwise e.g., 1,1 -cyclopropylene, 1,1 -cyclobutylene, 1,4-cyclohexylene, and the like.

[0051] “Cyclylaminylene” means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one or two ring atoms are nitrogen, the remaining ring atoms being carbon. More specifically, the term cyclylaminylene includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, piperazinylene, and the like.

[0052] “Deuterium” means refers to2H or D.

[0053] “Fused heterocyclylene” means a divalent bicyclic radical in which two adjacent ring atoms of a saturated monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, NH, O, and S(O)ni(where nl is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl, or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom is optionally oxidized and further wherein one of the carbon ring atoms of the saturated monocyclic ring is optionally replaced by a -C(=O)- group. The fused heterocyclylene can be attached at any two atoms of the ring. Representative examples include, but are not limited to, 1, 2,3,4- tetrahydroquinolin-l,4-diyl, 3,4-dihydro-2H-benzo[b][l,4]oxazin-5,8-diyl, 3,4-dihydro-2H- pyrido[3,2-b][l,4]oxazin-diyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazin-diyl, and the like.

[0054] “Halo” means fluoro, chloro, bromo, or iodo, e.g., fluoro or chloro.

[0055] “Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.

[0056] “Haloalkoxy” means an -ORPradical where Rpis haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like. When Rpis haloalkyl where the alkyl is substituted with only fluoro (in some examples, one or more fluoro), it is referred to in this Application as fluoroalkoxy.

[0057] “Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, NH, O, and S, the remaining ring atoms being carbon, unless otherwise stated. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, indazolyl, imidazo[l,2-a]pyridinyl, imidazo[l,2-a]pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5- or 6 ring atoms and is a monocyclic ring, it is also referred to herein as “five or six” or “5-or 6”-membered monocyclic heteroaryl. When the heteroaryl ring contains 9- or 10 ring atoms, it is also referred to herein as 9-or 10-membered fused bicyclic heteroaryl.

[0058] “Heteroarylene” means a divalent heteroaryl radical as defined above, unless stated otherwise. Representative examples include, but are not limited to, benzimidazoldiyl e.g., benzimidazole-l,5-diyl, and the like. When the heteroarylene ring contains 5- or 6 ring atoms and is a monocyclic ring, it is also referred to herein as monocyclic heteroarylene or as 5-or 6-membered monocyclic heteroarylene e.g., pyrazolyl-diyl (pyrazolyl-1.3-diyl, pyrazolyl-1,4- diyl, pyrazolyl-1.5-diyl and the like) and imidazol-diyl (imidazol-l,2-diyl, imidazol-l,4-diyl, imidazol-l,5-diyl). When the heteroarylene ring contains 9- or 10 ring atoms fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroarylene.

[0059] “Heterocyclylene” means a saturated, divalent, monocyclic radical of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, NH, O, and S(O)ni, where nl is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclylene ring can optionally be replaced by a -C(=O)- group. More specifically, the term heterocyclylene includes, but is not limited to, , piperidin-l,4-diyl, azeti din- 1,3 -diyl, and the like.

[0060] “Bicyclic heterocyclylene” means a saturated or unsaturated, divalent fused bicyclic radical of 8 to 12 ring atoms in which one, two, or three ring atoms are heteroatoms independently selected from N, O, and S(O)ni, where nl is an integer selected from 0 to 2, the remaining ring atoms being carbon, unless stated otherwise. Additionally, one or two ring carbon atoms of the bicyclic heterocyclylene ring can optionally be replaced by a -CO- group. More specifically the term bicyclic heterocyclylene includes, but is not limited to, isoindolin- diyl, decahydro-2, 6-naphthyridin-diyl, octahydrocyclopenta[c]pyrrol-diyl, octahydro- 1H- pyrrolo[3,4-c]pyridin-diyl, hexahydrofuro[3,2-b]furan-3,6-diyl, and the like. When the heterocyclylene ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.

[0061] “Phenylene” means divalent phenyl.

[0062] The phrase “optionally” or “optional” as used herein means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase “alkylene optionally substituted with halo” is intended to cover alkylene that is unsubstituted and alkylene that is substituted with halo.

[0063] “Spiro heterocyclylene" means a saturated bicyclic divalent radical having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S(O)ni, where nl is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, 2-azaspiro[3.3]heptan- diyl, 2,6-diazaspiro[3.3]heptan-diyl, l,7-diazaspiro[3.5]nonan-diyl, 2,7-diazaspiro[3.5]nonan-diyl, 3,9-diazaspiro[5.5]undecan-diyl, and the like. “Unsaturated heterocyclylene” means divalent, monocyclic nonaromatic radical of 5 to 8 ring atoms having one, two, or three double bonds and in which one or two ring atoms are heteroatom(s) independently selected from N, O, and S(O)ni, where nl is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the unsaturated heterocyclylene ring can optionally be replaced by a -C(=O)- group. Representative examples include, but are not limited to,

[0064] The present disclosure also includes protected derivatives of compounds of Formula (I) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof. For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom(s), these groups can be protected with suitable protecting groups. A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5thEd., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

[0065] The present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or (IA) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof.

[0066] Certain compounds of the present disclosure 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. For example, a compound of Formula (I) (IA) having a hydroxy substituted pyridyl ring can exist as a tautomer as shown below:

[0067] The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

[0068] A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy- 2-ene-l -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, A-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington ’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0069] The compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may have asymmetric centers. Compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa.

[0070] Certain compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) are within the scope of this disclosure.

[0071] The compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question, that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present disclosure, such as a compound of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36C1,123I, and1251, respectively. Isotopically labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with (or isotopically enriched for) heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds, including in Table 1 below, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as150,13N,nC, and15F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0072] A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.

[0073] “A pharmaceutically acceptable carrier / excipienf ’ as used in the specification and claims includes both one and more than one such excipient. The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.

[0074] Certain structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent(s) may be present on any atom of the ring to which it is attached, where chemically feasible and valency rules permitting.

[0075] For example, in the structure: , the Raasubstituent, and similarly the Rbbsubstituent, can replace hydrogen of any CH that is part of the benzo portion of the bicyclic ring that is not already substituted with Rbb(in the case of Raa), and similarly with Raa(in the case of Rbb).

[0076] Additionally, as used throughout the application, including in the embodiments, when a group is drawn out as divalent, the left bond of the divalent group is attached to the group which is to its left in the remainder of the molecule, and the right bond of the divalent group is attached to the group which is to its right in the remainder of the molecule. For example, in Formula (I), in the following divalent groups: the bond on the left of (a) and (b) is attached to the following ring: and the * on the right side of (a) and (b) is attached to Z of the Formula (I) structure:

[0077] Degron z alk1-Ar1H— alk-

[0078] \ / n . Similarly, for -Z-falk'-Ar1)-alk-Ar-, the bond on left side (i.e., Z) is attached to the group on its left side i.e., ring A of formula (i) or ring B of formula (ii) and the bond on right side (i.e., Ar) is attached to -SO2- that is attached to an atom of Hy. For example, when n is 0, -Z-alk-Ar- is a group of formula:

[0079] (a) and the * bond of phenyl in -Z-alk-Ar- is attached to -SO2- that is attached to Hy.

[0080] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life. The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0081] 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.

[0082] “Treating” or “treatment” of a disease includes:

[0083] (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;

[0084] (2) inhibiting the disease, i.e., delaying, arresting (stabilizing), or reducing the development or severity of the disease or its clinical symptoms; or

[0085] (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0086] In one embodiment, treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0087] A “therapeutically effective amount” means the amount of a compound of the present disclosure and / or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0088] A “condition associated with an autoimmune disease” means a condition that a patient with an autoimmune disease is susceptible to, e.g., sepsis, or a condition that is caused by the autoimmune disease, e.g., uveitis.

[0089] The compounds of Formula (I) or (IA) can also inhibit CDK2 and / or CDK4. The term “inhibiting” and “reducing,” or any variation of these terms in relation of CDK2 and / or CDK4, includes any measurable decrease or complete inhibition of enzymatic activity of CDK2 and / or CDK4, respectively, to achieve a desired result. For example, a compound of Formula (I) or (IA) may decrease about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, of CDK2 and / or CDK4 activity, compared to their / its normal activity. In some embodiments, the CDK2 and / or CDK4 activity is reduced by at least 40% in the presence of a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 and / or CDK4, respectively, in the absence of said compound. The inhibitory activity of a compound of Formula (I) or (IA) can be measure using Biological Example 1, by converting a compound of Formula ( (I) or (IA) to a corresponding compound of Formula (I) or (IA) that cannot be degraded by the ubiquitin proteosome pathway e.g., by methylating the nitrogen atom in group of ligase ligand

[0090] (i) or (ii) present in the compound of Formula (I).

[0091] The term “degrading” and “degrade,” or any variation of these terms in relation of CDK2, CDK4, and CDK1, means any measurable decrease in the concentration of CDK2, CDK4, CDK1, and CDK6, respectively, in a sample over time. For example, there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, in CDK2 and CDK4 concentration in a sample containing CDK2 or CDK4, respectively and a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 or CDK4, in the absence of said compound. The % degradation can be determined as described in Biological Example 2 below. In one embodiment, the decrease in the concentration of CDK2 is > 20%. In one embodiment, the decrease in the concentration of CDK2 is > 40%. In one embodiment, the decrease in the concentration of CDK2 is > 50%. In one embodiment, the decrease in the concentration of CDK2 is > 60%. In one embodiment, the decrease in the concentration of CDK2 > 70%. In one embodiment, the decrease in the concentration of CDK2 is > 80%.

[0092] In one embodiment, the decrease in the concentration of CDK4 is > 20%. In one embodiment, the decrease in the concentration of CDK4 is > 40%. In one embodiment, the decrease in the concentration of CDK4 is > 50%. In one embodiment, the decrease in the concentration of CDK4 is > 60%. In one embodiment, the decrease in the concentration of CDK4 > 70%. In one embodiment, the decrease in the concentration of CDK4 is > 80%.

[0093] “E3 ubiquitin ligase” refers to a family of proteins that operate in conjunction with El ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzyme, assist or directly catalyze the covalent ligation of ubiquitin to a lysine residue of a substrate protein. E3 ubiquitin ligases directly bind to substrate proteins and thus confer substrate specificity for the ubiquitination process. Ubiquitination can serve as a versatile signal mark for substrate proteins, which are targeted to degradation by proteasome or other regulations ranging from translocation to transcription. The cereblon (CRBN) and von Hippel-Lindau (VHL) proteins are substrate recognition subunits of two 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 (R0C1). VHL is part of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbxl.

[0094] Embodiments:

[0095] Embodiment A

[0096] In embodiments Al to A145, the present disclosure includes:

[0097] Al. In embodiment Al, provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described in the first aspect of the Summary.

[0098] A2. In embodiment A2, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is halo.

[0099] A3. In embodiment A3, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is haloalkyl or haloalkoxy.

[0100] A4. In embodiment A4, the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R1is haloalkyl.

[0101] A5. In embodiment A5, the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R1is haloalkoxy.

[0102] A6. In embodiment A6, the compound of any one of embodiments Al to A5, or a pharmaceutically acceptable salt thereof, is wherein R1is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, di fluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy, unless stated otherwise.

[0103] A7. In embodiment A7, the compound of any one of embodiments Al to A6, or a pharmaceutically acceptable salt thereof, is wherein R1is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy, unless stated otherwise.

[0104] A8. In embodiment A8, the compound of any one of embodiments Al, A2, A6 and A7, or a pharmaceutically acceptable salt thereof, is wherein R1is chloro or bromo. A9. In embodiment A9, the compound of any one of embodiments Al, A3, A4, A6, and A7, or a pharmaceutically acceptable salt thereof, is wherein R1is difluoromethyl or tri fluoromethyl.

[0105] A10. In embodiment A10, the compound of any one of embodiments Al, A3, A4, A6, A7, and A9, or a pharmaceutically acceptable salt thereof, is wherein R1is trifluoromethyl.

[0106] Al l. In embodiment Al l, the compound of any one of embodiments Al, A3, and A5 to A7, or a pharmaceutically acceptable salt thereof, is wherein R1is difluoromethoxy or trifluoromethoxy .

[0107] A12. In embodiment A12, the compound of any one of embodiments Al, A3, A5 to A7, and Al 1, or a pharmaceutically acceptable salt thereof, is wherein R1is difluoromethoxy.

[0108] A13. In embodiment A13, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is alkyl, alkenyl, or alkynyl.

[0109] A14. In embodiment A14, the compound of embodiment Al or A13, or a pharmaceutically acceptable salt thereof, is wherein R1is methyl, ethyl, propyl, vinyl, propenyl, ethynyl, or propynyl.

[0110] A15. In embodiment A15, the compound of embodiment Al, A13, or A14, or a pharmaceutically acceptable salt thereof, is wherein R1is methyl, ethyl, or propyl.

[0111] A16. In embodiment A16, the compound of embodiment Al, A13, or A14, or a pharmaceutically acceptable salt thereof, is wherein R1is vinyl, propenyl, ethynyl, or propynyl.

[0112] A17. In embodiment A17, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is alkoxy.

[0113] A18. In embodiment A18, the compound of embodiment Al, or A17, or a pharmaceutically acceptable salt thereof, is wherein R1is methoxy, ethoxy, or propoxy.

[0114] A19. In embodiment A19, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is aryloxy. In a subembodiment of Al 9, R1is phenoxy.

[0115] A20. In embodiment A20, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is cyano.

[0116] A21. In embodiment A21, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyl. In a subembodiment of A21, R1is cyclopropyl.

[0117] A22. In embodiment A22, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyl substituted with one to three halo. In a subembodiment of A22, R1is fluorocyclopropyl or difluorocyclopropyl. A22a. In embodiment A22a, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyloxy. In a subembodiment of A22a, R1is cyclopropyloxy.

[0118] A22b. In embodiment A22b, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyloxy substituted with one to three halo. In a subembodiment of A22b, R1is fluorocyclopropyloxy or difluorocyclopropyloxy.

[0119] A23. In embodiment A23, the compound of any one of embodiments Al to A22b, or a pharmaceutically acceptable salt thereof, is wherein R2and R2aare hydrogen.

[0120] A24. In embodiment A24, the compound of any one of embodiments Al to A22b, or a pharmaceutically acceptable salt thereof, is wherein one of R2and R2ais deuterium and the other of R2and R2ais hydrogen or both R2and R2aare deuterium.

[0121] A25. In embodiment A25, the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof, is wherein Hy is heterocyclylene, arylene is phenylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0122] A26. In embodiment A26, the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is heterocyclylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0123] A27. In embodiment A27 , the compound of any one of embodiments Al to A26, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is pyrrolidin-1,3- diyl or piperidin-l,4-diyl, each ring being substituted with Ra, Rb, and Rcwhere Raand Rbare independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy, Rcis hydrogen, and -SO2- is attached to the nitrogen atom of the piperidin-l,4-diyl or pyrrolidin-l,3-diyl ring of Hy.

[0124] A28. In embodiment A28, the compound of any one of embodiments Al to K 1 or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: where the N atom of the pyrrolidin- 1,3 -diyl or piperidin-l,4-diyl rings is attached to -SO2-. A29. In embodiment A29, the compound of any one of embodiments Al to A28, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: where the N atom of the pyrrolidin- 1,3 -diyl or piperidin-l,4-diyl rings is attached to -SO2-.

[0125] A29a. In embodiment A29a, the compound of any one of embodiments Al to A29, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: where the N atom of the piperidin-l,4-diyl ring is attached to -SO2-.

[0126] A30. In embodiment A30, the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is bridged heterocyclylene substituted with Ra, Rb, and Rcwhere Rcis hydrogen.

[0127] A31. In embodiment A31, the compound of any one of embodiments Al to A25 and A30, or a pharmaceutically acceptable salt thereof, is wherein the bridged heterocyclylene of Hy is a ring of formula: where each ring is substituted with Ra, Rb, and Rcwhere Rcis hydrogen, and the nitrogen atom of each ring is attached to -SO2-.

[0128] A32. In embodiment A32, the compound of embodiment A30 or A31, or a pharmaceutically acceptable salt thereof, is wherein Raand Rbare independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy.

[0129] A33. In embodiment A33, the compound of embodiment A30, A31, or A32, or a pharmaceutically acceptable salt thereof, is wherein Rbis hydrogen.

[0130] A34. In embodiment A34, the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is cycloalkylene substituted with Ra, Rb, and Rcwhere Rais deuterium, methyl, fluoro, methoxy, or hydroxy and Rband Rcare hydrogen. A35. In embodiment A35, the compound of any one of embodiments Al to A25 and A34, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is cyclohexylene.

[0131] A36. In embodiment A36, the compound of any one of embodiments Al to A25, A34, and A35, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is denotes the bond of -SO2-.

[0132] A37. In embodiment A37, the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is arylene wherein the arylene is phenylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0133] A38. In embodiment A38, the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is spiro heterocyclylene (such as 2-azaspiro[3.3]heptan-2-yl) substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0134] A39. In embodiment A39, the compound of embodiment A37, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Hy is 1,4-phenylene according to structure denotes the bond to -SO2- where Rais hydrogen, fluoro, methyl or methoxy and Rbis hydrogen.

[0135] A39a. In embodiment A39a, the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof, is wherein Hy is fused heterocyclylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0136] A39b. In embodiment A39b, the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof, is wherein Hy is bicyclic heterocyclylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0137] A39c. In embodiment A39c, the compound of any one of embodiments Al to A24, or a pharmaceutically acceptable salt thereof, is wherein Hy is heteroarylene substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0138] A40. In embodiment A40, the compound of any one of embodiments Al to A39c, or a pharmaceutically acceptable salt thereof, is wherein Degron is an E3 ubiquitin ligase ligand of formula (i):

[0139] A41. In embodiment A41, the compound of any one of embodiments Al to A40, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a):

[0140] A42. In embodiment A42, the compound of any one of embodiments Al to A41, or a pharmaceutically acceptable salt thereof, is wherein R4and R5are independently hydrogen or alkyl.

[0141] A43. In embodiment A43, the compound of any one of embodiments Al to A42, or a pharmaceutically acceptable salt thereof, is wherein R4and R5are hydrogen.

[0142] A44. In embodiment A44, the compound of any one of embodiments Al to 42, or a pharmaceutically acceptable salt thereof, is wherein R4is hydrogen and R5is methyl.

[0143] A45. In embodiment A45, the compound of any one of embodiments Al to A41, or a pharmaceutically acceptable salt thereof, is wherein R4and R5together with the carbon to which they are attached form >C =0.

[0144] A46. In embodiment A46, the compound of any one of embodiments Al to A40, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b): . In a subembodiment of A46, M is -NR6-.

[0145] A47. In embodiment A47, the compound of any one of embodiments Al to A40 and A46, or a pharmaceutically acceptable salt thereof, is wherein R6is hydrogen.

[0146] A48. In embodiment A48, the compound of any one of embodiments Al to A40 and A46, or a pharmaceutically acceptable salt thereof, wherein R6is alkyl. In a subembodiment of

[0147] A48, R6is methyl.

[0148] A49. In embodiment A49, the compound of any one of embodiments Al to A48, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[0149] A50. In embodiment A50, the compound of any one of embodiments Al to A49, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is: A51. In embodiment A51, the compound of any one of embodiments Al to A50, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: A52. In embodiment A52, the compound of any one of embodiments Al to A51, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rbb, Rcc, and Rddare hydrogen. A52a. In embodiment A52a, the compound of any one of embodiments Al to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rbbis hydrogen. A53. In embodiment A53, the compound of any one of embodiments Al to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rbbis hydrogen.

[0150] A54. In embodiment A54, the compound of any one of embodiments Al to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rbbis hydrogen.

[0151] A55. In embodiment A55, the compound of any one of embodiments Al to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Raaand Rbbare hydrogen.

[0152] A56. In embodiment A56, the compound of any one of embodiments Al to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rccand Rddare hydrogen.

[0153] A57. In embodiment A57, the compound of any one of embodiments Al to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: i.e., where Rccand Rddare hydrogen. A58. In embodiment A58, the compound of any one of embodiments Al to A54, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy, unless stated otherwise i.e., in embodiment A52, Rbb, Rcc, and Rddare hydrogen and A52a to A54, Rbbis hydrogen.

[0154] A59. In embodiment A59, the compound of any one of embodiments Al to A54, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano, unless stated otherwise.

[0155] A60. In embodiment A60, the compound of any one of embodiments Al to A54, A58, and A59, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy, unless stated otherwise.

[0156] A61. In embodiment A61, the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen and methyl, unless stated otherwise.

[0157] A62. In embodiment A62, the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen and methoxy, unless stated otherwise.

[0158] A63. In embodiment A63, the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen and fluoro, unless stated otherwise.

[0159] A64. In embodiment A64, the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, trifluoromethyl, and difluoromethyl, unless stated otherwise.

[0160] A65. In embodiment A65, the compound of any one of embodiments Al to A54, A58, and A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen and trifluoromethoxy, unless stated otherwise.

[0161] A66. In embodiment A66, the compound of any one of embodiments Al to A54, and A58 to A60, or a pharmaceutically acceptable salt thereof, is wherein Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, fluoro, and trifluoromethyl, unless stated otherwise.

[0162] A67. In embodiment A67, the compound of any one of embodiments Al to A39c, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (ii):

[0163] A68. In embodiment A68, the compound of any one of embodiments Al to A39c and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Yais CH.

[0164] A69. In embodiment A69, the compound of any one of embodiments Al to A39c and A41 to A67, or a pharmaceutically acceptable salt thereof, is wherein Yais N.

[0165] A70. In embodiment A70, the compound of any one of embodiments Al to A39c and A41 to A69, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond, -NH-, -O-, or -NHC(O)-.

[0166] A71. In embodiment A71, the compound of any one of embodiments Al to A39c and A41 to A70, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond, -NH-, or -NHC(O)-.

[0167] A72. In embodiment A72, the compound of any one of embodiments Al to A39c and A41 to A71, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond.

[0168] A73. In embodiment A73, the compound of any one of embodiments Al to A39c and A41 to A71, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-, or -NHC(O)-.

[0169] A74. In embodiment A74, the compound of any one of embodiments Al to A39c, A41 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-.

[0170] A74a. In embodiment A74a, the compound of any one of embodiments Al to A39c, A41 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Zais -NHC(O)-.

[0171] A75. In embodiment A75, the compound of any one of embodiments Al to A39c and A41 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is phenylene substituted with Reeand Rff.

[0172] A76. In embodiment A76, the compound of any one of embodiments Al to A39c, and A41 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is cyclylaminylene substituted with Reeand Rff.

[0173] A77. In embodiment A77, the compound of any one of embodiments Al to A39c and A41 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with Reeand Rff. A78. In embodiment A78, the compound of any one of embodiments Al to A39c, A41 to A74a, and A77, or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with Reeand Rff.

[0174] A79. In embodiment A79, the compound of any one of embodiments Al to A39c, A41 to A74a, and A77, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms and substituted with Reeand Rff.

[0175] A80. In embodiment A80, the compound of any one of embodiments Al to A39c, A41 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted with Reeand Rff.

[0176] A81. In embodiment A81, the compound of any one of embodiments Al to A39c and A41 to A80, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:

[0177] A82-1. In embodiment A82-1, the compound of any one of embodiments Al to A39c and A41 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:

[0178] where ring B is cyclylaminylene. For sake of clarity, it is to be understood that Reeand / or Rffare / is hydrogen when they are / is not drawn out in a structure of A82-1. A82. In embodiment A82, the compound of any one of embodiments Al to A39c and

[0179] A41 to A82-1, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is: where ring B is cyclylaminylene. As noted in the previous embodiment, Rffis hydrogen when it is not drawn out in a structure of A82. A82A. In embodiment A82A, the compound of any one of embodiments Al to A39c and A41 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula

[0180] A83. In embodiment A83, the compound of any one of embodiments Al to A39c and

[0181] A41 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:

[0182] A83A. In embodiment A83A, the compound of any one of embodiments Al to A39c and

[0183] A41 to A83, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula A84. In embodiment A84, the compound of any one of embodiments Al to A39c and

[0184] A41 to A83 A, or a pharmaceutically acceptable salt thereof, is wherein each Reeand Rffare independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy unless stated otherwise.

[0185] A85. In embodiment A85, the compound of any one of embodiments Al to A39c and A41 to A84, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano unless stated otherwise.

[0186] A86. In embodiment A86, the compound of any one of embodiments Al to A39c and A41 to A85, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano unless stated otherwise.

[0187] A87. In embodiment A87, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, and isopropyl unless stated otherwise.

[0188] A88. In embodiment A88, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen and methoxy unless stated otherwise.

[0189] A89. In embodiment A89, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro unless stated otherwise.

[0190] A90. In embodiment A90, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein one of Reeand Rffis hydrogen or fluoro and the other of Reeand Rffis selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl unless stated otherwise.

[0191] A91. In embodiment A91, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy unless stated otherwise.

[0192] A92. In embodiment A92, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, chloro, fluoro, and trifluoromethyl unless stated otherwise.

[0193] A93. In embodiment A93, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare hydrogen. A94. In embodiment A94, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare chloro unless stated otherwise.

[0194] A95. In embodiment A95, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare fluoro unless stated otherwise.

[0195] A96. In embodiment A96, the compound of any one of embodiments Al to A39c and A41 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently trifluoromethyl or 2,2,2-trifluoroethyl unless stated otherwise.

[0196] A97a. In embodiment A97a, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein Ar is phenylene, monocyclic heteroarylene, bridged heterocyclylene, heterocyclylene, or unsaturated heterocyclylene, where each ring is substituted with Rh, R1, and R1where R1is hydrogen.

[0197] A97. In embodiment A97, the compound of any one of embodiments Al to A97a, or a pharmaceutically acceptable salt thereof, is wherein Ar is phenylene, monocyclic heteroarylene, bridged heterocyclylene, or heterocyclylene, where each ring is substituted with Rh, R1, and R1where R> is hydrogen.

[0198] A98. In embodiment A98, the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is phenylene of formula or phenylene where alk and SO2 are attached at meta position or para position of the phenylene ring) substituted with Rh, R1, and R1where Rhand R1are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy and R> is hydrogen.

[0199] In one embodiment of A98, Ar is phenylene of formula substituted with Rh, R1, and

[0200] R> as defined therein.

[0201] A99. In embodiment A99, the compound of any one of embodiments Al to A98, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is or L

[0202] ' substituted with Rh, R1, and R1where Rhand R1are independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy (unless otherwise stated) and R> is hydrogen.

[0203] Al 00. In embodiment Al 00, the compound of any one of embodiments Al to A99, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is or QL

[0204] ' substituted with Rh, R1, and R1where Rhand R1independently selected from hydrogen, fluoro, cyano, and trifluoromethyl and R> is hydrogen.

[0205] A101-1. In embodiment A101-1, the compound of any one of embodiments Al to

[0206] Al 00, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is

[0207] A101. In embodiment A101, the compound of any one of embodiments Al to

[0208] Al 00, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Ar is

[0209] Al 02. In embodiment Al 02, the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is monocyclic heteroarylene (such as imidazol-l,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-2,5-diyl, or pyri din-3, 5 -diyl) substituted with Rh, R1, and R1where Rhand R1are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, cyano, and haloalkoxy and R> is hydrogen.

[0210] A103. In embodiment A103, the compound of any one of embodiments Al to A97, and A99 to Al 02, or a pharmaceutically acceptable salt thereof, is wherein the monocyclic heteroarylene of Ar is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-2,5-diyl, or pyridin-3,5-diyl, each ring substituted with Rh, R1, and R1where Rhand R1are independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy and R' is hydrogen. Al 04. In embodiment Al 04, the compound of any one of embodiments Al to A97 and A99 to A103, or a pharmaceutically acceptable salt thereof, is wherein the monocyclic heteroarylene of Ar is imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each ring substituted with Rh, R1, and R1where Rhand R1are independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and R> is hydrogen.

[0211] Al 05. In embodiment Al 05, the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is heterocyclylene substituted with Rh, R1, and R> where Rhand R1are independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy and R> is hydrogen.

[0212] Al 06. In embodiment Al 06, the compound of any one of embodiments Al to A97, A99 to A101, and A103 to A105, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Ar is divalent azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl.

[0213] A107. In embodiment A107, the compound of any one of embodiments Al to A97, or a pharmaceutically acceptable salt thereof, is wherein Ar is bridged heterocyclylene.

[0214] A108a. In embodiment A108a, the compound of any one of embodiments Al to A97a, or a pharmaceutically acceptable salt thereof, is wherein Ar is unsaturated heterocyclylene substituted with Rh, R1, and R1where R1is hydrogen.

[0215] A108b. In embodiment A108b, the compound of any one of embodiments Al to A97a, A99 to A101, A103, A104, A106, and 108a, or a pharmaceutically acceptable salt thereof, is wherein the unsaturated heterocyclylene

[0216] A108. In embodiment A108, the compound of any one of embodiments Al to A97, A99 to A101, A103, A104, A106, and A107 or a pharmaceutically acceptable salt thereof, is wherein the bridged heterocyclylene of Ar is selected from:

[0217] Al 09. In embodiment Al 09, the compound of any one of embodiments Al to Al 08, or a pharmaceutically acceptable salt thereof, is wherein Z is cycloalkylene selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene and substituted with Rdand Reas defined therein. A110. In embodiment Al 10, the compound of any one of embodiments Al to Al 09, or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Z is independently selected from 1,3-cyclopentylene, 1,3-cyclohexylene, and 1,4-cyclohexylene.

[0218] Al l i. In embodiment Al l i, the compound of any one of embodiments Al to Al 08 and A110, or a pharmaceutically acceptable salt thereof, is wherein Z is phenylene or monocyclic heteroarylene (such as imidazoldiyl, pyridindiyl and pyrimidindiyl) and substituted with Rdand Reas defined therein.

[0219] A112. In embodiment Al 12, the compound of any one of embodiments Al to A108, and Al 11, or a pharmaceutically acceptable salt thereof, is wherein Z is monocyclic heteroarylene selected from imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, and pyri din-3, 5 -diyl.

[0220] Al 13. In embodiment Al 13, the compound of any one of embodiments Al to A108 and Al 11, or a pharmaceutically acceptable salt thereof, is wherein Z is 1,3-phenylene or 1,4-phenylene.

[0221] Al 14. In embodiment Al 14, the compound of any one of embodiments Al to A108, or a pharmaceutically acceptable salt thereof, is wherein Z is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, each ring substituted with Rdand Reas defined therein.

[0222] Al 15. In embodiment Al 15, the compound of any one of embodiments Al to Al 08 and Al 14, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z are selected from: wherein each ring is substituted with Rdand Reindependently selected from hydrogen, deuterium, alkyl, and halo. Al 16. In embodiment Al 16, the compound of any one of embodiments Al to Al 08, Al 14, and Al 15, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z are independently selected from: respectively.

[0223] Al 17. In embodiment Al 17, the compound of any one of embodiments Al to A108 and Al 14 to Al 16, or a pharmaceutically acceptable salt thereof, is wherein Z is heterocyclylene selected from: Al 18. In embodiment Al 18, the compound of any one of embodiments Al to A108 and

[0224] Al 14 to Al 17, or a pharmaceutically acceptable salt thereof, is wherein Z is heterocyclylene,

[0225] Al 19. In embodiment Al 19, the compound of any one of embodiments Al to Al 08 or a pharmaceutically acceptable salt thereof, is wherein Z is -O-, -NH-, or -NCH3-. A120. In embodiment A120, the compound of any one of embodiments Al to A98 and

[0226] Al 14, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar-SCh- is:

[0227] wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and R1and R1are hydrogen.

[0228] A121. In embodiment A121, the compound of any one of embodiments Al to A98, Al 14, and A120, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar-SCh- is: wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and R1and R1are hydrogen.

[0229] A122. In embodiment A122, the compound of any one of embodiments Al to A98, Al 14, and A120, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar-SCh- is: wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and R1and R1are hydrogen.

[0230] A123. In embodiment A123, the compound of any one of embodiments Al to A98, Al 14, A120, and A121, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rd, Re, and Rhare as defined therein.

[0231] A124. In embodiment A124, the compound of any one of embodiments Al to A98, Al 14, A120, and A121, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rd, Re, and Rhare as defined therein.

[0232] A125. In embodiment A125, the compound of any one of embodiments Al to A98, Al 14, A120, and A121, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rd, Re, and Rhare as defined therein.

[0233] A126. In embodiment A126, the compound of any one of embodiments Al to A98, Al 14, A120, and A121, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rhis as defined therein.

[0234] A127. In embodiment A127, the compound of any one of embodiments Al to A98, Al 14, A120, and A121, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rd, Re, and Rhare as defined therein.

[0235] A128. In embodiment A128, the compound of any one of embodiments Al to A98, Al 14, A120, and A122, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rd, Re, and Rhare as defined therein.

[0236] A129. In embodiment A129, the compound of any one of embodiments Al to A98, Al 14, A120, and A122, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rd, Re, and Rhare as defined therein.

[0237] A130. In embodiment A130, the compound of any one of embodiments Al to A98, Al 14, A120, and A122, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rd, Re, and Rhare as defined therein.

[0238] A131. In embodiment A131, the compound of any one of embodiments Al to A98, Al 14, A120, and A122, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rhis as defined therein. A132. In embodiment A132, the compound of any one of embodiments Al to A98, Al 14, A120, and A122, or a pharmaceutically acceptable salt thereof, is wherein n is 0 and -Z-alk-Ar- SO2- is: wherein Rhis as defined therein.

[0239] A133. In embodiment A133, the compound of any one of embodiments Al to A98 and Al 14, or a pharmaceutically acceptable salt thereof, is wherein n is i and -Z-alk^Ar1- alk-Ar- SO2- is: wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and R1and R1are hydrogen.

[0240] A134a.In embodiment A134a, the compound of any one of embodiments Al to A98, Al 14, and A133, or a pharmaceutically acceptable salt thereof, is wherein n is 1 and -Z-alkkAr1- alk-Ar-SCh- is:

[0241] wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and R1and R1are hydrogen.

[0242] A134. In embodiment A134, the compound of any one of embodiments Al to A98, Al 14, and A133, or a pharmaceutically acceptable salt thereof, is wherein n is i and -Z-alkkArkalk-Ar-

[0243] SO2- is: wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and and R1and R1are hydrogen. A135. In embodiment A135, the compound of any one of embodiments A120, A121,

[0244] A123 to A127, A133, and A134a, or a pharmaceutically acceptable salt thereof, is wherein

[0245] A136. In embodiment A136, the compound of any one of embodiments A120, A121, A123 to A127, A133 and A134a, or a pharmaceutically acceptable salt thereof, is wherein A137. In embodiment A137, the compound of any one of embodiments Al to Al 19 and

[0246] A133 to 136, or a pharmaceutically acceptable salt thereof, is wherein alk1is absent.

[0247] A138. In embodiment A138, the compound of any one of embodiments Al to Al 19 and A133 to 136, or a pharmaceutically acceptable salt thereof, is wherein alk1is methylene, ethylene, propylene. A139a.In embodiment A139a, the compound of any one of embodiments Al to Al 19 and

[0248] A133 to 138, or a pharmaceutically acceptable salt thereof, is wherein -Ar1- is selected from:

[0249]

[0250] A139. In embodiment A139, the compound of any one of embodiments A120 to A125, A128 to A130, and A133 to 138, or a pharmaceutically acceptable salt thereof, is wherein Rdand Reare hydrogen.

[0251] A140. In embodiment A140, the compound of any one of embodiments Al to A139, or a pharmaceutically acceptable salt thereof, is wherein alk is alkynylene substituted with Rfand Rgindependently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano.

[0252] A140-1. In embodiment A140-1, the compound of any one of embodiments Al to A140, or a pharmaceutically acceptable salt thereof, is wherein alk is alkynylene substituted with Rfand Rgindependently selected from hydrogen, fluoro, difluoromethyl, trifluoromethyl, hydroxy, methoxy, and cyano.

[0253] A140-2. In embodiment A140-2, the compound of any one of embodiments Al to A139, or a pharmaceutically acceptable salt thereof, is wherein alk is alkynylene substituted with Rfand Rgwhich are attached to the same carbon atom of the alkynylene and are combined with the carbon to which they are attached to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R7and R8independently selected from hydrogen, alkyl, and halo.

[0254] A140-3. In embodiment Al 140-3, the compound of any one of embodiments Al to A140-2, or a pharmaceutically acceptable salt thereof, is wherein alk is:

[0255] .A141. In embodiment

[0256] A141, the compound of any one of embodiments Al to A140-1 and 140-3, or a pharmaceutically acceptable salt thereof, is wherein alk is:

[0257] A142. In embodiment A142, the compound of any one of embodiments Al to A140-1,

[0258] A140-3, and A141, or a pharmaceutically acceptable salt thereof, is wherein alk is A142-1. In embodiment A142-1, the compound of any one of embodiments Al to A43, A45, A46, A48 to A56, A58 to A74, A75, A77 to A82, A83 to A93, and A97a to A142, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand selected from: where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and Rffis hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0259] A143. In embodiment A143, the compound of any one of embodiments Al to A43, A45, A46, A48 to A56, A58 to A74, A75, A77 to A82, A83 to A93, and A97a to A142, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand selected from: where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and Rffis hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. A144. In embodiment A144, the compound of any one of embodiments Al to A43, A45, A46, A48 to A56, A58 to A67, A69 to A72, A77, A79 to A82, A83 to A87, A89, and A97a to A143, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ligase ligand selected from:

[0260] A145. In embodiment A145, the compound of embodiment A143, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, preferably methyl.

[0261] “Unless stated otherwise” as used in the embodiments means that when an embodiment refers to more than one preceding embodiment of varying scopes, only those groups that fall within the scope of group(s) recited in a preceding embodiment s) should be selected from the embodiment referring thereto. For example, of the groups recited in embodiment A6, while all the recited groups in A6 should be selected for embodiment Al, only fluoro, chloro, and bromo should be selected for embodiment A2 as scope of A2 is limited to halo; and only difluoromethyl, trifluoromethyl, di fluoroethyl, and trifluoroethyl should be selected for embodiment A4 as scope of A4 is limited to haloalkyl.

[0262] Furthermore, in the embodiments above, reference to an embodiment includes combination with a subembodiment thereof. For example, reference to embodiment A19, includes independent combination with subembodiment of embodiment Al 9.

[0263] Embodiment B:

[0264] Bl. In embodiment Bl, provided is a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, as described in the second aspect of the Summary where n is 0. B2-B22b. In embodiments B2-B22b, provided is a compound of Formula (IA), or a pharmaceutically acceptable salt thereof, wherein R1is as provided in embodiments A2 to A22b, respectively.

[0265] B23-B24. In embodiments B23 and B24, provided is a compound of any one of embodiments Bl to B22b, or a pharmaceutically acceptable salt thereof, wherein R2and R2aare as provided in embodiments A23 and A24, respectively.

[0266] B26 to B39c. In embodiments B26 to B39c, provided is a compound of any one of embodiments Bl to B24, or a pharmaceutically acceptable salt thereof, wherein Hy is as provided in embodiments A26 to A39c, respectively.

[0267] B40 to B55. In embodiments B40 to B55, provided is a compound of any one of embodiments Bl to B39c, or a pharmaceutically acceptable salt thereof, wherein Ar is as provided in embodiments A97a to Al 08, respectively.

[0268] B56 to B66. In embodiments B56 to B66, provided is a compound of any one of embodiments Bl to B55, or a pharmaceutically acceptable salt thereof, wherein Z is as provided in embodiments Al 09 to Al 19, respectively.

[0269] B67 to B79. In embodiments B67 to B79, provided is a compound of any one of embodiments Bl to B39c, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SCh- is as provided in embodiments A120 to A132, respectively.

[0270] B80 and B81. In embodiments B80 and B81, provided is a compound of any one of embodiments B67, B68, and B70 to B74, or a pharmaceutically acceptable salt thereof, wherein is as provided in embodiments A135 and A136, respectively.

[0271] B82 to B87. In embodiments B82 to B87, provided is a compound of any one of embodiments Bl to B81, or a pharmaceutically acceptable salt thereof, wherein -alk- is as provided in embodiments A140 to A142, respectively.

[0272] Representative compounds of Formula (I) and (IA) are shown in Compound Table 1 below:

[0273] Table 1

[0274] Contemplated compounds are disclosed in Table 2 below:

[0275] Table 2

[0276]

[0277] General Synthetic Scheme

[0278] Compounds Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) can be made by the methods depicted in the reaction schemes shown below.

[0279] The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0280] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.

[0281] Compounds of Formula (I), where Degron is an E3 ligase ligand of formula (i) and (ii) and Hy, R1, R2, R2a, Ar, alk, n is 0, and Z are as defined in the Summary or an embodiment thereof hereinabove, can be prepared as described in Scheme 1. Scheme 1

[0282] Treatment of a pyrimidine of formula 1-2 where A1is a halogen such as chlorine, or bromine, with an amine of formula 1-1 where Degron, Hy, R1, R2, R2a, Ar, alk, and Z are as defined in the Summary or an embodiment thereof hereinabove, under suitable conditions such as acidic, basic or transition metal catalyzed reaction conditions well known in the art, provides a compound of Formula (I).

[0283] Alternatively, a compound of Formula (I) such as where n is 0, R2ais hydrogen, Hy is 1,4-piperidindiyl, Degron is a group of formula (i) and alk is attached to Degron (i) via heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, each ring containing at least one nitrogen ring atom, can be synthesized as illustrated and described in Scheme 2.

[0284] Scheme 2

[0285] Treatment of a pyrimidine of formula 2-1 where A1is a halogen such as chlorine, or bromine and R1and R2are defined in the Summary or an embodiment thereof hereinabove, with a piperidine amine of formula 2-2 under conditions well known in the art, such as in the presence of DIPEA in tert-butanol at elevated temperature, provides a compound of formula 2-3. An amine compound of formula 2-4, prepared by removal of the Boc protecting group of 2-3 in the presence of an acid, such as TFA, is converted to a sulfonamide compound of formula 2-6 by treating it with a sulfonyl halide of formula 2-5 where A2is halogen such as chlorine and LG is a suitable leaving group such as halo or methylsulfonyl and Ar and alk are as defined in the Summary or an embodiment thereof hereinabove. Treatment of a compound of formula 2-6 with an amine compound of formula 2-7 where is heterocyclyl, bridged heterocyclyl or spiro heterocyclyl containing at least one nitrogen atom, where ring A is defined as in the Summary or an embodiment thereof hereinabove, under basic conditions such as in the presence of DIPEA, provides a compound of Formula (I).

[0286] Compounds of formula 2-1, 2-5, and 2-7 are either commercially available or they can be prepared by methods known in the art.

[0287] Alternatively, a compound of Formula (I) such as where n is 0, R2ais hydrogen, Degron is a group of formula (i) and alk is attached to Degron of formula (i) via heterocyclylene such as 4-piperidin-l-yl, can be synthesized as illustrated and described in Scheme 3.

[0288] Scheme 3

[0289] Cross coupling of a compound of formula 3-1, where A2is a halogen and ring A is as defined in the Summary or an embodiment thereof hereinabove, with a tetrahydropiperidinyl of formula 3-2 where M1is a metal, such as boronic ester or zinc, provides a compound of formula 3-3. The reaction typically proceeds in the presence of a palladium catalyst; for example, when M1is a boronic ester, a Suzuki reaction is conducted in the presence of Pd(dppf)C12 and Na2COs, in 1,4-di oxane and water. Reduction of the double bond in compound 3-3 under conditions well known in the art, such as in the presence of a palladium catalyst and under hydrogen atmosphere, provides compound of formula 3-4. Removal of the Boc protection group of 3-4 under acidic conditions provides an amine compound of formula 3-5. Reaction of 3-5 with an aldehyde of formula 3-6 where Ar is as defined in the Summary or an embodiment thereof hereinabove and -[alk]n-i is alk as defined in the Summary or an embodiment thereof hereinabove except having one less carbon atom, under conditions well known in the art in the presence of a reducing agent, such as NaBH(OAc)s, in a suitable solvent, such as DCM, provides compound of formula 3-7. Removal of the Boc protecting group in compound 3-7 using an acid like TFA provides an amine compound of formula 3-8. Treatment of compound 3-8 with a compound of formula 2-1 under suitable conditions such as acidic, basic or transition metal catalyzed reaction conditions well known in the art, provides a compound of Formula (I).

[0290] Alternatively, a compound of Formula (I) such as where R2ais hydrogen, Degron is a group of formula (i) and alk is attached to Degron of formula (i) via heterocyclylene such as 4-piperidin-l-yl, alk is 2,4-but-3-yndiyl, can be synthesized as illustrated and described in Scheme 4.

[0291] Scheme 4

[0292] Treatment of an alkyne containing compound 3-5, where LG is a suitable leaving group, such as chlorine or bromine, with an amine of formula 3-5 under basic or catalytic conditions known in the art provides an alkyne of formula 4-3. Coupling between alkyne 4-3 and compound of formula 4-5, where A2is a halogen such as bromine or iodine, gives compound of formula 4-6, under conditions known in the art, such as a Sonogashira coupling in the presence of a palladium catalyst, a copper (I) cocatalyst, and an amine base. Formula (I) can be prepared from compound of formula 2-1 by proceeding analogously as described in Scheme 3.

[0293] Compounds of formula 3-5, 4-5, and 2-1 are either commercially available or they can be prepared by methods known in the art.

[0294] Utility

[0295] The compound of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) i.e., compound of this disclosure cause degradation of CDK2 and CDK4 proteins and hence are useful in the treatment of diseases mediated by CDK2 and / or CDK4.

[0296] Increasing evidence suggests that overactivated CDK2 and / or CDK4 leads to abnormal cell cycle regulation and proliferation in cancer cells. While CDK2 / 4 mutations are rarely found, the kinase activity of CDK4 / Cyclin D, CDK2 / Cyclin E or CDK2 / Cyclin A complexes is elevated via several mechanisms in human cancers. Aberrations of CDK4 / cyclin D regulation have been identified in many human cancers. For example, amplification or overexpression of cyclin DI has been found in many cancers, including breast invasive ductal carcinoma, invasive breast carcinoma, bladder urothelial carcinoma, breast invasive lobular carcinoma, and lung adenocarcinoma. Translocation of cyclin DI Amplification of CDK4 is common in liposarcoma. CDK4 amplification has also been observed at lower frequency in other solid tumors and hematologic malignancies. Loss of the CDK4 inhibitor pl6 (CDKN2A) is also a common event in many cancers, including glioblastoma multiforme, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, lung squamous cell carcinoma, bladder urothelial carcinoma, skin cutaneous melanoma, diffuse large B-cell lymphoma, cholangiocarcinoma, lung adenocarcinoma, and stomach adenocarcinoma.

[0297] Cyclin E has been found to be frequently amplified in cancers, for example, in uterine cancer, ovarian cancer, stomach cancer, and breast cancer. In some cancer types, loss-of-function mutations in FBXW7 or overexpression of USP28, which control the turnover of cyclin E, leads to cyclin E overexpression and CDK2 activation. Alternatively, certain cancer cells express a hyperactive, truncated form of cyclin E or cyclin A. In addition, cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinomas, colorectal and breast cancers. In some tumors, catalytic activity of CDK2 is increased following loss of the expression or alteration of the location of the endogenous CDK2 inhibitor p27 or p21, or overexpression of SKP2, a negative regulator of p27. In addition, CDC25A and CDC25B, protein phosphatases responsible for the dephosphorylations that activate the CDK2, are overexpressed in various tumors. These various mechanisms of CDK2 activation have been validated using cancer cells or mouse cancer models. Furthermore, CDK2 / cyclin E phosphorylates oncogenic Myc to oppose ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. Inactivation of CDK2 has been shown to be synthetically lethal to myc over-expressing cancer cells. In aneuploid cancer cells, for example KRAS-mutant lung cancer, CDK2 inhibition resulted in anaphase catastrophe and apoptosis. Moreover, inhibiting CDK2 effectively induced granulocytic differentiation in AML cell lines and arrested tumor growth in AML mice models.

[0298] CDK2 activation as a result of cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway to HR+ or HER2+ breast cancers treated by CDK4 / 6 inhibitors or trastuzumab. Accordingly, compounds of Formula (I) can be used in combination with CDK4 / 6 inhibitors or anti-HER2 therapies for the treatment of cancers that become refractory to CDK4 / 6 inhibitors or anti-HER2 therapies.

[0299] Therefore, a compound of this disclosure may also be useful for treating tumors characterized by 1) overexpression of CDK2 and / or CDK4; 2) amplification / overexpression of cyclin D, cyclin E or cyclin A; 3) hyperphosphorylation of CDK2 (Thrl60) or CDK4 (Thrl72); 4) loss-of-function of mutation in FBXW7, depletion of AMBRA1, overexpression of USP28, or amplification / overexpression of CDC25A or / and CDC25B; 5) expression of truncated cyclin E or cyclin A, 6) dysregulation of pl 6, p21 or p27, or overexpression of SKP2;and 7) hyperactive MYC / RAS; 8) Aneuploid cancers, and 9) CDK4 and / or CDK6 inhibitor refractory cancers.

[0300] In some embodiments, the cancer is ovarian cancer (e.g. serous, clear cell, endometrioid, and mucinous ovarian carcinomas), uterine cancer (e.g. endometrial cancer and uterine sarcoma), stomach cancer (i.e. gastric cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, pleuropulmonary blastoma), renal cancer (e.g. clear cell renal cell carcinomas, papillary renal cell carcinomas, and chromophobe renal cell carcinomas), brain cancer (including astrocytoma, meningioma and glioblastoma), neuroblastoma, paraganglioma, pheochromocytoma, pancreatic neuroendocrine tumors, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors, pituitary tumors, leiomyomas, leiomyosarcomas, polycythaemia, retinal cancers, hereditary leiomyomatosis, renal cell cancer, astrocytoma, skin cancer (e.g. melanoma, squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), bladder cancer (including bladder urothelial carcinoma), cervical cancer, colorectal cancer (e.g., cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus), head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasopharynx, oropharynx, lips, tongue and mouth), liver cancer (e.g., hepatocellular carcinoma and cholangiocellular carcinoma), prostate cancer, testicular cancer, gall bladder cancer, pancreatic cancer (e.g. exocrine pancreatic carcinoma and neuroendocrine pancreatic cancer), thyroid cancer, and parathyroid cancer, fallopian tube cancer, peritoneal cancer, vaginal cancer, biliary tract cancer, esophageal cancer (e.g. esophageal squamous cell carcinoma and esophageal adenocarcinoma), sarcoma (e.g. liposarcoma and osteosarcoma), bone cancer, chondrosarcoma, leukemia (including acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), lymphoma (e.g. non-Hodgkin lymphoma NHL including mantel cell lymphoma, MCL and Hodgkin lymphoma) and multiple myeloma.

[0301] In other embodiments, the cancer is breast cancer, including, e.g., ER-positive / HR-positive breast cancer, HER2-negative breast cancer; ER-positive / HR-positive breast cancer, HER2- positive breast cancer; ER-negative / HR-negative, HER2-positive breast cancer, triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine resistant breast cancer, anti-HER2 therapy (e.g. trastuzumab) resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0302] Besides cancer, compounds of Formula (I) or (IA) as described in the Summary as described in the first aspect (or any of the embodiments thereof herein above) are useful in treating autoimmune diseases autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss.

[0303] Testing

[0304] CDK2 / 4 degradation activities of the compounds of the present disclosure can be tested using the in vitro assays described in Biological Examples below.

[0305] Pharmaceutical Compositions

[0306] In general, the compounds Formula (I) or (IA) (unless stated otherwise, reference to compound / compounds of Formula (I) or (lA)wherein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg / kg per day; about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds), i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

[0307] In general, compounds Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0308] The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.

[0309] The compositions are comprised of in general, a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0310] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0311] The compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0312] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0313] In addition to the formulations described previously, the compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated as a depot preparation. Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0314] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0315] The compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0316] Certain compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0317] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise from 0.1% to 1% w / w of the formulation.

[0318] For administration by inhalation, compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).

[0319] The level of the compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.

[0320] Combinations and Combination Therapies

[0321] The compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds). When a compound of Formula (I) or (IA)(or any embodiment thereof disclosed herein including specific compounds) is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) is preferred. However, the combination therapy may also include therapies in which the compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) or (IA)(and any embodiment thereof disclosed herein including specific compounds) and the other active ingredients may be used in lower doses than when each is used singly.

[0322] Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds).

[0323] The above combinations include combinations of a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) not only with one other drug, but also with two or more other active drugs. Likewise, a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds). When a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds). The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

[0324] Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) in any combination with one or more other anti-cancer agents including but not limited to: MAP kinase pathway (RAS / RAF / MEK / ERK) inhibitors including but not limited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818), TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corp); trametinib, selumetinib (AZD6244), TQ-B3234, PD184352, PD325901, TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib (GDC-0973), AZD8330, BVD-523, LTT462, Ulixertinib, AMG510, ARS853, and any RAS inhibitors disclosed in patents WO2016049565, WO2016164675, WO2016168540, WO2017015562, WO2017058728, WO2017058768, WO2017058792, W02017058805,W02017058807, W02017058902, WO2017058915, W02017070256, WO20 17087528, WO2017100546, WO2017172979, W02017201161, WO2018064510, W02018068017, WO2018119183; CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) TGF beta receptor kinase inhibitor such as LY2157299;

[0325] BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7); Saracatinib (AZD0530); and N-[2-[(lS,4R)-6-[[4-cyclobutylarmno)-5-(trifluoromethyl)-2- pyrimidinyl]amino]-l, 2,3,4-tetrahydronaphthalen-l,4-imin-9-yl]-2-oxoethyl]-acetamide (PF- 03814735, CAS 942487-16-3);

[0326] ALK inhibitors: PF-2341066 (XALKOPJ ®; crizotinib); 5-chloro-N4-(2- (isopropyl- sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiper azin-l-yl)piperi din-1- yl)phenyl)pyrimidine- 2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitors: 4-[2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l- yl]methyl]thieno[3,2-d]- pyrimidin-4-yl]morholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09 / 036082 and WO 09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8- (quinolin-3-yl)-2,3-dihydro- imidazo[4,5-c]quinolin-l-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06 / 122806);

[0327] Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademark Avastin® by Genentech / Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2- ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No. WO 01 / 002369), Brivanib Alaninate ((S)-((R)-l-(4-(4-fluoro-2-methyl-lH-indol- 5-yloxy)-5-methylpyrrolo[2,l-f][l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4- pyridinyl- methyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 02 / 066470), pasireotide (also known as SOM230, and described in PCT Publication No. WO 02 / 010192), sorafenib (sold under the tradename Nexavar®); AL-2846 MET inhibitor such as foretinib, carbozantinib, or crizotinib;

[0328] FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib;

[0329] Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), panitumumab (sold under the tradename Vectibix® by Amgen); HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech / Roche), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 05 / 028443), lapatinib or lapatinib ditosylate (sold under the trademark Tykerb® by GlaxoSmithKline); Trastuzumab emtansine (in the United States, ado- trastuzumab emtansine, trade name Kadcyla) - an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1); Trastuzumab deruxtecan (trade name Enhertu );

[0330] HER dimerization inhibitors: Pertuzumab (sold under the trademark Omnitarg®, by Genentech);

[0331] CD20 antibodies: Rituximab (sold under the trademarks Riuxan® and Mab Thera® by Genentech / Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);

[0332] Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech / Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No. 6,780,996), dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis);

[0333] DNA Synthesis inhibitors: Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar® by Eli Lilly and Company), nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline);

[0334] Antineoplastic agents: oxaliplatin (sold under the tradename Eloxatin® ay Sanofi -Aventis and described in US Patent No. 4,169,846);

[0335] Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename Neupogen® by Amgen);

[0336] Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the tradename Revlimid®), thalidomide (sold under the tradename Thalomid®); CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen / Genentech);

[0337] Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)- benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06 / 028958);

[0338] Phospholipase A2 inhibitors: Anagrelide (sold under the tradename Agrylin®);

[0339] BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]methyl]-l- piperazinyl]-N-[[4-[[(lR)-3-(4-morpholinyl)-l-[(phenylthio)m ethyl]propyl]amino]-3- [(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09 / 155386);

[0340] MC1-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991;

[0341] Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);

[0342] Topoisomerase I inhibitors: Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline);

[0343] Topoisomerase II inhibitors: etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®); mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,4S)-4-[(2R)-2[(lR,9S,12S,15R,16E, 18R,19R,21R, 23S,24E,26E,28Z,30S,32S,35R)-l,18-dihydroxy-19,30- dimethoxy-15, 17, 21, 23, 29, 35-hexamethyl-2,3, 10, 14,20-pentaoxo-l 1, 36-dioxa-4- azatri cyclo[30.3.1.0 4 ' 9] hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669, and described in PCT Publication No. WO 03 / 064383), everolimus (sold under the tradename Afinitor® by Novartis);

[0344] Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;

[0345] BET inhibitors such as INCB054329, OTX015, and CPI-0610;

[0346] LSD1 inhibitors such as GSK2979552, and INCB059872;

[0347] KAT6 inhibitors such as PF-07248144;

[0348] HIF-2a inhibitors such as PT2977, PT2385, imdatifan, and casdatifan;

[0349] Osteoclastic bone resorption inhibitors: l-Hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis); CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer / Wyeth);

[0350] CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0351] CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename Zevalin®);

[0352] Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®);

[0353] Synthetic Interleukin- 11 (IL-11): oprelvekin (sold under the tradename Neumega® by Pfizer / Wyeth);

[0354] Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by Amgen);

[0355] Receptor Activator for Nuclear Factor K B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen);

[0356] Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename Nplate® by Amgen);

[0357] Cell growth stimulators: Palifermin (sold under the tradename Kepivance® by Amgen);

[0358] Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6);

[0359] Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

[0360] CD52 antibodies: Alemtuzumab (sold under the tradename Campath®);

[0361] Histone deacetylase inhibitors (HDI): Voninostat (sold under the tradename Zolinza® by Merck);

[0362] Alkylating agents: Temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough / Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexal en®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexal en®), ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSP A, sold under the tradename Thioplex®; Biologic response modifiers: bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), denileukin diftitox (sold under the tradename Ontak®);

[0363] Anti-tumor antibiotics: doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence™), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®);

[0364] Anti -microtubule agents: Estramustine (sold under the tradename Emcyl®);

[0365] Cathepsin K inhibitors: Odanacatib (also known as MK-0822, N-(l-cyanocyclopropyl)-4- fluoro-N-2-{(lS)-2,2,2-trifluoro-l-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03 / 075836); Epothilone B analogs: Ixabepilone (sold under the tradename Lxempra® by Bristol-Myers Squibb);

[0366] Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- demethoxy- geldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No. 4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116

[0367] TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline);

[0368] Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® by Sanofi -Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cytadren®);

[0369] Anti-androgens: Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename Fulexin™);

[0370] Androgens: Fluoxymesterone (sold under the tradename Halotestin®);

[0371] CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDK11 / 12, or CDK16) inhibitors including but not limited to Alvocidib (pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4- chromenone, and described in US Patent No. 5,621,002);

[0372] CDK4 / 6 inhibitors pabociclib, ribociclib, abemaciclib, and Trilaciclib; CDK9 inhibitors AZD 4573, P276-00, AT7519M, TP-1287; CDK2 / 4 / 6 inhibitor such as PF-06873600;

[0373] SHP-2 inhibitor such as TNO155;

[0374] MDM2 / MDMX, MDM2 / p53 and / or MDMX / p53 modulators;

[0375] Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi -Aventis and Lupron® by Abbott Lab);

[0376] Taxane anti -neoplastic agents: Cabazitaxel (l-hydroxy-7, 10 -dimethoxy-9-oxo-5,20- epoxytax-1 l-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{ [(tert- butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), larotaxel ((2a,3^,4a,5p,7a,10p,13a)- 4, 10-bis(acetyloxy)-13-({(2R,3 S)-3-[(tert-butoxy carbonyl) amino] -2-hydroxy-3- phenylpropanoyl}oxy)-l-hydroxy-9-oxo-5,20-epoxy-7, 19-cyclotax-l l-en-2-yl benzoate);

[0377] 5HTla receptor agonists: Xaliproden (also known as SR57746, l-[2-(2-naphthyl)ethyl]-4- [3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No. 5,266,573); HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis);

[0378] Anti-metabolites: Claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5 -fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt™), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin™), methotrexate (also known as amethopterin, methotrexate sodium (MTX), sold under the tradenames Rheumatrex® and Trexall™), pentostatin (sold under the tradename Nipent®);

[0379] Bisphosphonates: Pamidronate (sold under the tradename Aredia®), zoledronic acid (sold under the tradename Zometa®); Demethylating agents: 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®);

[0380] Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and Onxal™);

[0381] Retinoids: Ali tretinoin (sold under the tradename Panretin®), tretinoin (all -trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);

[0382] Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R,10S,l lS,13S,14S,16R,17R)-9-fhroro-l l,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-6,7,8,9,10,1 l,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);

[0383] Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin- 11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®); Estrogen receptor downregulators: Fulvestrant (sold under the tradename Faslodex®);

[0384] Anti-estrogens: tamoxifen (sold under the tradename Novaldex®); Toremifene (sold under the tradename Fareston®);

[0385] Selective estrogen receptor modulators (SERMs): Raloxifene (sold under the tradename Evista®);

[0386] Estrogen receptor PROTACs: Vepdegestrant (ARV-471);

[0387] Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, sold under the tradename Megace®);

[0388] Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®); One or more immune checkpoint inhibitors CD27, CD28, CD40, CD 122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

[0389] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti-PDl antibody is pembrolizumab.

[0390] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

[0391] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti -CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti- LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or, INCAGNO 1949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MED 16383

[0392] Compounds of Formula (I) or (IA) (and any embodiment thereof disclosed herein including specific compounds) can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GV AX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.

[0393] Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.

[0394] A compound of Formula (I) or (IA) (or any embodiment thereof disclosed herein including specific compounds) can also be used in combination with the following adjunct therapies: antinausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and

[0395] Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).

[0396] Examples

[0397] The following preparations of Intermediates (References) and compounds of Formula (I) or (IA) (Examples) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0398] Reference 1

[0399] Synthesis of 3-(5-(azetidin-3-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione 2,2,2-trifluoroacetate Step 1 : ( l-(tert-Butoxycarbonyl)azeti din-3 -yl)zinc(II) iodide

[0400] To a mixture of Zn dust (300 mg, 4.59 mmol, 1.30 eq.) in DMA (3.0 mL) was added 1,2-dibromoethene (66 mg, 0.35 mmol, 0.10 eq.) and the mixture was stirred at 65 °C under N2 for 30 min. The mixture was allowed to cool to rt and TMSC1 (38 mg, 0.35 mmol, 0.10 eq.) was added. After stirring the mixture for 30 min, a solution of tert-butyl 3 -iodoazetidine- 1 -carboxylate (1.00 g, 3.53 mmol, 1.00 eq.) in DMA (1.0 mL) was added dropwise. The mixture was stirred at 65 °C under N2 for 2 h, and then cooled to rt. The solution was used in next step without further purification.

[0401] Step 2: tert-Butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)azetidine-l-carboxylate

[0402] A solution of (l-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (600 mg, 1.72 mmol, 3.00 eq.) in DMA was slowly added to a mixture of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine- 2, 6-dione (185 mg, 0.57 mmol, 1.00 eq.), Cui (12 mg, 0.06 mmol, 0.10 eq.), Pd(dppf)C12 (44 mg, 0.06 mmol, 0.10 eq.) in DMA (2.0 mL). The mixture was stirred at 90 °C under N2 overnight. The mixture was concentrated and purified by column chromatography on silica gel (EtOAc) to give the title compound as a brown solid.

[0403] Step 3: 3-(5-(Azetidin-3-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione 2,2,2-trifluoroacetate

[0404] To a solution of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)azetidine-l- carboxylate (44 mg, 0.11 mmol, 1.00 eq.) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise and the solution was stirred for 3 h. The resulting mixture was concentrated to give the title product as a brown oil.

[0405] Reference 2

[0406] Synthesis of 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione 2,2,2-trifluoroacetate

[0407] Step 1: tert-Butyl 3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]- imidazol-4-yl)azetidine- 1 -carboxylate

[0408] A solution of (l-(tert-butoxycarbonyl)azetidin-3-yl)zinc (II) iodide (600 mg, 1.72 mmol, 3.00 eq.) in DMA was slowly added to a mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione (193 mg, 0.57 mmol, 1.00 eq.) in DMA (2.0 mL) Cui (12 mg, 0.06 mmol, 0.10 eq.) and Pd(dppf)C12 (44 mg, 0.06 mmol, 0.10 eq.). The mixture was stirred at 90 °C under N2 overnight. The mixture was concentrated and purified by column chromatography on silica gel (EtOAc) to afford the title compound as a yellow solid. Step 2: 3-(4-(Azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine- 2,6-dione 2,2,2-trifluoroacetate

[0409] To a solution of tert-butyl 3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)azetidine-l -carboxylate (23 mg, 0.055 mmol, 1.00 eq.) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise and the solution was stirred at rt for 3 h. The resulting mixture was concentrated to give the title compound as a brown oil.

[0410] Reference 3

[0411] Synthesis of 3-(l-Oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione 2,2,2- tri fluoroacetate Step 1 : tert-Butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-l -carboxylate

[0412] To a stirred solution of methyl 2-cyano-4-fluorobenzoate (10.00 g, 55.80 mmol, 1.00 eq.) in DMSO (150.0 mL) was added tert-butyl piperazine- 1 -carboxylate (11.40 g, 61.38 mmol, 1.10 eq.) and DIEA (34.70 g, 268.96 mmol, 4.80 eq.), and the resulting mixture was stirred at 110 °C for 12 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers was washed with brine, dried over ISfeSC After filtration, the filtrate was concentrated and purified by silica gel column chromatography eluting with PEZEtOAc (3 : 1) to give the title compound as yellow solid.

[0413] Step 2: tert-Butyl 4-(3-formyl-4-(m ethoxy carbonyl)phenyl)piperazine-l -carboxylate

[0414] A mixture of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-l -carboxylate (8.00 g, 23.20 mmol, 1.00 eq.), NaH2PO2.H2O (5.20 g, 48.70 mmol, 2.10 eq.) and Raney-Ni (5.10 g) in pyridine:H2O:AcOH=2:l : l (80.0 mL) was stirred at 70 °C for 12 h. The mixture was adjusted pH=7~8 with aq.NaHCCh, and the mixture was filtered, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (3 : 1) to give the title compound as yellow solid.

[0415] Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine-l-carboxylate

[0416] A mixture of 3 -aminopiperidine-2, 6-dione hydrochloride (2.60 g, 15.50 mmol, 1.20 eq.) DIEA (4.03 g, 31.22 mmol, 2.42 eq.), AcOH (10.63 g, 188.76 mmol, 13.78 eq.) and tert-butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-l -carboxylate (4.50 g, 12.90 mmol, 1.00 eq.) in DCM (50.0 mL) was stirred at 35 °C for 4 h. Then NaBH(OAc)3 (8.20 g, 38.70 mmol, 3.00 eq.) was added the above mixture, and the mixture was stirred at 40 °C for 12 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1 :2) to give the title compound as white solid. Step 4: 3-(l-Oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione 2,2,2-trifluoroacetate

[0417] To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine- 1-carboxylate (72 mg, 0.17 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at rt for 2 h and then concentrated to give the title compound as yellow oil.

[0418] The following reference compounds were synthesized by proceeding analogously as described in Reference 3.

[0419] Reference 5

[0420] Synthesis of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2, 2, 2-2, 2, 2-tri fluoroacetate

[0421] To a stirred solution of 4-bromo-2-fluorobenzonitrile (10 g, 0.05 mol, 1.00 eq.) in EtOH (50.0 mL) was added methylhydrazine (57 g, 0.50 mol, 10.00 eq.) and the mixture was stirred at 100°C 30 h in sealed tube. Then the mixture was concentrated, and diluted water. The mixture was filtered to give the title compound as pale yellow solid. Step 2: Methyl 3-((6-bromo-l-methyl-lH-indazol-3-yl)amino)propanoate

[0422] Methyl acrylate (209.00 g, 2.43 mol, 10.00 eq.) was added to a solution of 6-bromo-l- methyl-lH-indazol-3-amine (55.00 g, 0.24 mol, 1.00 eq.), DBU (55.00 g, 0.36 mol, 1.50 eq.), lactic acid (33.00 g, 0.36 mol, 1.50 eq.) at 0 °C, and the mixture was stirred at 90 °C 20 h under N2. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EtOAc:PE = 0 to 100%) to give the title compound as yellow solid. Step 3: Methyl 3-(l-(6-bromo-l-methyl-lH-indazol-3-yl)ureido)propanoate

[0423] NaOCN (26.00 g, 0.32 mol, 2.00 eq.) was added to a solution of methyl 3-((6-bromo-l- methyl-lH-indazol-3-yl)amino)propanoate (50.00 g, 0.16 mol, 1.00 eq.) in AcOH (500.0 mL), and the mixture was stirred at 80 °C 20 h under N2. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over ISfeSC After filtration, the filtrate was concentrated to give the title compound as yellow solid.

[0424] Step 4: l-(6-Bromo-l -methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-di one

[0425] To a solution of methyl 3-(l-(6-bromo-l-methyl-lH-indazol-3-yl)ureido)propanoate (56.00 g, 0.16 mol, 1.00 eq.) in MeCN (500.0 mL) was added Tirton-B (7.90 g, 0.05 mol, 0.30 eq.) and stirred at rt for 20 h under N2. The mixture was concentrated, then diluted with water. The mixture was filtered and solid was washed with water, air dried to give the title compound as pale yellow solid. Step 5: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-5,6- dihydropyridine- 1 (2H)-carboxylate

[0426] To a mixture of l-(6-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (1.10 g, 3.41 mmol, 1.00 eq.) in l,4-dioxane / H2O (10 mL / 1 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (1.60 g, 5.11 mmol, 1.50 eq.), K3PO4 (2.20 g, 10.22 mmol, 3.00 eq.) and X-Phos-Pd G3 (289 mg, 0.34 mmol, 0.10 eq. ), and the mixture was stirred at 60 °C under N2 for 3 h. The mixture was diluted with DCM, and the organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (DCM:MeOH = 20 : 1) to give the title compound as yellow solid.

[0427] Step 6: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6- yl)piperidine- 1 -carboxylate

[0428] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)-5,6-dihydropyridine-l(2H)-carboxylate (300 mg, 0.71 mmol, 1.00 eq.), Pd / C (150 mg, 50% wt) and Pd(OH)2 (150 mg, 50% wt) in THF (20.0 mL) was stirred under H2 at 50 °C and 50 psi overnight. The mixture was filtered and the filtrate was concentrated and purified by column chromatography on silica gel (PE:EtOAc = 1 : 1) to give the title compound as yellow solid. Step 7: l-(l-Methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2, 2, 2-2, 2, 2-tri fluoroacetate

[0429] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)piperi dine- 1 -carboxylate (100 mg, 0.25 mmol, 1.00 eq.) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as brown oil.

[0430] The following Reference compounds were synthesized by proceeding analogously as described in

[0431] Reference 5.

[0432] Reference 8

[0433] Synthesis of 3-((4-(Piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione 2,2,2-trifluoroacetate Step 1 : tert-Butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-l(2H)-carboxylate

[0434] A mixture of l-bromo-4-nitrobenzene (1.0 g, 4.95 mmol, 1.00 eq), tert-butyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (2.30 g, 7.43 mmol, 1.50 eq.), K2CO3 (1.37 g, 9.90 mmol, 2.00 eq.), and Pd(dppf)C12 (724 mg, 0.99 mmol, 0.20 eq) in dioxane / EEO (15 mL, 5 / 1 ) was stirred at 100 °C for 4 h. The mixture was filtered and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was purified by silica flash column PEZEtOAc (10: 1) to give the title compound as yellow solid.

[0435] Step 2: tert-Butyl 4-(4-aminophenyl)piperidine-l -carboxylate

[0436] A mixture of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-l(2H)-carboxylate (1.20 g, 3.95 mmol, 1.00 eq.), Pd / C (360 mg, 10% w / w) in MeOH / THF (30 mL, 1 : 1) was stirred at 45 °C under EE overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica flash column PEZEtOAc (3 : 1) to give the title compound as yellow solid. Step 3: tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l-carboxylate

[0437] A mixture of tert-butyl 4-(4-aminophenyl)piperidine-l -carboxylate (332 mg, 1.20 mmol, 1.00 eq.), 3 -brom opiperidine-2, 6-dione (242 mg, 1.26 mmol, 1.05 eq.) and NaHCCh (302 mg, 3.60 mmol, 3.00 eq.) in DMF (4.0 mL) was stirred at 70 °C overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica flash column PE / EtOAc (1 : 1) to give the title compound as yellow solid.

[0438] Step 4: 3 -((4-(Piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione 2,2,2-trifluoroacetate

[0439] TFA (0.5 mL) was added to a mixture of tert-butyl 4-(4-((2, 6-dioxopiperi din-3 - yl)amino)phenyl)piperidine-l -carboxylate (100 mg, 0.26 mmol, 1.00 eq.) in DCM (2.0 mL) and the mixture was stirred at rt for 2 h. The mixture was concentrated to give the title compound as a yellow solid. Reference 9

[0440] Synthesis of 3-(4-(piperazin-l-yl)phenyl)piperidine-2, 6-dione 2,2,2-trifluoroacetate

[0441] Step 1 : 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine

[0442] A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (19.00 g, 0.05 mol, 1.00 eq.),

[0443] 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (19.60 g, 0.08 mol, 1.50 eq.), KO Ac (10.00 g, 0.10 mol, 2.00 eq.), and Pd(dppf)C12 (3.7 g, 5.00 mmol, 0.10 eq.) in 1,4-dioxane (200.0 mL) was stirred at 100 °C for 25 h under N2. The mixture was diluted with water and extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc:PE= 0 to 100% to give the title compound as yellow solid. Step 4: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0444] A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4.42 g, 10.60 mmol, 1.20 eq.), l-bromo-4-iodobenzene (2.50 g, 8.83 mol, 1.00 eq.), K3PO4 (5.63 g, 26.50 mmol, 3.00 eq.), and Pd(PPhs)4 (510 mg, 0.44 mmol, 0.05 eq.) in l,4-dioxane / H2O=10: l (40.0 mL) was stirred at 100 °C for 16 h under N2. The mixture was diluted with water and extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc:PE= 0 to 100% to give the title compound as yellow solid. Step 5: tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l-carboxylate

[0445] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (500 mg, 1.12 mmol, 1.00 eq.), tert-butyl piperazine- 1 -carboxylate (417 mg, 2.24 mmol, 2.00 eq.), CS2CO3 (730 mg, 2.24 mmol, 2.00 eq.), Pd2(dba)s (51 mg, 0.06 mmol, 0.05 eq.), and RuPhos (52 mg, 0.11 mmol, 0.10 eq.) in toluene (15.0 mL) was stirred at 110 °C for 20 h under N2. The mixture was diluted with water and extracted with EtOAc, and the combined organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with EtOAc:PE= 0 to 100% to give the title compound as yellow solid.

[0446] Step 6: tert-Butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l -carboxylate

[0447] A mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l- carboxylate (260 mg, 0.47 mmol, 1.00 eq.), 10% Pd / C (260 mg) in EtOAc (5.0 mL) and

[0448] 1,4-dioxane (5.0 mL) was stirred at rt for 20 h under H2. The mixture was filtered and the filtrate was concentrated to give the title compound as yellow oil.

[0449] Step 7: 3-(4-(Piperazin-l-yl)phenyl)piperidine-2, 6-dione 2,2,2-trifluoroacetate

[0450] TFA (0.5 mL) was added to a stirred solution of tert-butyl 4-(4-(2, 6-dioxopiperi din-3 - yl)phenyl)piperazine-l -carboxylate (160 mg, 0.43 mmol, 1.00 eq.) in DCM (2.0 mL) and the mixture was stirred at rt for 2 h under N2. The mixture was concentrated to give the title compound as yellow oil. Reference 10

[0451] Synthesis of 2-chloro-5-(difluoromethyl)pyrimidine

[0452] To a solution of 2-chloropyrimidine-5-carbaldehyde (250 mg, 1.60 mmol, 1.00 eq.) in DCM (3.0 mL) was added DAST (45 mg, 31.93 mmol, 20.00 eq.) at 0 °C and the mixture was stirred at r.t overnight. The mixture was diluted with water and extracted DCM. The organic layer was washed with brine, dried over Na2SO4. After filtration, the filtrate was concentrated, and the residue was purified by flash chromatography (PE:EtOAc=10: 1) to give the title compound as a white solid.

[0453] The following Reference compound was prepared by proceeding analogously as described in Reference 10.

[0454] Reference 11

[0455] Synthesis of 2-chloro-5-(difluoromethoxy)pyrimidine

[0456] A mixture of 2-chloropyrimidin-5-ol (1.00 g, 7.69 mmol, 1.00 eq.), methyl 2-chloro-2,2- difluoroacetate (3.32 g, 23.08 mmol, 3.00 eq.) and CS2CO3 (3.01 g, 9.23 mmol, 1.20 eq.) in DMF (10.0 mL) was stirred at 100 °C under N2 lh. The mixture was poured into water, and the resulting mixture was extracted with DCM. The combined organic layers was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by column chromatography on silica gel (PE : EtOAc =20: 1) give the title compound as yellow oil. Reference 12

[0457] Synthesis of l-(6-(piperidin-4-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-trifluoroacetate

[0458] Step 1 : 6-Bromo-l-(2,2,2-trifluoroethyl)-lH-indazol-3-amine

[0459] NaH (2.10 g, 52.83 mmol, 2.00 eq.) was added to a stirred solution of 6-bromo-lH- indazol-3 -amine (5.60 g, 26.42 mmol, 1.00 eq.) in DMF (20.0 mL) at 0 °C and the mixture was stirred at 0 °C for Ih. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.7 g, 29.06 mmol, 1.10 eq.) was added and the mixture was stirred at rt for 3 h under N2. The mixture was poured into cold water and filtered. The solid was washed with water and dried to give the title compound as yellow solid.

[0460] Step 2: l-(6-(Piperidin-4-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-trifluoroacetate

[0461] The title compound was synthesized by proceeding analogously as described in Reference

[0462] 5, Steps 2-7. Reference 13

[0463] Synthesis of 1 -(1 -methyl-6-(piperazin- 1 -yl)- lH-indazol-3 -yl)dihydropyrimidine-2,4( 1H,3H)- dione

[0464] Step 1 : Benzyl 4-(4-cyano-3-fluorophenyl)piperazine-l -carboxylate

[0465] A mixture of 2,4-difluorobenzonitrile (18.95 g, 136.20 mmol, 1.50 eq.), benzyl piperazine- 1-carboxylate (20 g, 90.80 mmol, 1.00 eq.) and potassium carbonate (25.10 g, 181.6 mmol, 2.00 eq.) in ACN (200.0 mL) was stirred at 80 °C under N2 for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3 : 1) to give the title compound as white solid.

[0466] Step 2: Benzyl 4-(3-amino-lH-indazol-6-yl)piperazine-l-carboxylate

[0467] A mixture of benzyl 4-(4-cyano-3-fluorophenyl)piperazine-l -carboxylate (11.00 g, 32.40 mmol, 1.00 eq.) and ^JL / LEO (10.14g, 161.99 mmol, 5.00 eq) in BuOH (100.0 mL) was stirred at 100 °C under N2 for 16 h. The mixture was concentrated and purified by flash chromatography to give the title compound as yellow solid.

[0468] Step 3: Benzyl 4-(3-amino-l-methyl-lH-indazol-6-yl)piperazine-l-carboxylate

[0469] To a solution of benzyl 4-(3-amino-lH-indazol-6-yl)piperazine-l-carboxylate (4.00 g, 11.40 mmol, 1.00 eq.) in dry DMF (50.0 mL) at 0 °C was added NaH (0.91 g, 22.80 mmol, 2.00 eq.) under N2, and the mixture was stirred at rt for 30 min. The mixture was cooled to 0 °C, CH3I (1.78 g, 12.54 mmol, 1.10 eq.) in dry DMF (10.0 mL) was added dropwise, and the mixture was stirred for 3 h. The mixture was quenched with water, extracted with EtOAc. The combined organic layers were washed with brine, dried with ISfeSC After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / MeOH = (50: 1) to give the title compound as yellow solid.

[0470] Step 4: Benzyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)- piperazine- 1 -carboxylate

[0471] The title compound was synthesized by proceeding analogously as described in Reference 5, Steps 2-4.

[0472] Step 5: l-(l-Methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

[0473] A mixture of benzyl 4-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl]piperazine- 1-carboxylate (500 mg, 1.08 mmol, 1.00 eq.), 10% Pd / C (400 mg) and ammonium formate (682 mg, 10.81 mmol, 10.00 eq.) in MeOH (20.0 mL) was stirred at 60 °C under N2 for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound as white solid.

[0474] The following Reference compound was synthesized by proceeding analogously as described in Reference 13. Reference 15

[0475] Synthesis of l-(6-(3,3-difluoropiperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0476] Step 1 : l-(l-Methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione

[0477] A mixture of l-(6-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (626 mg, 2.00 mmol, 1.00 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (762 mg, 3.00 mmol, 1.50 eq.), KO Ac (589 mg, 6.00 mmol, 3.00 eq.) and Pd(dppf)C12 (146 mg, 0.20 mmol, 0.10 eq.) in 1,4-dioxane (10 mL) was stirred at 85 °C under N2 overnight. The mixture was filtered and the filtrated was concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 100 : 1) to give the title compound as a yellow solid.

[0478] Step 2: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3- difluoro-3,6-dihydropyridine-l(2H)-carboxylate

[0479] A mixture of l-(l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (800 mg, 2.00 mmol, 1.00 eq.), tert-butyl 3,3-difluoro-4- (((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l(2H)-carboxylate (1.10 g, 3.00 mmol, 1.50 eq.), Na2CC>3 (636 mg, 6.00 mmol, 3.00 eq.), Pd(dppf)C12 (146 mg, 0.20 mmol, 0.1 eq.) and H2O (2.5 mL) in 1,4-dioxane (10.0 mL) was stirred at 55 °C under N2 overnight. The mixture was filtered and the filtrated was concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 120 : 1) to give the title compound as a yellow solid. Step 3: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3,3- difluoropiperidine-1 -carboxylate

[0480] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-l(2H)-carboxylate (940 mg, 2.00 mmol, 1.00 eq.), 10% Pd / C (900mg) and Pd(OH)2 (900mg) in MeOH (10.0 mL) was stirred at 50 °C under H2 (50 PSI) overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 1 : 1) to give the title as yellow solid.

[0481] Step 4: l-(6-(3,3-Difluoropiperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0482] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)-3,3-difluoropiperidine-l-carboxylate (102 mg, 0.22 mmol, 1.00 eq.) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at rt for 2h. The mixture was concentrated to give the title compound as brown oil.

[0483] Reference 16

[0484] Synthesis of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)- 2,6-diazaspiro[3 ,3]heptane-2-carboxylate 2,2,2-trifluoroacetate Step 1 : tert-Butyl 6-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-2,6- di azaspiro [3.3 ]heptane-2 -carb oxy 1 ate

[0485] A mixture of l-(6-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (300 mg, 0.93 mmol, 1.00 eq.), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (570 mg, 2.32 mmol, 2.50 eq.), t-BuOK(627 mg, 5.6 mmol, 6.00 eq.), t-BuBrettphos Pd G3 (81mg, 0.093 mmol, 0.10 eq.) and t-BuXphos (76mg, 0.186 mmol, 0.20 eq.) in 1,4-dioxane (6 mL) was stirred at 100 °C under N2 for 3 h. The mixture was diluted with DCM and the organic layer was washed with water and brine, dried over ISfeSC After filtration, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (DCM:MeOH = 20 : 1) to give the title compound as yellow solid.

[0486] Step 2: l-(l-Methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0487] A mixture of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (90 mg, 0.204 mmol, 1.00 eq.) in TFA / DCM (0.5 mL / 2 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as brown oil.

[0488] Reference 17

[0489] Synthesis of l-(l-methyl-6-(3-azaspiro[5.5]undecan-9-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione hydrochloride Step 1 : tert-Butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undec-8-ene-3-carboxylate

[0490] To a mixture of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate ( 300 mg, 1.12 mmol) in THF (5.0 mL) was added LiHMDS (IM in THF, 2.25 mL, 2.24 mmol) at -78 °C. The mixture was stirred at -78 °C under N2 for 30 mins. 1,1,1-Trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide was added and the mixture reaction was stirred at rt. for 3h. The mixture was diluted with DCM, washed with water and brine, dried over ISfeSCU, concentrated to afford the title compound as yellow solid.

[0491] Step 2: tert-Butyl 9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3- azaspiro[5.5 ]undec-8-ene-3 -carboxylate

[0492] To a mixture of tert-butyl 9-(((trifluoromethyl)sulfonyl)oxy)-3-azaspiro[5.5]undec-8-ene- 3-carboxylate (448 mg, 1.12 mmol) in dioxane / TBO (8.0 mL / 4.0 mL) was added 1-(1 -methyl -6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (457 mg, 1.23 mmol), ISfeCCL (357 mg, 3.36 mmol) and Pd(dppf)C12 (82 mg, 0.11 mmol). The mixture was stirred at 60 °C under N2 for 16 h. The mixture was diluted with EA, washed with water and brine, dried over ISfeSCU, concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20 : 1) to afford the title compound as yellow solid. Step 3: tert-Butyl 9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3- azaspiro[5.5 ]undecane-3 -carboxylate

[0493] A mixture of tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)-3-azaspiro[5.5]undec-8-ene-3-carboxylate (380 mg, 0.77 mmol), Pd / C (150 mg, 50% wt) and Pd(OH)2 (150 mg, 50% wt) in THF (20.0 mL) was stirred under H2 at 50 °C and 50 psi overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 20 : 1) to give the title compound as yellow solid. Step 4: l-(l-Methyl-6-(3-azaspiro[5.5]undecan-9-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione hydrochloride

[0494] A mixture of tert-butyl 9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)-3-azaspiro[5.5]undecane-3-carboxylate (176 mg, 0.36 mmol) and 4 M HC1 in dioxane (2 mL) was stirred at r.t for 2 h. The mixture was concentrated to give the title compound as brown oil.

[0495] The following reference compound was synthesized by proceeding analogously as described in reference 17.

[0496] Reference 18

[0497] Synthesis of tert-butyl N-[l-[4-cyano-3-(4-hydroxybut-l-ynyl)phenyl]sulfonyl-4-piperidyl]- carbamate

[0498] Step 1 : tert-Butyl N-[l-[3-[4-[tert-butyl(dimethyl)silyl]oxybut-l-ynyl]-4-cyano-phenyl]sulfonyl-4- piperidyl]carbamate

[0499] To a solution of tert-butyl N-[l-(3-bromo-4-cyano-phenyl)sulfonyl-4-piperidyl]carbamate (444 mg, 1 mmol), tert-butyl-but-3-ynoxy-dimethyl-silane (276.31 mg, 1.5 mmol) and triethylamine (505.56 mg, 5 mmol) in DMF (10 mL) was added cuprous iodide (57.09 mg, 0.3 mmol) and Pd(dppf)C12 (54.84 mg, 0.07 mmol) under argon atmosphere and the reaction mixture was stirred at 100 °C for 8 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the title compound.

[0500] Step 2: tert-Butyl N-[l-[4-cyano-3-(4-hydroxybut-l-ynyl)phenyl]sulfonyl-4-piperidyl]carbamate

[0501] To a solution of tert-butyl N-[l-[3-[4-[tert-butyl(dimethyl)silyl]oxybut-l-ynyl]-4-cyano- phenyl]sulfonyl-4-piperidyl]carbamate (400 mg, 0.73 mmol) in THF (5 mL) was added TBAF (IM in THF, 1.1 mL, 1.1 mmol), then the reaction mixture was stirred at r.t for 30 mins. The mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the title compound.

[0502] The following reference compounds were synthesized by proceeding analogously as described in Reference 18.

[0503] Reference 19

[0504] Synthesis of l-(2-cyanoethyl)prop-2-ynyl methanesulfonate Step 1 : 4-Oxobutanenitrile

[0505] To a solution of 4,4-diethoxybutanenitrile (950 mg, 6.04 mmol) in acetone (30 mL) was added HC1 (12 mL, 72 mmol) at 0 °C, then the mixture was stirred at 0 °C for 17 h. The mixture was concentrated to approximately 5 mL and the residue was extracted with DCM. The combined organic layers were dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was used in the next step without further purification.

[0506] Step 2: 4-Hydroxyhex-5-ynenitrile

[0507] To a solution of 4-oxobutanenitrile (220 mg, 2.65 mmol) in THF (5 mL) was added bromo(ethynyl)magnesium (1 M in THF, 3.97 mL) in THF (1 mL) at 0 °C under argon atmosphere, then the mixture was stirred at r.t for 2 h. The mixture was diluted with aqueous ammonium chloride solution, then extracted with EA. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound.

[0508] Step 3: l-(2-Cyanoethyl)prop-2-ynyl methanesulfonate

[0509] To a solution of 4-hydroxyhex-5-ynenitrile (200 mg, 1.83 mmol) and pyridine (0.44 mL, 5.5 mmol) in DCM (5 mL) was added methanesulfonic anhydride (542.67 mg, 3.12 mmol) at 0 °C, then the mixture was stirred at r.t. for 1 h. The mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was used in next step without further purification.

[0510] Reference 20

[0511] Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indol-6-yl)piperidine-l- carboxylate Step 1 : tert-Butyl 4-(l-methyl-lH-indol-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0512] To a stirred solution of 6-bromo-l-methylindole (5.0 g, 23.8 mmol) and tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (7.51 g, 24.3 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) was added XPhos Pd G3 (2.0 g, 2.4 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 60 °C under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (0-20%), to afford the title compound as an off-white solid.

[0513] Step 2: tert-Butyl 4-(l-methyl-lH-indol-6-yl)piperidine-l-carboxylate

[0514] To a stirred solution of tert-butyl 4-(l-methyl-lH-indol-6-yl)-3,6-dihydropyridine-l(2H)- carboxylate (4.0 g, 12.8 mmol) in THF (40 mL) was added 400 mg of 10% w / w Pd / C at room temperature. The mixture was hydrogenated at 50 °C for 16 h under hydrogen atmosphere using a hydrogen balloon. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-20%), to afford the title compound as a yellow oil.

[0515] Step 3: tert-Butyl 4-(3-iodo-l-methyl-lH-indol-6-yl)piperidine-l-carboxylate

[0516] To a stirred solution of tert-butyl 4-(l-methylindol-6-yl)piperidine-l -carboxylate (2.3 g, 7.3 mmol) in DMF (35 mL) was added NIS (1.64 g, 7.3 mmol) in portions at 0-5 °C, and the resulting mixture was stirred for 2 h at 0-5 °C. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / PE (0-30%), to afford the title compound as a yellow solid.

[0517] Step 4: tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indol-6-yl)piperidine-l- carboxylate

[0518] To a stirred mixture of tert-butyl 4-(3-iodo-l-methylindol-6-yl)piperidine-l-carboxylate (2.5 g, 5.7 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2.51 g, 6.0 mmol) in l,4-dioxane / H2O (10: 1, 25 mL) were added K2CO3 (2.38 g, 17.2 mmol) and Pd(dppf)C12-CH2C12 (462 mg, 0.57 mmol) at room temperature. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0-40%), to afford the crude product. The crude product was purified by prep-HPLC to afford the title compound as a light yellow solid.

[0519] Step 5: tert-Butyl 4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indol-6-yl) piperidine-1- carboxylate

[0520] To a stirred solution of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH- indol-6-yl)piperidine-l -carboxylate (50 mg, 0.083 mmol) in EtOH (1 mL) was added Pd / C (10% w / w, 50 mg) and 1 drop of AcOH at room temperature. The resulting mixture was stirred at room temperature for 3 h under hydrogen atmosphere using a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated to afford the title compound. Step 6: 3-(l-Methyl-6-(piperidin-4-yl)-lH-indol-3-yl)piperidine-2, 6-dione hydrochloride

[0521] The title compound was synthesized by proceeding analogously as described in Reference

[0522] 17, Step 4 with tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indol-6-yl)piperidine-l- carboxylate.

[0523] The following reference compound was synthesized by proceeding analogously as described in Reference 20.

[0524] Reference 21 Synthesis of tert-butyl N-[l-[4-(difluoromethyl)-3-(3-hydroxyprop-l-ynyl)phenyl]sulfonyl-4- piperidyl]carbamate

[0525] Step 1 : (3-Bromo-4-(difluoromethyl)phenyl)(4-(tert-butyl)benzyl)sulfane To a stirred solution of (4-(tert-butyl)phenyl)methanethiol (2.42 g, 13.42 mmol) in DMF

[0526] (20.0 mL) was added NaH (60 % in oil, 716 mg, 17.9 mmol) at 0 °C and the mixture was stirred at 0 °C for 1 h. Then 2-bromo-l-(difluoromethyl)-4-fluorobenzene (2.00 g, 8.95 mmol) was added and the resulting mixture was stirred at r.t. for 3 h under N2. The mixture was poured into cold water, the precipitate was collected by filtration and the solid was washed with water, dried to give the title compound.

[0527] Step 2: 3-Bromo-4-(difluoromethyl)benzenesulfonyl chloride

[0528] To a stirred solution of (3-bromo-4-(difluoromethyl)phenyl)(4-(tert-butyl)benzyl)sulfane (1.20 g, 8.85 mmol) in 22 mL mixed solvent (MeCN / AcOH / H2O=7:3: l) was added N- chlorosuccinimide (2.38 g, 17.90 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was diluted with EA, and the organic layer was washed with water and brine, dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow oil.

[0529] Step 3: tert-Butyl (l-((3-bromo-4-(difluoromethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0530] To a solution of tert-butyl piperidin-4-ylcarbamate (633 mg, 3.17 mmol) and TEA (533 mg, 5.28 mmol) in DCM (5 mL) was added 3-bromo-4-(difluoromethyl)benzenesulfonyl chloride (800 mg, 2.64 mmol), the reaction mixture was stirred at 0°C for 2 h. The mixture was diluted with DCM, and the organic layer was washed with water and brine, dried over ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow solid. Step 4: tert-Butyl N-[l-[3-[3-[tert-butyl(dimethyl)silyl]oxyprop-l-ynyl]-4-(difluoromethyl)- phenyl]sulfonyl-4-piperidyl]carbamate

[0531] To a solution of tert-butyl N-[l-[3-bromo-4-(difluoromethyl)phenyl]sulfonyl-4- piperidyl]carbamate (630 mg, 1.34 mmol), cuprous iodide (76.7 mg, 0.4 mmol), tert-butyl- dimethyl-prop-2-ynoxy-silane (343 mg, 2.01 mmol) and TEA (679.1 mg, 6.71 mmol) in DMF (10 mL) was added Pd(dppf)C12 (98.2 mg, 0.13 mmol), then the reaction mixture was stirred at 100 °C under the argon atmosphere for 5 h. Then the mixture was diluted with water. The resulting mixture was extracted with EA, and the combined organic layer was washed with brine, dried over anhydrous sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / PE (0-75%) to afford the title compound as a yellow solid.

[0532] Step 5: tert-Butyl N-[l-[4-(difluoromethyl)-3-(3-hydroxyprop-l-ynyl)phenyl]sulfonyl-4- piperidyl]carbamate

[0533] To a solution of tert-butyl N-[l-[3-[3-[tert-butyl(dimethyl)silyl]oxyprop-l-ynyl]-4- (difluoromethyl)phenyl]sulfonyl-4-piperidyl]carbamate (680 mg, 1.22 mmol) in THF (10 mL) at 0 °C was added TBAF (IM in THF, 2.43 mL, 2.43 mmol), and the mixture was stirred at 0 °C for 1 h. Then the mixture was treated with water. The resulting mixture was extracted with EA, and the combined organic layer was washed with brine, dried over anhydrous sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / DCM (0-3%) to afford the title compound as a yellow solid.

[0534] The following reference compounds were synthesized by proceeding analogously as described in Reference 21. Example 1

[0535] Synthesi s of 1 -(6-( 1 -(4-(3 -((4-((5 -(difluoromethoxy )pyrimidin-2-yl)amino)piperi din- 1 - yl)sulfonyl)phenyl)-2-methylbut-3-yn-2-yl)piperidin-4-yl)- 1 -methyl- lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione

[0536] Step 1 : l-(l-Methyl-6-(l-(2-methylbut-3-yn-2-yl)piperidin-4-yl)-lH-indazol-3-yl)dihydro- pyrimidine-2,4(lH,3H)-dione

[0537] To a solution of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione (720 mg, 2.2 mmol, 1.0 eq.) in DMSO (5 mL) was added 3-chloro-3-methylbut- 1-yne (451 mg, 4.4 mmol, 2.0 eq.), CuCl (21 mg, 22 mmol, 10.0 eq.) and TEA (0.92 mL, 6.6 mmol, 3.0 eq.), and the resulting mixture was stirred at r.t. for 20 min. The mixture was diluted with water, and the precipitated solid was collected by filtration. The solid was redissolved in DCM, and the organic layers were dried over ISfeSCU, filtered and concentrated under reduced pressure to give the title compound, which was used in next step without further purification. Step 2: tert-Butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol- 6-yl)piperidin- 1 -y l)-3 -methylbut- 1 -yn- 1 -yl)phenyl) sulfonyl) piperidin-4-yl)carbamate

[0538] To a solution of tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (211 mg, 0.5 mmol, 1.1 eq.) in DMF (1 mL) was added l-(l-methyl-6-(l-(2-methylbut-3-yn-2-yl)piperidin- 4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (180 mg, 0.46 mmol, 1.0 eq.), Pd(dppf)C12 (37 mg, 0.05 mmol, 0.1 eq.) and Cui (8 mg, 0.05 mmol, 0.1 eq.). The resulting mixture was stirred at 70 °C for 2 hr. The mixture was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure, the residue was purified by silica gel column, eluted with MeOH / DCM = 0 - 5% to give the title compound as yellow solid.

[0539] Step 3: l-(6-(l-(4-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2-methylbut-3-yn-2-yl)piperidin- 4-yl)- 1 -methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-di one hydrochloride

[0540] A mixture of tert-butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)piperidin-l-yl)-3-methylbut-l-yn-l-yl)phenyl) sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.41 mmol) in ethyl acetate (1 mL) and HCl / EtOAc (4 M, 1 mL) was stirred at r.t. for 2 hrs. The mixture was concentrated under reduced pressure to afford the title compound, which was used in next step without further purification.

[0541] Step 4: l-(6-(l-(4-(3-((4-((5-(Difluoromethoxy)pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- phenyl)-2-methylbut-3-yn-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione

[0542] To a solution of l-(6-(l-(4-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2-methylbut-3-yn-2- yl)piperidin-4-yl)-l -methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-di one hydrochloride (240 mg, 0.38 mmol, 1.0 eq.) in DMSO (1 mL) was added CsF (115 mg, 0.76 mmol, 2.0 eq.), 2- chloro-5-(difhioromethoxy)pyrimidine (137 mg, 0.76 mmol, 2.0 eq.) and TEA (0.16 mL, 1.1 mmol, 4.0 eq.), and the resulting mixture was stirred at 105 °C for 2 hrs. The reaction was quenched by water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure, the residue was purified by reverse phase column, eluted with ACN / water (0.05 % NH4HCO3) = 0 - 60% to give the title compound. MS (ES, m / z): [M+H]+=776.5. Example 2

[0543] Synthesis of 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)-2-(3-(4- (3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)but-l-yn-l-

[0544] Step 1 : l-(6-(l-(But-3-yn-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydro pyrimidine-

[0545] 2,4(lH,3H)-dione

[0546] To a solution of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione (500 mg, 1.53 mmol, 1.0 eq.), copper (I) chloride (45.36 mg, 0.46 mmol, 0.3 eq.) and triethylamine (772.7 mg, 7.64 mmol, 5.0 eq.) in DMSO (5 mL) was added 3-chlorobut-l- yne (270.41 mg, 3.05 mmol, 2.0 eq.) in DMSO (2 mL) dropwise, then the reaction mixture was stirred at r.t for 30 min. The mixture was diluted with water and filtered. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound.

[0547] Step 2: tert-Butyl (l-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)piperidin-l-yl)but-l-yn-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0548] To a solution of l-(6-(l-(but-3-yn-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (175 mg, 0.46 mmol, 1.0 eq.), Cui (7.98 mg, 0.04 mmol, 0.1 eq.), tert-butyl(l-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (225.41 mg, 0.51 mmol, 1.1 eq.) and triethylamine (212.12 mg, 2.1 mmol, 4.0 eq.) in DMF (3 mL) was added Pd(dppf)2C12 (30.68 mg, 0.04 mmol, 0.1 eq.) under argon atmosphere, then the resulting mixture was stirred at 100 °C for 2 hr. The reaction mixture was diluted with water and extracted with

[0549] EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound.

[0550] Step 3: 4-((4-Aminopiperidin-l-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 1 -methyl- lH-indazol-6-yl)piperi din- 1 -yl)but- 1 -yn- 1 -yl)benzonitrile hydrochloride

[0551] To a solution of tert-butyl (l-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)- yl)- 1 -methyl- lH-indazol-6-yl)piperi din- 1 -yl)but- 1 -yn- 1 -yl)phenyl)sulfonyl)piperidin-4- yl)carbamate (116.26 mg, 0.16 mmol) in DCM (3 mL) was added 4.0M HC1 in dioxane (1.5 mL, 6 mmol), then the resulting mixture was stirred at r.t for 1 h. The mixture was concentrated under reduced pressure to afford the title compound.

[0552] Step 4 : 4-((4-((5 -(Difluoromethoxy)pyrimidin-2-yl)amino)piperidin- 1 -yl)sulfonyl)-2-(3 -(4-(3 - (2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- lH-indazol-6-yl)piperidin- 1 -yl)but- 1 -yn- 1 - yl)benzonitrile

[0553] To a solution of 2-chloro-5-(difluoromethoxy)pyrimidine (47.75 mg, 0.26 mmol, 2.0 eq.) and 4-((4-aminopiperidin-l-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l- methyl-lH-indazol-6-yl)piperidin-l-yl)but-l-yn-l-yl)benzonitrile hydrochloride (85 mg, 0.13 mmol, 1.0 eq.) in DMSO (2 mL) was added DIPEA (85.45 mg, 0.66 mmol, 5.0 eq.) and CsF (60.26 mg, 0.4 mmol, 3.0 eq.) under argon atmosphere, then the resulting mixture was stirred at 90 °C for 17 hrs. The resulting mixture was purified by reverse flash chromatography to afford the title compound as a white solid. MS (ES, m / z): [M+H]+= 787.5 The following compounds were synthesized by proceeding analogously as described in Example 2.

[0554] Example 8 Synthesis of 4-((4-((5-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)-2-(3-(9- (3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]- undecan-3 -yl)but- 1 -yn- 1 -yl)benzonitrile Step 1 : tert-Butyl N-(l-{[4-cyano-3-(3-hydroxybut-l-yn-l-yl)benzene]sulfonyl}piperidin-4-yl)- carbamate

[0555] To a solution of tert-butyl N-{ l-[(3-bromo-4-cyanobenzene)sulfonyl]piperidin-4- yljcarbamate (3.00 g, 6.75 mmol) and but-3-yn-2-ol (568 mg, 8.10 mmol) in (DMF:TEA=1 : 1) (30.0 mL) were added Cui (257 mg, 1.35 mmol) and Pd(PPhs)4 (786 mg, 0.68 mmol). The mixture was stirred 50 °C under nitrogen for 16 h. The mixture was concentrated and the residue was purified by flash column chromatography (EA:PE=0~100%) to give product as a white solid. Step 2: tert-Butyl (l-((4-cyano-3-(3-iodobut-l-yn-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0556] To a solution of tert-butyl N-(l-{[4-cyano-3-(3-hydroxybut-l-yn-l-yl)benzene]- sulfonyl}piperidin-4-yl)carbamate (200 mg, 0.46 mmol) in DCM (30.0 mL) were added imidazole (31 mg, 0.46 mmol) and I2 (117 mg, 0.46 mmol). The reaction mixture was stirred 25 °C under nitrogen for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (EA:PE=0~100%) to give the title compound. Step 3: tert-Butyl (l-((4-cyano-3-(3-(9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)but-l-yn-l-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate

[0557] To a stirred solution of l-(l-methyl-6-(3-azaspiro[5.5]undecan-9-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride (108 mg, 0.25 mmol), tert-butyl (l-((4- cyano-3-(3-iodobut-l-yn-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (136 mg, 0.25 mmol) and K2CO3 (69 mg, 0.50 mmol) in ACN (3.0 mL), and stirred at 70°C for 16 h. The mixture was poured into water, extracted with EA. The combined organic layer was washed with water and

[0558] - I l l - brine, dried over Na2SO4, concentrated and purified by flash chromatography on silica gel (DCM:MeOH = 20 : 1) to give the title compound as a white solid.

[0559] Step 4: 4-((4-Aminopiperidin-l-yl)sulfonyl)-2-(3-(9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-

[0560] 1 -methyl- lH-indazol-6-yl)-3 -azaspiro[5.5]undecan-3 -yl)but- 1 -yn- 1 -yl)benzonitrile hydrochloride

[0561] A mixture of tert-butyl (l-((4-cyano-3-(3-(9-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-

[0562] 1 -methyl- lH-indazol-6-yl)-3 -azaspiro[5.5]undecan-3 -yl)but- 1 -yn- 1 -yl)phenyl)sulfonyl)piperidin- 4-yl)carbamate (100 mg, 0.12 mmol) in EA / HC1 (2.0 mL) was stirred at r.t for 2h. The mixture was concentrated to give the title compound.

[0563] Step 5 : 4-((4-((5 -(Difluoromethoxy)pyrimidin-2-yl)amino)piperidin- 1 -yl)sulfonyl)-2-(3 -(9-(3 - (2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3- yl)but- 1 -yn- 1 -yl)benzonitrile

[0564] To a stirred solution of 4-((4-aminopiperidin-l-yl)sulfonyl)-2-(3-(9-(3-(2,4- dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3-azaspiro[5.5]undecan-3-yl)but- l-yn-l-yl)benzonitrile hydrochloride (90 mg, 0.12 mmol) in DMSO (3.0 mL) was added 2-chloro- 5-(difluoromethoxy)pyrimidine (108 mg, 0.60 mmol), DIEA (78 mg, 0.60 mmol) and CsF (91 mg, 0.60 mmol), and the mixture was stirred at 60 °C for 16 h. The mixture was diluted with water and extracted with EA. The combined organic layers were washed with water, brine, and the organic layer was dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by / c -HPLC to afford the title compound as a white solid. MS (ES, m / z): [M+l]+= 855.1. Example 9

[0565] Synthesis of 4-[[4-[[5-(difhioromethoxy)pyrimidin-2-yl]amino]-l-piperidyl]sulfonyl]-2-[4-[4-[3-

[0566] (2, 4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]-l -piperidyl] but-l-ynyl]benzonitrile

[0567] Step 1 : 4-[5-[[4-(tert-Butoxycarbonylamino)-l-piperidyl]sulfonyl]-2-cyano-phenyl]but-3-ynyl methanesulfonate

[0568] To a solution of tert-butyl N-[l-[4-cyano-3-(4-hydroxybut-l-ynyl)phenyl]sulfonyl-4- piperidyl]carbamate (208 mg, 0.48 mmol) and triethylamine (145.65 mg, 1.44 mmol) in DCM (5 mL) was added methanesulfonic anhydride (142.07 mg, 0.82 mmol) at 0 °C, then the mixture was stirred at r.t for 1 h. The reaction mixture was diluted with water, the mixture was extracted with EA. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was used in next step without further purification.

[0569] Step 2: tert-Butyl N-[l-[4-cyano-3-[4-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl- indazol-6-yl]-l-piperidyl]but-l-ynyl]phenyl]sulfonyl-4-piperidyl]carbamate

[0570] To a solution of 4-[5-[[4-(tert-butoxycarbonylamino)-l-piperidyl]sulfonyl]-2-cyano- phenyl]but-3-ynyl methanesulfonate (230 mg, 0.45 mmol), l-[l-methyl-6-(4-piperidyl)indazol-3- yl]hexahydropyrimidine-2, 4-dione (147.18 mg, 0.45 mmol) and Nal (269.54 mg, 1.8 mmol) in MeCN (5 mL) was added DIPEA (174.3 mg, 1.35 mmol) under argon atmosphere, then the mixture was stirred at 100 °C for 17 h. The reaction mixture was diluted with water and DCM, then filtered through celite, the filter cake was washed with 5% MeOH in DCM, the filtrate was extracted with DCM. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the title compound. Step 3 : 4-[(4-Amino- 1 -piperidyl)sulfonyl]-2-[4-[4-[3 -(2,4-dioxohexahydropyrimidin- 1 -yl)- 1 - methyl-indazol-6-yl]- 1 -piperidyl]but- 1 -ynyl]benzonitrile hydrochloride

[0571] To a solution of tert-butyl N-[l-[4-cyano-3-[4-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)- l-methyl-indazol-6-yl]-l-piperidyl]but-l-ynyl]phenyl]sulfonyl-4-piperidyl]carbamate (58 mg, 0.08 mmol) in DCM (2 mL) was added HCl-Dioxane (1 mL, 4 M) at r.t, then the mixture was stirred at r.t for 1 h. The solvent was removed under reduced pressure, and the residue was used in the next step without further purification.

[0572] Step 4: 4-[[4-[[5-(Difluoromethoxy)pyrimidin-2-yl]amino]-l-piperidyl]sulfonyl]-2-[4-[4-[3-(2,4- dioxohexahydropyrimidin- 1 -yl)- 1 -methyl-indazol-6-yl]- 1 -piperidyl]but- 1 -ynyl]benzonitrile

[0573] To a mixture of 2-chloro-5-(difluoromethoxy)pyrimidine (28.09 mg, 0.16 mmol), 4-[(4- amino- 1 -piperidyl)sulfonyl]-2-[4-[4-[3 -(2,4-dioxohexahydropyrimidin- 1 -yl)- 1 -methyl-indazol-6- yl]-l-piperidyl]but-l-ynyl]benzonitrile hydrochloride (50 mg, 0.08 mmol) and CsF (35.45 mg, 0.23 mmol) in DMSO (1 mL) was added DIPEA (30.16 mg, 0.23 mmol) under argon atmosphere, then the reaction mixture was stirred at 90 °C for 17 h. The resulting mixture was purified by reverse flash chromatography to afford the title compound as a white solid. MS (ES, m / z): [M+H]+= 787.5.

[0574] The following compounds were synthesized by proceeding analogously as described in Example 9.

[0575] Example 12

[0576] Synthesis of 4-[[4-[(5-cyclopropylpyrimidin-2-yl)amino]-l-piperidyl]sulfonyl]-2-[3-[4-[3-(2,4- dioxohexahydropyrimidin- 1 -yl)- 1 -methyl-indazol-6-yl]- 1 -piperi dy 1 ] -3 -methyl-but- 1 -ynyl]- benzonitrile

[0577] Step 1 : l-[6-[l-(l,l-dimethylprop-2-ynyl)-4-piperidyl]-l-methyl-indazol-3-yl]hexahydro- pyrimidine-2, 4-dione To a solution of 3 -chi oro-3 -methyl-but- 1-yne (438.57 mg, 4.28 mmol) in DMSO (1.5 mL) were added l-[l-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2, 4-dione (700 mg, 2.14 mmol), Cui (40.72 mg, 0.21 mmol) and TEA (0.89 mL, 6.41 mmol). The resulting mixture was stirred at 25 °C for 15 minutes under argon atmosphere. The reaction was quenched by water and extracted with DCM. The combined organic layers were washed with brine, dried and evaporated in vacuum. The residue was purified by reverse flash, eluted with ACN / water (0.05% NH4HCO3) = 0-60% to afford the title compound as a yellow solid.

[0578] Step 2: tert-Butyl N-[l-[4-cyano-3-[3-[4-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl- indazol-6-yl]-l-piperidyl]-3-methyl-but-l-ynyl]phenyl]sulfonyl-4-piperidyl]carbamate To a stirred solution of l-[6-[l-(l,l-dimethylprop-2-ynyl)-4-piperidyl]-l-methyl-indazol- 3-yl]hexahydropyrimidine-2, 4-dione (65 mg, 0.17 mmol), tert-butyl N-[l-(3-bromo-4-cyano- phenyl)sulfonyl-4-piperidyl]carbamate (88.08 mg, 0.2 mmol) and TEA (0.05 mL, 0.33 mmol) in DMF (1.5 mL) was added Pd(PPh3)2Ch (14.04 mg, 0.02 mmol) and Cui (3.15 mg, 0.02 mmol). The mixture was stirred for 3 h at 100 °C under argon atmosphere. The reaction was quenched by water and extracted with DCM. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluted with MeOH / DCM = 0-8% to the title compound as yellow solid.

[0579] Step 3 : 4-[(4-Amino- 1 -piperidyl)sulfonyl]-2-[3 - [4 - [3 -(2,4-dioxohexahydropyrimidin- 1 -yl)- 1 - methyl-indazol-6-yl]-l-piperidyl]-3-methyl-but-l-ynyl]benzonitrile hydrochloride

[0580] To a stirred solution of tert-butyl N-[l-[4-cyano-3-[3-[4-[3-(2,4-dioxohexahydropyrimidin- 1 -yl)- 1 -methyl-indazol-6-yl]- 1 -piperi dy 1 ] -3 -methyl-but- 1 -ynyl]phenyl] sulfonyl-4-piperidyl]- carbamate (80 mg, 0.11 mmol) in DCM (1 mL) was added HCl / dioxane (1 mL, 4.0 M) and the mixture was stirred at 25 °C for 1 h under argon atmosphere. The reaction was concentrated, and the residue was used to the next step without further purification.

[0581] Step 4: 4-[[4-[(5-Bromopyrimidin-2-yl)amino]-l-piperidyl]sulfonyl]-2-[3-[4-[3-(2,4-dioxohexa- hydropyrimidin- 1 -yl)- 1 -methyl-indazol-6-yl]- 1 -piperi dy 1 ] -3 -methyl-but- 1 -ynyl]benzonitrile

[0582] To a solution of 4-[(4-amino-l-piperidyl)sulfonyl]-2-[3-[4-[3-(2,4-dioxohexahydro- pyrimidin- 1 -yl)- 1 -methyl -indazol-6-yl]- 1 -piperi dy 1 ] -3 -methyl-but- 1 -ynyl]benzonitrile (69 mg, 0.11 mmol) in DMSO (1 mL) were added 5-bromo-2-chloro-pyrimidine (0.02 mL, 0.13 mmol), CsF (31.92 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.04 mL, 0.21 mmol). The mixture was stirred for 2 h at 90 °C under argon atmosphere. The mixture was quenched by water and extracted with EA. The combined organic layers were washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluted with MeOH / DCM = 0-6% to give the title compound as a yellow solid. Step 5: 4-[[4-[(5-Cyclopropylpyrimidin-2-yl)amino]-l-piperidyl]sulfonyl]-2-[3-[4-[3-(2,4- dioxohexahydropyrimidin- 1 -yl)- 1 -methyl-indazol-6-yl]- 1 -piperi dy 1 ] -3 -methyl-but- 1 - ynyl]benzonitrile

[0583] To a solution of 4-[[4-[(5-bromopyrimidin-2-yl)amino]-l-piperidyl]sulfonyl]-2-[3-[4-[3- (2,4-dioxohexahydropyrimidin- 1 -yl)- 1 -methyl-indazol-6-yl]- 1 -piperi dy 1 ] -3 -methyl-but- 1 - ynyl]benzonitrile (60 mg, 0.07 mmol) in DMF (2 mL) was added cyclopropylboronic acid (12.67 mg, 0.15 mmol), TEA (0.03mL, 0.22mmol) and CataCXium A Pd G3 (5.37 mg, 0.01 mmol). The mixture was stirred at 95 °C for 2 h under argon atmosphere. The reaction was purified by reverse flash, eluted with ACN / water (0.05% FA) = 0-35% to afford the title compound as a yellow solid. MS (ES, m / z): [M+H]+= 775.5.

[0584] The following compounds were synthesized by proceeding analogously as described in Example 12.

[0585] Example 14

[0586] Synthesis of l-[6-[l-[3-[5-[[4-[[5-(difhioromethoxy)pyrimidin-2-yl]amino]-l-piperidyl]- sulfonyl]-2-(difluoromethyl)phenyl]prop-2-ynyl]-4-piperidyl]-l-methyl-indazol-3-yl]- hexahydropyrimidine-2, 4-dione Step 1 : 3-[5-[[4-(tert-Butoxycarbonylamino)-l-piperidyl]sulfonyl]-2-(difluoromethyl)phenyl]- prop-2-ynyl methanesulfonate

[0587] To a solution of tert-butyl N-[l-[4-(difluoromethyl)-3-(3-hydroxyprop-l-ynyl)phenyl]- sulfonyl-4-piperidyl]carbamate (300 mg, 0.67 mmol) and TEA (204.5 mg, 2.02 mmol) in anhydrous DCM (10 mL) at 0 °C, methanesulfonic anhydride (188.1 mg, 1.08 mmol) was added in portions. This mixture was stirred at 25 °C for 1 h. The mixture was diluted with water, and the mixture was extracted with EA. The combined organic layers was washed with brine, dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure to afford the title compound, which was used in next step without further purification.

[0588] Step 2: tert-Butyl N-[l-[4-(difhioromethyl)-3-[3-[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol- 6-y 1 ] - 1 -piperidyl ]prop- 1 -ynyl]phenyl] sulfonyl-4-piperidyl]carbamate

[0589] To a solution of 3-[l-methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2, 6-dione hydrochloride (220.6 mg, 0.61 mmol) and 3-[5-[[4-(tert-butoxycarbonylamino)-l- piperidyl]sulfonyl]-2-(difluoromethyl)phenyl]prop-2-ynyl methanesulfonate (352 mg, 0.67 mmol) and Nal (202.1 mg, 1.35 mmol) in anhydrous MeCN (35 mL) at 25 °C was added DIPEA (299 mg, 2.69 mmol). This mixture was stirred at 100 °C in a sealed tube for 16 h. The mixture was diluted with water, and the mixture was extracted with EA. The combined organic layers was washed with brine, dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / DCM (0-4%) to afford the title compound as a yellow solid.

[0590] Step 3: 3-[6-[l-[3-[5-[(4-Amino-l-piperidyl)sulfonyl]-2-(difhioromethyl)phenyl]prop-2-ynyl]-4- piperidyl]-l-methyl-indazol-3-yl]piperidine-2, 6-dione hydrochloride To a solution of tert-butyl N-[l-[4-(difluoromethyl)-3-[3-[4-[3-(2,6-dioxo-3-piperidyl)-l- methyl-indazol-6-yl]-l-piperidyl]prop-l-ynyl]phenyl]sulfonyl-4-piperidyl]carbamate (110 mg, 0.15 mmol) in anhydrous DCM (10 mL) at 0 °C, was added HC1 in dioxane (2 mL, 4.0 M) dropwise. This mixture was stirred at 25 °C for 16 h. The mixture was concentrated under reduced pressure to afford the title compound as a yellow solid.

[0591] Step 4: l-[6-[l-[3-[5-[[4-[[5-(Difluoromethoxy)pyrimidin-2-yl]amino]-l-piperidyl]sulfonyl]-2- (difluoromethyl)phenyl]prop-2-ynyl]-4-piperidyl]-l-methyl-indazol-3-yl]hexahydropyrimidine-

[0592] 2,4-dione A solution of 2-chloro-5-(difluoromethoxy)pyrimidine (74.6 mg, 0.41 mmol), CsF (62.7 mg, 0.41 mmol) in DMSO (3 mL) was stirred at 100 °C for 4 h. After cooled to room temperature, l-[6-[l-[3-[5-[(4-amino-l-piperidyl)sulfonyl]-2-(difluoromethyl)phenyl]prop-2-ynyl]-4- piperidyl]-l-methyl-indazol-3-yl]hexahydropyrimidine-2, 4-dione hydrochloride (95 mg, 0.14 mmol) and DIPEA (106.5 mg, 0.83 mmol) were added to the mixture. This mixture was stirred at 90 °C for 7 h. The mixture was concentrated, and the residue was purified by Cl 8 column chromatography, eluted with MeCN / water (0-50%, 0.05% NH4HCO3) to afford the title compound as a yellow solid. MS (ES, m / z): [M+H]+=797.5.

[0593] The following compounds were synthesized by proceeding analogously as described in Example 14.

[0594] Biological Examples

[0595] Biological Example 1 Phospho-Rb Measurement in Cells Phosphorylation of RB protein at S807 / 811 were measured using HTRF phospho-RB cellular kits (Cat# 64RBS807PEG) from Cisbio.

[0596] On Day 1, adherent cells, such as OVCAR3 (CDK2-dependent cell line) and T47D (CDK4-dependent) were seeded into 96-well tissue-culture treated plates at 20,000 cells / well in 200 pL and incubated overnight at 37 °C in CO2 atmosphere. On Day 2, the cells were treated with test compounds at concentrations from 0.3 to 3,000 nM using HP D300 digital dispenser.

[0597] Twenty -four hours after compound treatment, cell culture media of the adherent cells is removed by flicking the plate and tapping the plate against clean paper towel. 30 pL IX lysis buffer was supplemented from the kit was added to each well of adherent cells. The plates were then incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 pL cell lysate from cell culture plate was transferred to 384-well small volume white detection plate. 2 pL premixed detection solution was added and the plate was covered with sealer. To prepare the detection solution, d2 conjugated-phospho-RB antibody and Eu-cryptate conjugated phosphor-RB antibody were diluted into detection buffer following manufacturer’s instruction. Detection plates were incubated for 4 h at room temperature and read on ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM / 620 nM) was plotted against the compound concentration and normalized to DMSO controls. Half maximal inhibition concentration (IC50) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA).

[0598] In the table below, AA indicates a IC50 of less than 1 nM; A indicates a IC50 of greater than or equal to 1 nM but less than or equal to 100 nM; B indicates a IC50 of greater than 100 nM but less than or equal to 500 nM; C indicates a IC50 of greater than 500 nM but less than or equal to

[0599] 2.5 pM; D indicates a IC50 of greater than 2.5 pM but less than or equal to 5.0 pM; NT is not determined. Biological Example 2

[0600] High-throughput Measurement of Cellular Endogenous CDK 2 / 4

[0601] Effects of compounds on cellular CDK levels were monitored by a high-throughput HTRF assay.

[0602] To determine half maximal degradation concentration (DC50) and maximum degradation level (Dmax) values of compounds, cellular CDK level was measured in 96-well format using HTRF total CDK cellular kit (CDK2 Cat# 64CDK2TPEG; CDK4 Cat# 64CDK4TPEG;) from Cisbio / Revvity.

[0603] On Day 1, cells were seeded into 96-well tissue-culture treated plates at 20,000 cells / well in 200 pL and incubated overnight at 37°C in CO2 atmosphere. On Day 2 cells were treated with compounds at concentration ranging from 0.1 to 1,000 nM using HP D300 digital dispenser. 6 or 24 hours after compound treatment, cell culture media was removed by flicking the plate and tapping the plate against clean paper towel. Immediately 30 pL IX lysis buffer was supplemented from the kit and added to each well and the plate is incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 pL cell lysate from 96-well cell culture plate was transferred to 384-well small volume white detection plate. 2 pL premixed detection solution was added and the plate is covered with sealer. To prepare the detection solution, d2 conjugated-CDK antibody and Eu-cryptate conjugated CDK antibody were diluted into detection buffer following manufacturer’s instruction. Detection plates were incubated overnight at room temperature and read on ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM / 620 nM) was plotted against the compound concentration and normalized to DMSO controls (0% degradation) and lysis buffer controls (100% degradation). Half maximal degradation concentration (DC50) (0% degradation) and lysis buffer controls (100% degradation) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA).

[0604] Formulation Examples The following are representative pharmaceutical formulations containing a compound of the present disclosure. Tablet Formulation

[0605] The following ingredients are mixed intimately and pressed into single scored tablets.

[0606] Ingredient Quantity per tablet (mg) compound Formula (I) or (IA) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

[0607] Capsule Formulation

[0608] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

[0609] Ingredient Quantity per capsule (mg)

[0610] Compound Formula (I) or (IA) 200 lactose spray dried 148 magnesium stearate 2

[0611] Injectable Formulation

[0612] Compound of Formula (I) or (IA) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg / mL

[0613] Inhalation Composition

[0614] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula (I) or (IA) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration. Topical Gel Composition

[0615] To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I) or (IA) is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

[0616] Ophthalmic Solution Composition

[0617] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound of Formula (I) or (IA) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

[0618] Nasal spray solution

[0619] To prepare a pharmaceutical nasal spray solution, 10 g of a compound of Formula (I) or (IA) is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 pL of spray for each application.

Claims

What is Claimed:

1. A compound of F ormula (I) :wherein: n is 0 or 1;R1is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy (wherein cycloalkyl, either alone or as part of cycloalkoxy, is substituted with one to three halo), halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, or cyano;R2and R2aare independently hydrogen or deuterium;Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the aforementioned rings is substituted with Ra, Rb, and Rcindependently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano;Degron is an E3 ubiquitin ligase ligand selected from:(a) a group of formula (i):(b)(ii);Yais CH or N;Zais a bond, -CH2-, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is attached to Ya;ring A is a group of formula (a) or (b):where:Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;R4and R5are independently hydrogen or alkyl; or R4and R5together with the carbon to which they are attached form >C=O;M is -O- or -NR6-; andR6is hydrogen or alkyl; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three ring atoms that are heteroatoms independently selected from nitrogen, oxygen, and sulfur and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with Reeand Rffindependently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; andZ is -O-, -NR3- (where R3is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene and where each of the aforementioned rings is substituted with Rdand Reindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; alk is alkynylene substituted with Rfand Rgindependently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano; or when Rfand Rgare attached to the same carbon atom of the alkynylene, they can combine with the carbon atom to which they are attached to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R7and R8independently selected from hydrogen, alkyl, and halo; alk1is absent or alkylene optionally substituted with R9and R10independently selected from halo, hydroxy, and cyano;Ar is phenylene, monocyclic heteroarylene, heterocyclylene, unsaturated heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each of the aforementioned rings issubstituted with Rh, R1, and R1independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; andAr1is phenylene, monocyclic heteroarylene, or heterocyclylene where each of the aforementioned rings is substituted with Rk, Rm, and Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is halo.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is haloalkyl or haloalkoxy.

4. The compound of any one of claims 1 to3, or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2and R2aare hydrogen.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Hy is heterocyclylene, phenylene, spiro heterocyclylene, bridged heterocyclylene, or cycloalkylene, wherein each of the aforementioned rings is substituted with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the heterocyclylene of Hy is:where the N atom of the piperidin-l,4-diyl ring is attached to -SO2-.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the Degron is an E3 ubiquitin ligase ligand of formula (i):

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a):

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b):

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is:

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Raaand Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Raaand Rbb, Rcc, and Rddare independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

15. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the Degron is an E3 ubiquitin ligase ligand of formula (ii):(ii).

16. The compound of any one of claims 1 to 7 and 15, or a pharmaceutically acceptable salt thereof, wherein Yais CH.

17. The compound of any one of claims 1 to 7 and 15, or a pharmaceutically acceptable salt thereof, wherein Yais N.

18. The compound of any one of claims 1 to 7 and 15 to 17, or a pharmaceutically acceptable salt thereof, wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms and substituted with Reeand Rff.

19. The compound of any one of claims 1 to 7 and 15 to 18, or a pharmaceutically acceptable salt thereof, wherein the E3 ubiquitin ligase ligand of formula (ii) is:where ring B is cyclylaminylene.

20. The compound of any one of claims 1 to 7 and 15 to 19, or a pharmaceutically acceptable salt thereof, wherein the E3 ubiquitin ligase ligand of formula21. The compound of any one of claims 1 to 7 and 15 to 20, or a pharmaceutically acceptable salt thereof, wherein each Reeand Rffare independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy.

22. The compound of any one of claims 1 to 7 and 15 to 21, or a pharmaceutically acceptable salt thereof, wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2- trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Ar is phenylene, monocyclic heteroarylene, bridged heterocyclylene, heterocyclylene, or unsaturated heterocyclylene, where each ring is substituted with Rh, R1, and R1where R> is hydrogen.

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein Ar is phenylene of formulasubstituted with Rh, R1, and R> where Rhand R1are independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, and haloalkoxy and R> is hydrogen.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein the phenylene of Ar issubstituted with Rh, R1, andR> where Rhand R1are independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy and R> is hydrogen.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein the phenylene of Ar is27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein Z is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, each ring substituted with Rdand Re.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein the heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene of Z are selected from:wherein each ring is substituted with Rdand Reindependently selected from hydrogen, deuterium, alkyl, and halo.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein Z is heterocyclylene selected from:

30. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein n is 0 and -Z-alk-Ar-SCh- is:wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and R1and R1are hydrogen.

31. The compound of any one of claims 1 to 25 and 30, or a pharmaceutically acceptable salt thereof, wherein n is 0 and -Z-alk-Ar-SCh- is:wherein each Rd, Re, and Rhare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano and R1and R1are hydrogen.

32. The compound of any one of claims 30 and 31, or a pharmaceutically acceptable33. The compound of any one of claims 30 to 32, or a pharmaceutically acceptable salt thereof, wherein Rdand Reare hydrogen.

34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein alk is:

35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Degron is the E3 ubiquitin ligase ligand selected from:where Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and Rffis hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or tri fluoromethyl.

36. A pharmaceutical composition comprising a compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

37. A method of treating cancer mediated by CDK2 and / or CDK4 in a patient which method comprises administering to the patient in recognized need thereof, a therapeutically effective amount of a compound of any one of claims 1 to 35, or a pharmaceutical composition of claim 36.

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