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

Abstract

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

Description

[0001] BIFUNCTIONAL COMPOUNDS CONTAINING 2,4,5-SUBSTITUTED PYRIMIDINE DERIVATIVES FOR DEGRADING CERTAIN CYCLIN-DEPENDENT KINASE VIA UBIQUITIN PROTEASOME PATHWAY Cross-reference to Related Applications

[0002] This PCT International Patent Application claims the benefit of U.S. Provisional Application No. 63 / 643,888, filed on May 7, 2024; the entire contents of which are hereby incorporated by reference.

[0003] Field of the disclosure

[0004] The present disclosure provides certain bifunctional compounds containing 2,4,5- substituted pyrimidine derivatives that cause degradation of Cyclin-dependent kinase 2 (CDK2) and / or 2 and Cyclin-dependent kinase 2 (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. Anna. Rev. Cell. Dev. Biol. (1997) 13: 261-291). In the canonical model of cell cycle, mitogenic signaling upregulates D-type cy clins, 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 pl6, 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 tw o 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. Currently, multiple CDK2 inhibitors are under clinical development in solid tumors including PF-07104091 (NCT04553133), BLU-222 (NCT05252416), INCB123667 (NCT05238922), INX-315 (NCT05735080), ARTS-021 (NCT05867251), AZD8421 (NCT06188520) and BG-68501 (NCT06257264). Thus far. PF-07104091 and BLU-222 have demonstrated single agent activities in CDK.4 / 6 inhibitor refractory breast cancer patients. In addition, a CDK4 specific inhibitor PF-07220060 (NCT04557449), in combination with endocrine therapy, has demonstrated clinical responses and lower neutropenia adverse events in CDK4 / 6 inhibitor refractory breast cancer patients. Thus, a molecule blocking both CDK2 and CDK4 as single agent or in combination with endocrine therapy, may address the primary and acquired resistance to CDK4 / 6 inhibitors, leading to enhanced antitumor activities and reduced adverse effects to achieve greater therapeutic efficacy in HR+ HER2- breast cancer.

[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.

[0012] Compared to small molecule drugs that typically bind disease-relevant proteins and inhibit their function, PROTACs display several unique and attractive features that make them desirable drug candidates. For example, PROTACs have been shown to be more selective than their inhibitor counterparts, potentially reducing off-target toxicity. Moreover. PROTACs can perform multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can function at sub-stoichiometric receptor occupancies. The E3 ligases used in PROTACs mainly include cereblon (CRBN), Von Hippel-Lindau-containing complex (VHL), inhibitor of apoptosis protein (IAP), and mouse double minute 2 (MDM2).

[0013] Therefore, PROTACs that could recruit CDK2 and / or CDK.4 to a ubiquitin ligase, and thereby causing ubiquitylation and proteasomal degradation of CDK2 and / or CDK4 are desirable. The present disclosure fulfills this and related needs.

[0014] Summary

[0015] In a first aspect, provided is a compound of Formula (I): (I) wherein

[0016] R1is alkyl, alkenyl, alkynyl, alkylthio, pentafluorothio, halo, haloalkyl, haloalky Ithio, haloalkoxy, alkoxy, amino, alky lamino, dialkydamino, cyano, cycloalkyd, cycloalkoxy, cycloalkylalkyl, bridged cycloalkyl, bridged cycloalkoxy, bridged cycloalkylalkyl, cyanoalkyd, cyanoalkoxy, alkoxyalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkoxy, acyl, azidocarbonyl, alkoxy carbonyl, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, substituted sulfonyl, substituted sulfinyl, substituted ureido, aryl, aralkyl, aryloxy, heteroaryl, heteroaralkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, fused heterocyclyl, fused heterocyclyloxy, or fused heterocyclylalkyl, wherein cycloalkyd, by itself or as part of cycloalkoxy and cycloalkylalkyl, aryl, by itself or as part of aralkyl and aryloxy, heteroaryl, by itself or as part of heteroaralkyl and heteroaryloxy. heterocyclyl, by itself or as part of heterocyclylalkyl and heterocyclyloxy, bridged cycloalkyl, alone or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and fused heterocyclyl. by itself or as part of fused heterocyclylalkyl and fused heterocyclyloxy, are substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;

[0017] R2is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxy alkyl, amino, alkylamino, or dialkylamino;

[0018] R3are independently hydrogen or deuterium; and

[0019] 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;

[0020] Degron is an E3 ubiquitin ligase ligand selected from:

[0021] (a) a group of formula (i):

[0022] (i);

[0023] (b) a group of formula (ii):

[0024] (f) a group of formula (vi): where:

[0025] Yais CH or N;

[0026] Zais a bond, -CH2-, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is atached to Ya; ring A is a group of formula (a), (b), or (c): where:

[0027] Raa, Rbb, Rcc, and Rddare independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;

[0028] R4and R5are independently hydrogen or alkyl; or R4and R5together with the carbon to which they are atached form >C=O;

[0029] M is -O- or -NR6-; and

[0030] R6is hydrogen or alkyl; and

[0031] R6is hydrogen or alkyl; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene. wherein in each heteroarylene one to three ring atoms are independently selected from nitrogen or oxygen atoms and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with Reeand Rffindependently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and X1, X2, X3, and X4are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NRgg-alkylene)-, -(alkyl ene-NRhh)-, -N(alkyl)-, -C(=O)-, -NR“C(=O)-, or -C(=O)NRkk- where Rgg, R1'1'. R>', and Rkkare independently hydrogen, alkyl, or cycloalkyl and each alkylene, itself or as part of another group, is optionally substituted with one or two fluoro;

[0032] Ry, Ryl, and Ry2are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with Rdand Rfselected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino; and

[0033] Wais bond. O, S, or alkylene; and

[0034] L is -Z'-Z2-Z -Z4-Z5-Z6- where:

[0035] Z1is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O)2NR-, -NR’S(O)2-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with Rhand R' independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

[0036] Z2is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR’(CO)-, -(O-alkylene)b-, -(alkylene-O)b-, -O(CH2)?-, -O(CH2)s-, cycloalkylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R' and Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

[0037] Z3is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -C(O)NR-, -NR’ (CO)-, -O-, -NR”-, -(O-alkylene)c-, -(alkylene-O)c-, cycloalkylene, spiro cyclolalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)- monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-. unsaturated heterocyclylene. heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, -spiro heterocyclylene-(alkylene)-, or 11 to 13 membered spiro heterocyclylene. where each ring, by itself or as part of another group, is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialky lamino;

[0038] Z4is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -(alkylene-NR”)-. -(NR”- alkylene)-, -O-, -C(O)-, -NR”-, -(O-alkylene)a-, -(alkylene-O)d-, cycloalkylene, -(alkylene)- cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-helerocyclylene-. -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene. -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene- (alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene- (alkylene)-, where each ring, by itself or as part of another group, is substituted with R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

[0039] Z3is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O)2-, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or unsaturated heterocyclylene, or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy , halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; and

[0040] Z6is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR’ (CO)-, or -C(O)NR-; where each R, R' and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z1-, -Z2-, -Z3-, -Z4-, -Z5- and -Z6-, by itself or as part of another group and heteroalkylene of -Z3- and -Z4- are independently substituted with Rs, R\ and Ruwhere Rsis hydrogen, deuterium, or halo, Rlis hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyd, halo, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalky 1, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl. heterocyclyl. heterocyclyloxy. heterocyclylcarbonyl, or bridged heterocyclyl (where cycloalky 1, either by itself or as part of cycloalkyloxy, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, either by itself or as part of heterocyclyloxy or heterocyclylcarbony l, and bridged heterocyclyl are substituted with R7and R8independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxy carbonyl, amino, alkylamino, dialkylamino, and cyano), and Ruis hydrogen or halo; or when Rland Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the alky dene or heteroalkydene, Rland Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by Rland Ruare substituted with R9and R10independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkydoxycarbonyl, amino, alkylamino, dialkylamino, and cyano), alkenylene of -Z3- and -Z4- are substituted with Rvselected from hydrogen, fluoro, and cyano, and alkynylene of -Z3- and -Z4- are substituted with Rwand Rxindependently selected from hydrogen, halo, haloalkyl. alkoxy, hydroxy, and cyano; or yvhen R" and Rxare attached to the same carbon atoms of the alkynylene, they can combine to form cycloalkylene or heterocyclylene yvherein the cycloalkylene and heterocyclylene are substituted with R11and R12independently selected from hydrogen, alkyl, and halo; provided that at least one of -Z'-Z2-Z -Z4-Z5-Z6- is not a bond; or a pharmaceutically acceptable salt thereof.

[0041] In a second aspect, provided is a compound of Formulae (IB): wherein:

[0042] R1, R2, R3, and Hy are as defined in Formula (I) above or any of the embodiments thereof herein below;

[0043] L is a Linker (in one embodiment, Linker is -Z'-Z2-Z -Z4-Z5-Z6- as defined in Formula (I) above or any one of embodiments thereof herein below); and

[0044] Degron is an E3 ubiquitin ligase ligand; or a pharmaceutically acceptable salt thereof.

[0045] In a third aspect, provided is a method of treating a disease mediated by CDK2 and / or CDK4 in a patient, in one embodiment the patient is in need of such treatment, which method comprises administering to the patient, in one embodiment a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the third aspect, the disease is cancer. In a second embodiment of the third aspect, the disease is cancer selected from lung cancer (e.g.. adenocarcinoma, small cell lung cancer, non-small cell lung carcinomas, parvicellular and non-parvicellular carcinoma, bronchial carcinoma, bronchial adenoma, and / or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi sarcoma, and / or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, endometrial cancer, gastric cancer, head and neck cancer (e.g., cancers of the larynx, hypopharynx, nasophary nx, oropharynx, lips, and / or mouth), liver cancer (e.g., hepatocellular carcinoma and / or cholangiocellular carcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g., exocrine pancreatic carcinoma), stomach cancer, thyroid cancer, parathyroid cancer, bone cancer, biliary tract cancer, vaginal cancer, astrocytoma, liposarcomas, glioblastoma, neuroblastoma and / or kidney cancer. In a third embodiment of the third aspect, the cancers are those that are resistant to CDK4 / 6 inhibitors through CDK2 -mediated mechanisms e.g., breast cancer. In a fourth embodiment of the third aspect, the disease is an autoimmune disease, or a condition associated with an autoimmune disease, which method comprises administering to the patient, in one embodiment a patient in need of such treatment, a therapeutically effective amount of a compound of any one of first and second aspects (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), uveitis, pemphigus vulgaris, and sepsis. In a fifth embodiment of the third aspect, the disease is gout. In a sixth embodiment of the third aspect, the therapeutically effective amount of a compound of Formulas (I) and (IB) (or any embodiment thereof disclosed herein including specific compounds), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.

[0046] In a fourth aspect, provided is a method of treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss, which method comprises administering to a patient, in one embodiment a patient in need of such treatment, a therapeutically effective amount of a compound of any one of first and second aspects, (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In some embodiments of the fourth aspect, the amount of hearing loss is reduced when compared to an age-matched control. In some embodiments, the hearing loss is prevented when compared to an age-matched control.

[0047] In a fifth aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0048] In a sixth aspect, provided is a compound of (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment of the sixth aspect, the compound of Formula (1) or (IB) (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof is useful for the treatment of one or more diseases disclosed in the third and fourth aspects above.

[0049] In a seventh aspect, provided is the use of a compound of Formula (I) or (IB) (or any of the embodiments thereof described herein), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which the activity of CDK2 and / or CDK4 contributes to the pathology and / or symptoms of the disease. In one embodiment of the seventh aspect, the disease is one or more diseases disclosed in the third or fourth aspect above.

[0050] In an eighth aspect, provided is a method of degrading CDK2 and / or CDK4 in a cell via ubiquitin proteasome pathway which method comprises contacting the cell with a compound of Formula (I) or (IB) (or embodiments thereof as disclosed herein, including specific compounds). In one embodiment of the eighth aspect. CDK2 and / or CDK4 are degraded in vitro. In another embodiment of the eighth aspect, CDK2 and / or CDK.4 are degraded in vivo. In another embodiment of the eighth aspect, CDK2 and / or CDK.4 are degraded in a cell in a patient.

[0051] In an embodiment of any one of above aspects, CDK2 is selectively degraded over CDK1 by a compound of Formula (I) or (IB). In another embodiment of any one of above aspects, CDK2 is selectively degraded over CDK1 and CDK4; or CDK.4 is selectively degraded over CDK1 and CDK2 by a compound of Formula (I) or (IB). In some embodiments, both CDK2 and CDK4 are degraded by a compound of Formula (I) or (IB), including selectively degraded over CDK1.

[0052] The ability of compounds of Formula (I) and (IA) to degrade CDK2 and CDK4 selectively over CDK1 was measured by determining potency of the compounds in inhibiting retinoblastoma protein (Rb) phosphorylation in OVCAR3 (CDK2 dependent cell line), T47D (CDK4 dependent cell line) and KYSE520 (CDK1 dependent cell line) as described in Biological Example 1 below, and then determining the ratio of Rb IC50 from 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, cause degradation of CDK2 to a greater extent than CDK4 or visa-versa. The degree of degradation of CDK2 and CDK4 can be determined by determining the ratio of Rb IC50 from OVCAR3 and T47D. For sake of clarity, selectively degrade as used herein means the compound disclosed herein may cause degradation of one protein to a greater extent than the other.

[0053] In the aforementioned aspects involving the treatment of cancer, further embodiments are provided comprising administering the compound of any one of first aspect, second aspect, third aspect, and Formula (la), or a pharmaceutically acceptable salt thereof (or any embodiments thereof disclosed herein) or the pharmaceutical composition of the seventh aspect, in combination with at least one additional anticancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially. Detailed Description

[0054] Definitions:

[0055] 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:

[0056] “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.

[0057] “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.

[0058] “Alkymyl” 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.

[0059] “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 Cs to C6alkylene, Examples include, but are not limited to, methylene, ethylene, propylene. 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0060] “Alkenylene” means a linear or branched unsaturated divalent hydrocarbon radical of two to six carbon atoms containing a double bond, e.g., ethen-diyl, propen-diyl, 2-propen-diyl, buten- diyl, penten-diyl, and the like.

[0061] “Alkynylene” means a linear or branched unsaturated divalent hydrocarbon radical of two to eight carbon atoms containing a triple bond, e.g., like.

[0062] “Alkoxy” means a -ORZradical where Rzis alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, «-, iso-, or / c / 7-butoxy , and the like.

[0063] “Alkoxyalkyl” means alky l as defined above that is substituted with alkoxy as defined above e.g., methoxymethyl, methoxy ethyl, ethoxyethyl, and the like.

[0064] “Alkydthio” means an -SRZradical where Rzis alkyl as defined above, e.g., methylthio, ethylthio, n-propylthio, 2-propylthio, n-, iso-, or / e / v-butylthio. and the like.

[0065] “Alkoxy carbonyl” and “alkyloxy carbonyl” mean a -C(O)ORZradical where Rzis alkyl as defined above, e.g., methoxy carbonyl, ethoxy carbonyl, and the like.

[0066] “Alkylcarbonylamino” means a -NRz'C(O)Rzradical where Rzis alkyl and Rz" is H or alkyl, as defined above, e.g.. methylcarbonylamino, ethylcarbonylamino, and the like.

[0067] “Acyl” means a -C(O)RZradical where Rzis alkyl, haloalky 1, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, as defined herein, e.g., methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, and the like. When Rzis alkyl, acyl is also referred to herein as “alkylcarbonyl.”

[0068] “Azidocarbonyl” means -C(O)N2 radical.

[0069] “Amido” means an -NRZC(O)- or -C(O)NRZ- group, where Rzis hydrogen or alkyd as defined above.

[0070] “Sulfonamido” means an -NRZS(O)2- or -S(O)2NRZ- group, where Rzis hydrogen or alkyl as defined above.

[0071] “Amino” means -NH2.

[0072] “Aminoalky 1” means alkyl as defined above that is substituted with -NH2 e.g., NFhmethyl, NH2ethyl, and the like.

[0073] “Aminoalkyloxy” and “aminoalkoxy” mean -ORZradical where Rzis aminoalkyl as defined above e.g., NH2methyloxy, NH2ethyloxy, and the like.

[0074] “Aminocarbonyl” means -C(O)NH2.

[0075] “Alky laminocarbonyl” means -C(O)NHRZradical where Rzis alkyl as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.

[0076] “Dialky laminocarbonyl” means -C(O)NRzlRzradical where Rzand Rzlare independently alkyd as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.

[0077] “Alkydamino” means -NHRZradical where Rzis alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like.

[0078] “Aminosulfony 1” means -S(O)2NH2.

[0079] “Alkylaminosulfonyd” means -S(O)2NHRZradical where Rzis alkyd as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.

[0080] “Dialkydaminosulfonyl” means -S(O)2NRzlRzradical where Rzand Rzlare independently alkyl as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.

[0081] “Alkylaminoalkyl” means alkyl as defined above that is substituted with alkylamino as defined above e.g.. methyaminomethyl. methylaminoethyl, ethylaminoethyl, and the like.

[0082] “Alkydaminoalkydoxy” means -ORZradical where Rzis alky daminoalkyl as defined above e.g., methyaminomethyloxy, methylaminoethyloxy, ethylaminoethyloxy, and the like.

[0083] “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

[0084] “Aralkyl” means an -(alkylene)-Rzradical where Rzis aryl as defined above e.g. benzyl. “Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene.

[0085] “Aryloxy” means a -OR- radical where R- is ary l as defined above e.g., phenyloxy (or phenoxy), or naphthyl oxy.

[0086] “Bicyclic heterocyclylene” means a saturated or unsaturated, divalent fused bicyclic group of 8 to 12 ring atoms in which one, two, or three ring atoms are heteroatoms independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being carbon, unless stated otherwise. Additionally, one or two ring 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.

[0087] “Bridged cycloalkyl” means a saturated monovalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRzRz’)ngroup where n is an integer selected from 1 to 3 and Rzand Rz’ are independently H or methyl (also may be referred to herein as “bridging” group). Examples include, but are not limited to, bicyclof l. 1. l]pent-l-yl, bicyclo[2.2.1]heptyl. (in one embodiment bicyclo[2.2.1]hept-2-yl), and the like.

[0088] “Bridged cycloalkylalkyl” means a -(alkylene)-Rzradical where Rzis bridged cycloalkyl as defined above e.g., bicyclofl. l.l]pent-l-ylmethyl, and the like.

[0089] “Bridged cycloalkyloxy” and “bridged cycloalkoxy” mean a -ORZradical where Rzis bridged cycloalkyl as defined above e.g., bicyclo[2.2.1]hept-2-yloxy.

[0090] “Bridged cycloalkylene” means a saturated divalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRzRz’)ngroup where n is an integer selected from 1 to 3 and Rzand Rz’ are independently H or methyl (also may be referred to herein as “bridging” group). Bridged cycloalkyl 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, bicyclo[2.2.1]heptylene. In one embodiment bicyclo[2.2.1]hept-2,5-ylene.

[0091] “Bridged heterocyclyl” means a saturated monovalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRpRp’)ngroup where n is an integer selected from 1 to 3 and Rpand Rp' are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, NH. O, and S(O)n, where n is an integer selected from 0 to 2. Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octanyl,

[0092] 7-oxabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo-[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2. l]octanyl, 6-azabicyclo[3.1.1]heptanyl.

[0093] 8-azabicyclo[3.2.1]octanyl, and the like.

[0094] “Bridged heterocyclylene” means a saturated divalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRzRz')ngroup where n is an integer selected from 1 to 3 and Rzand Rz’ are independently H or methyl (also may be referred to herein as “bridging’’ group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2. Bridged heterocyclylene is optionally substituted with one or two substituents independently selected from alkyd, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to. 3,8-diazabicyclo[3.2. l]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. l]heptan-diyl, 8-azabicyclo[3.2. l]octan-diyl, and the like.

[0095] “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.

[0096] “Cycloalkyloxy’’ and “cycloalkoxy” mean a -ORZradical where Rzis cycloalky l as defined above. Examples include, but are not limited to. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0097] “Cycloalkylalkyl” means an -(alkylene)-Rzradical where Rzis cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0098] “Cycloalkylene” means a divalent saturated cyclic hydrocarbon radical of three to six carbon atoms, unless stated otherwise e.g., 1,1 -cyclopropylene, 1,1 -cyclobutylene, 1,4-cyclohexylene, and the like.

[0099] “Carbonyl” means -C(O)-.

[0100] “Carboxy” means -COOH.

[0101] “Cyclylaminylene” means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one or two ring atoms are nitrogen, the remaining ring atoms being carbon. More specifically, the term cyclylaminyl includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene. piperazinylene, and the like.

[0102] “Cyanoalkyl” means alkyl as defined above that is substituted with a cyano e.g., cyanomethyl, cyanoethyl, and the like.

[0103] “Cyanoalkoxy” and “cyanoalkyloxy” mean an -OR7radical where R7is cyanoalkyl as defined above. Examples include, but are not limited to, cyanomethoxy, cyanoethoxy, and the like.

[0104] “Deuterium” means refers to2H or D.

[0105] "Dialkylamino" means a -NRZRZradical where each Rzis independently alkyl as defined above, e.g.. dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, iso-, or tert-butylmethylamino. and the like.

[0106] "Dialkylaminoalkyl" means alkyl as defined above that is substituted with dialkylamino as defined above e.g., dimethy aminomethyl, dimethylaminoethyl, ethylmethylaminoethyl, and the like.

[0107] “Dialkylaminoalkyloxy” and “dialkylaminoalkoxy” mean -OR7radical where Rzis dialkylaminoalkyl as defined above e.g., dimethyaminomethyloxy, dimethylaminoethyloxy, ethylmethylaminoethyloxy, and the like.

[0108] “Ether” means an -O- group.

[0109] “Fused heterocyclyl” means a monovalent bicyclic ring in which two adjacent ring atoms of a saturated or partially unsaturated (but not aromatic) monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl, or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom is optionally oxidized or quatemized. The fused heterocyclylene can be attached at any atom of the ring. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazinyl, and the like.

[0110] “Fused heterocyclylene” means a divalent bi cyclic ring in which two adjacent ring atoms of a saturated or partially unsaturated (but not aromatic) monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl, or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom is optionally oxidized or quatemized. 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.

[0111] “Fused heterocyclylalkyl” means an -(alkyl ene)-Rzradical where Rzis fused heterocyclyl as defined above e.g., 1,2,3,4-tetrahydroquinolinylmethyl, 3,4-dihydro-2H- benzo[b][l,4]oxazinylmethyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazinylmethyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazinylmethyl, and the like.

[0112] “Fused heterocyclyloxy” means an -ORZradical where Rzis fused heterocyclyl as defined above e.g., 1,2,3,4-tetrahydroquinolinyloxy, 3,4-dihydro-2H-benzo[b][l,4]oxazinyloxy,

[0113] 3.4-dihydro-2H-pyrido[3,2-b][1.4]oxazinyloxy, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazinyloxy, and the like.

[0114] “Halo” means fluoro, chloro, bromo, or iodo, in one embodiment fluoro or chloro.

[0115] “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.

[0116] -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.

[0117] “Haloalkoxy” means a -ORZradical where Rzis haloalkyl as defined above e. g; -OCF3, -OCHF2, and the like. When Rzis haloalkyl where the alkyl is substituted with only fluoro (in some examples, one or more fluoro), it is referred to in this Application as fluoroalkoxy.

[0118] “Haloalkylthio” means an -SRZradical where Rzis haloalkyl as defined above e.g., -SCF3, -SCHF2, and the like.

[0119] “Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both present on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy -ethyl, 2-hydroxypropyl, 3 -hydroxy propyl, 1 -(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3 -hydroxy butyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, l-(hydroxymethyl)-2- hydroxy ethyl, 2.3-dihydroxybutyl. 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl (in one embodiment 2-hydroxy ethyl, 2,3-dihydroxypropyl, and 1 -(hydroxymethyl)-2- hydroxy ethyl).

[0120] “Heteroalkylene” means is a linear or branched saturated divalent hydrocarbon radical of (a) two to six carbon atoms where one carbon atom of the linear portion of the divalent hydrocarbon radical is replaced by Xawhere Xais -O-, -S-, -SO-, -SO2-, -CO-, or -NRql- or (b) three to six carbon atoms where two adjacent carbon atoms of the linear portion of the divalent hydrocarbon radical are replaced by Xalwhere Xalis -NRqlCO-, -CONRq1-, -NRqlSO-, -SONRq1-, -NRqlSO2-, or -SO2NR41- (where each Rqlis hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl) and furthermore wherein, when the linear portion of the hydrocarbon radical of (a) has 3 to 6 carbon atoms and the hydrocarbon radical of (b) has 4 to 6 carbon atoms, then an additional carbon atom in the linear portion of the hydrocarbon radical of (a) and (b) that is not adjacent to Xaand Xalabove, can be replaced by Xywhere Xyis -O- or -NRq2- (where each Rq2is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl). For sake of clarity, as used in this definition, the linear portion of the heteroalkylene means the consecutive atoms of the heteroalkylene connecting Z2and Z4when Z3is heteroalkylene and Z3and Z5when Z4is heteroalkylene; e.g., in the structure , the atoms with * form the linear portion of Cs heteroalkylene. When the heteroalkylene contains only one or two -O-, it can be referred to herein as “oxoalkylene.” When the heteroalkylene contains only one or two -NRq- and / or -NRq1-, it can be referred to herein as “aminylalkylene.” When the heteroalkylene contains only -S-, it can be referred to herein as

[0121] “sulfanylalkylene.” When the heteroalkylene contains only -SO-, it can be referred to herein as “sulfinylalkylene.” When the heteroalkylene contains only -SO2-, it can be referred to herein as “sulfonylalkydene.” Representative examples, of heteroalkylene include, e.g.. and the like.

[0122] “Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon. 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 5-or 6-membered monocy clic heteroaryl or monocyclic heteroarylene. When the heteroaryl ring contains 9- or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroaryl.

[0123] “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-1.4-diyl. When the heteroarylene ring contains 9- or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9- or 10-membered fused bicyclic heteroarylene.

[0124] “Heteroarylalkyl” and “heteroaralkyl” mean an -(alkylene)-Rzradical where Rzis heleroaryl as defined above.

[0125] “Heteroaryloxy” means an -ORZradical where Rzis heleroaryl as defined above.

[0126] “Heterocyclyl” means a saturated, monovalent, monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)n. where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro-furanyl, tetrahydro-pyranyl, thiomorpholinyl, and the like. When the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds provided that the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

[0127] “Heterocyclylcarbonyl” means a -C(O)R radical where R is heterocyclyl as defined herein. More specifically, the term heterocyclyl includes, but is not limited to, piperidinylcarbonyl, piperazinylcarbonyl, pyrrolidinylcarbonyl, azetidinylcarbonyl, and the like.

[0128] “Heterocyclylalkyl” means an -(alkyl ene)-Rzradical where Rzis heterocyclyl as defined above e.g. piperidinylmethyl and piperazinylmethyl. “Heterocyclyloxy” means an -ORZradical where Rzis heterocyclyl as defined above e.g. l-methylpyrrolidin-3-oxy. l-methylpyrrolidin-2-oxy. piperidin-3-oxy, piperidin-4-oxy and the like.

[0129] “Heterocyclylene” means a saturated or unsaturated, divalent, monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclylene ring can optionally be replaced by a -CO- group. More specifically, the term heterocyclylene includes, but is not limited to, , piperi din-1, 4-diyl, azeti din- 1,3 -diyl, and the like.

[0130] The term “Linker ‘L‘ ’’ is a connector with a linear non-hydrogen atom number in the range of 1 to 20 (preferably, 2, 3, 4, 5. 6, 7, 8, 9, 10. 11. 12, 13, 14, 15, 16, 17, 18, 19, or 20; more preferably. 8 to 16, 9 to 14, 9 to 13, 9 to 12; more preferably 8, 9. 10. 11. 12. or 13; most preferably, 12 or 13). Linker “L” can contain one or more (preferably 2, 3, 4, 5, 6, 7, or 8; more preferably, 3 to 6 or 3, 4, 5, or 6; most preferably, 4 or 5), groups which are independently selected, such as, but not limited to, ether, polyether, thioether, -NH-. -N(alkyl)-, amido, sulfonamido. alkylene, alkenylene, alkynylene, carbonyl, -C(O)O-, -OC(O)-. sulfinyl, sulfonyl, ureido, thioureido, cycloalkylene, bridged cycloalkylene, spiro cycloalkylene, arylene, heteroarylene, heterocyclylene, bridged heterocycylene, spiro heterocyclylene, bicyclic heterocyclylene, or fused heterocyclylene. and wherein cycloalkylene, bridged cycloalkylene, spiro cycloalkylene, arylene, heteroarylene, heterocyclylene, bridged heterocycylene, spiro heterocyclylene, bicyclic heterocyclylene, and fused heterocyclylene are optionally substituted with one, two, or three substituents independently selected from deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino, and wherein alkylene is optionally substituted with one or two halo (in one embodiment fluoro). In some or any embodiments, Linker L contains 3 to 5 groups independently selected from -O-, -NH-. -N(CH3)-, sulfonyl, phenylene, alkylene (in one embodiment -CH2-, -CH2CH2-, -CH2CH2CH2- , -CH2CH(CH3)CH2-, -CH(CH3)CH2-, -CH(CH3)-, -CH2C(CH3)2CH2-, heterocyclylene (in one embodiment azetidin-diyl, piperidin-diyl, or piperazin-diyl), spiro heterocyclylene (in one embodiment 2.6-diazaspiro[3.3]heptan-diyl), and monocyclic heteroarylene (in one embodiment imidazolyl or pyridinyl; in another embodiment imidazolyl), wherein heterocyclylene, spiro heterocyclylene, and monocyclic heteroarylene are optionally substituted with one, two, or three substituents independently selected from halo (in one embodiment fluoro) and alky l (in one embodiment methyl), and wherein alkylene is optionally substituted with one or two halo (in one embodiment the group is -CH(CHF2)-.

[0131] “Phenylene” means divalent phenyl.

[0132] “Polyether” means a group where d is an integer selected from 2 to 5 and Rzis C2-salkylene.

[0133] The term “oxo.” as used herein, alone or in combination, means =(O).

[0134] 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 alkyene that is substituted with halo.

[0135] “Spiro cycloalkylene” means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 ring atoms wherein the rings are connected through only one atom, the connecting atom is also called the spiroatom. most often a quaternary carbon (“spiro carbon”). Spiro cy cloalkylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, spiro[3,5]nonandiyl e.g., spiro[3.5]nonane-2,7-diyl, and the like.

[0136] “Spiro heterocyclylene" means a saturated bicyclic divalent ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to. 2-azaspiro[3.3]heptan-diyl, 2,6-diazaspiro[3.3]heptan-diyl, l,7-diazaspiro[3.5]nonan-diyl, 2,7-diazaspiro[3.5]nonan-diyl, 3,9-diazaspiro[5.5]undecan-diyl, and the like.

[0137] “11 to 13 membered spiro heterocyclylene” means a saturated bicyclic divalent ring having 11 to 13 ring atoms in which one, two. or three ring atoms are heteroatom(s) selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary' carbon (“spiro carbon”). The 11 to 13 membered spiro heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, diazaspiro[5.5]undecan-diyl. 1-oxa-di azaspiro [5.5] undecan-diyl, and the like.

[0138] “Pentafluorothio” means an -SF5.

[0139] “Sulfinyl” means an -S(O)- group.

[0140] “Substituted sulfinyl” means an -S(O)RZwhere Rzis alkyl as defined above e.g., methyl or ethylsulfinyl.

[0141] “Sulfonyl” means an -S(O)2- group.

[0142] “Substituted sulfonyl” means an -S(O)2RZwhere Rzis alkyl as defined above e.g., methyl or ethylsulfonyl. Substituted sulfonyl is also referred to herein as alkylsulfonyl.

[0143] “Thioether” means an -S- group.

[0144] “Thioureido” means an -NHC(S)NH- group.

[0145] “Ureido” means an -NHC(O)NH- group.

[0146] “Substituted ureido” means an -NHC(O)NRZRZwhere Rzis hydrogen or alkyl and Rzis alkyl, as defined above e.g., -NHC(O)NHmethyl, -NHC(0)NMe2, and the like.

[0147] “Unsaturated heterocyclylene” means divalent, monocyclic nonaromatic group of 5 to 8 ring atoms having one, two, or three double bonds and in which one or two ring atoms are heteroatom(s) independently selected from N, O, and S(O)n, where n is an integer selected from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclylene ring can optionally be replaced by a-C(=O)- group.

[0148] The present disclosure also includes protected derivatives of compounds of first aspect or second aspect (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof. For example, when compounds of Formula (la) contain groups such as hy droxy , 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 entirety7. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

[0149] The present disclosure also includes polymorphic forms and deuterated forms of the compound of first aspect or second aspect (or any embodiments thereof disclosed herein), or a pharmaceutically acceptable salt thereof.

[0150] The term “prodrug” refers to a compound that is made more active in vivo. C6rtain compounds Formula (I) and (IB) (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 prodmg. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodmg”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

[0151] 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, hydroxy naphthoic 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.

[0152] The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may have asymmetric centers. Compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recry stallization, 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 impurify and vice versa. C6rtain compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are yvithin 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, yvhen the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) are within the scope of this disclosure.

[0153] The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100% of the atom in question, that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present disclosure, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,13N,15N,15O,170,180,32P,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 (z.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with (or isotopically enriched for) heavier isotopes such as deuterium (i.e..2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds, including in Table 1 below, one or more hydrogen atoms are replaced by2H or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,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.

[0154] 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.

[0155] “A pharmaceutically acceptable carrier / excipienf ' as used in the specification and claims includes both one and more than one such excipient.

[0156] 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%. In one embodiment, the range for “about” encompasses ± 5%. The recited value and the range is included. C6rtain structures provided herein are draw n 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.

[0157] For example, in the structure: , the Raasubstituent, and similarly the Rbband X1substituents, can replace hydrogen of any CH that is part of the benzo portion of the bicyclic ring that is not already substituted with Rbband X1(in the case of Raa), and similarly with Raaand X1(in the case of Rbb), and with Raaand Rbb(in the case of X1).

[0158] 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 (la), in the following divalent groups: the bond on the left of (a), (b) and (c) is attached to the following ring: and the on the right side of (a), (b). and (c) (i.e., X1, X2, and X3) is attached to Z1of L of the following structure:

[0159] Similarly, for L i.e, -71-Z2-Z3-Z4-Z5-Z6-. the left side in L (i.e., Z1) is attached to X1, X2, X3. or X4or point of attachment delineated in Degrons of formula (c), (d), (e), or (f) and Z6is attached to an atom of Hy. For example, when L is a group of formula:

[0160] and Degron is a group of formula (a), i.e., , the left bond in L (i.e., the -NH- group) is attached to X1and the right hand bond in L (i.e., -SO2-) is attached to an atom of the Hy

[0161] 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.

[0162] 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.

[0163] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. In one embodiment, the patient is a human.

[0164] “Treating” or “treatment” of a disease includes:

[0165] (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;

[0166] (2) inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] The compounds of Formula (I) or (IB) can also inhibit CDK2 and / or CDK4. The term “inhibiting” and “reducing,” or any variation of these terms in relation to CDK2 and / or CDK4, includes any measurable decrease or complete inhibition of enzymatic activity of CDK2 and / or CDK4, respectively, to achieve a desired result. For example, a compound of Formula (I) or (IB) may independently decrease about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%. 75%. 80%. 85%. 90%, 95%, 99%, or more, or any range derivable therein, of CDK2 and / or CDK4 activity, compared to their / its normal activity. In some embodiments, the CDK2 and / or CDK4 activity’ is reduced by at least 40% in the presence of a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 and / or CDK4, respectively, in the absence of said compound. The inhibitory activity of a compound of Formula (I) or (IB) can be measure using Biological Example 1, by converting a compound of Formula ( (I) or (IB) to a corresponding compound of Formula (I) or (IB) that cannot be degraded by the ubiquitin proteosome pathway e.g. , by methylating the nitrogen atom in group of ligase ligand (i) or (ii) present in the compound of Formula (I) or (IB).

[0171] The term “degrading” and “degrade,” or any variation of these terms in relation to CDK2, CDK4, and CDK1, means any measurable decrease in the concentration of CDK2, CDK4, and CDK.1. respectively, over time in a sample containing of Formula (I) or (IB. For example, there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, in CDK2 and CDK4 concentration in a sample containing CDK2 or CDK4, respectively and a compound disclosed herein in the Summary, Embodiments, and Compound Table 1 disclosed herein as compared to an equivalent sample comprising CDK2 or CDK4, in the absence of said compound. The % degradation can be determined as described in Biological Example 2 below. In one embodiment, the decrease in the concentration of CDK2 is > 20%. In another embodiment, the decrease in the concentration of CDK2 is > 40%. In another embodiment, the decrease in the concentration of CDK2 is > 50%. In another embodiment, the decrease in the concentration of CDK2 is > 60%. In another embodiment, the decrease in the concentration of CDK2 > 70%. In another embodiment, the decrease in the concentration of CDK2 is > 80%.

[0172] In one embodiment, the decrease in the concentration of CDK4 is > 20%. In another embodiment, the decrease in the concentration of CDK4 is > 40%. In another embodiment, the decrease in the concentration of CDK4 is > 50%. In another embodiment, the decrease in the concentration of CDK4 is > 60%. In another embodiment, the decrease in the concentration of CDK4 > 70%. In another embodiment, the decrease in the concentration of CDK4 is > 80%.

[0173] “E3 ubiquitin ligase” refers to a family of proteins that operate in conjunction with El ubiquitin-activating enzy me 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. C6reblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). VHL is part of the E3 ligase complex VCB, which also consists of elongins B and C, Cul2 and Rbxl.

[0174] “E3 ubiquitin ligase ligand” means a small molecule ligand (i.e., having a molecular weight of below 2,000, 1,000. 500, or 200 Daltons), which is capable of binding to an E3 ubiquitin ligase or a subunit of E3 ligase, such as C6reblon, VHL. 1AP, or MDM2.

[0175] Embodiments:

[0176] In embodiments Al to A253, the present disclosure includes:

[0177] AL In embodiment Al . provided is a compound of Formula (I) or a pharmaceutically acceptable salt as described in the first aspect of the Summary. A2. In embodiment A2. the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyl, halo, haloalkyl. haloalkoxy, alkoxy, cyano, or cycloalkyl substituted with one to three halo.

[0178] A3. In embodiment A3, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is alkyl, alkenyl, alkynyl, or aryloxy.

[0179] A4. In embodiment A4. the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is halo, haloalkyl. or haloalkoxy.

[0180] A5. In embodiment A5, the compound of any one of embodiments Al, A2, and A4, or a pharmaceutically acceptable salt thereof, is wherein R1is halo.

[0181] A6. In embodiment A6. the compound of any one of embodiments Al, A2, and A4, or a pharmaceutically acceptable salt thereof, is wherein R1is haloalkyl.

[0182] A7. In embodiment A7, the compound of any one of embodiments Al, A2, and A4, or a pharmaceutically acceptable salt thereof, is wherein R1is haloalkoxy.

[0183] A8. In embodiment A8. the compound of any one of embodiments Al, A2, and A4 to A7, or a pharmaceutically acceptable salt thereof, is wherein R1is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

[0184] A9. In embodiment A9. the compound of any one of embodiments Al, A2, and A4 to A8, or a pharmaceutically acceptable salt thereof, is wherein R1is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

[0185] A10. In embodiment A10, the compound of any one of embodiments Al, A2, A4, A5, A8, and A9, or a pharmaceutically acceptable salt thereof, is wherein R1is chloro.

[0186] Al l. In embodiment Al 1, the compound of any one of embodiments Al. A2, A4, A6, A8, and A9, or a pharmaceutically acceptable salt thereof, is wherein R1is difluoromethyl or trifluoromethyl.

[0187] Al 2. In embodiment Al 2, the compound of any one of embodiments Al, A2, A4, A6, A8, A9, and Al l, or a pharmaceutically acceptable salt thereof, is wherein R1is trifluoromethyl.

[0188] A13. In embodiment A13, the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R1is alkyl, alkenyl, or alkynyl.

[0189] A14. In embodiment A14, the compound of embodiment Al, A3, or A13, or a pharmaceutically acceptable salt thereof, is wherein R1is methyl, ethyl, propyl, vinyl, propeny l, ethynyl, or propynyl.

[0190] A15. In embodiment A15, the compound of embodiment Al, A3, A13, or A14, or a pharmaceutically acceptable salt thereof, is wherein R1is methyl, ethyl, or propyl. A16. In embodiment A16, the compound of embodiment Al, A3. A13, or A14, or a pharmaceutically acceptable salt thereof, is wherein R1is vinyl, propenyl, ethynyl. or propynyl.

[0191] Al 7. In embodiment Al 7, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is alkoxy.

[0192] A18. In embodiment A18, the compound of embodiment Al, A2. or A17, or a pharmaceutically acceptable salt thereof, is wherein R1is methoxy, ethoxy, or propoxy.

[0193] Al 9. In embodiment Al 9, the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R1is aryloxy’ (such as phenoxy).

[0194] A20. In embodiment A20, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is cyano.

[0195] A21. In embodiment A21, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyl (such as cyclopropyl).

[0196] A22. In embodiment A22, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkyl substituted with one to three halo (such as fluorocyclopropyl or difluorocyclopropyl).

[0197] A22-1. In embodiment A22-1, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylthio, pentafluorothio, haloalkylthio, amino, alkylamino, dialkylamino, cycloalkoxy, cycloalkylalkyl, bridged cycloalkyl, bridged cycloalkoxy, bridged cycloalkylalkyl, cyanoalkyl, cyanoalkoxy, alkoxyalkyl, aminoalkyl, aminoalkoxy, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkoxy, acyl, azidocarbonyl, alkoxycarbonyl, alkylcarbonylamino, aminocarbonyl, alkyl aminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, substituted sulfonyl, substituted sulfinyl, substituted ureido, aryl, aralkyl, aryloxy, heteroaryl, heteroaralkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, fused heterocyclyl, fused heterocyclyloxy, or fused heterocyclylalkyl, wherein cycloalkyl, as part of cycloalkoxy and cycloalkylalkyl, aryl, by itself or as part of aralkyl and aryloxy, heteroaryl, by itself or as part of heteroaralkyl and heteroaryloxy. heterocyclyl, by itself or as part of heterocyclylalkyl and heterocyclyloxy. bridged cycloalkyl, alone or as part of bridged cycloalkoxy and bridged cycloalkylalkyl, and fused heterocyclyl, by itself or as part of fused heterocyclylalkyl and fused heterocyclyloxy, are substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0198] A22-la. In embodiment A22-la, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is aryl, heteroaryl, heterocyclyl, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylammoalkyl. heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF3. -SF5. fused heterocyclyl, bridged cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, aminoalkoxy, alkoxycarbonyl, alkylcarbonylamino, acyl, azidocarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, substituted ureido, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, and substituted sulfonyl, wherein aryl, by itself and in arylalkyl, heteroaryl, alone and in heteroaryloxy, heterocyclyl, fused heterocyclyl, bridged cycloalkyl, by itself and in cycloalkylalkyl, and heterocyclyl, by itself and in heterocyclylalkyl, are substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-la, R1is phenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrahydrofuranyl. tetrahydropyranyl. pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2,3-dihydrobenzofuranyl, benzodihydropyranyl, 1 ,4-benzodioxanyl, 2,3-dihydrofuro[3,2-c]pyridinyl, 2,3-dihydrofuro[2,3- c]pyridinyl, or 1.2.3,4-tetrahydroquinolinyl, wherein each of the rings is substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0199] A22-lb. In embodiment A22-lb, the compound of embodiment Al, A22-1, or A22- la, or a pharmaceutically acceptable salt thereof, is wherein R1is ary 1, heteroaryl, heterocyclyl, cyanoalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, heteroaryloxy, cyanoalkoxy, alkylthio, amino, alkylamino, dialkylamino, -SCF3. or -SF5; wherein each of the rings is substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano. In a subembodiment of embodiment A22-lb, R1is phenyl (substituted with hydrogen, alkyl, alkoxy, halo, cyano, haloalkyl, or haloalkoxy), py razoly l, imidazolyl, oxazolyl, thiazolyl, triazolyl (substituted with hydrogen or alkyl), tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl (substituted with hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano) cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl, or dimethylaminomethyl.

[0200] A22-lc. In embodiment A22-lc, the compound of embodiment Al, A22-1, A22-la, or A22-lb. or a pharmaceutically acceptable salt thereof, is wherein R1is alkylthio (such as methylthio).

[0201] A22-ld. In embodiment A22-ld, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is pentafluorothio.

[0202] A22-le. In embodiment A22-le, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is haloalkylthio (such as trifluoromethylthio). A22-lf. In embodiment A22-lf, the compound of embodiment Al, A22-1, A22-la, or A22-lb. or a pharmaceutically acceptable salt thereof, is wherein R1is amino.

[0203] A22-lg. In embodiment A22-lg, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylamino (such as methylamino).

[0204] A22-lh. In embodiment A22-lh, the compound of embodiment Al, A22-1, A22-la. or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is dialkylamino (such as dimethylamino).

[0205] A22-li. In embodiment A22-li, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkoxy where the cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-li, cycloalkyloxy is cyclopropyloxy, cyclobuty loxy, or cyclopentyloxy, where each cycloalkyl ring of cycloalkyloxy is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0206] A22-lj. In embodiment A22-lj, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is cycloalkylalkyl where the cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alky l, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lj. cycloalkylalkyl is cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl, where each ring of cycloalkylalkyd is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0207] A22-lk. In embodiment A22-k, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is bridged cycloalkyl (such as bicyclofl. l.l]pent-l-yl or bicyclo[2.2.1]heptyl) where the bridged cycloalkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lk, the bridged cycloalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0208] A22-lm. In embodiment A22-lm, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is bridged cycloalkoxy (such as bi cyclof l. 1.1 ]pent-l-yloxy or bicyclo[2.2.1]heptyloxy) where the bridged cycloalkyl of bridged cycloalkoxy is substituted with one, two, or three substituents independently selected from hydrogen, alkyd, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lm, the bridged cycloalkyloxy is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0209] A22-ln. In embodiment A22-ln, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is bridged cycloalkylalkyl (such as bicyclofl. 1.1] pent- 1-ylmethyl or bicyclo[2.2.1]heptylmethyl) where the bridged cycloalkyl of bridged cyclylalkylalkyl is substituted with one. two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-ln, the bridged cycloalkylalkyl is substituted with one or two substituents independently selected from hydrogen, methyl, fluoro, and cyano.

[0210] A22-lo. In embodiment A22-1O, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is cyanoalkyl. In a subembodiment of embodiment A22-lo, R1is cyanomethyl or cyanoethyl,

[0211] A22-lp. In embodiment A22-lp, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is cyanoalkoxy (such as cyanomethoxy or cyanoethoxy).

[0212] A22-lq. In embodiment A22-lq, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is alkoxyalkyl. In a subembodiment of embodiment A22-lq, R1is methoxy methyl.

[0213] A22-lr. In embodiment A22-lr, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is aminoalkyl. In a subembodiment of embodiment A22-lr, R1is aminomethyl.

[0214] A22-ls. In embodiment A22-ls, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is aminoalkoxy. In a subembodiment of embodiment A22-ls, R1is aminomethyloxy.

[0215] A22-lt. In embodiment A22-lt, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylaminoalkyd. In a subembodiment of embodiment A22-1, R1is methylaminomethyl.

[0216] A22-lu. In embodiment A22-lu, the compound of embodiment Al, A22-1, A22-la. or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is dialkylaminoalkyl. In a subembodiment of embodiment A22-lu, R1is dimethylaminomethyl.

[0217] A22-lv. In embodiment A22-lv, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylaminoalkoxy. In a subembodiment of embodiment A22-lv, R1is methylaminomethyloxy. A22-lw. In embodiment A22-lw, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is dialkylaminoalkoxy. In a subembodiment of embodiment A22-lw, R1is dimethylaminomethyloxy.

[0218] A22-lx. In embodiment A22-lx, the compound of embodiment Al, A22-1, or

[0219] A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is acyl. In a subembodiment of embodiment A22-lx, acyl is alkylcarbonyl (such as methylcarbonyl).

[0220] A22-ly. In embodiment A22-ly, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is azidocarbonyl.

[0221] A22-lz. In embodiment A22-lz, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is alkoxy carbonyl. In a subembodiment of embodiment A22-lz, R1is methoxy carbonyl or ethoxy carbonyl.

[0222] A22-laa. In embodiment A22-laa, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylcarbonylamino.

[0223] A22-lbb. In embodiment A22-lbb. the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is aminocarbonyl.

[0224] A22-lcc. In embodiment A22-lcc, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylaminocarbonyl (such as methylaminocarbonyl).

[0225] A22-ldd. In embodiment A22-ldd. the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is dialky laminocarbonyl (such as dimethylaminocarbonyl).

[0226] A22-lee. In embodiment A22-lee, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is aminosulfonyl.

[0227] A22-lff. In embodiment A22-lff, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is alkylaminosulfonyl (such as methylaminosulfonyl).

[0228] A22-lgg. In embodiment A22-lgg, the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is dialkylaminosulfonyl (such as dimethylaminosulfonyl).

[0229] A22-lhh. In embodiment A22-lhh, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is substituted sulfonyl.

[0230] A22-lii. In embodiment A22-lii, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is substituted sulfinyl. A22- Ijj . In embodiment A22-ljj, the compound of embodiment Al, A22-1, or

[0231] A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is substituted ureido.

[0232] A22-lkk. In embodiment A22-lkk, the compound of embodiment Al, A22-1, A22-1a, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is aryl substituted with one. two, or three substituents independently selected from hydrogen, alky l, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In the first embodiment of subembodiment A22-lkk, R1is phenyl substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a second subembodiment of embodiment A22-lkk, R1is phenyl substituted with one, two, or three substituents independently selected from hydrogen, methyl, fluoro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

[0233] A22-lmm. In embodiment A22-lmm, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is aralkyl (such as benzy l) where the ary l is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lmm, R1is benzyl where phenyl of benzyl is substituted with one, two, or three substituents independently selected from hydrogen, methyl, fluoro, cyano, difluoromethyl, trill uoromethyl, difluoromethoxy and trifluoromethoxy.

[0234] A22-lnn. In embodiment A22-lnn. the compound of embodiment Al. A22-1. A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is heteroaryl where the heteroaryl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a first embodiment of subembodiment A22-lnn, R1is pyrazolyl. imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a second subembodiment of embodiment A22-lnn, R1is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one substituent selected from hydrogen and alkyl.

[0235] A22-loo. In embodiment A22-loo. the compound of embodiment Al or A22-1. or a pharmaceutically acceptable salt thereof, is wherein R1is heteroaralkyl where the heteroaryl of heteroaralkyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-loo. the heteroaryl of heteroaralkyl of R1is pyrazolyl, imidazolyl, oxazolyl. thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. A22-lpp. In embodiment A22-lpp. the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is heteroaryloxy where the heteroaryl is substituted with one, two, or three substituents independently selected from hydrogen, alky l, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lpp, the heteroaryl of heteroaryloxy of R1is pyrazolyl. imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two. or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0236] A22-lqq. In embodiment A22-lqq, the compound of embodiment Al, A22-1, A22-la, or A22-lb, or a pharmaceutically acceptable salt thereof, is wherein R1is heterocyclyl where the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lqq, R1is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0237] A22-lrr. In embodiment A22-lrr, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is heterocyclylalkyl where the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lrr, the heterocyclyl of heterocyclylalkyl of R1is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0238] A22-lss. In embodiment A22-lss, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is heterocyclyloxy where the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-lss, the heterocyclyl of heterocyclyloxy of R1is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

[0239] A22-ltt. In embodiment A22-ltt, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R1is fused heterocyclyl substituted with one, two, or three substituents independently selected from hydrogen, alky l, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a subembodiment of embodiment A22-ltt, R1is 2,3-dihydrobenzofuranyl, benzodihydropyranyl, 1,4-benzodioxanyl, 2,3-dihydrofuro[3,2- c]pyridinyl, 2,3-dihydrofuro[2,3-c]pyridinyl, or 1,2,3,4-tetrahydroquinolinyl, each of which is substituted with one. two, or three substituents independently selected from hydrogen, alkyd, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0240] A22-luu. In embodiment A22-luu, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is fused heterocyclyloxy where the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0241] A22-lvv. In embodiment A22-lvv, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R1is fused heterocyclylalkyl where the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

[0242] A22-lww. In embodiment A22-lww, the compound of embodiment Al and A22-1 to A22-lvv, or a pharmaceutically acceptable salt thereof, is wherein R1is selected from:

[0243] and isomers (R and / or S isomers, and / or geometric isomers) thereof.

[0244] A23. In embodiment A23, the compound of any one of embodiments Al to A22-lww, or a pharmaceutically acceptable salt thereof, is wherein R3is hydrogen.

[0245] A24. In embodiment A24, the compound of any one of embodiments Al to A22-lww, or a pharmaceutically acceptable salt thereof, is wherein one of R3is deuterium.

[0246] 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, 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.

[0247] 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, haloalky l, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0248] 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, where Hy is substituted with Ra, Rb, and Rcwhere Raand Rbare independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy, Rcis hydrogen, and L is attached to the nitrogen atom of the piperidin-l,4-diyl or pyrrolidin-l,3-diyl ring of Hy.

[0249] A28. In embodiment A28, the compound of any one of embodiments Al to A27. or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylene of Hy is: where the N atom of the pyrrolidin-l,3-diyl or piperi din-1, 4-diyl rings is attached to L. 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 piperi din-1, 4-diyl rings is attached to L.

[0250] 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 piperi din- 1.4-diyl ring is attached to L.

[0251] 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 Rcindependently selected from hydrogen, deuterium, alkyl, halo, haloalky 1, alkoxy, hydroxy, and cyano.

[0252] 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: and each ring is substituted with Ra, Rb, and Rcwhere Rcis hydrogen, and L is attached to the nitrogen atom of each ring.

[0253] 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.

[0254] A33. In embodiment A33, the compound of embodiment A30, A31, or A32, or a pharmaceutically acceptable salt thereof, is wherein Rbis hydrogen.

[0255] A34. In embodiment A34, the compound of any one of embodiments Al to A25, or a pharmaceutically acceptable salt thereof, is wherein Hy is cycloalkydene 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

[0256] A34. or a pharmaceutically acceptable salt thereof, is wherein the cycloalkylene of Hy is cyclohexylene.

[0257] 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 bond of L.

[0258] 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.

[0259] 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 substituted (such as 2-azaspiro[3.3]heptan-2-yl) with Ra, Rb, and Rcwhere Raand Rbare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and Rcis hydrogen.

[0260] A39. In embodiment A39, the compound of any one of embodiments Al to A25. and A37. or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Hv is 1,4-

[0261] ' "9 phenylene according to structure -L. where denotes bond to NH and denotes bond of L and where Rbis hydrogen (in one embodiment Rais methoxy).

[0262] 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.

[0263] 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.

[0264] A40A. In embodiment A40A, the compound of any one of embodiments Al to A39b, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i) or (ii). A40. In embodiment A40, the compound of any one of embodiments Al to A40A, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i):

[0265] 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):

[0266] 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.

[0267] 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.

[0268] A44. In embodiment A44, the compound of any one of embodiments Al to A42. or a pharmaceutically acceptable salt thereof, is wherein R4is hydrogen and R5is methyl.

[0269] 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.

[0270] 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): where M is -NR6-. 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.

[0271] 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 one embodiment R6is methyl.

[0272] 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: A50. In embodiment A50, the compound of any one of embodiments Al to and 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:

[0273] 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, Raais hydrogen in groups (when Raais not drawn in the above rings) and Rbb, Rcc, and Rddare

[0274] H.

[0275] A52a. In embodiment A52a, the compound of any one of embodiments Al to A41, A45, and A47 to A52. or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: A53. In embodiment A53, the compound of any one of embodiments Al to A41. A45, and A47 to A52. or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[0276] A54. In embodiment A54, the compound of any one of embodiments Al to A43 and A47 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[0277] A55. In embodiment A55, the compound of any one of embodiments Al to A43 and A47 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[0278] A56. In embodiment A56, the compound of any one of embodiments Al to A40. A42 to

[0279] A46, and A48 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:

[0280] A57. In embodiment A57, the compound of any one of embodiments Al to A40. A42 to

[0281] A46, and A48 to A52, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is: A58. In embodiment A58, 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. For sake of clarity, in embodiments A52 to A54, Raa, Rbb, Rcc, and / or Rddare hydrogen when they are not specifically drawn out in structures of formula (i) and (ii), respectively.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] A67. In embodiment A67, the compound of any one of embodiments Al to A40A, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (ii):

[0291] (ii).

[0292] A68. In embodiment A68, the compound of any one of embodiments Al to A40A and A67, or a pharmaceutically acceptable salt thereof, is wherein Yais CH.

[0293] A69. In embodiment A69, the compound of any one of embodiments Al to A40A, and A67, or a pharmaceutically acceptable salt thereof, is wherein Yais N.

[0294] A70. In embodiment A70, the compound of any one of embodiments Al to A40A, and A67 to A69, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond, -NH-, -O-, or -NHC(O)-.

[0295] A71. In embodiment A71, the compound of any one of embodiments Al to A40A, and A67 to A70, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond. -NH-, or -NHC(O)-.

[0296] A72. In embodiment K12, the compound of any one of embodiments Al to A40A, and A67 to A71, or a pharmaceutically acceptable salt thereof, is wherein Zais a bond.

[0297] A73. In embodiment A73, the compound of any one of embodiments Al to A40A. and A67 to A71, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-, or -NHC(O)-.

[0298] A74. In embodiment A74, the compound of any one of embodiments Al to A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Zais -NH-.

[0299] A74a. In embodiment A74a, the compound of any one of embodiments Al to A40A, A67 to A71, and A73, or a pharmaceutically acceptable salt thereof, is wherein Zais -NHC(O)-.

[0300] A75. In embodiment A75, the compound of any one of embodiments Al to A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is phenylene substituted with Reeand Rff.

[0301] A76. In embodiment A76, the compound of any one of embodiments Al to A40A. and A67 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is cyclylaminylene substituted with Reeand Rff.

[0302] A77. In embodiment A77, the compound of any one of embodiments Al to A40A, and A67 to A74a, or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with Reeand Rff. A78. In embodiment A78, the compound of any one of embodiments Al to A40A, A67 to A74a. and A77. or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6- membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with Reeand Rff.

[0303] A79. In embodiment A79, the compound of any one of embodiments Al to A40A, A67 to A74a, and A77, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms (and not containing any additional heteroatoms) and substituted with Reeand Rff

[0304] A80. In embodiment A80, the compound of any one of embodiments Al to A40A, A67 to A74a, A77, and A79, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and substituted with Reeand Rff.

[0305] A81. In embodiment A81, the compound of any one of embodiments Al to A40A, and A67 to A80, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:

[0306] A82-1. In embodiment A82-1, the compound of any one of embodiments Al to A40A, and A67 to A81, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:

[0307] is cyclylaminylene. For sake of clarity, Reeand Rffare hydrogen if they are not specifically drawn out in the above structures of embodiment A82-1. A82. In embodiment A82, the compound of any one of embodiments Al to A40A, and

[0308] A67 to A82-1, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase is cyclylaminylene and Rfiis hydrogen when not drawn out in the above structures. A82A. In embodiment A82A, the compound of any one of embodiments Al to A40A,

[0309] A67. A68, A70 to A72, A77, and A79 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula

[0310] A83. In embodiment A83. the compound of any one of embodiments Al to A40A. and A67 to A82, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:

[0311] A83A. In embodiment A83A, the compound of any one of embodiments Al to A40A, and A67, A69 to A72, A77, A79 to A82, and A83, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula

[0312] A84. In embodiment A84, the compound of any one of embodiments Al to A40A, and A67 to A83A, or a pharmaceutically acceptable salt thereof, is wherein each Reeand Rffare independently selected from hydrogen, alkyl, alkoxy, halo, cyano, haloalky 1, and haloalkoxy. A85. In embodiment A85, the compound of any one of embodiments Al to A40A, and A67 to A83A, or a pharmaceutically acceptable salt thereof, is wherein R6eand Rflare independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.

[0313] A86. In embodiment A86, the compound of any one of embodiments Al to A40A, and A67 to A85, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.

[0314] A87. In embodiment A87, the compound of any one of embodiments Al to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, methyl, ethyl, and isopropyl.

[0315] A88. In embodiment A88, the compound of any one of embodiments Al to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen and methoxy.

[0316] A89. In embodiment A89, the compound of any one of embodiments Al to A40A. and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rflare independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.

[0317] A90. In embodiment A90, the compound of any one of embodiments Al to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein one of Rccand Rffis hydrogen or fluoro and the other of Reeand Rffis selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl.

[0318] A91. In embodiment A91, the compound of any one of embodiments Al to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.

[0319] A92. In embodiment A92, the compound of any one of embodiments Al to A40A, and A67 to A86, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently selected from hydrogen, chloro, fluoro, and trifluoromethyl.

[0320] A93. In embodiment A93, the compound of any one of embodiments Al to A40A. and A67 to A92, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rflare hydrogen.

[0321] A94. In embodiment A94, the compound of any one of embodiments Al to A40A, A67 to A86, A89, and A92. or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare chloro. A95. In embodiment A95, the compound of any one of embodiments Al to A40A, A67 to A86, A89. and A92. or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare fluoro.

[0322] A96. In embodiment A96, the compound of any one of embodiments Al to A40A, A67 to A86, and A90, or a pharmaceutically acceptable salt thereof, is wherein Reeand Rffare independently trifluoromethyl or 2,2,2-trifluoroethyl.

[0323] A96a. In embodiment A96a, the compound of any one of embodiments Al to A39b, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iii), (iv), (v), or (vi).

[0324] A96b. In embodiment A96b, the compound of any one of embodiments Al to A39b, and A96a, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iv) or (v).

[0325] A96c. In embodiment A96c, the compound of any one of embodiments Al to A39b, A96a, and A96b. or a pharmaceutically acceptable salt thereof, is wherein Ry, Ryl, and Ry2are 1 -fluorocycloprop- 1-yl and Wais bond, S. or methylene.

[0326] A96d. In embodiment A96d, the compound of any one of embodiments Al to A39b and A96a to A96c, or a pharmaceutically acceptable salt thereof, is wherein Wais S.

[0327] A97. In embodiment A97, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1. X2. X3. and X4are each a bond.

[0328] A98. In embodiment A98, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each independently selected from alkylene. In a subembodiment of embodiment A98, X1, X2, X3. and X4are each methylene.

[0329] A99. In embodiment A99, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each -O-.

[0330] Al 00. In embodiment Al 00, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1. X2. X3. and X4are each independently selected from -(O-alkylene)-.

[0331] Al 01. In embodiment Al 01, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each independently selected from -(alkylene-O)-.

[0332] Al 02. In embodiment Al 02, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3. and X4are each independently selected from -(NRgg-alkylene)-. Al 03. In embodiment Al 03, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1. X2. X3, and X4are each independently selected from -(alkyl ene-NRhh)-.

[0333] Al 04. In embodiment Al 04, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1. X2. X3. and X4are each .

[0334] A105. In embodiment A105, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, and X4are each -NH-.

[0335] Al 06. In embodiment Al 06, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1. X2. X3. and X4are each independently selected from -N(alkyl)-. In a subembodiment of embodiment Al 06, X1, X2, X3, and X4are each independently -N(methyl)- or -N(ethyl)-.

[0336] Al 07. In embodiment Al 07, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1. X2. X3, and X4are each -C(=O)-.

[0337] Al 08. In embodiment Al 08, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3. and X4are each independently -NRjjC(=O)-.

[0338] Al 09. In embodiment Al 09, the compound of any one of embodiments Al to A96, or a pharmaceutically acceptable salt thereof, is wherein X1. X2. X3. and X4are each independently -C(=O)NRkk-.

[0339] Al 10. In embodiment Al 10, the compound of any one of embodiments Al to A96, A102, Al 03, Al 08, and Al 09, or a pharmaceutically acceptable salt thereof, is wherein Rgg, Rhh, R^, and Rkkare each independently hydrogen or alkyl.

[0340] Al 10a. In embodiment Al 10a, the compound of any one of embodiments Al to Al 10 is wherein at least two of -Zk-Z2-Z3-Z4-Z3-Z6- are not a bond. In a sub-embodiment of Al 10a, the compound is wherein at least three of -Zk-Z2-Z3-Z4-Z5-Z6- are not a bond. In a sub-embodiment of Al 10a, the compound is wherein at least four of -Z’-Z2-Z3-Z4-Z5-Z6- are not a bond.

[0341] Al l i. In embodiment Al 11, the compound of any one of embodiments Al to Al 10a, or a pharmaceutically acceptable salt thereof, is wherein Z6is -S(O>2-.

[0342] Al 12. In embodiment Al 12, the compound of any one of embodiments Al to Al 11, or a pharmaceutically acceptable salt thereof, is wherein Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr.

[0343] Al 13. In embodiment Al 13, the compound of any one of embodiments Al to Al 12, or a pharmaceutically acceptable salt thereof, is wherein Z3is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rrand one and only one of Z1and X1is a bond, one and only one of Z1and X2is a bond, one and only one of Z1and X3. and one and only one of Z1and X4is a bond (for sake of clarity, when X1, X2, X3, and X4are not a bond, then X1, X2, X3, and X4are as described in any one of embodiments Al and A98 to Al 10).

[0344] Al 14. In embodiment Al 14, the compound for use of any one of embodiments Al to A96d and Al 11. or a pharmaceutically acceptable salt thereof, is wherein:

[0345] X1, X2, X3, and X4are independently a bond, -(O-alkylene)-, -(NRgg-alkylene)-, Hc=c—- NH-, or -N(alkyl)-, where Rggis hydrogen or alkyl and each alkylene is independently optionally substituted with one or two fluoro (or X1, X2, X3, and X4are absent in ligands (iii) to (vi));

[0346] Z1is a bond, alkylene, -(CO)NR-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, or heterocyclylene, where each ring is substituted with Rhand R1;

[0347] Z2is a bend, alkylene, -(O-alkylene)b-, -(alkylene-O)b-, cycloalkylene, or heterocyclylene, where each ring is substituted with R' and Rk;

[0348] Z3is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)- monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)- heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-. spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, -spiro heterocyclylene-(alkylene)-, or monocyclic heteroarylene, where each ring, by itself or as part of another group, is substituted with Rmand Rn;

[0349] Z4is a bond, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-. -heterocyclylene- (alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, is substituted with R° and Rp;

[0350] Z5is a bond; and

[0351] Z6is -S(O)2-; and wherein each alkylene in Z1, Z2, Z3, and Z4, by itself or as part of another group, is independently substituted with Rs. R‘, and Ru.

[0352] Al 15. In embodiment Al 15, the compound of any one of embodiments Al to A96d, A97, and Al 11, or a pharmaceutically acceptable salt thereof, is wherein:

[0353] X1, X2, X3, X4, and Z1are each a bond; Z2is a bond, alkylene, cycloalkylene, or heterocyclylene, where each ring is substituted with R' and Rk;

[0354] Z3is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;

[0355] Z4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and Rp;

[0356] Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr: and

[0357] Z6is -S(O)2-; and wherein each alkylene in Z2, Z3, and Z4is independently substituted with Rs, R‘, and Ru.

[0358] Al 16. In embodiment Al 16, the compound of any one of embodiments Al to A96d, A97, Al l i, and Al 15, or a pharmaceutically acceptable salt thereof, is wherein:

[0359] X1. X2. X3. X4. Z1. and Z2are each a bond;

[0360] Z’ is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;

[0361] Z4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[0362] Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and

[0363] Z6is -S(O)2-; and wherein alky lene in Z4is substituted with Rs, R‘, and Ru.

[0364] Al 17. In embodiment Al 17, the compound of any one of embodiments Al to A96d, A97, Al 11, Al 15. and Al 16, or a pharmaceutically acceptable salt thereof, is wherein:

[0365] X1, X2, X3, X4, Z1, and Z2are each a bond;

[0366] Z3is heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z4is alkylene, -0-. cycloalkylene, monocyclic heteroaiyiene. heterocyclylene, fused heterocyclylene. or spiro heterocyclylene. where each ring is substituted with R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[0367] Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand R1independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

[0368] Z6is -S(O)2-; and wherein alkylene in Z4is substituted with substituted with Rs, R\ and Ru.

[0369] Al 18. In embodiment Al 18, the compound of any one of embodiments Al to A96d, A97, Al 11, and Al 15 to Al 17, or a pharmaceutically acceptable salt thereof, is wherein:

[0370] X1, X2, X3, and X4, Z1, and Z2are each a bond;

[0371] Z3is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[0372] Z4is alkylene. -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy;

[0373] Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalky l, and haloalkoxy; and

[0374] Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, R‘, and Ru.

[0375] Al 19. In embodiment Al 19, the compound of any one of embodiments Al to A96d, A97, Al 11, and Al 15 to Al 18, or a pharmaceutically acceptable salt thereof, is wherein:

[0376] X1, X2, X3, X4, Z1, and Z2are each a bond;

[0377] Z3is heterocyclylene, bridged heterocyclylene or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalky l, and haloalkoxy;

[0378] Z4is alky lene, -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy (in one embodiment R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy, (in a subembodiment Z4is alkylene or -O-)); Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

[0379] Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, R‘, and Ru.

[0380] A120. In embodiment A120, the compound of any one of embodiments Al to A96d, A97, Al 11, and Al 15, or a pharmaceutically acceptable salt thereof, is wherein:

[0381] X1, X2, X3, X4, and Z1are each a bond;

[0382] Z2is cycloalkylene or heterocyclylene, where each ring is substituted with R1and Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl. and haloalkoxy;

[0383] Z3is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyd, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

[0384] Z4is a bond, alkylene, or -O-;

[0385] Z5is phenylene, monocyclic heteroarylene (e g., pyridindiyl), or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alky l, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

[0386] Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, R\ and Ru.

[0387] A121. In embodiment A121, the compound of any one of embodiments Al to A96d, A97, Al 11, Al 15, and A120, or a pharmaceutically acceptable salt thereof, is wherein:

[0388] X1, X2, X3, X4, and Z1are each a bond;

[0389] Z2is heterocyclylene substituted with R' and Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

[0390] Z3is heterocyclylene substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy ;

[0391] Z4is a bond, alkylene, or -O-;

[0392] Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

[0393] Z6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, R\ and Ru. A122. In embodiment A122, the compound of any one of embodiments Al to A96d, A97, Al l i, and Al 12, or a pharmaceutically acceptable salt thereof, is wherein:

[0394] X1, X2, X3, X4, and Z1are each a bond;

[0395] Z2is heterocyclylene substituted with R' and Rk(in one embodiment R' and Rkare independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy);

[0396] Z3is a bond, alkylene, or -O-;

[0397] Z4is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and Rp(in one embodiment R° and Rpare independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy);

[0398] Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rr(in one embodiment Rqand Rrare independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy); and

[0399] Z6is -S(O)2-; and wherein alkylene in Z3is substituted with Rs, R‘, and Ru.

[0400] A123. In embodiment A123, the compound of any one of embodiments Al to Al 17 and Al 22, or a pharmaceutically acceptable salt thereof, is wherein Z4is heterocyclylene or spiro heterocyclylene, where each ring is substituted with R° and Rp(in one embodiment R° and Rpare independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy).

[0401] Al 24. In embodiment Al 24, the compound of any one of embodiments Al to A96d, or a pharmaceutically acceptable salt thereof, is wherein one and only one of X1and Z1, or one and only one of X2and Z1, or one and only one of X3and Z1, or one and only one of X4and Z1is a bond.

[0402] A125. In embodiment A125, the compound of any one of embodiments Al to A96d, or a pharmaceutically acceptable salt thereof, is wherein X1, X2, X3, X4, and Z1are each a bond.

[0403] A126. In embodiment A126, the compound of any one of embodiments Al to A96d, A124, and A125, or a pharmaceutically acceptable salt thereof, is wherein Z2is heterocyclylene or bridged heterocyclylene. each ring substituted with R and Rk.

[0404] Al 27. In embodiment Al 27, the compound of any one of embodiments Al to A96d, A124, and A125, or a pharmaceutically acceptable salt thereof, is wherein Z2is a bond.

[0405] A128. In embodiment A128, the compound of any one of embodiments Al to A96d, and A124 to A127. or a pharmaceutically acceptable salt thereof, is wherein:

[0406] Z3is alkydene, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene- (alkylene)-, heterocyclylene. -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene. bridged heterocyclylene. -(alkylene)-bridged heterocyclylene-, -bndged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, or -spiro heterocyclylene-(alkylene), where each ring, by itself or as part of another group, is substituted with Rmand Rn;

[0407] Z4is alkylene, -(alkylene-NR”)-. -(NR”-alkylene)-, -O-. -NR”-, -(O-alkylene)a-, -(alkylene-O)d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, is substituted with R° and Rp;

[0408] Z5is a bond, -alky lene, -NR”-, -O-, -C(O)-, -S(O)2-, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and

[0409] Z6is a bond, alkylene. -NR”-, -O-. -(alkylene-O)-. -C(O)-, -S(O)2-. -NR’ (CO)-, or -C(O)NR-; and and each alky lene in Z3, Z4, Z5, and Z6, itself or as part of another group, is independently substituted with Rs, R‘. and Ru.

[0410] A129. In embodiment A129, the compound of any one of embodiments Al to A97, Al l i, Al 12, A125, A127, and A128, or a pharmaceutically acceptable salt thereof, is wherein:

[0411] X1, X2, X3, X4, Z1, and Z2are each a bond;

[0412] Z3is -heterocyclylene-(alkylene)-, where heterocyclylene is substituted with Rmand Rnand alkylene is substituted with Rs, R‘, and Ru;

[0413] Z4is phenylene or monocyclic heteroarylene, where each ring is substituted with R° and RP;

[0414] Z5is phenylene substituted with Rqand Rr; and

[0415] Z6is -S(O)2-.

[0416] A130. In embodiment ABO. the compound of any one of embodiments Al to Al 12 and A124 to A128, or a pharmaceutically acceptable salt thereof, is wherein:

[0417] Z3is alky lene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-. or -spiro heterocyclylene-(alkylene), where each ring, by itself or as part of another group, is substituted with Rmand Rn;

[0418] Z4is alkylene, -(alkylene-NR”)-, -(NR”-alkylene)-, -O-, -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, is substituted with R° and Rp;

[0419] Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; and

[0420] Z6is -S(O)2-; and and each alky lene in Z3and Z4, itself or as part of another group, is independently substituted with Rs, R‘. and Ru.

[0421] A131. In embodiment Al 31, the compound of any one of embodiments Al to Al l i, A124 to A128, and A130, or a pharmaceutically acceptable salt thereof, is wherein:

[0422] Z3is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;

[0423] Z4is alkylene, -O-. heterocyclylene, -(alkylene)-heterocyclylene-. -(alkylene)-bridged heterocyclylene-, where each ring, by itself or as part of another group, is substituted with R° and RP;

[0424] Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr: and

[0425] Z6is -S(O)2; and and each alky lene in Z4, itself or as part of another group, is substituted with Rsand Rl

[0426] Al 32. In embodiment Al 32, the compound of any one of embodiments Al to A96d and Al 11, or a pharmaceutically acceptable salt thereof, is wherein:

[0427] X1. X2. X3. X4. Z1, and Z2are each a bond;

[0428] Z’ is -O-, -NR - (where R is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;

[0429] Z4is alkylene, alkenylene, alkynylene, heteroalkylene, where alkylene and heteroalkylene are substituted with Rs, R\ and Ruand alkenylene is substituted with Rv; Z5is phenylene, monocyclic heteroarylene, heterocycylene. bridged heterocyclylene. or spiro heterocyclylene, where each ring is substituted with Rqand Rr; and

[0430] Z6is -S(O)2.

[0431] Al 33. In embodiment Al 33, the compound of any one of embodiments Al to A96d, Al 11, and Al 32, or a pharmaceutically acceptable salt thereof, is wherein:

[0432] X1. X2. X3. X4. Z1, and Z2are each a bond;

[0433] Z3is -O-, -NR - (where R is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;

[0434] Z4is alkylene, alkenylene, or heteroalkylene where alkylene and heteroalkylene substituted with Rs, R\ and Ruand alkenylene is substituted with Rv;

[0435] Z5is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rqand Rr; and

[0436] Z6is -S(O)2.

[0437] A 134. In embodiment Al 34, the compound of any one of embodiments Al to A96d, Al 11, and A132, or a pharmaceutically acceptable salt thereof, is wherein:

[0438] X1, X2, X3, X4, Z1, and Z2are each a bond;

[0439] Z3is -O-, -NR - (where R is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;

[0440] Z4is alkynylene where alkynylene substituted with Rwand Rx;

[0441] Z5is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rqand Rr; and

[0442] Z6is -S(O)2.

[0443] Al 34a. In embodiment Al 34a, the compound of any one of embodiments Al to A97, and

[0444] Al 11, or a pharmaceutically acceptable salt thereof, is wherein:

[0445] X1, X2, X3, X4, Z1, Z2and Z5are each a bond;

[0446] Z3is -O-. -NR - (where R is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;

[0447] Z4is Cs to C6alkylene substituted with Rs, R‘, and Ru; and

[0448] Z6is -S(O)2. A135. In embodiment Al 35, the compound of any one of embodiments Al to Al 13 and

[0449] Al 15 to A134, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is (i.e.,

[0450] Z5is pheny lene where Z4and Z6are attached at meta position of the phenylene ring) substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, and haloalkoxy.

[0451] A136. In embodiment A136, the compound of any one of embodiments Al to Al 13, Al 15 to A134, and A135, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is substituted with Rqand Rrindependently selected from hydrogen, deuterium, methyl, methoxy, cyano, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0452] Al 37. In embodiment Al 37, the compound of any one of embodiments Al to Al 13, Al 15 to A134, A135, and A136, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is

[0453] Al 38. In embodiment Al 38, the compound of any one of embodiments Al to Al 13, Al 15 to A128. and A130 to A134, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is monocyclic heteroarylene (such as imidazol-l,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyri din-3, 5-diyl) substituted with Rqand Rrindependently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

[0454] Al 39. In embodiment Al 39, the compound of any one of embodiments Al to Al 13, Al 15 to A128. A 130 to A134. and A138, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is imidazol-2, 5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3, 5-diyl, each ring substituted with Rqand Rrindependently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2.2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy.

[0455] A140. In embodiment A140, the compound of any one of embodiments Al to Al 13, Al 15 to A128, A130 to A134, A138, and A139, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is imidazol-2, 5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3, 5-diyl, each ring substituted with Rqand Rrindependently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethvl. difluoromethoxy, and trifluoromethoxy. A141. In embodiment A141, the compound of any one of embodiments Al to Al 13, Al 15 to Al 18. ABO, A123 to A128, and ABO to Al 34. or a pharmaceutically acceptable salt thereof, is wherein -Z5- is heterocyclylene substituted with Rqand Rrindependently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy.

[0456] A142. In embodiment A142, the compound of any one of embodiments Al to Al 13, A115 to A118, A120, A123 to A128, ABO to A134, and A141, or a pharmaceutically acceptable salt thereof, is wherein -Z5- is azetidinyl, pyrrolidinyl, piperazinyl, or piperidinyl.

[0457] A143. In embodiment A143, the compound of any one of embodiments Al to A142, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1, Z2, Z3, Z4, Z5, and Z6, by itself and when present, is methylene, ethylene, propylene, or butylene, each substituted with Rs, R\ and Ru.

[0458] A144. In embodiment A144, the compound of any one of embodiments Al to A134 and A135 to A143. or a pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1. Z2, Z3. Z4, Z5, and Z6, by itself, and when present, is methylene substituted with Rs, R‘, and Ru.

[0459] A145. In embodiment A145, the compound of any one of embodiments Al to A134 and A135 to A142, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1, Z2, Z3, Z4, Z5, and Z6, by itself or as part of -(O-alkylene)a- in Z1, -(alkylene-O)a- in Z1, -(O- alkylene)b- in Z2, -(alkylene-O)b- in Z2, -(O-alkylene)c- in Z3. -(alkylene-O)c- in Z3, -(O- alkylene)a- in Z4, and -(alkylene-O)a- in Z4, and -(alkylene-O)- in Z6, and when present, is ethylene or propylene; as part of -(alkylene-NR”)- and -(NR”-alkylene)-, and when present, is methylene, ethylene or propylene; and as part of-(alkylene)-cycloalkylene-, -cycloalkylene- (alkylene)-, -(alkylene)-phenylene-, -phenylene-(alkylene)-, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, -(alkylene)-heterocyclylene- , -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene- (alkylene)-, -(alkylene)-spiro heterocyclylene-, and -spiro heterocyclylene-(alkylene)- is methylene, ethylene, propylene, or butylene, wherein each of above alkylene group is substituted with Rs, R‘, and Ru.

[0460] A146. In embodiment A146, the compound of any one of embodiments Al to A134, A135 to A142 and A145, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of Z1, Z2, Z3, Z4, Z5, and Z6, by itself or as part of -(O-alkylene)a- in Z1, -(alkylene-O)a- in Z1, -(O- alkylene)b- in Z2, -(alkylene-O)b- in Z2, -(O-alkylene)c- in Z3. -(alkylene-O)c- in Z3, -(O-alkylene)d- in Z4, and -(alkylene-O)d- in Z4, and -(alkylene-O)- in Z6, and when present, is ethylene; as part of -(alkylene-NR”)-) and -(NR”-alkylene)-, and when present, is methylene; and as part of -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, -(alkylene)-phenylene-. -phenylene- ( alkylene)-, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene-, and -spiro heterocyclylene-(alkylene)-, and when present, is methylene.

[0461] A147. In embodiment A147, the compound of any one of embodiments Al to A146, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of Z1, Z2, Z3, Z4, Z5, and Z6, when present, is independently hydrogen or methyl.

[0462] A148. In embodiment A148, the compound of any one of embodiments Al to A147, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R " of Z1. Z2. Z3, Z4, Z5, and Z6, when present, is hydrogen.

[0463] A149. In embodiment A149, the compound of any one of embodiments Al to A147, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of Z1, Z2, Z3, Z4, Z5, and Z6, when present, is methyl.

[0464] A150. In embodiment A150, the compound of any one of embodiments Al to A149, or a pharmaceutically acceptable salt thereof, is wherein each cycloalkylene of Z2, Z3, and Z4, by itself or as part of-(alkylene)-cycloalkylene- and -cycloalkylene-(alkylene)-, and when present, is independently selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

[0465] A151. In embodiment Al 51, the compound of any one of embodiments Al to Al 50, or a pharmaceutically acceptable salt thereof, is wherein each cycloalkylene of Z2, Z3, and Z4, by itself or as part of -(alkylene)-cycloalkylene and -cycloalkylene-(alkylene)-, and when present, is independently selected from 1,2-cyclopropylene, 1.3-cyclopentylene. 1,3-cyclohexylene, and 1,4-cyclohexylene.

[0466] A152. In embodiment A152, the compound of any one of embodiments Al to A134a, Al 38, and A 143 to Al 51, or a pharmaceutically acceptable salt thereof, is wherein heteroarylene is monocyclic heteroarylene and each monocyclic heteroarylene ofZ1, Z3, Z4, and Z5, by itself or as part of -(alkylene)-monocyclic heteroarylene- and -monocyclic heteroarylene-(alkylene)-. and when present, is independently selected from imidazoldiyL pyridindiyl and pyrimidindiyl.

[0467] Al 53. In embodiment Al 53, the compound of any one of embodiments Al to A134a, Al 38, and Al 43 to Al 52, or a pharmaceutically acceptable salt thereof, is wherein heteroarylene is monocyclic heteroarylene and each monocyclic heteroarylene of Z1, Z3, Z4, and Z5, by itself or as part of -(alkylene)-monocyclic heteroarylene- and -monocyclic heteroarylene-(alkylene)-. and when present, is independently selected from imidazol-2,5-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, and pyridin-3,5-diyl. A154. In embodiment A154, the compound of any one of embodiments Al to A134a and A143 to A153. or a pharmaceutically acceptable salt thereof, is wherein each phenylene of Z1. Z3. and Z4, by itself or as part of -(alkylene)-phenylene- and -phenylene-(alkylene)-, and when present, is independently selected from 1,3-phenylene and 1,4-phenylene. A155. In embodiment A155, the compound of any one of embodiments Al to A141 and

[0468] A143 to A154. or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene. bridged heterocyclylene, and spiro heterocyclylene of Z1, Z2, Z3, Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene- and -spiro heterocyclylene-(alkylene)-, respectively, and when present, are independently selected from: respectively, and wherein each ring is optionally substituted with 1, 2, or 3 fluoro or methyl, unless stated otherwise in any of the embodiments above.

[0469] Al 56. In embodiment Al 56, the compound of any one of embodiments Al to A141 and A143 to A155, or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene, of Z1, Z2. Z3, Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -helerocyclylene-(alkylene)-. -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, -(alkylene)-spiro heterocyclylene- and -spiro heterocyclylene-(alkylene)-, respectively, and when present, are independently selected from: respectively, and wherein each ring is optionally substituted with 1 or 2 fluoro, unless stated otherw ise in any of the embodiments above.

[0470] A157. In embodiment A157, the compound of any one of embodiments Al to A141 and A143 to A156, or a pharmaceutically acceptable salt thereof, is wherein heterocyclylene of Z1, Z2.

[0471] Z3. Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)- and when present, is selected from:

[0472] A158. In embodiment A158, the compound of any one of embodiments Al to A141 and A143 to A157, or a pharmaceutically acceptable salt thereof, is wherein heterocyclylene of Z1, Z2, Z3, Z4, and Z5, by itself or as part of -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)- and when present, is

[0473] A159. In embodiment A159, the compound of any one of embodiments Al to Al 12, Al 15 to A121, A124 to A128, and A130 to A134, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0474] wherein each Rm, Rn, and Rqare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano(i.e., Rris hydrogen). In a subembodiment, each Rqand Rmare independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl.

[0475] A 160. In embodiment Al 60, the compound of any one of embodiments Al to Al 12, Al 15 to A121, A124 to A128, A130 to A134, and A159, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0476] wherein each Rm, Rn, and Rqare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e., Rr is hydrogen).

[0477] A161. In embodiment A161, the compound of any one of embodiments Al to Al 12, Al 15 to A121. A124 to A128. ABO to A134. A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0478] A162. In embodiment A162, the compound of any one of embodiments Al to Al 12, Al 15 to A121. A124 to A128. A130 to A134. A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0479] A164. In embodiment A164, the compound of any one of embodiments Al to Al 12,

[0480] Al 15 to A121. A124 to A128. A130 to A134. A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0481] A165. In embodiment A165, the compound of any one of embodiments Al to Al 12, Al 15 to A121, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0482] Al 66. In embodiment Al 66, the compound of any one of embodiments Al to Al 11 ,

[0483] Al 15 to A120, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0484] A167. In embodiment A167, the compound of any one of embodiments Al to Al l i, Al 15 to A120, A124 to A128, A130 to A134, A159, A160, or a pharmaceutically acceptable salt thereof, is wherein -Z?-Z4-Z5-Z6- is:

[0485] A168A. In embodiment A 168 A, the compound of any one of embodiments Al to

[0486] Al l i, Al 15 to A120, A124 to A128, A130 to A134, A159, and A160, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0487] A168. In embodiment A168, the compound of any one of embodiments Al to Al 12,

[0488] Al 15 to A136, and A159 to 168A, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Z5is and is selected from:

[0489] A169. In embodiment A169, the compound of any one of Al to Al 14, A124 to A128, A130, A131, A135 to A154, and A159 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z4is -(alkylene)-heterocyclylene-, where heterocyclylene is substituted with R° and Rp. Al 70. In embodiment Al 70, the compound of any one of Al to Al 14. A124 to A128. A130, A131. A135 to A154. and A159 to A169 or a pharmaceutically acceptable salt thereof, is wherein Z4is -(CH2)-heterocyclylene- where heterocyclylene is substituted with R° and Rp.

[0490] Al 71. In embodiment Al 71, the compound of any one of Al to Al 14, Al 24 to Al 28, A130, A131, A135 to A154, and A159 to A170, or a pharmaceutically acceptable salt thereof, is wherein Z4is:

[0491] A172. In embodiment A172, the compound of any one of Al to A96, A97 to Al 12. A124 to A128, A130, A131, A135 to A137, and A143 to A171, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0492] A173. In embodiment A173, the compound of any one of Al to A96, A97 to Al 12, A124 to A128, ABO, A131, A135 to A137, and A143 to A172, or a pharmaceutically acceptable salt thereof, is wherein -Z3-Z4-Z5-Z6- is:

[0493] A174. In embodiment A174, the compound of any one of embodiments Al to Al 12, A124 to A127, A132, A133. and A135 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkenylene substituted with Rvwhere Rvis hydrogen.

[0494] Al 75. In embodiment Al 75, the compound of any one of embodiments Al to Al 12, A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkenylene substituted with Rvwhere Rvis fluoro or cyano.

[0495] A176. In embodiment A176, the compound of any one of embodiments Al to Al 12, Al 15 to A121, A124 to A128, Al 30 to A133, A134a, and A135 to A168 (except for Z4in A143 and Al 44), or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, R‘, and Ruwhere Rs, R\ and Ruare hydrogen.

[0496] Al 77. In embodiment Al 77, the compound of any one of embodiments Al to Al 12, Al 15 to A121, A124 to A128, Al 30 to A133, A134a, and A135 to A148 (except for Z4in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, R\ and Ruwhere Rs, R\ and Ruare hydrogen or halo, provided at least one of R8, Rh, and R1is halo, in one embodiment the halo is fluoro. Al 78. In embodiment Al 78, the compound of any one of embodiments Al to Al 12, Al 15 to A121. A124 to A128. A130 to A133. A134a, and A135 to A148 (except for Z4in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to Cg alkylene substituted with Rs, R\ and Ruwhere Rlis other than hydrogen and Ruis hydrogen or when Rland Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3to C6alkylene. Rland Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R‘ and Ruare substituted with R9and R10.

[0497] Al 79. In embodiment Al 79, the compound of embodiment Al 78, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to Cg alkylene substituted with Rs, R\ and Ruwhere Rlis other than hydrogen and Ruis hydrogen.

[0498] A180. In embodiment A180, the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof, is wherein the C3to Cg alkenylene and C3to Cg alkylene of Z4are linear alkenylene and alkylene, respectively, and substituted as defined therein.

[0499] A181. In embodiment A181, the compound of any one of embodiments A174 to A180, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to Cg alkenylene is -CH=C(RV)CH2-, -CH2CH=CH-, -CH2CH2CH=CH-, -CH2CH=CHCH2-, and the linear alkylene of C3to Cg alkylene of Z4is -CH2CH(R‘)CH2-. -CH2CH2CH(R‘)-, -CH2C(Rs)(Rl)CH2-, -CH2CH2C(Rs)(Rt)- where Rsand R‘ are as defined therein and Ruis hydrogen.

[0500] Al 82. In embodiment Al 82, the compound of any one of embodiments A178 to A181, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to Cg alky lene of Z4is -CH2CH(Rt)CH2- where Rlis other than hydrogen.

[0501] A183. In embodiment A183, the compound of any one of embodiments A178 to A182, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to Cg alkylene ofZ4is as defined therein and Rlof linear C3to Cg alkylene of Z4is halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, di alky I ami nocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl. each ring substituted as defined therein unless stated otherwise.

[0502] Al 84. In embodiment Al 84, the compound of any one of embodiments Al 78 to Al 83, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to Cg alkylene ofZ4is hydrogen and R‘ of linear C3to Cg alkylene of Z4is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, each ring substituted as defined therein.

[0503] A185. In embodiment A185, the compound of any one of embodiments A178 to A184, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl of Rlof linear C3to C6alkylene of Z4, when present, are five or six membered rings and each ring is substituted as defined therein.

[0504] Al 86. In embodiment Al 86, the compound of any one of embodiments Al 78 to Al 85, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to C6alkylene ofZ4is as defined therein and R‘ of linear C3to C6alkylene of Z4is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or tetrahydrofuranyl, where each ring of Rlis substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano, unless stated otherwise.

[0505] A187. In embodiment A187, the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof, is wherein the C3to C6alkenylene and C3to C6alkylene of Z4are branched C4 to C6alkenylene and C4 to C6alkylene, respectively, and each is substituted as defined therein.

[0506] Al 88. In embodiment Al 88, the compound of any one of embodiments Al 76 to Al 79 and Al 87, or a pharmaceutically acceptable salt thereof, is wherein Z4is branched C4 to C6alkylene substituted as defined therein.

[0507] Al 89. In embodiment Al 89, the compound of any one of embodiments A174 to A179, Al 87, and Al 88, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6alkeny lene of Z4is -CH2CH2C(CH3)=C(RV)-, -CH2CH2C(CH2RV)=CH-, -CH2C(CH3)=C(RV)-, or -CH2C(=CH2)CH2- and the branched C4 to C6alkylene of Z4is -CH2C(CH3)(R‘)CH2-,

[0508] Al 90. In embodiment Al 90, the compound of any one of embodiments Al 74 to A179 and A187 to A189, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6alkenylene of Z4is -CH2C(CH3)=C(RV)- or -CH2C(=CH2)CH2- and the branched C4to C6alky lene of Z4is -CH2C(CH3)(Rl)CH2-, -CH2CH(CH2Rl)CH2-, - where Rs, Rl. and Ruare as defined therein.

[0509] A191. In embodiment A191, the compound of any one of embodiments A176 to A179 and Al 87 to Al 90, or a pharmaceutically acceptable salt thereof, is wherein the Rsand Ruof branched C4 to C6alkylene of Z4are independently hydrogen or halo (unless stated otherwise) and Rlof branched C4 to C6alkylene of Z4is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy. alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of R1is substituted as defined therein.

[0510] A192. In embodiment A192, the compound of any one of embodiments A176 to A179 and A187 to A191, or a pharmaceutically acceptable salt thereof, is wherein the Rsand Ruof branched C4 to C6alkylene of Z4are hydrogen or fluoro (unless stated otherwise) and R1of branched C4 to C6alkylene of Z4is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of Rlis substituted as defined therein.

[0511] A193. In embodiment A193, the compound of any one of embodiments A176 to A179 and Al 87 to Al 92, or a pharmaceutically acceptable salt thereof, is wherein Rsand Ruof branched C4 to C6alkylene of Z4are hydrogen or fluoro (unless stated otherwise) and Rlof branched C4 to C6alkylene ofZ4is hydrogen, halo, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.

[0512] Al 94. In embodiment Al 94, the compound of embodiment Al 78, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6 alkylene substituted with Rs, Rl, and Ruwhere Rland Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3to C6alkydene and Rland Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R‘ and Ruare substituted with R9and R10.

[0513] Al 95. In embodiment Al 95, the compound of any one of embodiments Al 78 and Al 94, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, R\ and Ruwhere Rland Ruare attached to the same carbon atom of the linear portion of C3to C6alkylene and together with the carbon atom to which they are attached can form cycloalkylene substituted with R9and R10' Al 96. In embodiment Al 96, the compound of embodiment Al 78 or Al 94, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, Rtand Ruwhere Rland Ruare attached to the same carbon atom of the linear portion of the C3to C6alkydene and together with the carbon atom to which they are attached can form heterocyclylene substituted with R9and R10.

[0514] Al 97. In embodiment Al 97, the compound of embodiment Al 78 or Al 94, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, R\ and Ruwhere Rland Ruare attached to adjacent carbon atoms of the linear portion of the C3to C6alky lene and together with the carbon atoms to which they are attached can form cycloalkylene substituted with R9and R10.

[0515] A198. In embodiment A198, the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6alkylene substituted with Rs, R\ and Ruwhere Rland Ruare attached to adjacent same carbon atoms of the linear portion of the C3to C6alkylene and together with the carbon atoms to which they are attached can form heterocyclylene substituted with R9and R10.

[0516] Al 99. In embodiment Al 99, the compound of any one of embodiments Al 78 and Al 94 to Al 96, or a pharmaceutically acceptable salt thereof, is wherein Rland Ruare attached to the same carbon atom of the linear portion C3to C6alky lene and together with the carbon atom to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R9and R10(in one embodiment R9is hydrogen, halo, methyl or ethyl and R10is hydrogen).

[0517] A200. In embodiment A200, the compound of any one of embodiments Al 78. Al 94, A197, and A198, or a pharmaceutically acceptable salt thereof, is wherein R‘ and Ruare attached to adjacent carbon atoms of the linear portion of the C3to C6alkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R9and R10, in one embodiment R9is hydrogen, halo, methyl or ethyl and R10is hydrogen.

[0518] A201. In embodiment A201, the compound of any one of embodiments Al to Al 12, A124 to A127, A132, A133, and A135 to A168, or a pharmaceutically acceptable salt thereof, is wherein the Z4is C3to Ci, heteroalkylene substituted with Rs, R\ and Ru.

[0519] A202. In embodiment A202, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein the Z4is C3to C6heteroalkylene substituted with Rs, R\ and Ruwhere Rs, R\ and Ruare hydrogen.

[0520] A203. In embodiment A203, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein the Z4is C3to C6heteroalkylene substituted with Rs, R‘. and Ruwhere Rs, Rl. and Ruare hydrogen or halo, provided at least one of Rs, R‘, and Ruis halo.

[0521] A204. In embodiment A204, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein Z4is C3to C6heteroalkylene substituted with Rs, R‘, and Ruwhere R‘ is other than hydrogen and Ruis hydrogen, or when R‘ and Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the C3to C6heteroalkylene. Rland Rutogether with the carbon atom to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R9and R10'

[0522] A205. In embodiment A205, the compound of embodiment A204, or a pharmaceutically acceptable salt thereof is wherein R‘ and Ruare attached to the same carbon atom of the linear portion of the C3to C6heteroalkylene and together with the carbon atom to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R9and R10. In one embodiment R9is hydrogen, halo, methyl or ethyl and R10is hydrogen.

[0523] A206. In embodiment A206, the compound of embodiment A204. or a pharmaceutically acceptable salt thereof, is wherein Rtand Ruare attached to adjacent carbon atoms of the linear portion of the C3to C6heteroalkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R9and R10. In one embodiment R9is hydrogen, halo, methyl or ethyl and R10is hydrogen.

[0524] A207. In embodiment A207, the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof, is wherein the C3to C6heteroalky lene of Z4is linear C3to C6heteroalkylene substituted with Rs, R‘, and Ru.

[0525] A208. In embodiment A208, the compound of any one of embodiments A201 to A204, and A207, or a pharmaceutically acceptable salt thereof, is wherein the linear heteroalkydene of Z4is -CH2CH2XaCH2-, -CH2XaCH2CH2-, -CH2CH2CH2Xa-, -XaCH2CH2CH2-, - XyCH2CH2Xa-, -XyCH2CH2XaCH2-, -CH2CH2CH2XaCH2-, -CH2XaCH2-, -XaCH2CH2-. -CH2CH2Xa-, -CH2CONRqlCH2-, -CH2SO2NRqlCH2-. -CH2NRqlCOCH2-, -CH2NRqlSO2CH2-, -CH2CH2CH2NRqlCO-, -CH2CONRq1-, -CH2SO2NRq1-, -CH2NRqlCO-, -CH2NRqlSO2-, -CONRqlCH2-, -SO2NRqlCH2-, -NRqlCOCH2-, or -NRqlSO2CH2- substituted with Rs, R‘, and Ruas defined therein and Xais -NRq1-, -O-, -S-, -SO-, -SO2-, or -CO-.

[0526] A209. In embodiment A209, the compound of any one of embodiments A201 to A204, A207, and A208, or a pharmaceutically acceptable salt thereof, is wherein Rqlis hydrogen, methyl, ethyl, methylcarbonyl, or methylsulfonyl. A210. In embodiment A210, the compound of any one of embodiments A201 to A204, and A207 to 209, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to Cs heteroalkylene of Z4is -CH2XaCH2-, -XaCH2CH2-, -CH2CH2Xa-. -CH2CH2CH2Xa- , -CH2CH(Rt)Xa-, -XaCH(Rl)CH2-, -CH2CONRq1-, -CH2SO2NRq1-, -CH2NRqlCO-, -CH2NRq1SO2-, -CONRq1CH2-, -SO2NRq1CH2-. -NRq1COCH2-, or -NRqlSO2CH2- where Xais -S-, -SO2-, -O-. or -NRql- substituted with Rs, R‘, and Ruas defined therein.

[0527] A211. In embodiment A211, the compound of any one of embodiments A201 to A204, and A207 to 210, or a pharmaceutically acceptable salt thereof, is wherein the linear C3to Cs heteroalkylene of Z4is -CH2CH2CH2Xa- or -CH2CH2Xa- substituted with Rs, Rtand Ruas defined therein.

[0528] A212. In embodiment A212, the compound of any one of embodiments A201 to A204, and A207 to A211, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to Cs heteroalkylene of Z4is hydrogen or halo (unless stated otherw ise therein above) and Rlof linear heteroalkylene of Z4is (unless stated otherwise therein above) hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkydoxy. alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, or bridged heterocyclyl, each ring substituted as defined therein and Ruis hydrogen.

[0529] A213. In embodiment A213, the compound of any one of embodiments A201 to A204, and A207 to A212, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear C3to Cs heteroalkylene of Z4is hydrogen or fluoro (unless stated otherwise therein above) and R1of linear heteroalkylene of Z4(unless stated otherwise therein above) is hydrogen halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.

[0530] A214. In embodiment A214, the compound of any one of embodiments A201 to A204, and A207 to A213, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclyl, and bridged heterocyclyl of Rlof linear C3to Cs heteroalkyl ene of Z4, when present, are five or six membered ring and each ring is substituted as defined therein.

[0531] A215. In embodiment A215, the compound of any one of embodiments A201 to A204, and A207 to A214, or a pharmaceutically acceptable salt thereof, is wherein Rsof linear heteroalkylene of Z4, when present and unless stated otherwise herein above, is hydrogen, deuterium, or fluoro, and Rlof linear heteroalky lene of Z4, unless stated otherwise, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy’, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyL piperidinyl, piperazinyl, tetrahydrofuranyl. each ring substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethyl amino, and cyano.

[0532] A216. In embodiment A216, the compound of any one of embodiments A201 to A215, or a pharmaceutically acceptable salt thereof, is wherein Xais -NRq1-, -O-, -S-, or -SO2-. In one embodiment -NRql- (where Rqlis hydrogen or methyl). -O-, or -S-.

[0533] A217. In embodiment A217, the compound of any one of embodiments A201 to A216, or a pharmaceutically acceptable salt thereof, is wherein Xyis -O-.

[0534] A218. In embodiment A218, the compound of any one of embodiments A201 to A216, or a pharmaceutically acceptable salt thereof, is wherein Xyis -NH- or -NCH3-.

[0535] A219. In embodiment A219, the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof, is wherein the C3to G, heteroalkylene of Z4is branched C4 to G, hetcroalkylene substituted with Rs, R\ and Ru.

[0536] A220. In embodiment A220, the compound of any one of embodiments A201 to A204, and A219, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6heteroalkylene of Z4is -CH2XaCH(CH3)CH2-, -CH2XyCH2CH(CH3)Xa-, -CH2CH2CH(CH3)Xa-, -XaCH(CH3)CH2CH2-, -XyCH2CH(CH3)Xa-, -XyCH(CH3)CH2Xa-, -CH2CH2CH2CH(CH3)Xa-, -XaCH(CH2R‘)CH2-, -CH2CH(CH2R‘)Xa-, -XaCH(CH2CH2R‘)CH2-, -CH2CH(CH2CH2R‘)Xa-, -CH2C(CH3)(CH3)Xa-. -XaC(CH3)(CH3)CH2-. -CH(CH3)CH(CH3)Xa-, -CONRqCH2CH(CH3)Xa-, -CH2NRqCOCH(CH3)CH2-, or -NRqlCOCH(CH3)CH2- where Xais -NRq1-, -O-, -S-, -SO-, -SO2-, or -CO- and R‘ is as defined therein above.

[0537] A221. In embodiment A221, the compound of any one of embodiments A201 to A204, A219, and A220, or a pharmaceutically acceptable salt thereof, is wherein the branched C4 to C6heteroalkylene of Z4is -CH2C(CH3)(CH3)Xa-, -CH(CH3)CH(CH3)Xa-, -XaCH(CH2CH2Rt)CH2-, -CH2CH(CH2CH2Rt)Xa-, -XaCH(CH2Rt)CH2-, or -CH2CH(CH2Rl)Xa-.

[0538] A222. In embodiment A222, the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof, is wherein the Rsand Ruof branched C4 to C6heteroalkylene of Z4are hydrogen or halo (unless stated otherwise herein above) and Rlof branched C4 to C6heteroalkylene ofZ4is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl substituted as defined therein.

[0539] A223. In embodiment A223, the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof, is wherein Rsand Ruare hydrogen and R‘ is hydrogen, heteroaryl, alkylaminocarbonyl, or cyano (unless stated otherwise herein above).

[0540] A224. In embodiment A224, the compound of any one of embodiments A201 to A204, and A219 to A221, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl, heterocyclyl of branched C4 to C6heteroalkylene of Z4, by itself or as part of heterocyclyloxy, heterocyclylcarbonyl, and bridged heterocyclyl. when present, are five or six membered ring and each ring is substituted as defined therein.

[0541] A225. In embodiment A225, the compound of any one of embodiments A201 to A204, and A219 to A224, or a pharmaceutically acceptable salt thereof, is wherein R’ of branched C4 to C6heteroalkylene of Z4, when present and unless stated otherwise herein above, is hydrogen, deuterium, fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbony lamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyrrolidinyk pyridinyl, piperidinyl, piperazinyl, or tetrahydrofuranyl, where each ring is substituted with R7and R8independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano.

[0542] A226. In embodiment A226, the compound of any one of embodiments A201 to A204 and A219 to A225, or a pharmaceutically acceptable salt thereof, is wherein Xais -NRq1-, -O-. -S-, or -SO2-. In one embodiment Xais -NRql- or -O-.

[0543] A227. In embodiment A227 , the compound of any one of embodiments Al to Al 12, A124 to A127, A132, and A134 to A168, or a pharmaceutically acceptable salt thereof, is wherein Z4is alkynylene substituted with R" and Rxindependently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano.

[0544] A228. In embodiment A228, the compound of any one of embodiments K2T1 , or a pharmaceutically acceptable salt thereof, is wherein Z4is alkynylene substituted with R" and Rxindependently selected from hydrogen, fluoro, difluoromethyl, trifluoromethyl, hydroxy, methoxy, and cyano.

[0545] A229. In embodiment A229, the compound of embodiment A227, or a pharmaceutically acceptable salt thereof, is wherein Z4is alkynylene substituted with Rwand Rxwhich are attached to the same carbon atoms of the alkynylene and are combined to form cycloalkylene or heterocyclylene wherein the cycloalkylene and heterocyclylene are substituted with R11and R12independently selected from hydrogen, alkyl, and halo. A230. In embodiment A230, the compound of any one of embodiments A227 to A229, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of Z4is:

[0546] A231. In embodiment A231, the compound of any one of embodiments A227 , A228, and

[0547] A230, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of Z4is:

[0548] A232. In embodiment A232, the compound of any one of embodiments Al 74 to A226, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, and alkenylene of Z4are selected from: respectively.

[0549] A233. In embodiment A233, the compound of any one of embodiments Al 74 to A226, and A232, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, and alkenylene of Z4are selected from:

[0550] respectively.

[0551] A234. In embodiment A234, the compound of any one of embodiments Al 74 to A226, A232, and A233, or a pharmaceutically acceptable salt thereof, is wherein the alkylene, heteroalkylene, and alkenylene of Z4are selected from:

[0552] respectively.

[0553] A235. In embodiment A235, the compound of any one of embodiments A174. A176, A178, A179 to A184, A187 to A193, A201. A202, A204. A217, A219 to A223, A225, A226, and

[0554] A232 to 234, or a pharmaceutically acceptable salt thereof, is wherein Z4is:

[0555] A236. In embodiment A236, the compound of any one of embodiments A174. A176,

[0556] A178, A179 to A184, A187 to A193, A201. A202, A204. A217, A219 to A223, A225, A226, and A232 to 235, or a pharmaceutically acceptable salt thereof, is wherein Z4is:

[0557] A238. In embodiment A238, the compound of any one of embodiments Al to A96d, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X^L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently:

[0558]

[0559] A239. In embodiment A239, the compound of any one of embodiments Al to A96d and

[0560] A238, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)). -X'-L-. -X2-L-. -X3-L-, and -X4-L- (when the Degron is a group of formula

[0561] A240. In embodiment A240, the compound of any one of embodiments Al to A96d, A238, and A239, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X^L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently:

[0562]

[0563] A241. In embodiment A241, the compound of any one of embodiments Al to A96d and A238 to A240. or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (hi) to (vi)), -X^L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of

[0564] A242. In embodiment A242, the compound of any one of embodiments Al to A96d, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X^L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: wherein each Rm, Rn. and Rqare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano (i.e. , Rris hydrogen). In a subembodiment, each Rqand Rmare independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; and

[0565] Z4is alkylene, alkynylene, alkenylene, or heteroalkylene wherein alky lene and heteroalkylene are substituted with Rs, R‘, and Ru. alkenylene is substituted with Rvand alkynylene is substituted with R" and Rxas defined in the first aspect of the Summary.

[0566] A243. In embodiment A243, the compound of any one of Al to A96d and A242, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X^L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently: wherein each Rm, Rn, and Rqare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e.. Rris hydrogen).

[0567] A244. In embodiment A244, the compound of embodiment A242 or A243, or a pharmaceutically acceptable salt thereof, is wherein: alkynylene is as provided in embodiment A230 (in a subembodiment alkynylene is as provided in embodiment 231); and alkylene, alkenylene, and heteroalkylene of Z4are those as provided in embodiment A233. In one subembodiment alkylene, alkenylene, and heteroalkylene of Z4are those as provided in embodiment A234, respectively. In another subembodiment alkydene, alkenylene, and heteroalkylene ofZ4are those as provided in embodiment A235, respectively. In yet another subembodiment alkylene, alkenylene, and heteroalkylene ofZ4are those as provided in embodiment A236. respectively. In one subembodiment alkylene, alkenylene, and heteroalkylene of Z4are those as provided in embodiment A237, respectively.

[0568] A245. In embodiment A245, the compound of any one of embodiments Al to A96d and Al 34a, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)); and -X^L-, -X2-L-, -X3-L- and -X4-L- (when the Degron is a group of formula (i) or (ii)) are independently:

[0569] wherein each Rmand Rnare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy , and cyano; and Z4is C3to C6alkylene substituted with Rs, R\ and Ru.

[0570] A246. In embodiment A246, the compound of embodiment A245, or a pharmaceutically acceptable salt thereof, is wherein:

[0571] L is where Rmand Rnare independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; alkynylene; and

[0572] Z4is propylene, butylene, or pentylene.

[0573] A247. In embodiment A247, the compound of embodiment A245 or A246, or a pharmaceutically acceptable salt thereof, is wherein Z4is n-propylene.

[0574] A248. In embodiment A248, the compound of any one of embodiments Al to A46, A48 to A56, A59 to A67, A69 to A75, A77 to A82, A83 to A93, A97, and Al 10a to A247, 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.

[0575] A249. In embodiment A249, the compound of any one of embodiments Al to A46, A48 to A56, A59 to A67. A69 to A75, A77 to A82, A83 to A93, A97. and Al 10a to A248. 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. A250. In embodiment A250, the compound of embodiment A249, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ligase ligand selected from:

[0576] A251. In embodiment A251, the compound of embodiment A249 or A250, or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and

[0577] Rff. when present, is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0578] A252. In embodiment A252, the compound of embodiment A251 , or a pharmaceutically acceptable salt thereof, is wherein Degron is the E3 ubiquitin ligase ligand

[0579] A253. In embodiment A253, the compound of any one of embodiments Al to A252, or a pharmaceutically acceptable salt thereof, is wherein R2is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino.

[0580] A254. In embodiment A254, the compound of any one of embodiments Al to A252, or a pharmaceutically acceptable salt thereof, is wherein R2is alkoxy.

[0581] A255. In embodiment A255, the compound of any one of embodiments Al to A252, or a pharmaceutically acceptable salt thereof, is wherein R2is halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino.

[0582] A256. In embodiment A256, the compound of any one of embodiments Al to A255, or a pharmaceutically acceptable salt thereof, is wherein R2is methyl, ethyl, methoxy, ethoxy, amino, methylamino, dimethylamino, hydroxy, chloro, fluoro, hydroxymethyl, or methoxymethyl. Reference to an embodiment includes combination of the embodiment and subembodiment(s) thereof. For example reference to embodiment A includes combination of embodiments A and subembodiment(s) thereof.

[0583] For the sake of clarity, when an embodiment refers to more than one preceding embodiments of vary ing scopes, the scope of the preceding embodiments control i.e., only those groups that fall within the scope of group(s) recited in a preceding embodiment(s) should be selected from the embodiment referring thereto. For example, of the groups recited in embodiment A8, while all the recited groups in A8 should be selected for embodiment Al, only fluoro, chloro, and bromo should be selected for embodiment A5 as scope of R1in A5 is limited to halo; and only difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl should be selected for embodiment A6 as scope of R1in A6 is limited to haloalkyl.

[0584] It is understood that the embodiments and subembodiments set forth above include all combinations of embodiments and subembodiments listed therein. Representative compounds of Formula (I) are shown in Compound Table 1 below:

[0585] Table 1 Contemplated compounds of Formula (I) and (IB) are provided in the following table:

[0586] Compounds Formula (I) (and any embodiment thereof disclosed herein including specific compounds) can be made by the methods depicted in the reaction schemes shown below.

[0587] 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)(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.

[0588] 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.

[0589] Compounds of Formula (I), where Degron is an E3 ligase ligand of formula (i)-(vi) where R3is hydrogen, ring Hy, R1, R2, and L are as defined in the first aspect of the Summary', can be prepared as described in Scheme 1 below.

[0590] Scheme 1

[0591] Treatment of a pyrimidine of formula 1-1 where A1is a halogen such as chlorine or bromine and R1and R2are as defined in the first aspect of the Summary, with an amine of formula 1-2, where Hy is as defined in the Summary and FG1is a suitable functional group such as an acid or amine, under conditions well known in the art (such as in the presence of TEA and ZnCU in tert-butanol), provides a compound of formula 1-3. A compound of formula 1-4 where L is as defined in the first aspect of the Summary with a suitable functional group (FG2), such as acid, amine, or alkyl halide, reacts with FG1in 1-3 to afford compound of Formula (I). For example, the reaction is a peptide coupling reaction, where the resulting amide bond is part of L as defined in the Summary, and FG1and FG2are a combination of carboxylic acid and an amine, in the presence of suitable coupling reagents, such as a combination of HATU and DIPEA in DMF. Alternatively, a compound of Formula (I) such as where R3is hydrogen, Hy is 1,4- piperidindiyl, Degron is a group of formula (i) and L is attached to Degron (i) via heterocyclylene containing at least one nitrogen ring atom and to Hy via -SO2-, can be synthesized as illustrated and described in Scheme 2.

[0592] Scheme 2

[0593] Treatment of a pyrimidine of formula 1-1 where A1is a halogen such as chlorine or bromine, with a piperidine amine of formula 2-2 under conditions well known in the art, such as in the presence of TEA, and ZnCE in tert-butanol, provides a compound of formula 2-3. An amine compound of formula 2-4, prepared by removal of the Boc protecting group of 2-3 in the presence of an acid, such as TFA, is converted to a sulfonamide compound of formula 2-6 by treating it with a sulfonyl halide of formula 2-5 where L’ is a precursor group of L in the compound of Formula (I) as defined in the Summary and A2is halogen such as chlorine and LG is a suitable leaving group such as halo or methylsulfonyl.

[0594] Treatment of a compound of formula 2-6 with an amine compound of formula 2-7, where ring A is defined as in the Summary and is heterocyclylene containing at least one nitrogen ring atom (e.g. piperidin-l,4-diyl), under basic conditions such as in the presence of DIPEA, provides a compound of formula (I).

[0595] Compounds of formula 1-1, 2-5, and 2-7 are either commercially available or they can be prepared by methods known in the art. Alternatively, compounds of Formula (I) where R3is hydrogen. R1. R2. Hy, L, and Degron are as defined in the Summary can be prepared as described in Scheme 3 below:

[0596] Scheme 3 Treatment of a pyrimidine of formula 1-1 with an amine of formula 4-1, where R1. R2. Hy.

[0597] L and Degron are as defined in the Summary, under suitable conditions such as acidic, basic or transition metal catalyzed reaction conditions well known in the art, provides a compound of Formula (I). A compound of Formula (I) such as where R3is hydrogen, Degron is a group of formula

[0598] (i), Z1is heterocyclylene such as 4-piperidin- 1 -yl. Z2and Z3are bond, Z4is aryl (Ar), and Z6is -SO2- can be synthesized as illustrated and described in Scheme 4.

[0599] Scheme 4

[0600] Treatment of an alkyne containing compound 4-2. where A1is a suitable leaving group, such as chlorine or bromine, with an amine of formula 4-1 under basic or catalytic conditions known in the art provides an alkyne of formula 4-3. Coupling betw een 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 4-6 by proceeding analogously as described in Scheme 3.

[0601] Compounds of formula 4-2, 4-5, and 4-8 are either commercially available or they can be prepared by methods known in the art.

[0602] Utility

[0603] The compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) i.e., compound of this disclosure can cause degradation of CDK2 and / or CDK4 proteins and hence are useful in the treatment of diseases mediated by CDK2 and / or CDK4.

[0604] Increasing evidence suggests that overactivated CDK2 and / or CDK.4 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.

[0605] 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 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 my c / 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.

[0606] 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.

[0607] Therefore, a compound of this disclosure may be useful for treating tumors characterized by 1) overexpression of CDK2 and / or CDK4; 2) amplification / overexpression of cyclin D, cyclin E or cyclin A; 3) hyperphosphorylation of CDK2 (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 pl6, p21 or p27, or overexpression of SKP2;and 7) hyperactive MYC / RAS; 8) Aneuploid cancers, and 9) CDK4 and / or CDK6 inhibitor refractory cancers.

[0608] 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.

[0609] 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.

[0610] Besides cancer, compounds of Formula (I) as described in the Summary as described in the first aspect (or any of the embodiments thereof herein above) are useful in treating autoimmune diseases autoimmune diseases e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS), multiple sclerosis (MS), Crohn’s disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss.

[0611] Testing

[0612] CDK2 / 4 potency and CDK2 / 4 degradation activities of the compounds of the present disclosure can be tested using the in vitro assays described in Biological Examples below.

[0613] Pharmaceutical Compositions

[0614] In general, the compounds Formula (I) (unless stated otherwise, reference to compound / compounds of Formula (I) herein 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) (and any embodiment thereof disclosed herein including specific compounds) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg / kg per day; about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to about 250 mg / kg per day, about 0.05 to about 100 mg / kg per day, or about 0. 1 to about 50 mg / kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600. 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds), i.e., the active ingredient, will depend upon numerous factors such as the severity7of 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.

[0615] In general, compounds Formula (1) (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.

[0616] 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.

[0617] The compositions are comprised of in general, a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). Such excipient may be any solid, liquid, semi-solid or. in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0618] - Il l - 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.

[0619] The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi -dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0620] 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.

[0621] In addition to the formulations described previously, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated as a depot preparation. Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0622] 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.

[0623] The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. C6rtain compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0624] 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.

[0625] For administration by inhalation, compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).

[0626] The level of the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. % of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.

[0627] Combinations and Combination Therapies

[0628] The compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) or the other drugs may have utility. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). When a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is preferred. However, the combination therapy may also include therapies in which the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) and the other active ingredients may be used in lower doses than when each is used singly.

[0629] Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds).

[0630] The above combinations include combinations of a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) not only with one other drug, but also with two or more other active drugs. Likewise, a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). When a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds). The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

[0631] Where the subject in need is suffering from or at risk of suffering from cancer, the subject can be treated with a compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) in any combination with one or more other anti-cancer agents including but not limited to: MAP kinase pathway (RAS / RAF / MEK / ERK) inhibitors including but not limited to: Vemurafanib (PLX4032), Dabrafenib, Encorafenib (LGX818), TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corp); trametinib, selumetinib (AZD6244), TQ-B3234, PD 184352, 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,

[0632] WO2017058805, WO2017058807, W02017058902, WO2017058915, W02017070256. WO2017087528, W02017100546, WO2017172979, W02017201161, W02018064510, W02018068017, WO2018119183;

[0633] CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) TGF beta receptor kinase inhibitor such as LY2157299;

[0634] 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] -1, 2,3,4-tetrahydronaphthalen-l,4-imin-9-yl]-2-oxoethyl]-acetamide (PF- 03814735, CAS 942487-16-3);

[0635] ALK inhibitors: PF-2341066 (XALKOPJ ®; crizotinib); 5-chloro-N4-(2- (isopropyl- sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiper azin-1 -yl)piperi din-1- yl)phenyl)pyrimidine- 2,4-diamine; GSK1838705 A; CH5424802; C6ntinib (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);

[0636] Vascular Endothelial Grow th Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademark Avastin® by Genentech / Roche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2- ylethenyl]4H-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;

[0637] FLT3 inhibitors - sunitinib malate (sold under the tradename Sutent® by Pfizer); PK.C412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib;

[0638] 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);

[0639] HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech / Roche), Trastuzumab deruxtecan (sold under the trademark Enhertu), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7- ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 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);

[0640] HER dimerization inhibitors: Pertuzumab (sold under the trademark Omnitarg®, by Genentech);

[0641] CD20 antibodies: Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech / Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);

[0642] 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);

[0643] 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);

[0644] Antineoplastic agents: oxaliplatin (sold under the tradename Eloxatin® ay Sanofi-Aventis and described in US Patent No. 4,169.846);

[0645] Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename Neupogen® by Amgen);

[0646] 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®);

[0647] 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);

[0648] 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);

[0649] Phospholipase A2 inhibitors: Anagrelide (sold under the tradename Agrylin®); BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]methyl]-l- piperazinyl]-N-[[4-[[(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);

[0650] MC1-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991;

[0651] Aromatase inhibitors: Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);

[0652] Topoisomerase I inhibitors: Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by GlaxoSmithKline);

[0653] 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- azatricyclo[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);

[0654] Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;

[0655] BET inhibitors such as INCB054329, OTX015, and CPI-0610;

[0656] LSD1 inhibitors such as GSK2979552, and INCB059872;

[0657] HIF-2a inhibitors such as PT2977 and PT2385;

[0658] 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);

[0659] CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0660] CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename Zevalin®);

[0661] Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®); Synthetic Interleukin- 11 (IL-11): oprelvekin (sold under the tradename Neumega® by Pfizer / Wyeth);

[0662] Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by Amgen);

[0663] Receptor Activator for Nuclear Factor K B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen);

[0664] Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename Nplate® by Amgen); C6ll grow th stimulators: Palifermin (sold under the tradename Kepivance® by Amgen);

[0665] 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);

[0666] Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

[0667] CD52 antibodies: Alemtuzumab (sold under the tradename Campath®);

[0668] Histone deacetylase inhibitors (HD I): Voninostat (sold under the tradename Zolinza® byMerck);

[0669] 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 C6eNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®), ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the tradename Thioplex®; Biologic response modifiers: bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), denileukin diftitox (sold under the tradename Ontak®); Anti-tumor antibiotics: doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®). daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename C6rubidine®), 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®);

[0670] Anti -microtubule agents: Estramustine (sold under the tradename Emcyl®);

[0671] 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);

[0672] 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, ATI 3387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116

[0673] TpoR agonists: Eltrombopag (sold under the tradenames Promacta® and Revolade® by GlaxoSmithKline);

[0674] Anti-mitotic agents: Docetaxel (sold under the tradename Taxotere® by Sanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the tradename Cytadren®);

[0675] Anti-androgens: Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename Fulexin™);

[0676] Androgens: Fluoxymesterone (sold under the tradename Halotestin®);

[0677] 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);

[0678] CDK4 / 6 inhibitors palbociclib, ribociclib, abemaciclib, and Trilaciclib; CDK9 inhibitors AZD 4573, P276-00, AT7519M, TP-1287; CDK2 / 4 / 6 inhibitor such as PF-06873600;

[0679] SHP-2 inhibitor such as TNO155;

[0680] MDM2 / MDMX, MDM2 / p53 and / or MDMX / p53 modulators; Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi- Aventis and Lupron® by Abbott Lab);

[0681] 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,3S)-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);

[0682] 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: C6rvarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: Deferasinox (sold under the tradename Exjade® by Novartis);

[0683] 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®);

[0684] 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®);

[0685] 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™);

[0686] Retinoids: Ah 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®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);

[0687] Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R,10S.l lS.13S,14S,16R,17R)-9-fluoro-l l,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16- trimethyl-6,7, 8,9, 10,1 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 Dural one®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);

[0688] 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®) and elacestrant and ARV-471(vepdegestrant);

[0689] Anti-estrogens: tamoxifen (sold under the tradename Novaldex®); Toremifene (sold under the tradename Fareston®);

[0690] Selective estrogen receptor modulators (SERMs): Raloxifene (sold under the tradename E vista®);

[0691] Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, sold under the tradename Megace®);

[0692] 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®);

[0693] 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, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

[0694] 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.

[0695] 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).

[0696] 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, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383

[0697] Compounds of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be used to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GV AX® (granulocytemacrophage 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.

[0698] 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.

[0699] A compound of Formula (I) (or any embodiment thereof disclosed herein including specific compounds) can also be used in combination with the following adjunct therapies: antinausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and

[0700] Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).

[0701] Examples

[0702] The following preparations of Intermediates (References) and compounds of Formula (I) (Examples) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

[0703] Reference 1

[0704] Synthesis of 4-((14-amino-3, 6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l, 3-dione, 2,2,2-trifluoroacetate

[0705] Step 1 : tert-Butyl (14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxatetradecyl)carbamate

[0706] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- 1,3-dione (500.0 mg, 1.81 mmol, 1.00 eq.), tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (609.0 mg, 1.81 mmol, 1.00 eq.), DIPEA (467.9 mg, 3.62 mmol, 2.00 eq.) in DMF (6.0 mL) was stirred for 16 h at 90 °C under nitrogen atmosphere. The mixture was cooled, diluted with water, and then extracted with EtOAc. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5: 1), to afford the title compound as a yellow solid.

[0707] Step 2: 4-((14-Amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione, 2,2,2-trifluoroacetate

[0708] TFA (0.3 mL, 3.92 mmol, 46.67 eq.) was added to a stirred solution of tert-butyl (14-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (50 mg, 0.084 mmol, 1.00 eq.) in DCM (1.0 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 h, and then concentrated to give crude title compound as light yellow oil.

[0709] Reference 2

[0710] Synthesis of 2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)- acetamido)ethoxy) ethoxy)ethyl methanesulfonate

[0711] Step 1 : tert-Butyl 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetate

[0712] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-l, 3-dione (1.5 g, 5.47 mmol, 1.00 eq.), tert-butyl 2-bromoacetate (1.3 g, 6.66 mmol, 1.22 eq.) and K2CO3 (1.1 g, 7.96 mmol, 1.46 eq.) in DMF (20.0 mL) was stirred at RT for 2 h. The mixture was diluted with H2O and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, concentrated to get title compound as a white solid.

[0713] Step 2: 2-((2-(2,6-Dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-4-yl)oxy)acetic acid A solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)- acetate (1.0 g, 2.57 mmol. 1.00 eq.) and TFA (5.0 mL) in DCM (10.0 mL) was stirred at rt for 2 h. The mixture was concentrated and the residue was triturated with ether to get title compound as a white solid.

[0714] Step 3: 2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2 -hydroxyethoxy) ethoxy )ethyl)acetamide

[0715] HATU (513 mg, 1.35 mmol, 1.5 eq) was added to a stirred solution of 2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq.), 2-(2-(2-aminoethoxy)ethoxy)ethanol (201 mg, 1.35 mmol, 1.50 eq.) and DIPEA (348 mg, 2.69 mmol, 2.99 eq.) in DMF (6.0 mL) at 0 °C and the mixture was stirred at RT for 1 h. The mixture was diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over NaiSCfi. concentrated to get crude title compound as a yellow oil, which was used for next step without further purification.

[0716] Step 4: 2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy) ethoxy )ethyl methanesulfonate

[0717] MsCl (298 mg, 2.60 mmol, 1 .50 eq.) was added to a stirred solution of 2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-(2- hydroxyethoxy)ethoxy)ethyl)acetamide (800 mg, 1.73 mmol, 1.00 eq.) and TEA (524 mg, 5.18 mmol, 2.99 eq.) in DCM (8.0 mL) at 0 °C and the mixture was stirred at 0 °C for 1 h. The mixture w as diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over ISfeSCfi, concentrated and purified by flash silica gel chromatography (DCM:MeOH = 50: 1) to get title compound as a white solid. Reference 3

[0718] Synthesis of 2-(2-(2-((2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4- yl)oxy)acetamido)ethoxy)-ethyl methanesulfonate

[0719] Step 1 : 2-((2-(2,6-Dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2 -hydroxy ethoxy )- ethyl) acetamide

[0720] A mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (180 mg, 0.54 mmol, 1.00 eq.), 2-(2-aminoethoxy)ethan-l-ol (85 mg, 0.81 mmol, 1.50 eq.), HATU (308 mg, 0.81 mmol, 1.50 eq.) and DIPEA (209 mg, 1.62 mmol, 3.00 eq.) in DMF (5.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried overlSfeSCL and concentrated to give crude title compound as a yellow oil, which was used for next step without further purification. Step 2: 2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)- ethvl methanesulfonate

[0721] MsCl (162 mg, 1.41 mmol, 1.48 eq.) was added slowly to a stirred solution of 2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-hydroxyethoxy)ethyl) acetamide (400 mg. 0.95mmol. 1.00 eq.) and TEA (288 mg, 2.85 mmol. 3.00 eq.) in DCM (8.0 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over TSfeSCL, concentrated and the residue was purified by flash silica gel chromatography (DCM:MeOH = 50: 1) to give the title compound as a white solid. Reference 4

[0722] Synthesis of l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3- azatetradecan- 14-yl methanesulfonate

[0723] Step 1 : 2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N-(2-(2-(2-(2- hydroxyethoxy) ethoxy)ethoxy)ethyl)acetamide

[0724] HATU (513 mg. 1.35 mmol, 1.50 eq.) and DIPEA (348 mg, 2.69 mmol, 3.00 eq.) were added to a mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq.) and 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-l-ol (259 mg, 1.34 mmol, 1.49 eq.) in DMF (5.0 mL) at 0 °C. The mixture was stirred at 0 °C for Ih, diluted with H2O, and then extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to get crude title compound as a yellow oil, which was used for next step without further purification.

[0725] Step 2: l-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3- azatetradecan- 14-yl methanesulfonate

[0726] MsCl (271 mg, 2.37 mmol, 1.50 eq.) was added slowly to a stirred solution of 2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N- (2-(2-(2-(2 -hydroxy ethoxy)ethoxy)- ethoxy)ethyl)acetamide (800 mg, 1.58 mmol, 1.00 eq.) and TEA (479 mg, 4.73 mmol, 3.00 eq.) in DCM (8.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH = 50: 1) to get the title compound as a white solid.

[0727] Reference 6

[0728] Synthesis of l-((2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12,15- tetraoxa-3- azaheptadecan-17-yl methanesulfonate

[0729] Step 1 : 2-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N-(14-hydroxy-3, 6,9,12- tetraoxatetradecyl)acetamide

[0730] A mixture of 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (300 mg, 0.90 mmol, 1.00 eq.), 14-amino-3,6,9,12-tetraoxatetradecan-l-ol (320 mg, 1.35 mmol, 1.50 eq.), HATU (513 mg, 1.35 mmol, 1.50 eq.) and DIPEA (348 mg, 2.69 mmol, 2.99 eq.) in DMF (6.0 mL) was stirred at 0 °C for 1 h. The reaction mixture was diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated to get crude title compound as a yellow oil, which was used for next step without further purification.

[0731] Step 2: l-((2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12,15-tetraoxa-3- azaheptadecan-17-yl methanesulfonate

[0732] MsCl (271 mg, 2.37 mmol, 1.63 eq.) was added slowly to a stirred solution of 2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)-N- (14-hydroxy-3,6,9,12- tetraoxatetradecyl)acetamide (800 mg, 1.45 mmol, 1.00 eq.) and TEA (479 mg, 4.73 mmol, 326 eq.) in DCM (8.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. diluted with H2O and extracted with DCM. The combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by flash silica gel chromatography (DCM:MeOH = 50: 1) to give the title compound as a white solid. Reference 7

[0733] Synthesis of 5-(3-(4-((4-aminopiperidin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)-2-(2,6- dioxopiperidin-3-yl) isoindoline- 1, 3-dione

[0734] Step 1 : tert-Butyl (l-((4-fluorophenyl)sulfonyl)piperidin-4-yl)carbamate

[0735] Asolution of 4-fhrorobenzenesulfonyl chloride (2.6 g, 13.36 mmol, 1.07 eq.) in DCM (10.0 mL) was added dropwise to a stirred solution of tert-butyl piperidin-4-ylcarbamate (2.5 g, 12.48 mmol, 1.00 eq.) in DCM (10.0 mL) and TEA (5.2 mL) at 0 °C. The resulting mixture was stirred at RT overnight, concentrated and diluted with DCM. The mixture was stirred at RT for 1 h and filtered to give the title compound as a white solid.

[0736] Step 2: tert-Butyl (l-((4-((l-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate

[0737] To a stirred solution of l-benzhydrylazetidin-3-ol (1.0 g, 4.18 mmol, 1.00 eq.) in THF (5.0 mL) was added NaH (60%, 251 mg. 6.28 mmol, 1.50 eq.) at 0°C under N2. The resulting mixture was stirred at RT for 15 min, then a solution of tert-butyl (l-((4-fluorophenyl)sulfonyl)piperidin-4- yl)carbamate (1.65 g, 4.60 mmol, 1.10 eq.) in THF (5.0 mL) was added slowly and the mixture was stirred at RT overnight. The mixture was diluted with H2O, and then extracted with DCM. The combined organic layer was washed with aq. NaCl, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel flash column (PE: EA = 3: 1) to give the title compound as a white solid. Step 3: tert-Butyl (l-((4-(azeti din-3 -yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0738] A mixture of tert-butyl (l-((4-((l-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl) piperidin- 4-yl)carbamate (500 mg, 0.87 mmol, 1.00 eq.), Pd(OH)2 (300 mg, 20% on carbon) in THF (20.0 mL) was stirred at 50 °C under H2 (50 psi) overnight. The mixture was cooled, filtrated, concentrated. The residue was purified by silica gel flash column (DCM: MeOH = 10: 1) to give the title compound as a white solid.

[0739] Step 4: tert-Butyl (l-((4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidin-3-yl) oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0740] A mixture of tert-butyl (l-((4-(- 131 -zetidine-3-yloxy)phenyl)sulfonyl)piperidin-4-yl) carbamate (100 mg, 0.24 mmol, 1.00 eq.). 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3- dione (74 mg, 0.27 mmol, 1.13 eq.) and DIPEA (94 mg, 0.73 mmol, 3.04 eq.) in NMP (1.5 mL) was stirred at 140 °C 2 h under micro wave irradiation. The mixture was cooled, diluted with water, extracted with DCM, and then concentrated. The residue was purified by silica gel flash column (PE: EA= 1:1) to give the title product as a yellow solid.

[0741] Step 5: 5-(3-(4-((4- Aminopiperidin-l-yl)sulfonyl)phenoxy)azeti din-1 -yl)-2-(2.6-dioxopiperidin-3- yl) isoindoline-1, 3-dione

[0742] A mixture of tert-butyl (l-((4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-isoindolin-5- yl)- 131 -zetidine-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (144 mg, 0.21 mmol, 1.00 eq.), TFA (1.0 mL) in DCM (4.0 mL) was stirred at RT for 2 h. The mixture was concentrated to give the title compound as a yellow oil, which was used for next step without further purification. Reference 8

[0743] Synthesis of 5-((3-(4-((4-aminopiperidin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)methyl)-2-(2,6- dioxo-piperidin-3-yl)isoindoline-l.3-dione

[0744] Step 1 : 5-(Bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0745] NBS (196 mg, 1.10 mmol. 1.10 eq.) and AIBN (32.8 mg, 0.20 mmol. 0.20 eq.) were added to a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-methylisoindoline-l, 3-dione (272 mg, 1.00 mmol, 1.00 eq.) in MeCN (15.0 mL) and the mixture was stirred at 80 °C overnight under N2. The mixture was cooled, and concentrated and the residue was purified by flash column chromatography (EA:PE = 0-100%) gave the title compound as a white solid.

[0746] Step 2: tert-Butyl (l-((4-((l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)methyl) azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0747] A mixture of tert-butyl (l-((4-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.24 mmol, 1.00 eq., from Reference 7, Step 3). 5-(bromomethyl)-2-(2.6-dioxopiperidin- 3-yl)isoindoline- 1.3-dione (111 mg. 0.32 mmol. 1.33 eq.) and K2CO3 (67 mg, 0.48 mmol, 2.00 eq.) in MeCN (2.0 mL) was stirred at 80 °C overnight. The reaction mixture was cooled, concentrated and purified by silica gel flash column (DCM: MeOH = 20: 1) to give the title compound as a white solid. Step 3: 5-((3-(4-((4-Aminopiperidin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)methyl)-2-(2,6-dioxo- piperi din-3-yl)isoindoline- 1.3-dione

[0748] A mixture of tert-butyl (l-((4-((l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) methyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (33 mg, 0.048 mmol, 1.00 eq.) and TFA (1.0 mL) in DCM (4.0 mL) was stirred at RT for 3 h. The mixture was concentrated to give the title compound as a yellow solid.

[0749] Reference 9

[0750] Synthesis of 4-amino-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- ethoxy )ethoxy)ethyl)piperidine-l-sulfonamide

[0751] Step 1 : tert-Butyl (2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)- ethoxy)ethyl)carbamate

[0752] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l, 3-dione (100 mg, 0.36 mmol, 1.10 eq.), tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (81.7 mg, 0.33 mmol, 1.00 eq.), DIPEA (127 mg, 0.98 mmol, 2.97 eq.) in NMP (1.5 mL) was stirred at 140 °C under microwave for 2 h. The mixture was cooled and diluted with ethyl acetate, and then washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (EA:PE = 1 :3) to give the title compound as a yellow oil. Step 2: 4-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1.3- di one

[0753] A mixture of tert-butyl (2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-isoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)carbamate (180 mg, 0.36 mmol. 1.00 eq.). TFA (0.5 mL) in DCM (2.0 mL) was stirred at RT for 2 h. The mixture was concentrated to give title compound as a yellow oil, which was used for next step without further purification.

[0754] Step 3: tert-Butyl (l-(chlorosulfonyl)piperidin-4-yl)carbamate

[0755] Sulfuryl dichloride (81 mg, 0.60 mmol, 1.20 eq.) was added to a stirred solution of tertbutyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol, 1.00 eq.) and TEA (76 mg, 0.75 mmol, 1.50 eq.) in DCM (2.0 mL) at 0 °C and the mixture was stirred at 0 °C for 3 h. The mixture was diluted with water, and then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and then concentrated to give the title compound as a white solid, which was used for next step directly.

[0756] Step 4: tert-Butyl (l-(N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate

[0757] To a stirred solution of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxo- piperidin-3-yl)isoindoline-l, 3-dione (70 mg, 0.17 mmol, 1.00 eq.) and tert-butyl (l-(chloro- sulfonyl)piperidin-4-yl)carbamate (51.9 mg, 0.17 mmol, 1.00 eq.) in DCM (2.0 mL) was added TEA (52.4 mg. 0.52 mmol, 3.00 eq.). The mixture was stirred at 35 °C overnight, and then concentrated. The residue was purified by silica gel chromatography (DCM:MeOH =30: 1) to give the title compound as a yellow oil. Step 5: 4-Amino-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- ethoxy )eth oxy )ethyl)piperi dine- 1 -sulfonamide

[0758] A mixture of tert-butyl (l-(N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethyl)sulfamoyl)piperidin-4-yl)carbamate (60 mg. 0.090 mmol. 1.00 eq.) in DCM (2.0 mL) and TFA (0.5 mL) was stirred at RT for 2 h. The mixture was concentrated to give the title compound as a yellow oil.

[0759] Reference 10

[0760] Synthesis of 4-amino-N-(3-(3-(2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)propoxy)- propyl)-N-methylpiperidine-l-sulfonamide

[0761] Step 1 : 4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione

[0762] A mixture of 4-bromoisobenzofuran-l, 3-dione (22.8 g, 100.44 mmol. 1.00 eq.), 3- aminopiperidine-2, 6-dione (18.0 g, 109.36 mmol. HCI, 1.09 eq.) and KOAc (29.4 g, 299.54 mmol, 2.98 eq.) in HOAc (200.0 mL) was stirred at 90 °C for 16 h. The reaction mixture was cooled, diluted with ice water and then stirred at 0 °C for 1 h. The mixture was filtered and the filter cake w as dried in vacuo to give the title compound as gray solid.

[0763] Step 2: tert-Butyl methyl(3-(prop-2-yn-l-yloxy)propyl)carbamate

[0764] A mixture of tert-butyl (3-hydroxypropyl)(methyl)carbamate (3.0 g, 15.85 mmol, 1.00 eq.) in DCM (50.0 mL), 3-bromoprop-l-yne (3.0 g, 25.22 mmol, 1.59 eq.), 40% aqueous NaOH (30.0 mL) and tetrabutyl ammonium hydrogen sulfate (270 mg, 0.80 mmol, 0.050 eq.) was stirred at RT overnight under N2. The mixture was diluted with w ater, and then extracted with DCM. The organic layer was washed with water, brine, dried over NazSCL. concentrated. The residue was purified by flash column chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow oil.

[0765] Step 3: tert-Butyl (3-((3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)prop-2-yn-l- yl)oxy)propyl)(methyl)carbamate

[0766] A mixture of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (1.38 g, 4.09 mmol, 1.00 eq.), tert-butyl methyl(3-(prop-2-yn-l-yloxy)-propyl)carbamate (1.4 g, 6.16 mmol, 1.51 eq.), Cui (78 mg, 0.41 mmol. 0.10 eq.), TEA (7.5 g, 74.12 mmol, 18.12 eq.) and Pd(PPh3)2C12(288 mg, 0.41 mmol. 0.10 eq.) in DMF (15.0 mL) was stirred at 80 °C for 2h under N2. The mixture was cooled, diluted with water and then extracted with ethyl acetate. The organic layer was washed wi th water, brine, dried over Na2SO4, and concentrated. Purification by flash column chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow7oil. Step 4: tert-Butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)propoxy)propyl)- (methyl)carbamate

[0767] A mixture of tert-butyl (3-((3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)prop- 2-yn-l-yl)oxy)propyl)(methyl)carbamate (1.86 g, 3.85 mmol, 1.00 eq.), Pd(OH)2 / C (0.93 g, 50% w / w) in THF (50.0 mL) was stirred at RT overnight under H2 atmosphere. The reaction mixture w as filtered, concentrated and the residue was purified by flash chromatography (EA:PE = 0 to 100%) to give the title compound as a yellow oil.

[0768] Step 5: 2-(2,6-Dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)propyl)isoindoline-l, 3-dione

[0769] A mixture of tert-butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)propoxy)propyl)(methyl)carbamate (1.45 g, 2.97 mmol, 1.00 eq.), TFA (1.0 mL) in DCM (10.0 mL) was stirred at RT for 2 h under N2. The mixture was concentrated and adjusted pH to 9 using aqueous Na2COs, and then the mixture was extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, and then concentrated to give the title compound as a yellow oil.

[0770] Step 6: tert-Butyl (l-(N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)propoxy)- propyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate

[0771] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(3-(methylamino)propoxy)- propyl)isoindoline- 1,3-dione (150 mg, 0.39 mmol, 1.00 eq.), tert-butyl (l-(chlorosulfonyl)- piperidin-4-yl)carbamate (173 mg, 0.58 mmol, 1.49 eq.) and TEA (118 mg, 1.17 mmol, 3.00 eq.) in DCM (2.0 mL) was stirred at 40 °C overnight under N2. The mixture was cooled, diluted with water and then extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, concentrated to give the title compound as a yellow solid.

[0772] Step 7: 4-Amino-N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)propoxy)propyl)- N-methylpiperidine-1 -sulfonamide

[0773] To a stirred solution of tert-butyl (l-(N-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)propoxy)propyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate (200 mg, 0.31 mmol, 1.00 eq.) in DCM (2.0 mL) was added TFA (0.5 mL). The resulting mixture was stirred at RT for 3h under N2, concentrated and adjusted pH to 9 using aqueous Na2CC>3. and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated to give the title compound as a yellow oil, which was used for next step without further purification.

[0774] Reference 11

[0775] Synthesis of 4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3- dione Step 1 : te / 7- Butyl (2-(2-(prop-2-yn-l-yloxy)ethoxy)ethyl)carbamate

[0776] NaH (1.2 g, 60%, 30.00 mmol, 1.50 eq.) was added to a stirred solution of tert-butyl (2-(2- hydroxyethoxy)ethyl)carbamate (4.1 g, 19.98 mmol, 1.00 eq.) in THF (50.0 mL) in portions at 0 °C and the mixture was stirred for Ih. Then 3 -bromoprop- 1-yne (2.83 g, 23.79 mmol, 1.19 eq.) was added at 0 °C. The reaction mixture was warmed to RT and stirred for 16 h, poured into water and extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, concentrated and purified by flash column chromatography (EA:PE=0 to 100%) to give the title compound as a yellow oil.

[0777] Step 2: 4-Amino- / V-(2-(2-(3-(2-(2.6-dioxopiperidin-3-yl)- l .3-dioxoisoindolin-4- yl)propoxy)ethoxy)ethyl)piperidine-l -sulfonamide

[0778] Proceeding analogously as described in Reference 10, Step 3-7 above, but using ter / -Butyl (2-(2-(prop-2-yn-l-yloxy)ethoxy)ethyl)carbamate provided the title compound.

[0779] Reference 12

[0780] Synthesis of 5-(3-(3-((4-aminopiperidin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)-2-(2,6- dioxopiperi din-3 -y l)isoindoline- 1 ,3 -di one

[0781] Step 1 : Benzyl (l-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)carbamate A solution of 3 -methoxy benzene- 1 -sulfonyl chloride (3.24 g, 15.68 mmol, 1.05 eq.) in DCM (20.0 mL) was added dropwise to a stirred solution of benzyl piperidin-4-ylcarbamate (3.5 g, 14.94 mmol, 1.00 eq.) and TEA (4.52 g, 44.82 mmol, 3.00 eq.) in DCM (50.0 mL) at 0 °C and the mixture was stirred at RT for 3 h. The mixture was diluted with DCM and the organic layer was washed with water and brine, dried over Na2SO4. and concentrated. The residue was purified by silica gel chromatography (EA : PE = 1 : 3) gave the title compound as a white solid.

[0782] Step 2: 3-((4-Aminopiperidin-l-yl)sulfonyl)phenol

[0783] The solution of benzy l (l-((3-methoxyphenyl)sulfonyl)piperidin-4-yl)carbamate (3.5 g,

[0784] 8.66 mmol, 1.00 eq.) in CF3SO3H (20.0 mL) was stirred under N2 at 100 °C for 3 h. The reaction mixture was cooled and concentrated to give the title compound as a brown oil, which was used for next step without further purification.

[0785] Step 3: tert-Butyl (l-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate

[0786] A solution of (BochO (852 mg, 3.91 mmol, 1.00 eq.) in DCM (5.0 mL) was added to a stirred solution of 3-((4-aminopiperidin-l-yl)sulfonyl)phenol (1.0 g, 3.91 mmol, 1.00 eq.) in DCM (20.0 mL) and TEA (1.18 g, 11.73 mmol, 3.00 eq.) at 0 °C. The mixture was stirred at RT for 2 h, diluted with DCM and the organic layer w as washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by flash silica gel chromatography (ACN / water = (35%- 75%)) to give the title compound as a white solid.

[0787] Step 4: l-Benzhydrylazetidin-3-yl methanesulfonate

[0788] To a stirred solution of 1-benzhydrylazeti din-3 -ol (500 mg, 2.09 mmol, 1.00 eq.) in DCM (10.0 mL) was added TEA (633 mg, 6.27 mmol, 3.00 eq.) and MsCl (479 mg, 4.18 mmol, 2.00eq.) at 0 °C. The mixture was stirred at RT overnight, diluted with DCM and then washed with water. The organic layer was washed with brine, dried over Na^SCfi. concentrated and then purified by silica gel chromatography (EA : PE = 1 : 3) to give the title compound as a white solid. Step 5: tert-Butyl (l-((3-(( l-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate

[0789] A mixture of tert-butyl (l-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate (533 mg,

[0790] 1.49 mmol, 1.00 eq.), l-benzhydrylazetidin-3-yl methanesulfonate (570 mg, 1.79 mmol, 1.20 eq.).

[0791] CS2CO3 (1.46 g, 4.49 mmol. 3.00 eq.) in DMSO (10.0 mL) was stirred at 90 °C under N2 for 3 h.

[0792] The mixture was cooled, diluted with EtOAc and the organic layer was washed with brine, dried over Na2SO4, concentrated. The residue was purified by silica gel chromatography (EA:PE = 1:3) to give the title compound as a pale yellow solid.

[0793] Step 6: tert-Butyl (l-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0794] To a stirred solution of tert-butyl (l-((3-((l-benzhydrylazetidin-3-yl)oxy)phenyl)sulfonyl)- piperidin-4-yl)carbamate (400 mg, 0.69 mmol, 1.00 eq.) in MeOH (15.0 mL) were added Pd(OH)2 / C (20 wt. %, 250 mg) and AcOH (0.5 mL) at RT. The resulting mixture was stirred at 50 °C under H2 (50 psi) overnight. The reaction mixture was cooled and filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (MeOH:DCM = 1: 15) to give the title compound as a white solid.

[0795] Step 7: tert-Butyl (l-((3-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidin-3-yl)- oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0796] Proceeding analogously as described in Reference 7, Step 4 above, but using tert-butyl (l-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and 2-(2,6-dioxopiperidin-3- yl)-5-fluoroisoindoline-l , 3-dione provided the title compound. Step 8: 5-(3-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-l.3-dione

[0797] Proceeding analogously as described in Reference 7, Step 5 above, but using tert-buty l (l-((3-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)azetidin-3-yl)oxy)phenyl)- sulfonyl)piperidin-4-yl)carbamate provided the title compound.

[0798] Reference 13

[0799] Synthesis of 3-(4-(3-((l-((l-((4-arninopiperidin-l-yl)sulfonyl)piperidin-4-yl)methyl)piperi din-4- yl)-oxy)prop-l-yn-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-

[0800] Step 1 : tert-Butyl 4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH- benzo[d]imidazol-4-yl)prop-2-yn- 1 -yl)oxy)piperidin- 1 -yl)methyl)piperidine-l -carboxylate

[0801] A mixture of 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-l-yn-l-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2.6-dione (300 mg. 0.76 mmol, 1.00 eq., prepared byproceeding as described in Reference 11, Steps 1 and 2 above), tert-butyl 4-(bromomethyl)piperidine-l -carboxy late (421 mg, 1.51 mmol, 2.00 eq.), Nal (114 mg, 0.76 mmol, 1.00 eq.), K2CO3 (634.8 mg, 4.59 mmol, 6.00 eq.) in ACN (5.0 mL) was stirred at 70 °C overnight. The reaction mixture was cooled, concentrated and then purified with chromatograph on silica gel (DCM / MeOH = 20 / 1) to give the title compound as a yellow solid. Step 2: 3-(3-Methyl-2-oxo-4-(3-((l-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-l-yn-l-yl)-2.3- dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0802] Proceeding analogously as described in Reference 10. Step 5 above, but using tert-butyl 4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4- yl)prop-2-yn-l-yl)oxy)piperidin-l-yl)methyl)piperidine-l-carboxylate provided the title compound.

[0803] Step 3: tert-Butyl (l-((4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo [d] imidazol-4-y l)prop-2-yn- 1 -yl)oxy )piperidin- 1 -y l)methyl)piperidin- 1 - yl)sulfonyl)piperidin-4-yl)carbamate

[0804] Proceeding analogously as described in Reference 10, Step 6 above, but using 3-(3- methyl-2-oxo-4-(3-((l-(piperidin-4-ylmethyl)piperidin-4-yl)oxy)prop-l-yn-l-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione and tert-butyl(l-(chlorosulfonyl)piperidin-4- yl)carbamate provided the title compound.

[0805] Step 4: 3-(4-(3-((l-((l-((4-Aminopiperidin-l-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)- oxy)prop-l-yn-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0806] Proceeding analogously as described in Reference 10, Step 7 above, but using tert-butyl (l-((4-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-4- yl)-prop-2-yn-l-yl)oxy)piperidin-l-yl)methyl)piperidin-l-yl)sulfonyl)piperidin-4-yl)carbamate provided the title compound. Reference 14

[0807] Synthesis of 3-(4-(3-((l-((4-aminopiperidin-l-yl)sulfonyl)piperidin-4-yl)oxy)prop-l-yn-l-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2?6-dione

[0808] Step 1 : 3-Hydroxy-l-(4-methoxybenzyl)piperidine-2, 6-dione t-BuOK (2.3 g, 20.50 mmol, 1 .02 eq.) was added to a stirred mixture of N-(4- methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (5.0 g, 20.06 mmol, 1.00 eq.) in THF (50.0 mL) at -78 °C. After stirring at -78 °C for Ih, the mixture was quenched with saturated aqueous NH4CI and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and then punfied with silica gel chromatograph (PE / EA = 3 / 1) to give the title compound as a white solid.

[0809] Step 2: l -(4-Methoxybenzyl)-2.6-dioxopiperidin-3-yl trifluoromethanesulfonate

[0810] Trifluoromethanesulfonic anhydride (3.2 g, 11.34 mmol, 1.49 eq.) was added slowly to a stirred solution of 3-hydroxy-l-(4-methoxybenzyl)piperidine-2, 6-dione (1.9 g, 7.62 mmol. 1.00 eq.) and pyridine (1.2 g, 15.17 mmol, 1.99 eq.) in DCM (40.0 mL) at 0 °C. After stirring at 0 °C for 2 h, the reaction mixture was quenched with water and then extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated and then purified by silica gel chromatograph (PE / EA = 5 / 1) to give the title compound as a yellow oil.

[0811] Step 3: 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzoLd]imidazol-l-yl)-l-(4-methoxy- benzyl)piperidine-2, 6-dione To a stirred solution of 7-bromo-l-methyl-lH-benzo[d]imidazol-2(3H)-one (1.1 g, 4.84 mmol, 1.23 eq.) in THF (30.0 mL) was added t-BuOK (632 mg, 5.63 mmol, 1.43 eq.) at 0 °C. After stirring at 0 °C for 0.5 h, a solution of l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.5 g, 3.93 mmol, 1.00 eq.) in THF (10.0 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, diluted with water and then extracted with EtOAc.

[0812] The organic layer was washed with brine, dried over Na2SO4. concentrated and the residue was purified by silica gel chromatograph (PE / EA =2 / 1) to give the title compound as a white solid.

[0813] Step 4: 3-(4-Bromo-3-methyl-2 -oxo-2, 3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0814] A mixture of 3-(4-bromo-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4- methoxybenzyl)piperidine-2, 6-dione (900 mg, 1.96 mmol, 1.00 eq.) in toluene / methanesulfonic acid =2 / 1 (3.0 mL) was stirred at 120 °C for 3 h. The reaction mixture was cooled, concentrated and poured into ice water. The resulting mixture was filtered, and the cake was dried to give the title compound as a white solid.

[0815] Step 5: tert-Butyl 4-(prop-2-yn-l-yloxy)piperidine-l -carboxylate

[0816] NaH (60%. 240 mg, 6.00 mmol, 1.21 eq.) was added to a stirred solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (1.0 g, 4.97 mmol, 1.00 eq.) in THF (20.0 mL) at 0 °C, followed by 3 -bromoprop- 1-yne (704 mg, 5.92 mmol 1.19 eq.). The resulting mixture was stirred at RT for 2 h, quenched with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated and then purified by silica gel chromatograph (PE / EA =10 / 1) to give the title compound as a white solid.

[0817] Step 6: tert-Butyl 4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)prop-2-yn-l-yl)oxy)piperidine-l-carboxylate Proceeding analogously as described in Reference 10. Step 3 above, but using 3-(4-bromo-

[0818] 3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2.6-dione and tert-butyl

[0819] 4-(prop-2-yn-l-yloxy)piperidine-l-carboxylate in DMF provided the title compound.

[0820] Step 7: 3-(3-Methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-l-yn-l-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0821] Proceeding analogously as described in Reference 10, Step 5 above, but using tert-butyl 4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)prop-2- yn-l-yl)oxy)piperidine-l -carboxylate provided the title compound.

[0822] Step 8: tert-Butyl (l-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)prop-2-yn-l-yl)oxy)piperidin-l-yl)sulfonyl)piperidin-4-yl)carbamate

[0823] Proceeding analogously as described in Reference 10, Step 6 above, but using 3-(3- methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-l-yn-l-yl)-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione and tert-butyl (l-(chlorosulfonyl)piperidin-4-yl)carbamate in DMF provided the title compound.

[0824] Step 9: 3-(4-(3-((l-((4-aminopiperidin-l-yl)sulfonyl)piperidin-4-yl)oxy)prop-l-yn-l-yl)-3-methyl- 2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0825] Proceeding analogously as described in Reference 10. Step 7 above, but using tert-butyl (l-((4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4- yl)prop-2-yn-l-yl)oxy)piperidin-l-yl)sulfonyl)piperidin-4-yl)carbamate provided the title compound. Reference 15

[0826] Synthesis of 4-amino-N-(4-((2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)amino)- cyclohexyl)-N-methylpiperidine-l -sulfonamide 2,2,2-trifluoroacetate

[0827] Step 1 : 4- Aminocyclohexanone hydrochloride

[0828] A mixture of tert-butyl (4-oxocyclohexyl)carbamate (500 mg, 2.34 mmol, 1.00 eq.) in a solution of HC1 in ethyl acetate (1.0 M, 10.0 mL) was stirred at RT for 1 h. The reaction mixture was concentrated to give the title compound, which was used for next step without further purification.

[0829] Step 2: 2-(2,6-Dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)isoindoline-l, 3-dione

[0830] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1.3-dione (276 mg. 1.00 mmol, 1.00 eq.) and 4-aminocyclohexanone hydrochloride (300 mg, 2.00 mmol, 2.00 eq.) in NMP (2.5 mL) was stirred at 140 °C under microwave for 3 h. The reaction mixture was cooled, diluted with DCM and then washed with brine. The organic layer was concentrated, and then the residue was triturated with DCM, filtered to give the title compound as a yellow solid.

[0831] Step 3: 2-(2,6-Dioxopiperidin-3-yl)-4-((4-(methylamino)cy cl ohexyl)amino)isoindoline- 1,3-dione

[0832] To a stirred mixture of 2-(2,6-dioxopiperidin-3-yl)-4-((4-oxocyclohexyl)amino)- isoindoline-1, 3-dione (200 mg, 0.54 mmol, 1.00 eq.) and methylamine (40% in MeOH, 210 mg, 2.71 mmol, 5.02 eq.) in MeOH / DCE (2.0 mL / 2.0 mL) was added one drop of AcOH. The resulting mixture was stirred at RT for 1 h, and then NaBH(OAc)3 (345mg, 1.63 mmol, 3.02 eq.) was added. The reaction mixture was stirred at RT overnight, diluted with DCM. washed with saturated aqueous NaHCCh and then brine. The organic layer was dried over NazSCh and then concentrated to give the title compound as a yellow solid.

[0833] Step 4: tert-Butyl (l-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)- cyclohexyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate

[0834] Proceeding analogously as described in Reference 10, Step 6 above, but using 2-(2,6- di oxopiperidin-3-yl)-4-((4-(methylamino)cyclohexyl)amino)isoindoline-l, 3-dione and tert-butyl

[0835] (l-(chlorosulfonyl)piperidin-4-yl)carbamate provided the title compound.

[0836] Step 5: 4-Amino-N-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)cyclohexyl)-

[0837] N-methylpiperidine-1 -sulfonamide 2,2,2-trifluoroacetate

[0838] Proceeding analogously as described in Reference 10. Step 7 above, but using tert-butyl (l-(N-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)cyclohexyl)-N- methylsulfamoyl)piperidin-4-yl)carbamate provided the title compound.

[0839] Reference 16

[0840] Synthesis of tert-butyl 4-((3-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]-imidazol-4-yl)prop-2-yn-l-yl)oxy)piperidine-l -carboxylate

[0841] Step 1 : tert-Butyl 4-((3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]- imidazol-4-yl)prop-2-yn-l-yl)oxy)piperi dine- 1 -carboxylate Proceeding analogously as described in Reference 10. Step 3 above, but using 3-(4-bromo-

[0842] 3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2.6-dione and tert-butyl

[0843] 4-(prop-2-yn-l-yloxy)piperidine-l-carboxylate provided the title compound.

[0844] Reference 17

[0845] Synthesis of 5-((3-(3-((4-aminopiperidin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)methyl)-2-(2.6- dioxopiperi din-3 -y l)i soindoline- 1 ,3 -di one

[0846] Step 1 : tert-Butyl (l-((3-((l-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)methyl)- azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0847] Proceeding analogously as described in Reference 8, Step 5 above, but using tert-butyl (l-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate and 5-(bromomethyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione provided the title compound.

[0848] Step 2: 5-((3-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenoxy)azetidin-l-yl)methyl)-2-(2,6- dioxopiperidin-3-yl)isoindoline- 1 ,3-dione

[0849] Proceeding analogously as described in Reference 8, Step 6 above, but using (l-((3-((l- ((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)methyl)azetidin-3-yl)oxy)phenyl)- sulfonyl)piperidin-4-yl)carbamate and TFA provided the title compound. Reference 18

[0850] Synthesis of 4-amino-N-(2-(3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)propoxy)ethyl)piperidine-l -sulfonamide

[0851] Step 1 : tert-Butyl (2-(prop-2-yn-l-yloxy)ethyl)carbamate

[0852] Proceeding analogously as described in Reference 10, Step 2 above, but using tert-butyl (2-hydroxyethyl)carbamate and 3 -bromoprop- 1-yne provided the title compound.

[0853] Step 2: 4-Amino-N-(2-(3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH- benzo[d]imidazol-4-yl)propoxy)ethyl)piperidine-l -sulfonamide

[0854] Proceeding analogously as described in Reference 10, Step 3-7 above, but using tert-butyl (2-(prop-2-yn-l-yloxy)ethyl)carbamate provided the title compound.

[0855] Reference 19

[0856] Synthesis of tert-butyl (l-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate

[0857] Step 1 : l-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-4- carbaldehyde

[0858] A mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)- piperidine-2, 6-dione (700 mg, 2.07 mmol, 1.00 eq.), TEA (630 mg, 6.23 mmol, 3.01 eq.), Pd(dppf)Ch (230.6 mg, 0.32 mmol, 0.15 eq ), EtsSiH (733 mg, 6.30 mmol. 3.04 eq.) in DMF (10 mL) was stirred at 80 °C under 15 psi carbon monoxide atmosphere overnight. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and then concentrated. The residue was purified by chromatograph on silica gel (DCM / MeOH = 20 / 1) to give the title compound as a yellow oil. Step 2: tert-Butyl (l-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH- benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)carbamate

[0859] A mixture of l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]- imidazole-4-carbaldehyde (360 mg, 1.25 mmol, 1.00 eq.), tert-butyl N-methyl (piperidin-4- yl)carbamate (403 mg, 1.88 mmol, 1.50 eq. ) in THF / DMF = 2 / 1 (5 mL) was stirred at RT for 2h. NaBH(OAC)3 (413 mg, 1.95 mmol, 1.60 eq.) was added at RT. After the reaction was complete, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4and then concentrated. The residue was purified by Prep-HPLC to give the title compound as a yellow solid.

[0860] Reference 20

[0861] Synthesis of tert-butyl (2-((4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)(methyl)amino) benzyl)(methyl)amino)ethyl ((methyl (carbamate

[0862] Step 1 : Dimethyl 3-iodophthalate

[0863] To a stirred mixture of 3 -iodophthalic acid (5.00 g, 17.12 mmol, 1.00 eq.), NaeCO? (5.40 g, 50.95 mmol, 2.98 eq.) in DMF (30 mL) was added iodomethane (7.30 g, 51.43 mmol, 3.00 eq.) at RT. The reaction mixture was stirred at 70 °C overnight, cooled, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 10 / 1) to give the title compound as a white solid.

[0864] A mixture of (4-aminophenyl)methanol (2.00 g. 16.24 mmol. 1.00 eq.). DMAP (595 mg. 4.87 mmol, 0.30 eq ), TEA (2.00 g, 19.76 mmol, 1.22 eq.) and TBSCl (2.70 g, 17.91 mmol, 1.10 eq.) in DMF (40 mL) was stirred at RT overnight. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 10 / 1) to give the title compound as a colorless oil.

[0865] Step 3 : Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)amino)phthalate

[0866] A mixture of 3-iodo-phthalic acid dimethyl ester (3.00 g, 9.37 mmol, 1.00 eq.). 4-(tert- butyl-dimethyl-silanyloxymethyl)-phenylamine (2.67 g, 11.25 mmol, 1.20 eq.), Pd2(dba)s (436 mg, 0.48 mmol, 0.051 eq.), CS2CO3 (6.11 g, 18.75 mmol, 2.00 eq.), BINAP (143 mg, 0.23 mmol, 0.025 eq.) in toluene (30.0 rnL) was stirred at 120 °C overnight under nitrogen atmosphere. The reaction mixture was cooled, concentrated and the residue was purified by chromatograph on silica gel (PE / EA = 10 / 1) to give the title compound as a yellow oil.

[0867] Step 4: Dimethyl 3-((4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)(methyl)amino)phthalate

[0868] A mixture of dimethyl 3-((4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)- amino)phthalate (1.50 g, 3.49 mmol, 1.00 eq ), iodomethane (991 mg, 6.98 mmol, 2.00 eq.), CS2CO3 (3.41 g, 10.47 mmol, 3.00 eq.) in DMF (30.0 mL) was stirred at 20 °C for 8h under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 5 / 1) to give the title compound as a yellow oil. Step 5: 3-[(4-Hydroxymethyl-phenyl)-methyl-amino]-phthalic acid dimethyl ester

[0869] A solution of TBAF in THF (3.0 M, 2.0 mL) was added To a stirred solution of dimethyl 3- ((4-(((tert-butyl dimethylsilyl)oxy)methyl)phenyl)-(methyl)amino)phthalate (500 mg, 1.13 mmol, 1.00 eq.) in THF (5.0 mL) at rt. After 2 h. the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and then concentrated. The residue was purified by chromatograph on silica gel (PE / EA = 2 / 1) to give the title compound as a yellow oil.

[0870] Step 6: Dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate

[0871] A mixture of 3-[(4-yydroxymethyl-phenyl)methylamino]phthalic acid dimethyl ester (300 mg, 0.91 mmol, 1.00 eq.) and MnOz (800 mg. 9.20 mmol, 10.11 eq.) in DCM (10.0 mL) was stirred at rt overnight. The reaction mixture was filtered and concentrated to give the title compound as a yellow oil, which was used for next step without further purification.

[0872] Step 7 : Dimethyl 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl) phenyl)(methyl)amino)phthalate

[0873] A mixture of dimethyl 3-((4-formylphenyl)(methyl)amino)phthalate (300 mg, 0.92 mmol, 1.00 eq.), methyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (205 mg, 1.09 mmol, 1.18 eq.) and a drop of AcOH in DCE (5.0 mL) was stirred at RT for 2 h. NaBH(OAc)? (290 mg. 1.37 mmol, 1.49 eq.) was then added and stirred for 4 h. The reaction mixture was concentrated and purified by prep-HPLC to give the title compound as a white solid. Step 8 : 3-((4-(((2-((tert-Butoxycarbonyl)(methy l)amino)ethyl)(methyl)amino)methy l)phenyl) (methyl)amino)phthalic acid

[0874] A mixture of dimethyl 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl) amino)methyl)phenyl)(methyl)amino)phthalate (250 mg, 0.50 mmol, 1.00 eq.) and NaOH (40 mg, 1.00 mmol, 2.00 eq.) in EtOH / H2O =2 / 1 (5.0 mL) was stirred at 80 °C for 5 h. The reaction mixture was concentrated and purified by prep-HPLC to give the title compound as a white solid. Step 9: tert-Butyl (2-((4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)(methyl)amino) benzyl)(methyl)amino)ethyl)(methyl)carbamate

[0875] A mixture of 3-((4-(((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(methyl)amino)methyl) phenyl)(methyl)amino)phthalic acid (120 mg, 0.25 mmol, 1.00 eq.) and 3-aminopiperidine-2,6- dione hydrochloride (41 mg. 0.25 mmol, 1.00 eq.) in pyridine (3.0 mL) was stirred at 100 °C overnight. The reaction mixture was cooled and concentrated. The residue was purified by chromatograph on silica gel (DCM / MeOH = 30 / 1) to give the title compound as a yellow solid.

[0876] Reference 21

[0877] Synthesis of tert-butyl (3-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]-imidazol-4-yl)piperidin-l-yl)propyl)(methyl)carbamate

[0878] Step 1: tert-Butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]- imidazol-4-yl)-3,6-dihydropyridine-l(2H)-carboxylate A mixture of 3-(4-bromo-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)- piperidine-2.6-dione (100 mg. 0.30 mmol. 1.00 eq.), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (119 mg, 0.38 mmol, 1.27 eq.), X-Phos-Pd-Gs (38 mg, 0.045 mmol, 0.15 eq.), and K3PO4 (191 mg, 0.90 mmol, 3.0 eq.) in l,4-dioxane / H2O = 10 / 1 (2.2 mL) was stirred at 60 °C for 3 h. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by chromatograph on silica gel (DCM / MeOH = 20 / 1) to give the title compound as a brown solid.

[0879] Step 2: tert-Butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH- benzo[d]imidazol-4-yl)piperidine-l -carboxylate

[0880] A mixture of tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)-5,6-dihydropyridine-l(2H)-carboxylate (70 mg, 0.16 mmol, 1.00 eq.), 10% Pd / C (30 mg) and Pd(OH)2 (30 mg) in THF (10 mL) was stirred at 50°C under 50psi H2 pressure. The reaction mixture was filtered and then concentrated to give the title as a white solid. Step 3: 3-(3-Methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine- 2,6-dione TFA salt

[0881] A mixture of tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)piperidine-l-carboxylate (60 mg, 0.14 mmol, 1.00 eq.) and TFA (0.5 mL) in DCM (2 mL) was stirred at RT for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

[0882] Step 4: tert-Butyl (3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]-

[0883] To a stirred mixture of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione TFA salt (60 mg, 0.13 mmol, 1.00 eq.) in THF (5.0 mL) and DMF (1.0 mL) was added one drop of AcOH. After stirring at RT for 0.5h, tert-butyl methyl(3-oxopropyl)carbamate (63.6 mg. 0.34 mmol. 2.0 eq) was added at RT. The mixture was stirred at 20 °C for 2 h followed by addition of NaBH(OAC)s (72 mg, 0.34 mmol, 2.62 eq.). After stirring at RT overnight, the mixture was diluted with water and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by chromatograph on silica gel (DCM / MeOH = 50 / 1) to give the title compound as a yellow solid.

[0884] Reference 22

[0885] Synthesis of tert-butyl (14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)-14-oxo- 3.6.9, 12-tetraoxatetradecy l)carbamate

[0886] Step 1 : 2,2-Dimethyl-4-oxo-3.8.11,14,17-pentaoxa-5-azanonadecan-19-oic acid

[0887] NaH (60 % in mineral oil, 204 mg, 5. 10 mmol, 3.00 eq.) was added to a stirred solution of tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl) carbamate (500 mg, 1.70 mmol, 1.00 eq.) in DMF (2 mL) at 0 °C under nitrogen. After stirring at 0 °C for 1 h, 2-iodoacetic acid (793 mg, 4.26 mmol, 2.51 eq.) was added at 0 °C. The resulting mixture was slowly warmed to RT and then stirred overnight. This reaction mixture was quenched with H2O at 0 °C, the pH was adjusted to 2~3 with 1 N aqueous HC1 and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and then concentrated to give the title compound as a yellow oil.

[0888] Step 2: tert-Butyl (14-((2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindolin-4-yl)amino)-14-oxo- 3,6,9, 12-tetraoxatetradecyl)carbamate

[0889] To a stirred solution of 2,2-dimethyl-4-oxo-3.8.11,14.17-pentaoxa-5-azanonadecan-19-oic acid (372 mg, 1.06 mmol, 2.00 eq.) in THF (6 mL) was added isobutyl chloroformate (109 mg, 0.80 mmol, 1.51 eq.) and N-methylmorpholine (161 mg, 1.59 mmol, 3.00 eq.), followed by a solution of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (145 mg. 0.53 mmol, 1.00 eq.) in DMF (2 mL) dropwise at 0 °C. The resulting mixture was stirred at 30 °C overnight, quenched with saturated NaHCCE. extracted with EtOAc. The organic layer was washed with brine, dried over ISfeSCL, filtered and then concentrated. The residue was purified by column chromatography on silica gel (PE : EA=1 : 1) to give the title compound as a yellow solid.

[0890] Reference 23

[0891] Synthesis of tert-butyl (l-((3-((l-(l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4- yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0892] Step 1 : Benzyl 4-(3-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenoxy)- azetidin-l-yl)piperidine-l-carboxylate

[0893] A solution of tert-butyl (l-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.24 mmol, 1.00 eq.), benzyl 4-oxopiperidine-l -carboxylate (113 mg, 0.48 mmol, 2.00 eq.) and 1 drop of AcOH in THF (3.0 mL) was stirred at RT for Ih, followed by addition of NaBH(OAc)3 (102 mg, 0.48 mmol, 2.00 eq.). The reaction mixture was stirred at RT overnight, diluted with water and then extracted with DCM. The organic layer was concentrated and then purified by silica gel flash column (DCM / MeOH=20 / l) to give the title compound as a white solid.

[0894] Step 2: tert-Butyl ( 1 -((3-(( 1 -(piperidin-4-yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate

[0895] To a stirred solution of benzyl 4-(3-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l- yl)sulfonyl)phenoxy)azeti din- l-yl)piperi dine- 1 -carboxylate (60 mg, 0.095 mmol, 1.00 eq.) in MeOH(10.0 mL) was added 10% Pd / C (20 mg). The resulting mixture was stirred at 45°C under H2 atmosphere overnight. The reaction mixture was filtered and concentrated to give the title compound as a white solid.

[0896] Step 3: tert-Butyl (l-((3-((l-(l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4- yl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0897] A mixture of tert-buty l (l-((3-((l-(piperidin-4-yl)- 157 -zetidine-3-yl)oxy)phenyl) sulfonyl)piperidin-4-yl)carbamate (39.6 mg, 0.080 mmol. 1.00 eq.), 3-(5-bromo-l-oxoisoindolin- 2-yl)piperidine-2, 6-dione (38 mg, 0.12 mmol. 1.50 eq.). CS2CO3 (78 mg. 0.24 mmol. 3.00 eq.), Xantphos (15 mg, 0.027 mmol, 0.34 eq.) and Pd(OAc)2 (15 mg, 0.067 mmol, 0.84 eq.) in 1,4- di oxane (2.0 mL) was stirred at 100 °C overnight under N2 atmosphere The mixture was cooled and then filtered. The filtrate was diluted with water and then extracted with DCM. The organic layer was concentrated and then purified by prep-TLC (DCM / MeOH=10 / l) to give the title compound as a yellow solid.

[0898] Reference 24

[0899] Synthesis of tert-buty l (l-((3-((l-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4- yl)-carbamate

[0900] Step 1 : tert-Butyl (l-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0901] The title compound was prepared by proceeding as described in Reference 12, Steps 1 to 6 using l-benzhydry lpiperidin-4-yl methanesulfonate. Step 2: tert-Butyl (l-((3-((l-(azetidin-3-yl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)- carbamate tert-Butyl (l-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate was converted to the title compound by proceeding analogously as described in Reference 27, Steps 1 and 2 above using benzyl 3 -oxoazetidine- 1 -carboxylate.

[0902] Reference 25

[0903] Synthesis of tert-butyl (l-((3-((l-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)- oxy)ethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0904] Step 1 : Methyl 3-(2 -hydroxy ethoxy )-2-methylbenzoate

[0905] A mixture of methyl 3-hydroxy -2 -methylbenzoate (2.50 g, 15.04 mmol, 1.00 eq.) and l,3-dioxolan-2-one (1.98 g, 22.48 mmol, 1.50 eq.), K2CO3 (2.07 g, 14.98 mmol, 1.00 eq.) in DMF (30.0 rnL) was stirred at 120 °C under N2 for 2 h. The reaction mixture was cooled, diluted with water and then extracted with EtOAc. The organic layer was washed water, brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (EA:PE = 1 :4) to give the title compound as a white solid. Step 2: Methyl 2-(bromomethyl)-3-(2-hydroxyethoxy)benzoate

[0906] A mixture of methyl 3-(2-hydroxyethoxy)-2-methylbenzoate (1.50 g, 7.14 mmol, 1.00 eq.) in CCI4 (45.0 mL), NBS (1.46 g, 8.20 mmol, 1.15 eq.) and AIBN (117 mg, 0.71 mmol, 0.10 eq was stirred under N2 at 75 °C for 3 h. The mixture was cooled and then concentrated. The residue was purified by silica gel chromatography (EA PE = 1 :3) to give the title compound as a white solid.

[0907] Step 3 : 3-(4-(2-Hydroxyethoxy)-l -oxoisoindolin-2-yl)piperidine-2, 6-dione

[0908] To a stirred solution of methyl 2-(bromomethyl)-3-(2-hydroxy ethoxy )benzoate (2.00 g, 6.92 mmol, 1.00 eq.) in ACN (70.0 mL) was added 3-aminopiperidine-2.6-dione hydrochloride (1.48 g, 8.99 mmol, 1.30 eq.) and TEA (1.04 g, 10.28 mmol, 1.49 eq.). The resulting mixture was stirred under N2 at 80 °C overnight, cooled and then concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=20: 1) to give the title compound as a blue solid.

[0909] Step 4: 2-((2-(2,6-Dioxopiperidin-3-yl)-l -oxoisoindolin-4-yl)oxy)ethyl 4-methylbenzenesulfonate

[0910] To a stirred solution of 3-(4-(2-hydroxyethoxy)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (500 mg, 1.64 mmol, 1.00 eq.) in DCM (10.0 mL) was added TEA (333 mg, 3.29 mmol. 2.00 eq.), TsCl (377 mg, 1.98 mmol. 1.21 eq.) and DMAP (20 mg, 0.16 mmol, 0.10 eq.) at 0 °C. The resulting mixture was stirred at RT overnight, diluted with DCM, washed with water, brine, dried over Na2SO4, filtered, and then concentrated. The residue was purified by silica gel chromatography (DCM:MeOH = 30: 1) to give the title compound as a green solid.

[0911] Step 5: Benzyl 4-((methylsulfonyl)oxy)piperidine-l -carboxylate To a stirred solution of benzy l 4-hydroxypiperidine-l -carboxylate (2.00 g, 8.50 mmol, 1.00 eq.) in DCM (20.0 mL) was added TEA (2.57 g. 25.40 mmol. 3.00 eq.) and MsCl (1.16 g, 10. 13 mmol, 1 .20 eq.) at 0 °C. The resulting mixture was stirred at RT overnight, diluted with water and then extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated to give the crude title compound as a yellow oil, which was used for next step without further purification.

[0912] Step 6: tert-Butyl (l-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0913] Benzyl 4-((methylsulfonyl)oxy)piperidine-l -carboxylate was converted to the title compound by proceeding analogously as described in Reference 12, Steps 5-6 above. Step 7: tert-Butyl (l-((3-((l-(2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)oxy)ethyl)piperidin-4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0914] A mixture of of 2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)ethyl 4-methylbenzenesulfonate (50 mg, 0.11 mmol, 1.10 eq.), tert-butyl (l-((3-(piperidin-4- yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate (44 mg, 0.10 mmol, 1.00 eq.). KI (15 mg. 0.090 mmol, 0.90 eq.) and DIPEA (35 mg, 0.27 mmol, 2.70 eq.) in ACN (2.0 mL) was stirred at 100 °C under microwave for 3 h. The reaction mixture was cooled and concentrated, and the residue was purified by silica gel chromatography (DCM:MeOH= 20: 1) to give the title as a yellow oil. Reference 26

[0915] Synthesis of tert-butyl (l-((3-((l-(2-((2-(2.6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)- ethyl)azetidin-3-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl (l-((3-(azetidin-3-yloxy)phenyl)sulfonyl)piperidin-4-yl)carbamate was converted to the title compound by proceeding analogously as described in Reference 25, Step 7.

[0916] Reference 27

[0917] Synthesis of tert-butyl (l-((3-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4- yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0918] A mixture of tert-butyl (l-((3-(piperidin-4-yloxy)phenyl)sulfonyl)piperidin-4-yl) carbamate (300 mg, 0.93 mmol, 1.00 eq.), 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (448 mg, 1.02 mmol, 1.10 eq. ), CS2CO3 (603 mg, 1.86 mmol, 2.00eq.), Pd(OAc)2 (41 mg, 0.19 mmol, 0.20 eq.) and X-Phos (176 mg, 0.37 mmol, 0.40 eq.) in 1,4-dioxane (10.0 mL) was stirred at 105 °C under N2 for 2 days. The reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine and dried over Na2SO4and concentrated. The residue was purified by flash chromatography gave title compound as a yellow solid.

[0919] Reference 28

[0920] Synthesis of tert-butyl (l-((3-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-piperidin-

[0921] 4-yl)methyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0922] Step 1 : Benzy l 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenyl)-5,6- dihy dropyridine- 1 (2H)-carboxylate

[0923] A mixture of tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (3.00 g, 7.18 mmol, 1.00 eq.), benzyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- l(2H)-carboxylate (3.20 g, 9.33 mmol, 1.30 eq.), X-Phos-Pd-G3 (608.0 mg, 0.72 mmol, 0.10 eq.) and K3PO4 (4.57 g, 21.54 mmol, 3.00 eq.) in 1,4-dioxane (70.0 mL) and H2O (7.0 mL) was stirred at 60 °C under N2 for 6 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with PE / EtOAc (4: 1), to afford the title compound as a yellow solid.

[0924] Step 2: tert-Butyl (l-((3-(piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0925] A mixture of benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperi din-1 -yl)sulfonyl)phenyl)- 5,6-dihydropyridine-l(2H)-carboxylate (4.00 g, 7.20 mmol, 1.00 eq.) and Pd / C (800 mg) in MeOH (40.0 mL) was stirred at 50 °C under H2 (50 psi) for 16 h. The mixture was filtered and concentrated to afford the title compound as a white solid. Step 3: Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin- 1 -y l)methy l)piperidine- 1 -carboxylate

[0926] To a solution of tert-butyl (l-((3-(piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (3.00g. 7.10 mmol, 1.00 eq.) in DCE (20.0 mL) and MeOH (20.0 mL) was added benzyl 4-formylpiperidine-l-carboxylate (2.63 g, 10.65 mmol, 1.50 eq.) and AcOH (426.0 mg, 7.10 mmol, 1.00 eq.) and the solution was stirred at RT for 1 h. NaBEECN (1.34 g, 21.30 mmol, 3.00 eq.) was added and the mixture was stirred at RT for 3 h. The resulting mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (60: 1), to afford the title compound as a white solid.

[0927] Step 4: tert- Butyl (l-((3-(l-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate

[0928] A mixture of benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)- sulfonyl)phenyl)piperidin-l-yl)methyl)piperidine-l-carboxylate (3.80 g, 5.81 mmol, 1.00 eq.) and Pd / C (800 mg) in MeOH (40.0 mL) was stirred at 50 °C under H2 (50 psi) for 16 h. The mixture was filtered and concentrated to afford the title compound as a white solid.

[0929] Step 5: Methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)- phenyl)piperidin-l -yl)methyl)piperidin- 1 -yl)-2-cy anobenzoate

[0930] A solution of tert-butyl (l-((3-(l-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)- sulfonyl)piperidin-4-yl)carbamate (2.80 g, 5.40 mmol, 1.00 eq.), methyl 2-cyano-4-fluorobenzoate (1.06 g, 5.94 mmol, 1.10 eq.) and DIEA (2.09 g, 16.20 mmol, 3.00 eq.) in DMSO (30.0 mL) was stirred at 120 °C under N2 for 16 h. The mixture was cooled to RT, diluted with water, and then extracted with EtOAc. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by sihca gel column chromatography, eluted with DCM / MeOH (100: 1), to afford the title compound as a browni solid. Step 6: Methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)- pheny l)piperidin- 1 -y l)methyl)piperidin- 1 -y l)-2-formy Ibenzoate

[0931] A mixture of methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)- sulfonyl)phenyl)piperidin-l-yl)methyl)piperidin-l-yl)-2-cy anobenzoate (1.01g, 1.50 mmol, 1.00 eq.), NaEEPCh.EbO (1.59 g, 15.00 mmol, 10.00 eq.) and Raney Ni (1.60 g) in pyridine (10.0 mL), H2O (5.0 mL) and AcOH (5.0 mL) was stirred for 16 h at 70 °C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous Na2SO4and concentrated. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (80: 1), to afford the title compound as a light-yellow solid.

[0932] Step 7: tert-Butyl (l-((3-(l-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4- yl)methyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0933] A mixture of 3-aminopiperidine-2.6-dione hydrochloride (126 mg, 0.77 mmol, 1.30 eq.) and DIEA (184 mg, 1.43 mmol, 2.40 eq.) in dry DCM (5.0 mL) was stirred at RT for 10 min and then a solution of methyl 4-(4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l- yl)sulfonyl)phenyl)piperidin-l-yl)methyl)piperidin-l-yl)-2-formylbenzoate (400 mg, 0.59 mmol, 1.00 eq.) in dry DCM (5.0 mL) and AcOH (134 mg, 2.23 mmol, 3.80 eq.) was added. The mixture was stirred at 45 °C under N2 for 3 h. The mixture was cooled to 0 °C and NaBH(OAc)s (375 mg, 1.77 mmol, 3.00 eq.) was added. The mixture was stirrd at rt for Ih and then at 45 °C under N2 for 16 h. The mixture was cooled, diluted with water, and then extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (40: 1). to afford the title compound as a yellow solid.

[0934] Reference 29

[0935] Synthesis of tert-buty l (l-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-l- yl)methyl)piperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

[0936] Step 1 : 3-5-Bromo-l-oxoisoindolin-2-ylpiperidine-2, 6-dione

[0937] A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (20.00 g, 64.91 mmol, 1.00 eq.) and 3-aminopiperidine-2, 6-dione (11.71 g, 71.41 mmol, 1.10 eq.), K2CO3 (26.87 g, 194.71 mmol, 3.00 eq.) in DMF was stirred at 70 °C overnight under N2 atmosphere. The mixture was poured into water after the reaction was complete and extracted with DCM. The combined organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (PE:EA=2:1) to give the title compound as a white solid.

[0938] Step 2: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-5.6-dihydropyridine- l(2H)-carb...

Claims

What is Claimed:

1. A compound of Formula (I):DegronwhereinR1is cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, or cycloalky l substituted with one to three halo;R2is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino;R3are independently hydrogen or deuterium; andHy 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):(i);(b) a group of formula (ii):(c) a group of formula (iii):(f) a group of formula (vi): where:Yais CH or N;Zais a bond, -CH2-, -NH-, -O-. or -NHC(O)- where NH of -NHC(O)- is attached to Ya; ring A is a group of formula (a), (b), or (c):(a) Raawhere: e 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; 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 in each heteroarylene one to three ring atoms are independently selected from nitrogen or oxygen atoms and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with Reeand Rffindependently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; andX1, X2, X3, and X4are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NRgg-alkylene)-, -(alkyl ene-NRhh)-,-N(alkyl)-, -C(=O)-, are independently hydrogen, alkyl, orcycloalkyl and each alkylene, itself or as part of another group, is optionally substituted with one or two fluoro;Ry, Ryl, and Ry2are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with Rdand Rfselected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino; andWais bond. O, S, or alkylene; andL is -Z'-Z2-Z -Z4-Z5-Z6- where:Z1is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O)2NR-, -NR’S(O)2-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with Rhand R' independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;Z2is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR’(CO)-, -(O-alkylene)b-, -(alkylene-O)b-, -O(CH2)?-, -O(CH2)s-, cycloalkylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R' and Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;Z3is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -C(O)NR-, -NR’ (CO)-, -O-, -NR”-, -(O-alkylene)c-, -(alkylene-O)c-, cycloalkylene, spiro cyclolalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)- monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-. unsaturated heterocyclylene. heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, -spiro heterocyclylene-(alkylene)-, or 11 to 13 membered spiro heterocyclylene. where each ring, by itself or as part of another group, is substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialky lamino;Z4is a bond, alkylene, alkenylene, alkynylene, heteroalkylene, -(alkylene-NR”)-. -(NR”- alkylene)-, -O-, -C(O)-, -NR”-, -(O-alkylene)a-, -(alkylene-O)d-, cycloalkylene, -(alkylene)- cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene,heterocyclylene, -(alkylene)-helerocyclylene-. -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene. -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene- (alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene- (alkylene)-, where each ring, by itself or as part of another group, is substituted with R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;Z3is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O)2-, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or unsaturated heterocyclylene, or heterocycylene, where each ring is substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy , halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; andZ6is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR’ (CO)-, or -C(O)NR-; where each R, R' and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z1-, -Z2-, -Z3-, -Z4-, -Z5- and -Z6-, by itself or as part of another group and heteroalkylene of -Z3- and -Z4- are independently substituted with Rs, R\ and Ruwhere Rsis hydrogen, deuterium, or halo, Rlis hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyd, halo, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalky 1, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl. heterocyclyl. heterocyclyloxy. heterocyclylcarbonyl, or bridged heterocyclyl (where cycloalky 1, either by itself or as part of cycloalkyloxy, bridged cycloalkyl, phenyl, heteroaryl, heterocyclyl, either by itself or as part of heterocyclyloxy or heterocyclylcarbony l, and bridged heterocyclyl are substituted with R7and R8independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxy carbonyl, amino, alkylamino, dialkylamino, and cyano), and Ruis hydrogen or halo; or when Rland Ruare attached to the same carbon or to adjacent carbon atoms of the linear portion of the alky dene or heteroalkydene, Rland Rutogether with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by Rland Ruare substituted with R9and R10independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkydoxycarbonyl, amino, alkylamino, dialkylamino, and cyano), alkenylene of -Z3- and -Z4- are substituted with Rvselected from hydrogen, fluoro, and cyano, and alkynylene of -Z3- and -Z4- are substituted with Rwand Rxindependently selected from hydrogen, halo, haloalkyl. alkoxy, hydroxy, and cyano; or yvhen R" and Rxare attached to the same carbon atoms of the alkynylene, they can combine to form cycloalkylene or heterocyclylene yvherein the cycloalkylene andheterocyclylene are substituted with R11and R12independently selected from hydrogen, alkyl, and halo; provided that at least one of -Z'-Z2-Z -Z4-Z5-Z6- is not a bond; or a pharmaceutically acceptable salt thereof.

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

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2is alkoxy.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2is halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino.

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

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 pyrrolidin- 1,3 -diyl or piperidin-l,4-diyl rings is attached to L.

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 hgand of formula (i) is:

10. 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):(u).

11. The compound of any one of claims 1 to 7 and 10, or a pharmaceutically acceptable salt thereof, wherein the E3 ubiquitin ligase hgand of formula (ii) is:cyclylaminylene.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Z6is -S(O)2-.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X4, Z1, and Z2are each a bond;Z3is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;Z4is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and Rpindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr: andZ6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, R\ and Ru.

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X4, and Z1are each a bond;Z2is heterocyclylene substituted with RJand Rkindependently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;Z3is heterocyclylene substituted with Rmand Rnindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;Z4is a bond, alkylene, or -O-;Z3is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rrindependently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; andZ6is -S(O)2-; and wherein alkylene in Z4is substituted with Rs, R\ and Ru.

15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X4, and Z1are each a bond;Z2is heterocyclylene substituted with R' and Rkare independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;Z3is a bond, alkylene, or -O-;Z4is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and Rp;Z5is phenylene or monocyclic heteroarylene, each ring substituted with Rqand Rr; andZ6is -S(O)2-; and wherein alkylene in Z3is substituted with Rs, R\ and Ru.

16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:Z3is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;Z4is alkylene, -O-, heterocyclylene, -(alkylene)-heterocyclylene-, -(alkylene)-bridged heterocyclylene-, where each ring, by itself or as part of another group, is substituted with R° and Rp;Z5is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rqand Rr; andZ6is -S(O)2; and each alkylene in Z4, itself or as part of another group, is substituted with Rsand Rl.

17. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:X1, X2, X3, X4, Z1, and Z2are each a bond;Z3is -O-. -NR - (where R is hydrogen or alkyl), cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with Rmand Rn;Z4is alky lene, alkenylene, alkynylene, heteroalkylene, where alkylene and heteroalkylene are substituted with Rs, R‘, and Ruand alkenylene is substituted with Rv;Z5is phenylene, monocyclic heteroarylene, heterocycylene. bridged heterocyclylene. or spiro heterocyclylene, where each ring is substituted with Rqand Rr; andZ6is -S(O)2.

18. The compound of any one of claims 1 to 13, 16, and 17, or a pharmaceutically acceptable salt thereof, wherein -Z3-Z4-Z5-Z6- is:wherein each Rm, Rn. and Rqare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano.

19. The compound of any one of claims 1 to 13 and 16 to 18, or a pharmaceutically acceptable salt thereof, wherein -Z3-Z4-Z5-Z6- is:wherein each Rm, Rn, and Rq are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the phenylene of Z5isand is selected from:

21. The compound of any one of 1 to 12, 16, and 18 to 20, or a pharmaceutically acceptable salt thereof, wherein Z4is -(alkylene)-heterocyclylene-, where heterocyclylene is substituted with R° and Rp.

22. The compound of any one of claims 1 to 14, and 16 to 20, or a pharmaceutically acceptable salt thereof, wherein Z4is C3to C6alkydene substituted with Rs, R\ and Ruwhere Rs, R‘, and Ruare hydrogen.

23. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein-X2-L-, -X3-L- and -X4-L- are independently:wherein each Rmand Rnare independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano; andZ4is C3to C6alkylene substituted with Rs, R\ and Ru.

24. The compound of any one of claims 1 to 7 and 10 to 23, or a pharmaceutically acceptable salt thereof wherein Degron is the E3 ubiquitin ligase ligandwhere Reeis hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl.

25. A pharmaceutical composition comprising a compound of any one of claims 1 to24. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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

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