WO2025235261A1 - Bifunctional compounds containing 2,4,5-substituted pyrimidine derivatives for degrading certain cyclin-dependent kinase via ubiquitin proteasome pathway - Google Patents

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

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

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.

Field of the disclosure

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.

Background

Cyclin-dependent kinases (CDKs) are essential cellular serine/threonine kinases that play an important role in orchestrating signaling events, such as DNA replication and protein synthesis, to ensure faithful eukaryotic cell division and proliferation. The regulation of CDK activity' is tightly controlled by the fluctuating levels of various cyclins, which form heterodimeric complexes with CDKs to activate them. Out of the 21 identified CDKs, 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).

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 SCF^Fbw7ubiquitin E3 ligase responsible for cyclin E degradation. (Smalley et al. Cancer Res. (2008) 68: 5743-52).

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).

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.

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.

PROTACs are bifunctional molecules comprised of target protein-recruitment moiety and a ligand for E3 ligase, connected by a biocompatible linker. PROTACs bring the protein of interest and the E3 ligase into close proximity and induce ubiquitination and subsequent degradation of the target protein by proteasome.

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

Therefore, PROTACs that could recruit CDK2 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.

Summary

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

R¹ is 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;

R² is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxy alkyl, amino, alkylamino, or dialkylamino;

R³ are independently hydrogen or deuterium; and

Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene. where each of the aforementioned rings is substituted with R^a, R^b, and R^c independently 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):

(f) a group of formula (vi): where:

Y^a is CH or N;

Z^a is a bond, -CH2-, -NH-, -O-, or -NHC(O)- where NH of -NHC(O)- is atached to Y^a; ring A is a group of formula (a), (b), or (c): where:

R^aa, R^bb, R^cc, and R^dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;

R⁴ and R⁵ are independently hydrogen or alkyl; or R⁴ and R⁵ together with the carbon to which they are atached form >C=O;

M is -O- or -NR⁶-; and

R⁶ is hydrogen or alkyl; and

R⁶ is 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 R^ee and R^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and X¹, X², X³, and X⁴ are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NR^gg-alkylene)-, -(alkyl ene-NR^hh)-, -N(alkyl)-, -C(=O)-, -NR“C(=O)-, or -C(=O)NR^kk- where R^gg, R¹'¹'. R>', and R^kk are independently hydrogen, alkyl, or cycloalkyl and each alkylene, itself or as part of another group, is optionally substituted with one or two fluoro;

R^y, R^yl, and R^y2 are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with R^d and R^f selected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino; and

W^a is bond. O, S, or alkylene; and

L is -Z'-Z²-Z -Z⁴-Z⁵-Z⁶- where:

Z¹ is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O)2NR-, -NR’S(O)2-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with R^h and R' independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z² is 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 R^k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z³ is 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 R^m and Rⁿ independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialky lamino;

Z⁴ is 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 R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z³ is 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 R^q and R^r independently selected from hydrogen, deuterium, alkyl, alkoxy , halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; and

Z⁶ is 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 R^s, R\ and R^u where R^s is hydrogen, deuterium, or halo, R^l is 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 R⁷ and R⁸ independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxy carbonyl, amino, alkylamino, dialkylamino, and cyano), and R^u is hydrogen or halo; or when R^l and R^u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the alky dene or heteroalkydene, R^l and R^u together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by R^l and R^u are substituted with R⁹ and R¹⁰ independently 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 R^v selected from hydrogen, fluoro, and cyano, and alkynylene of -Z³- and -Z⁴- are substituted with R^w and R^x independently selected from hydrogen, halo, haloalkyl. alkoxy, hydroxy, and cyano; or yvhen R" and R^x are 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 R¹¹ and R¹² independently 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.

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

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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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

Definitions:

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

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

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

“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.

“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 C₆ alkylene, Examples include, but are not limited to, methylene, ethylene, propylene. 1 -methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

“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.

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

“Alkoxy” means a -OR^Z radical where R^z is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, «-, iso-, or /c/7-butoxy , and the like.

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

“Alkydthio” means an -SR^Z radical where R^z is alkyl as defined above, e.g., methylthio, ethylthio, n-propylthio, 2-propylthio, n-, iso-, or /e/v-butylthio. and the like.

“Alkoxy carbonyl” and “alkyloxy carbonyl” mean a -C(O)OR^Z radical where R^z is alkyl as defined above, e.g., methoxy carbonyl, ethoxy carbonyl, and the like.

“Alkylcarbonylamino” means a -NR^z'C(O)R^z radical where R^z is alkyl and R^z" is H or alkyl, as defined above, e.g.. methylcarbonylamino, ethylcarbonylamino, and the like.

“Acyl” means a -C(O)R^Z radical where R^z is 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 R^z is alkyl, acyl is also referred to herein as “alkylcarbonyl.”

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

“Amido” means an -NR^ZC(O)- or -C(O)NR^Z- group, where R^z is hydrogen or alkyd as defined above.

“Sulfonamido” means an -NR^ZS(O)2- or -S(O)2NR^Z- group, where R^z is hydrogen or alkyl as defined above.

“Amino” means -NH2.

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

“Aminoalkyloxy” and “aminoalkoxy” mean -OR^Z radical where R^z is aminoalkyl as defined above e.g., NH₂methyloxy, NH2ethyloxy, and the like.

“Aminocarbonyl” means -C(O)NH2.

“Alky laminocarbonyl” means -C(O)NHR^Z radical where R^z is alkyl as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.

“Dialky laminocarbonyl” means -C(O)NR^zlR^z radical where R^z and R^zl are independently alkyd as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.

“Alkydamino” means -NHR^Z radical where R^z is alkyl as defined above e.g., methylamino, ethylamino, propylamino, and the like.

“Aminosulfony 1” means -S(O)2NH2.

“Alkylaminosulfonyd” means -S(O)2NHR^Z radical where R^z is alkyd as defined above e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.

“Dialkydaminosulfonyl” means -S(O)2NR^zlR^z radical where R^z and R^zl are independently alkyl as defined above e.g., dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, and the like.

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

“Alkydaminoalkydoxy” means -OR^Z radical where R^z is alky daminoalkyl as defined above e.g., methyaminomethyloxy, methylaminoethyloxy, ethylaminoethyloxy, and the like.

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

“Aralkyl” means an -(alkylene)-R^z radical where R^z is aryl as defined above e.g. benzyl. “Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene.

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

“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.

“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 (CR^zR^z’)_n group where n is an integer selected from 1 to 3 and R^z and R^z’ are independently H or methyl (also 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.

“Bridged cycloalkylalkyl” means a -(alkylene)-R^z radical where R^z is bridged cycloalkyl as defined above e.g., bicyclofl. l.l]pent-l-ylmethyl, and the like.

“Bridged cycloalkyloxy” and “bridged cycloalkoxy” mean a -OR^Z radical where R^z is bridged cycloalkyl as defined above e.g., bicyclo[2.2.1]hept-2-yloxy.

“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 (CR^zR^z’)_n group where n is an integer selected from 1 to 3 and R^z and R^z’ are independently H or methyl (also 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.

“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 (CR^pR^p’)_n group where n is an integer selected from 1 to 3 and R^p and R^p' are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, NH. O, and S(O)_n, where n is an integer selected from 0 to 2. Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octanyl,

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

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

“Bridged heterocyclylene” means a saturated divalent bicyclic ring having 5 to 9 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR^zR^z')_n group where n is an integer selected from 1 to 3 and R^z and R^z’ are independently H or methyl (also 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.

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

“Cycloalkyloxy’’ and “cycloalkoxy” mean a -OR^Z radical where R^z is cycloalky l as defined above. Examples include, but are not limited to. cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

“Cycloalkylalkyl” means an -(alkylene)-R^z radical where R^z is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

“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.

“Carbonyl” means -C(O)-.

“Carboxy” means -COOH.

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

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

“Cyanoalkoxy” and “cyanoalkyloxy” mean an -OR⁷ radical where R⁷ is cyanoalkyl as defined above. Examples include, but are not limited to, cyanomethoxy, cyanoethoxy, and the like.

“Deuterium” means refers to ²H or D.

"Dialkylamino" means a -NR^ZR^Z radical where each R^z is independently alkyl as defined above, e.g.. dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, iso-, or tert-butylmethylamino. and the like.

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

“Dialkylaminoalkyloxy” and “dialkylaminoalkoxy” mean -OR⁷ radical where R^z is dialkylaminoalkyl as defined above e.g., dimethyaminomethyloxy, dimethylaminoethyloxy, ethylmethylaminoethyloxy, and the like.

“Ether” means an -O- group.

“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.

“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.

“Fused heterocyclylalkyl” means an -(alkyl ene)-R^z radical where R^z is 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.

“Fused heterocyclyloxy” means an -OR^Z radical where R^z is fused heterocyclyl as defined above e.g., 1,2,3,4-tetrahydroquinolinyloxy, 3,4-dihydro-2H-benzo[b][l,4]oxazinyloxy,

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

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

“Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3. -CF2CF3.

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

“Haloalkoxy” means a -OR^Z radical where R^z is haloalkyl as defined above e. g; -OCF3, -OCHF2, and the like. When R^z is 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.

“Haloalkylthio” means an -SR^Z radical where R^z is haloalkyl as defined above e.g., -SCF3, -SCHF2, and the like.

“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).

“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 X^a where X^a is -O-, -S-, -SO-, -SO2-, -CO-, or -NR^ql- or (b) three to six carbon atoms where two adjacent carbon atoms of the linear portion of the divalent hydrocarbon radical are replaced by X^al where X^al is -NR^qlCO-, -CONR^q1-, -NR^qlSO-, -SONR^q1-, -NR^qlSO₂-, or -SO₂NR⁴¹- (where each R^ql is 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 X^a and X^al above, can be replaced by X^y where X^y is -O- or -NR^q2- (where each R^q2 is 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 Z² and Z⁴ when Z³ is heteroalkylene and Z³ and Z⁵ when Z⁴ is 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 -NR^q- and/or -NR^q1-, it can be referred to herein as “aminylalkylene.” When the heteroalkylene contains only -S-, it can be referred to herein as

“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.

“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.

“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.

“Heteroarylalkyl” and “heteroaralkyl” mean an -(alkylene)-R^z radical where R^z is heleroaryl as defined above.

“Heteroaryloxy” means an -OR^Z radical where R^z is heleroaryl as defined above.

“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.

“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.

“Heterocyclylalkyl” means an -(alkyl ene)-R^z radical where R^z is heterocyclyl as defined above e.g. piperidinylmethyl and piperazinylmethyl. “Heterocyclyloxy” means an -OR^Z radical where R^z is heterocyclyl as defined above e.g. l-methylpyrrolidin-3-oxy. l-methylpyrrolidin-2-oxy. piperidin-3-oxy, piperidin-4-oxy and the like.

“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.

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)-.

“Phenylene” means divalent phenyl.

“Polyether” means a group where d is an integer selected from 2 to 5 and R^z is C2-salkylene.

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

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.

“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.

“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.

“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.

“Pentafluorothio” means an -SF5.

“Sulfinyl” means an -S(O)- group.

“Substituted sulfinyl” means an -S(O)R^Z where R^z is alkyl as defined above e.g., methyl or ethylsulfinyl.

“Sulfonyl” means an -S(O)2- group.

“Substituted sulfonyl” means an -S(O)2R^Z where R^z is alkyl as defined above e.g., methyl or ethylsulfonyl. Substituted sulfonyl is also referred to herein as alkylsulfonyl.

“Thioether” means an -S- group.

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

“Ureido” means an -NHC(O)NH- group.

“Substituted ureido” means an -NHC(O)NR^ZR^Z where R^z is hydrogen or alkyl and R^z is alkyl, as defined above e.g., -NHC(O)NHmethyl, -NHC(0)NMe2, and the like.

“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.

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, 5^th Ed., 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.

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.

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.

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.

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.

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 as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷0, ¹⁸0, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I, and ¹²⁵1, respectively. Isotopically labeled compounds (e.g., those labeled with ³H and ¹⁴C) 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 by ²H or ³H, or one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ⁿC, and ¹⁵F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

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

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

The term “about.” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%. 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.

For example, in the structure: , the R^aa substituent, and similarly the R^bb and X¹ substituents, can replace hydrogen of any CH that is part of the benzo portion of the bicyclic ring that is not already substituted with R^bb and X¹ (in the case of R^aa), and similarly with R^aa and X¹ (in the case of R^bb), and with R^aa and R^bb (in the case of X¹).

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 Z¹ of L of the following structure:

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 X⁴ or point of attachment delineated in Degrons of formula (c), (d), (e), or (f) and Z⁶ is attached to an atom of Hy. For example, when L is a group of formula:

and Degron is a group of formula (a), i.e., , the left bond in L (i.e., the -NH- group) is attached to X¹ and the right hand bond in L (i.e., -SO2-) is attached to an atom of the Hy

The term “disease’’ as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

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

“Treating” or “treatment” of a disease includes:

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

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

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

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

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

The 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).

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%.

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%.

“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.

“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.

Embodiments:

In embodiments Al to A253, the present disclosure includes:

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 R¹ is cycloalkyl, halo, haloalkyl. haloalkoxy, alkoxy, cyano, or cycloalkyl substituted with one to three halo.

A3. In embodiment A3, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkyl, alkenyl, alkynyl, or aryloxy.

A4. In embodiment A4. the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R¹ is halo, haloalkyl. or haloalkoxy.

A5. In embodiment A5, the compound of any one of embodiments Al, A2, and A4, or a pharmaceutically acceptable salt thereof, is wherein R¹ is halo.

A6. In embodiment A6. the compound of any one of embodiments Al, A2, and A4, or a pharmaceutically acceptable salt thereof, is wherein R¹ is haloalkyl.

A7. In embodiment A7, the compound of any one of embodiments Al, A2, and A4, or a pharmaceutically acceptable salt thereof, is wherein R¹ is haloalkoxy.

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 R¹ is chloro, bromo, fluoro, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluoroethoxy, or trifluoroethoxy.

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 R¹ is chloro, bromo, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy.

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 R¹ is chloro.

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 R¹ is difluoromethyl or trifluoromethyl.

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 R¹ is trifluoromethyl.

A13. In embodiment A13, the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkyl, alkenyl, or alkynyl.

A14. In embodiment A14, the compound of embodiment Al, A3, or A13, or a pharmaceutically acceptable salt thereof, is wherein R¹ is methyl, ethyl, propyl, vinyl, propeny l, ethynyl, or propynyl.

A15. In embodiment A15, the compound of embodiment Al, A3, A13, or A14, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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 R¹ is vinyl, propenyl, ethynyl. or propynyl.

Al 7. In embodiment Al 7, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkoxy.

A18. In embodiment A18, the compound of embodiment Al, A2. or A17, or a pharmaceutically acceptable salt thereof, is wherein R¹ is methoxy, ethoxy, or propoxy.

Al 9. In embodiment Al 9, the compound of embodiment Al or A3, or a pharmaceutically acceptable salt thereof, is wherein R¹ is aryloxy’ (such as phenoxy).

A20. In embodiment A20, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R¹ is cyano.

A21. In embodiment A21, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R¹ is cycloalkyl (such as cyclopropyl).

A22. In embodiment A22, the compound of embodiment Al or A2, or a pharmaceutically acceptable salt thereof, is wherein R¹ is cycloalkyl substituted with one to three halo (such as fluorocyclopropyl or difluorocyclopropyl).

A22-1. In embodiment A22-1, the compound of embodiment Al, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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.

A22-la. In embodiment A22-la, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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, R¹ is phenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, tetrahydrofuranyl. tetrahydropyranyl. pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, cyanomethyl, cyanoethyl, methoxymethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2,3-dihydrobenzofuranyl, benzodihydropyranyl, 1 ,4-benzodioxanyl, 2,3-dihydrofuro[3,2-c]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.

A22-lb. In embodiment A22-lb, the compound of embodiment Al, A22-1, or A22- la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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, R¹ is 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.

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 R¹ is alkylthio (such as methylthio).

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 R¹ is pentafluorothio.

A22-le. In embodiment A22-le, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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 R¹ is amino.

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 R¹ is alkylamino (such as methylamino).

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 R¹ is dialkylamino (such as dimethylamino).

A22-li. In embodiment A22-li, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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.

A22-lj. In embodiment A22-lj, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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.

A22-lk. In embodiment A22-k, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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.

A22-lm. In embodiment A22-lm, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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.

A22-ln. In embodiment A22-ln, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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.

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 R¹ is cyanoalkyl. In a subembodiment of embodiment A22-lo, R¹ is cyanomethyl or cyanoethyl,

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 R¹ is cyanoalkoxy (such as cyanomethoxy or cyanoethoxy).

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 R¹ is alkoxyalkyl. In a subembodiment of embodiment A22-lq, R¹ is methoxy methyl.

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 R¹ is aminoalkyl. In a subembodiment of embodiment A22-lr, R¹ is aminomethyl.

A22-ls. In embodiment A22-ls, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is aminoalkoxy. In a subembodiment of embodiment A22-ls, R¹ is aminomethyloxy.

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 R¹ is alkylaminoalkyd. In a subembodiment of embodiment A22-1, R¹ is methylaminomethyl.

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 R¹ is dialkylaminoalkyl. In a subembodiment of embodiment A22-lu, R¹ is dimethylaminomethyl.

A22-lv. In embodiment A22-lv, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkylaminoalkoxy. In a subembodiment of embodiment A22-lv, R¹ is methylaminomethyloxy. A22-lw. In embodiment A22-lw, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is dialkylaminoalkoxy. In a subembodiment of embodiment A22-lw, R¹ is dimethylaminomethyloxy.

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

A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is acyl. In a subembodiment of embodiment A22-lx, acyl is alkylcarbonyl (such as methylcarbonyl).

A22-ly. In embodiment A22-ly, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is azidocarbonyl.

A22-lz. In embodiment A22-lz, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkoxy carbonyl. In a subembodiment of embodiment A22-lz, R¹ is methoxy carbonyl or ethoxy carbonyl.

A22-laa. In embodiment A22-laa, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkylcarbonylamino.

A22-lbb. In embodiment A22-lbb. the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is aminocarbonyl.

A22-lcc. In embodiment A22-lcc, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkylaminocarbonyl (such as methylaminocarbonyl).

A22-ldd. In embodiment A22-ldd. the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is dialky laminocarbonyl (such as dimethylaminocarbonyl).

A22-lee. In embodiment A22-lee, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is aminosulfonyl.

A22-lff. In embodiment A22-lff, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is alkylaminosulfonyl (such as methylaminosulfonyl).

A22-lgg. In embodiment A22-lgg, the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is dialkylaminosulfonyl (such as dimethylaminosulfonyl).

A22-lhh. In embodiment A22-lhh, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is substituted sulfonyl.

A22-lii. In embodiment A22-lii, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is substituted sulfinyl. A22- Ijj . In embodiment A22-ljj, the compound of embodiment Al, A22-1, or

A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is substituted ureido.

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 R¹ is 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, R¹ is 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, R¹ is phenyl substituted with one, two, or three substituents independently selected from hydrogen, methyl, fluoro, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy.

A22-lmm. In embodiment A22-lmm, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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, R¹ is 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.

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 R¹ is 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, R¹ is pyrazolyl. imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. In a second subembodiment of embodiment A22-lnn, R¹ is pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one substituent selected from hydrogen and alkyl.

A22-loo. In embodiment A22-loo. the compound of embodiment Al or A22-1. or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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 R¹ is pyrazolyl, imidazolyl, oxazolyl. thiazolyl, or triazolyl, each of which is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano. A22-lpp. In embodiment A22-lpp. the compound of embodiment Al. A22-1. or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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 R¹ is pyrazolyl. imidazolyl, oxazolyl, thiazolyl, or triazolyl, each of which is substituted with one, two. or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

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 R¹ is 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, R¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

A22-lrr. In embodiment A22-lrr, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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 R¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

A22-lss. In embodiment A22-lss, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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 R¹ is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl where the piperazinyl is optionally substituted with alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano.

A22-ltt. In embodiment A22-ltt, the compound of embodiment Al, A22-1, or A22-la, or a pharmaceutically acceptable salt thereof, is wherein R¹ is 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, R¹ is 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.

A22-luu. In embodiment A22-luu, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is fused heterocyclyloxy where the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

A22-lvv. In embodiment A22-lvv, the compound of embodiment Al or A22-1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is fused heterocyclylalkyl where the heterocyclyl is substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

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 R¹ is selected from:

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

A23. In embodiment A23, the compound of any one of embodiments Al to A22-lww, or a pharmaceutically acceptable salt thereof, is wherein R³ is hydrogen.

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 R³ is deuterium.

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 R^a, R^b, and R^c where R^a and R^b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R^c is hydrogen.

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 R^a, R^b, and R^c where R^a and R^b are independently selected from hydrogen, deuterium, alkyl, halo, haloalky l, alkoxy, hydroxy, and cyano, and R^c is hydrogen.

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 R^a, R^b, and R^c where R^a and R^b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy, R^c is hydrogen, and L is attached to the nitrogen atom of the piperidin-l,4-diyl or pyrrolidin-l,3-diyl ring of Hy.

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.

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.

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 R^a, R^b, and R^c independently selected from hydrogen, deuterium, alkyl, halo, haloalky 1, alkoxy, hydroxy, and cyano.

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 R^a, R^b, and R^c where R^c is hydrogen, and L is attached to the nitrogen atom of each ring.

A32. In embodiment A32, the compound of embodiment A30 or A31, or a pharmaceutically acceptable salt thereof, is wherein R^a and R^b are independently hydrogen, deuterium, methyl, fluoro, methoxy, or hydroxy.

A33. In embodiment A33, the compound of embodiment A30, A31, or A32, or a pharmaceutically acceptable salt thereof, is wherein R^b is hydrogen.

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 R^a, R^b, and R^c where R^a is deuterium, methyl, fluoro, methoxy, or hydroxy and R^b and R^c are hydrogen. A35. In embodiment A35, the compound of any one of embodiments Al to A25. and

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

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.

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 R^a, R^b, and R^c where R^a and R^b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R^c is hydrogen.

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 R^a, R^b, and R^c where R^a and R^b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R^c is hydrogen.

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-

' "9 phenylene according to structure -L. where denotes bond to NH and denotes bond of L and where R^b is hydrogen (in one embodiment R^a is methoxy).

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 R^a, R^b, and R^c where R^a and R^b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R^c is hydrogen.

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 R^a, R^b, and R^c where R^a and R^b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R^c is hydrogen.

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):

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):

A42. In embodiment A42, the compound of any one of embodiments Al to A41. or a pharmaceutically acceptable salt thereof, is wherein R⁴ and R⁵ are independently hydrogen or alkyl.

A43. In embodiment A43, the compound of any one of embodiments Al to A42, or a pharmaceutically acceptable salt thereof, is wherein R⁴ and R⁵ are hydrogen.

A44. In embodiment A44, the compound of any one of embodiments Al to A42. or a pharmaceutically acceptable salt thereof, is wherein R⁴ is hydrogen and R⁵ is methyl.

A45. In embodiment A45, the compound of any one of embodiments Al to A41, or a pharmaceutically acceptable salt thereof, is wherein R⁴ and R⁵ together with the carbon to which they are attached form >C =0.

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 R⁶ is hydrogen.

A48. In embodiment A48, the compound of any one of embodiments Al to A40, and A46, or a pharmaceutically acceptable salt thereof, wherein R⁶ is alkyl. In one embodiment R⁶ is methyl.

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:

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, R^aa is hydrogen in groups (when R^aa is not drawn in the above rings) and R^bb, R^cc, and R^dd are

H.

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:

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:

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:

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

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:

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

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 R^aa, R^bb, R^cc. and R^dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy. For sake of clarity, in embodiments A52 to A54, R^aa, R^bb, R^cc, and/or R^dd are hydrogen when they are not specifically drawn out in structures of formula (i) and (ii), respectively.

A59. In embodiment A59, the compound of any one of embodiments Al to A54. or a pharmaceutically acceptable salt thereof, is wherein R^aa, R^bb, R^cc, and R^dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.

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 R^aa, R^bb. R^cc, and R^dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy.

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 R^aa, R^bb, R^cc. and R^dd are independently selected from hydrogen and methyl.

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 R^aa, R^bb, R^cc, and R^dd are independently selected from hydrogen and methoxy.

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 R^aa, R^bb, R^cc, and R^dd are independently selected from hydrogen and fluoro.

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 R^aa, R^bb, R^cc. and R^dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.

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 R^aa, R^bb, R^cc, and R^dd are independently selected from hydrogen and trifluoromethoxy.

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 R^aa, R^bb, R^cc, and R^dd are independently selected from hydrogen, fluoro, and trifluoromethyl.

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):

(ii).

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

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

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 Z^a is a bond, -NH-, -O-, or -NHC(O)-.

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 Z^a is a bond. -NH-, or -NHC(O)-.

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 Z^a is a bond.

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 Z^a is -NH-, or -NHC(O)-.

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 Z^a is -NH-.

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 Z^a is -NHC(O)-.

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 R^ee and R^ff.

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 R^ee and R^ff.

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 R^ee and R^ff. 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 R^ee and R^ff.

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 R^ee and R^ff

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 R^ee and R^ff.

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:

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:

is cyclylaminylene. For sake of clarity, R^ee and R^ff are 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

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

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

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:

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

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 R^ee and R^ff are 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 R^6e and R^fl are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.

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 R^ee and R^ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.

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 R^ee and R^ff are independently selected from hydrogen, methyl, ethyl, and isopropyl.

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 R^ee and R^ff are independently selected from hydrogen and methoxy.

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 R^ee and R^fl are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.

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 R^cc and R^ff is hydrogen or fluoro and the other of R^ee and R^ff is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl.

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 R^ee and R^ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.

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 R^ee and R^ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl.

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 R^ee and R^fl are hydrogen.

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 R^ee and R^ff are 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 R^ee and R^ff are fluoro.

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 R^ee and R^ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.

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).

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).

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 R^y, R^yl, and R^y2 are 1 -fluorocycloprop- 1-yl and W^a is bond, S. or methylene.

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 W^a is S.

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 X⁴ are each a bond.

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 X⁴ are each independently selected from alkylene. In a subembodiment of embodiment A98, X¹, X², X³. and X⁴ are each methylene.

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 X⁴ are each -O-.

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 X⁴ are each independently selected from -(O-alkylene)-.

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 X⁴ are each independently selected from -(alkylene-O)-.

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 X⁴ are each independently selected from -(NR^gg-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 X⁴ are each independently selected from -(alkyl ene-NR^hh)-.

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 X⁴ are each .

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 X⁴ are each -NH-.

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 X⁴ are each independently selected from -N(alkyl)-. In a subembodiment of embodiment Al 06, X¹, X², X³, and X⁴ are each independently -N(methyl)- or -N(ethyl)-.

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 X⁴ are each -C(=O)-.

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 X⁴ are each independently -NRjjC(=O)-.

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 X⁴ are each independently -C(=O)NR^kk-.

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 R^gg, R^hh, R^, and R^kk are each independently hydrogen or alkyl.

Al 10a. In embodiment Al 10a, the compound of any one of embodiments Al to Al 10 is wherein at least two of -Z^k-Z²-Z³-Z⁴-Z³-Z⁶- are not a bond. In a sub-embodiment of Al 10a, the compound is wherein at least three of -Z^k-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.

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 Z⁶ is -S(O>2-.

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 Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r.

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 Z³ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r and one and only one of Z¹ and X¹ is a bond, one and only one of Z¹ and X² is a bond, one and only one of Z¹ and X³. and one and only one of Z¹ and X⁴ is a bond (for sake of clarity, when X¹, X², X³, and X⁴ are not a bond, then X¹, X², X³, and X⁴ are as described in any one of embodiments Al and A98 to Al 10).

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:

X¹, X², X³, and X⁴ are independently a bond, -(O-alkylene)-, -(NR^gg-alkylene)-, H^c=c— - NH-, or -N(alkyl)-, where R^gg is hydrogen or alkyl and each alkylene is independently optionally substituted with one or two fluoro (or X¹, X², X³, and X⁴ are absent in ligands (iii) to (vi));

Z¹ is a bond, alkylene, -(CO)NR-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, or heterocyclylene, where each ring is substituted with R^h and R¹;

Z² is a bend, alkylene, -(O-alkylene)b-, -(alkylene-O)b-, cycloalkylene, or heterocyclylene, where each ring is substituted with R' and R^k;

Z³ is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, cycloalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)- monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)- heterocyclylene-, -heterocyclylene-(alkylene)-, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-. 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 R^m and Rⁿ;

Z⁴ is 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 R^p;

Z⁵ is a bond; and

Z⁶ is -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 R^s. R‘, and R^u.

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:

X¹, X², X³, X⁴, and Z¹ are each a bond; Z² is a bond, alkylene, cycloalkylene, or heterocyclylene, where each ring is substituted with R' and R^k;

Z³ is 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 R^m and Rⁿ;

Z⁴ is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and R^p;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r: and

Z⁶ is -S(O)2-; and wherein each alkylene in Z², Z³, and Z⁴ is independently substituted with R^s, R‘, and R^u.

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:

X¹. X². X³. X⁴. Z¹. and Z² are each a bond;

Z’ is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ;

Z⁴ is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r; and

Z⁶ is -S(O)2-; and wherein alky lene in Z⁴ is substituted with R^s, R‘, and R^u.

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:

X¹, X², X³, X⁴, Z¹, and Z² are each a bond;

Z³ is heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; Z⁴ is alkylene, -0-. cycloalkylene, monocyclic heteroaiyiene. heterocyclylene, fused heterocyclylene. or spiro heterocyclylene. where each ring is substituted with R° and R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R¹ independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

Z⁶ is -S(O)2-; and wherein alkylene in Z⁴ is substituted with substituted with R^s, R\ and R^u.

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:

X¹, X², X³, and X⁴, Z¹, and Z² are each a bond;

Z³ is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

Z⁴ is alkylene. -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with R° and R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalky l, and haloalkoxy; and

Z⁶ is -S(O)2-; and wherein alkylene in Z⁴ is substituted with R^s, R‘, and R^u.

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:

X¹, X², X³, X⁴, Z¹, and Z² are each a bond;

Z³ is heterocyclylene, bridged heterocyclylene or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalky l, and haloalkoxy;

Z⁴ is alky lene, -O-, cycloalkylene, or heterocyclylene, where each ring is substituted with R° and R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, and hydroxy (in one embodiment R° and R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy, (in a subembodiment Z⁴ is alkylene or -O-)); Z⁵ is phenylene or monocyclic heteroarylene, each ring substituted with R^q and R^r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

Z⁶ is -S(O)2-; and wherein alkylene in Z⁴ is substituted with R^s, R‘, and R^u.

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:

X¹, X², X³, X⁴, and Z¹ are each a bond;

Z² is cycloalkylene or heterocyclylene, where each ring is substituted with R¹ and R^k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl. and haloalkoxy;

Z³ is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ independently selected from hydrogen, deuterium, alkyd, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

Z⁴ is a bond, alkylene, or -O-;

Z⁵ is phenylene, monocyclic heteroarylene (e g., pyridindiyl), or heterocycylene, where each ring is substituted with R^q and R^r independently selected from hydrogen, deuterium, alky l, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

Z⁶ is -S(O)2-; and wherein alkylene in Z⁴ is substituted with R^s, R\ and R^u.

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:

X¹, X², X³, X⁴, and Z¹ are each a bond;

Z² is heterocyclylene substituted with R' and R^k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z³ is heterocyclylene substituted with R^m and Rⁿ independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy ;

Z⁴ is a bond, alkylene, or -O-;

Z⁵ is phenylene or monocyclic heteroarylene, each ring substituted with R^q and R^r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

Z⁶ is -S(O)2-; and wherein alkylene in Z⁴ is substituted with R^s, R\ and R^u. 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:

X¹, X², X³, X⁴, and Z¹ are each a bond;

Z² is heterocyclylene substituted with R' and R^k (in one embodiment R' and R^k are independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy);

Z³ is a bond, alkylene, or -O-;

Z⁴ is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and R^p (in one embodiment R° and R^p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy);

Z⁵ is phenylene or monocyclic heteroarylene, each ring substituted with R^q and R^r (in one embodiment R^q and R^r are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy); and

Z⁶ is -S(O)2-; and wherein alkylene in Z³ is substituted with R^s, R‘, and R^u.

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 Z⁴ is heterocyclylene or spiro heterocyclylene, where each ring is substituted with R° and R^p (in one embodiment R° and R^p are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy).

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 X¹ and Z¹, or one and only one of X² and Z¹, or one and only one of X³ and Z¹, or one and only one of X⁴ and Z¹ is a bond.

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 Z¹ are each a bond.

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 Z² is heterocyclylene or bridged heterocyclylene. each ring substituted with R and R^k.

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 Z² is a bond.

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:

Z³ is 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 R^m and Rⁿ;

Z⁴ is 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 R^p;

Z⁵ is 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 R^q and R^r; and

Z⁶ is 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 R^s, R‘. and R^u.

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:

X¹, X², X³, X⁴, Z¹, and Z² are each a bond;

Z³ is -heterocyclylene-(alkylene)-, where heterocyclylene is substituted with R^m and Rⁿ and alkylene is substituted with R^s, R‘, and R^u;

Z⁴ is phenylene or monocyclic heteroarylene, where each ring is substituted with R° and RP;

Z⁵ is phenylene substituted with R^q and R^r; and

Z⁶ is -S(O)₂-.

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:

Z³ is 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 R^m and Rⁿ;

Z⁴ is 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 R^p;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r; and

Z⁶ is -S(O)2-; and and each alky lene in Z³ and Z⁴, itself or as part of another group, is independently substituted with R^s, R‘. and R^u.

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:

Z³ is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ;

Z⁴ is 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;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r: and

Z⁶ is -S(O)2; and and each alky lene in Z⁴, itself or as part of another group, is substituted with R^s and R^l

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:

X¹. X². X³. X⁴. Z¹, and Z² are each a bond;

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 R^m and Rⁿ;

Z⁴ is alkylene, alkenylene, alkynylene, heteroalkylene, where alkylene and heteroalkylene are substituted with R^s, R\ and R^u and alkenylene is substituted with R^v; Z⁵ is phenylene, monocyclic heteroarylene, heterocycylene. bridged heterocyclylene. or spiro heterocyclylene, where each ring is substituted with R^q and R^r; and

Z⁶ is -S(O)₂.

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:

X¹. X². X³. X⁴. Z¹, and Z² are each a bond;

Z³ 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 R^m and Rⁿ;

Z⁴ is alkylene, alkenylene, or heteroalkylene where alkylene and heteroalkylene substituted with R^s, R\ and R^u and alkenylene is substituted with R^v;

Z⁵ is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^q and R^r; and

Z⁶ is -S(O)₂.

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:

X¹, X², X³, X⁴, Z¹, and Z² are each a bond;

Z³ 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 R^m and Rⁿ;

Z⁴ is alkynylene where alkynylene substituted with R^w and R^x;

Z⁵ is phenylene, monocyclic heteroarylene, heterocycylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^q and R^r; and

Z⁶ is -S(O)₂.

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

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

X¹, X², X³, X⁴, Z¹, Z² and Z⁵ are each a bond;

Z³ 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 R^m and Rⁿ;

Z⁴ is Cs to C₆ alkylene substituted with R^s, R‘, and R^u; and

Z⁶ is -S(O)₂. A135. In embodiment Al 35, the compound of any one of embodiments Al to Al 13 and

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

Z⁵ is pheny lene where Z⁴ and Z⁶ are attached at meta position of the phenylene ring) substituted with R^q and R^r independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, and haloalkoxy.

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 R^q and R^r independently selected from hydrogen, deuterium, methyl, methoxy, cyano, fluoro, chloro, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

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

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 R^q and R^r independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

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 R^q and R^r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2.2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy.

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 R^q and R^r independently 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 R^q and R^r independently selected from hydrogen, methyl, methoxy, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy.

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.

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 R^s, R\ and R^u.

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 R^s, R‘, and R^u.

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 R^s, R‘, and R^u.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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

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

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:

wherein each R^m, Rⁿ, and R^q are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano(i.e., R^r is hydrogen). In a subembodiment, each R^q and R^m are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl.

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:

wherein each R^m, Rⁿ, and R^q are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e., Rr is hydrogen).

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:

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:

A164. In embodiment A164, 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:

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:

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

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:

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:

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

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:

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

Al 15 to A136, and A159 to 168A, or a pharmaceutically acceptable salt thereof, is wherein the phenylene of Z⁵ is and is selected from:

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 Z⁴ is -(alkylene)-heterocyclylene-, where heterocyclylene is substituted with R° and R^p. 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 Z⁴ is -(CH2)-heterocyclylene- where heterocyclylene is substituted with R° and R^p.

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 Z⁴ is:

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:

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:

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 Z⁴ is C₃ to C₆ alkenylene substituted with R^v where R^v is hydrogen.

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 Z⁴ is C₃ to C₆ alkenylene substituted with R^v where R^v is fluoro or cyano.

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 Z⁴ in A143 and Al 44), or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to C₆ alkylene substituted with R^s, R‘, and R^u where R^s, R\ and R^u are hydrogen.

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 Z⁴ in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to C₆ alkylene substituted with R^s, R\ and R^u where R^s, R\ and R^u are hydrogen or halo, provided at least one of R⁸, R^h, and R¹ is 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 Z⁴ in A143 and A144), or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to Cg alkylene substituted with R^s, R\ and R^u where R^l is other than hydrogen and R^u is hydrogen or when R^l and R^u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C₃ to C₆ alkylene. R^l and R^u together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R‘ and R^u are substituted with R⁹ and R¹⁰.

Al 79. In embodiment Al 79, the compound of embodiment Al 78, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to Cg alkylene substituted with R^s, R\ and R^u where R^l is other than hydrogen and R^u is hydrogen.

A180. In embodiment A180, the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof, is wherein the C₃ to Cg alkenylene and C₃ to Cg alkylene of Z⁴ are linear alkenylene and alkylene, respectively, and substituted as defined therein.

A181. In embodiment A181, the compound of any one of embodiments A174 to A180, or a pharmaceutically acceptable salt thereof, is wherein the linear C₃ to Cg alkenylene is -CH=C(R^V)CH₂-, -CH₂CH=CH-, -CH₂CH₂CH=CH-, -CH₂CH=CHCH₂-, and the linear alkylene of C₃ to Cg alkylene of Z⁴ is -CH₂CH(R‘)CH2-. -CH₂CH₂CH(R‘)-, -CH₂C(R^s)(R^l)CH₂-, -CH₂CH₂C(R^s)(R^t)- where R^s and R‘ are as defined therein and R^u is hydrogen.

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 C₃ to Cg alky lene of Z⁴ is -CH₂CH(R^t)CH₂- where R^l is other than hydrogen.

A183. In embodiment A183, the compound of any one of embodiments A178 to A182, or a pharmaceutically acceptable salt thereof, is wherein R^s of linear C₃ to Cg alkylene ofZ⁴ is as defined therein and R^l of linear C₃ to Cg alkylene of Z⁴ is 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.

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 R^s of linear C₃ to Cg alkylene ofZ⁴ is hydrogen and R‘ of linear C₃ to Cg alkylene of Z⁴ is halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, heterocyclyl, or heteroaryl, each ring substituted as defined therein.

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 R^l of linear C₃ to C₆ alkylene of Z⁴, when present, are five or six membered rings and each ring is substituted as defined therein.

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 R^s of linear C₃ to C₆ alkylene ofZ⁴ is as defined therein and R‘ of linear C₃ to C₆ alkylene of Z⁴ is fluoro, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or tetrahydrofuranyl, where each ring of R^l is substituted with R⁷ and R⁸ independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano, unless stated otherwise.

A187. In embodiment A187, the compound of any one of embodiments A174 to A179, or a pharmaceutically acceptable salt thereof, is wherein the C₃ to C₆ alkenylene and C₃ to C₆ alkylene of Z⁴ are branched C4 to C₆ alkenylene and C4 to C₆ alkylene, respectively, and each is substituted as defined therein.

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 Z⁴ is branched C4 to C₆ alkylene substituted as defined therein.

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 C₆ alkeny lene of Z⁴ is -CH₂CH₂C(CH₃)=C(R^V)-, -CH₂CH₂C(CH₂R^V)=CH-, -CH₂C(CH₃)=C(R^V)-, or -CH₂C(=CH₂)CH₂- and the branched C4 to C₆ alkylene of Z⁴ is -CH₂C(CH3)(R‘)CH₂-,

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 C₆ alkenylene of Z⁴ is -CH₂C(CH3)=C(R^V)- or -CH₂C(=CH₂)CH₂- and the branched C₄ to C₆ alky lene of Z⁴ is -CH₂C(CH3)(R^l)CH₂-, -CH₂CH(CH₂R^l)CH₂-, - where R^s, R^l. and R^u are as defined therein.

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 R^s and R^u of branched C4 to C₆ alkylene of Z⁴ are independently hydrogen or halo (unless stated otherwise) and R^l of branched C4 to C₆ alkylene of Z⁴ is hydrogen, halo, haloalkoxy, cycloalkyl, cycloalkyloxy. alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of R¹ is substituted as defined therein.

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 R^s and R^u of branched C4 to C₆ alkylene of Z⁴ are hydrogen or fluoro (unless stated otherwise) and R¹ of branched C4 to C₆ alkylene of Z⁴ is hydrogen, halo, cycloalkyl, cycloalkyloxy, alkoxy, hydroxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, or bridged heterocyclyl (unless stated otherwise), where each ring of R^l is substituted as defined therein.

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 R^s and R^u of branched C4 to C₆ alkylene of Z⁴ are hydrogen or fluoro (unless stated otherwise) and R^l of branched C4 to C₆ alkylene ofZ⁴ is hydrogen, halo, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.

Al 94. In embodiment Al 94, the compound of embodiment Al 78, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to C6 alkylene substituted with R^s, R^l, and R^u where R^l and R^u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C₃ to C₆ alkydene and R^l and R^u together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene formed by R‘ and R^u are substituted with R⁹ and R¹⁰.

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 Z⁴ is C₃ to C₆ alkylene substituted with R^s, R\ and R^u where R^l and R^u are attached to the same carbon atom of the linear portion of C₃ to C₆ alkylene and together with the carbon atom to which they are attached can form cycloalkylene substituted with R⁹ and R¹⁰' Al 96. In embodiment Al 96, the compound of embodiment Al 78 or Al 94, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to C₆ alkylene substituted with R^s, R^t and R^u where R^l and R^u are attached to the same carbon atom of the linear portion of the C₃ to C₆ alkydene and together with the carbon atom to which they are attached can form heterocyclylene substituted with R⁹ and R¹⁰.

Al 97. In embodiment Al 97, the compound of embodiment Al 78 or Al 94, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to C₆ alkylene substituted with R^s, R\ and R^u where R^l and R^u are attached to adjacent carbon atoms of the linear portion of the C₃ to C₆ alky lene and together with the carbon atoms to which they are attached can form cycloalkylene substituted with R⁹ and R¹⁰.

A198. In embodiment A198, the compound of embodiment A178 or A194, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to C₆ alkylene substituted with R^s, R\ and R^u where R^l and R^u are attached to adjacent same carbon atoms of the linear portion of the C₃ to C₆ alkylene and together with the carbon atoms to which they are attached can form heterocyclylene substituted with R⁹ and R¹⁰.

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 R^l and R^u are attached to the same carbon atom of the linear portion C₃ to C₆ alky 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 R⁹ and R¹⁰ (in one embodiment R⁹ is hydrogen, halo, methyl or ethyl and R¹⁰ is hydrogen).

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 R^u are attached to adjacent carbon atoms of the linear portion of the C₃ to C₆ alkylene and together with the carbon atoms to which they are attached can form cycloalkylene of formula: or heterocyclylene of formula: where each ring is substituted with R⁹ and R¹⁰, in one embodiment R⁹ is hydrogen, halo, methyl or ethyl and R¹⁰ is hydrogen.

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 Z⁴ is C₃ to Ci, heteroalkylene substituted with R^s, R\ and R^u.

A202. In embodiment A202, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein the Z⁴ is C₃ to C₆ heteroalkylene substituted with R^s, R\ and R^u where R^s, R\ and R^u are hydrogen.

A203. In embodiment A203, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein the Z⁴ is C₃ to C₆ heteroalkylene substituted with R^s, R‘. and R^u where R^s, R^l. and R^u are hydrogen or halo, provided at least one of R^s, R‘, and R^u is halo.

A204. In embodiment A204, the compound of embodiment A201, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is C₃ to C₆ heteroalkylene substituted with R^s, R‘, and R^u where R‘ is other than hydrogen and R^u is hydrogen, or when R‘ and R^u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the C₃ to C₆ heteroalkylene. R^l and R^u together with the carbon atom to which they are attached can form cycloalkylene or heterocyclylene where the cycloalkylene and heterocyclylene are substituted with R⁹ and R¹⁰'

A205. In embodiment A205, the compound of embodiment A204, or a pharmaceutically acceptable salt thereof is wherein R‘ and R^u are attached to the same carbon atom of the linear portion of the C₃ to C₆ heteroalkylene 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 R⁹ and R¹⁰. In one embodiment R⁹ is hydrogen, halo, methyl or ethyl and R¹⁰ is hydrogen.

A206. In embodiment A206, the compound of embodiment A204. or a pharmaceutically acceptable salt thereof, is wherein R^t and R^u are attached to adjacent carbon atoms of the linear portion of the C₃ to C₆ heteroalkylene 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 R⁹ and R¹⁰. In one embodiment R⁹ is hydrogen, halo, methyl or ethyl and R¹⁰ is hydrogen.

A207. In embodiment A207, the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof, is wherein the C₃ to C₆ heteroalky lene of Z⁴ is linear C₃ to C₆ heteroalkylene substituted with R^s, R‘, and R^u.

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 Z⁴ is -CH₂CH₂X^aCH₂-, -CH₂X^aCH₂CH₂-, -CH₂CH₂CH₂X^a-, -X^aCH₂CH₂CH₂-, - X^yCH₂CH₂X^a-, -X^yCH₂CH₂X^aCH₂-, -CH₂CH₂CH₂X^aCH₂-, -CH₂X^aCH₂-, -X^aCH₂CH₂-. -CH₂CH₂X^a-, -CH₂CONR^qlCH₂-, -CH₂SO₂NR^qlCH₂-. -CH₂NR^qlCOCH₂-, -CH₂NR^qlSO₂CH₂-, -CH₂CH₂CH₂NR^qlCO-, -CH₂CONR^q1-, -CH₂SO₂NR^q1-, -CH₂NR^qlCO-, -CH₂NR^qlSO₂-, -CONR^qlCH₂-, -SO₂NR^qlCH₂-, -NR^qlCOCH₂-, or -NR^qlSO₂CH₂- substituted with R^s, R‘, and R^u as defined therein and X^a is -NR^q1-, -O-, -S-, -SO-, -SO₂-, or -CO-.

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 R^ql is 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 C₃ to Cs heteroalkylene of Z⁴ is -CH₂X^aCH₂-, -X^aCH₂CH₂-, -CH₂CH₂X^a-. -CH₂CH₂CH₂X^a- , -CH₂CH(R^t)X^a-, -X^aCH(R^l)CH₂-, -CH₂CONR^q1-, -CH₂SO₂NR^q1-, -CH₂NR^qlCO-, -CH₂NR^q1SO₂-, -CONR^q1CH₂-, -SO₂NR^q1CH₂-. -NR^q1COCH₂-, or -NR^qlSO₂CH₂- where X^a is -S-, -SO₂-, -O-. or -NR^ql- substituted with R^s, R‘, and R^u as defined therein.

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 C₃ to Cs heteroalkylene of Z⁴ is -CH₂CH₂CH₂X^a- or -CH₂CH₂X^a- substituted with R^s, R^t and R^u as defined therein.

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 R^s of linear C₃ to Cs heteroalkylene of Z⁴ is hydrogen or halo (unless stated otherw ise therein above) and R^l of linear heteroalkylene of Z⁴ is (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 R^u is hydrogen.

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 R^s of linear C₃ to Cs heteroalkylene of Z⁴ is hydrogen or fluoro (unless stated otherwise therein above) and R¹ of linear heteroalkylene of Z⁴ (unless stated otherwise therein above) is hydrogen halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano, or heteroaryl substituted as defined therein.

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 R^l of linear C₃ to Cs heteroalkyl ene of Z⁴, when present, are five or six membered ring and each ring is substituted as defined therein.

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 R^s of linear heteroalkylene of Z⁴, when present and unless stated otherwise herein above, is hydrogen, deuterium, or fluoro, and R^l of 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 R⁷ and R⁸ independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethyl amino, and cyano.

A216. In embodiment A216, the compound of any one of embodiments A201 to A215, or a pharmaceutically acceptable salt thereof, is wherein X^a is -NR^q1-, -O-, -S-, or -SO2-. In one embodiment -NR^ql- (where R^ql is hydrogen or methyl). -O-, or -S-.

A217. In embodiment A217, the compound of any one of embodiments A201 to A216, or a pharmaceutically acceptable salt thereof, is wherein X^y is -O-.

A218. In embodiment A218, the compound of any one of embodiments A201 to A216, or a pharmaceutically acceptable salt thereof, is wherein X^y is -NH- or -NCH3-.

A219. In embodiment A219, the compound of any one of embodiments A201 to A206, or a pharmaceutically acceptable salt thereof, is wherein the C₃ to G, heteroalkylene of Z⁴ is branched C4 to G, hetcroalkylene substituted with R^s, R\ and R^u.

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 C₆ heteroalkylene of Z⁴ is -CH₂X^aCH(CH₃)CH₂-, -CH₂X^yCH₂CH(CH3)X^a-, -CH₂CH₂CH(CH₃)X^a-, -X^aCH(CH₃)CH₂CH₂-, -X^yCH₂CH(CH₃)X^a-, -X^yCH(CH₃)CH₂X^a-, -CH₂CH₂CH₂CH(CH₃)X^a-, -X^aCH(CH₂R‘)CH₂-, -CH₂CH(CH₂R‘)X^a-, -X^aCH(CH2CH2R‘)CH2-, -CH2CH(CH₂CH2R‘)X^a-, -CH₂C(CH₃)(CH₃)X^a-. -X^aC(CH₃)(CH₃)CH₂-. -CH(CH₃)CH(CH₃)X^a-, -CONR^qCH₂CH(CH₃)X^a-, -CH₂NR^qCOCH(CH₃)CH₂-, or -NR^qlCOCH(CH₃)CH₂- where X^a is -NR^q1-, -O-, -S-, -SO-, -SO2-, or -CO- and R‘ is as defined therein above.

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 C₆ heteroalkylene of Z⁴ is -CH₂C(CH₃)(CH₃)X^a-, -CH(CH₃)CH(CH₃)X^a-, -X^aCH(CH₂CH₂R^t)CH₂-, -CH₂CH(CH₂CH₂R^t)X^a-, -X^aCH(CH₂R^t)CH₂-, or -CH2CH(CH₂R^l)X^a-.

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 R^s and R^u of branched C4 to C₆ heteroalkylene of Z⁴ are hydrogen or halo (unless stated otherwise herein above) and R^l of branched C4 to C₆ heteroalkylene ofZ⁴ is 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.

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 R^s and R^u are hydrogen and R‘ is hydrogen, heteroaryl, alkylaminocarbonyl, or cyano (unless stated otherwise herein above).

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 C₆ heteroalkylene 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.

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 C₆ heteroalkylene 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 R⁷ and R⁸ independently selected from hydrogen, deuterium, methyl, methoxy, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxy, amino, methylamino, dimethylamino and cyano.

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 X^a is -NR^q1-, -O-. -S-, or -SO2-. In one embodiment X^a is -NR^ql- or -O-.

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 Z⁴ is alkynylene substituted with R" and R^x independently selected from hydrogen, halo, haloalkyl, alkoxy, hydroxy, and cyano.

A228. In embodiment A228, the compound of any one of embodiments K2T1 , or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is alkynylene substituted with R" and R^x independently selected from hydrogen, fluoro, difluoromethyl, trifluoromethyl, hydroxy, methoxy, and cyano.

A229. In embodiment A229, the compound of embodiment A227, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is alkynylene substituted with R^w and R^x which 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 R¹¹ and R¹² independently 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 Z⁴ is:

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

A230, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of Z⁴ is:

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 Z⁴ are selected from: respectively.

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 Z⁴ are selected from:

respectively.

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 Z⁴ are selected from:

respectively.

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

A232 to 234, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is:

A236. In embodiment A236, 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 A232 to 235, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is:

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:

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

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

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:

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

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 R^m, Rⁿ. and R^q are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano (i.e. , R^r is hydrogen). In a subembodiment, each R^q and R^m are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; and

Z⁴ is alkylene, alkynylene, alkenylene, or heteroalkylene wherein alky lene and heteroalkylene are substituted with R^s, R‘, and R^u. alkenylene is substituted with R^v and alkynylene is substituted with R" and R^x as defined in the first aspect of the Summary.

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 R^m, Rⁿ, and R^q are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy and cyano (i.e.. R^r is hydrogen).

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 Z⁴ are those as provided in embodiment A233. In one subembodiment alkylene, alkenylene, and heteroalkylene of Z⁴ are those as provided in embodiment A234, respectively. In another subembodiment alkydene, alkenylene, and heteroalkylene ofZ⁴ are those as provided in embodiment A235, respectively. In yet another subembodiment alkylene, alkenylene, and heteroalkylene ofZ⁴ are those as provided in embodiment A236. respectively. In one subembodiment alkylene, alkenylene, and heteroalkylene of Z⁴ are those as provided in embodiment A237, respectively.

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:

wherein each R^m and Rⁿ are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy , and cyano; and Z⁴ is C₃ to C₆ alkylene substituted with R^s, R\ and R^u.

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

L is where R^m and Rⁿ are independently selected from hydrogen, methyl, fluoro, chloro, cyano, methoxy, difluoromethoxy, difluoromethyl, and trifluoromethyl; alkynylene; and

Z⁴ is propylene, butylene, or pentylene.

A247. In embodiment A247, the compound of embodiment A245 or A246, or a pharmaceutically acceptable salt thereof, is wherein Z⁴ is n-propylene.

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 R^ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

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 R^ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl and R^ff is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl. 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:

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

R^ff. when present, is hydrogen, methyl, cyclopropyl, fluoro, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

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

A253. In embodiment A253, the compound of any one of embodiments Al to A252, or a pharmaceutically acceptable salt thereof, is wherein R² is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino.

A254. In embodiment A254, the compound of any one of embodiments Al to A252, or a pharmaceutically acceptable salt thereof, is wherein R² is alkoxy.

A255. In embodiment A255, the compound of any one of embodiments Al to A252, or a pharmaceutically acceptable salt thereof, is wherein R² is halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino.

A256. In embodiment A256, the compound of any one of embodiments Al to A255, or a pharmaceutically acceptable salt thereof, is wherein R² is 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.

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 R¹ in A5 is limited to halo; and only difluoromethyl, trifluoromethyl, difluoroethyl, and trifluoroethyl should be selected for embodiment A6 as scope of R¹ in A6 is limited to haloalkyl.

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:

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

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

The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds. Volumes 1-5 and 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.

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.

Compounds of Formula (I), where Degron is an E3 ligase ligand of formula (i)-(vi) where R³ is 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.

Scheme 1

Treatment of a pyrimidine of formula 1-1 where A¹ is a halogen such as chlorine or bromine and R¹ and R² are 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 FG¹ is 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 FG¹ in 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 FG¹ and FG² are 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 R³ is 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.

Scheme 2

Treatment of a pyrimidine of formula 1-1 where A¹ is 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 A² is halogen such as chlorine and LG is a suitable leaving group such as halo or methylsulfonyl.

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).

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 R³ is hydrogen. R¹. R². Hy, L, and Degron are as defined in the Summary can be prepared as described in Scheme 3 below:

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

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 R³ is hydrogen, Degron is a group of formula

(i), Z¹ is heterocyclylene such as 4-piperidin- 1 -yl. Z² and Z³ are bond, Z⁴ is aryl (Ar), and Z⁶ is -SO2- can be synthesized as illustrated and described in Scheme 4.

Scheme 4

Treatment of an alkyne containing compound 4-2. where A¹ is 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 A² is 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.

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.

Utility

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.

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.

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.

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

Therefore, a compound of this disclosure may be useful for treating tumors characterized by 1) overexpression of CDK2 and/or CDK4; 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.

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.

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.

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

Testing

CDK2/4 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.

Pharmaceutical Compositions

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 severity⁷ of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

In general, compounds Formula (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.

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

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

- 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.

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

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

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

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

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

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

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

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

Combinations and Combination Therapies

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

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

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

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

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

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

BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (Gleevec®); Inilotinib hydrochloride; Nilotinib (Tasigna®); Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafetinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS 1133385-83-7); Saracatinib (AZD0530); and N-[2-[(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);

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);

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;

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

Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), panitumumab (sold under the tradename Vectibix® by Amgen);

HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), 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);

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

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

Tyrosine kinase inhibitors: Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No. 6,780.996), dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib. sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis);

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

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

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

Immunomodulators: Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the tradename Revlimid®), thalidomide (sold under the tradename Thalomid®);

CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc); Pro-apoptotic receptor agonists (PARAs): Dulanermin (also known as AMG-951, available from Amgen/Genentech);

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

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

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

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

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

Topoisomerase II inhibitors: etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®); mTOR inhibitors: Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR.2R,4S)-4-[(2R)-2[(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);

Proteasome inhibitor such as carfilzomib, MLN9708, delanzomib, or bortezomib;

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

LSD1 inhibitors such as GSK2979552, and INCB059872;

HIF-2a inhibitors such as PT2977 and PT2385;

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

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

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

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

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

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

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

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

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

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

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

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 C₆ eNU®), 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®);

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

Cathepsin K inhibitors: Odanacatib (also known as MK-0822, N-(l-cyanocyclopropyl)-4- fluoro-N-2-{(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);

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

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

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

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

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

CDK (CDK1, CDK2, CDK3, 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);

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;

SHP-2 inhibitor such as TNO155;

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

Taxane anti-neoplastic agents: Cabazitaxel (l-hydroxy-7, 10 -dimethoxy-9-oxo-5,20- epoxytax-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);

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);

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®);

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

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

Retinoids: 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®);

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®);

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);

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

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

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

Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);

One or more immune checkpoint inhibitors CD27, CD28. CD40, 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.

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.

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).

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

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.

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

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

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

Examples

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

Reference 1

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

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

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.

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

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.

Reference 2

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

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

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.

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.

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

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.

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

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

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

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

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

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

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

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

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.

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

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.

Reference 6

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

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

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.

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

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

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

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

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.

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

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

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.

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

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.

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

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

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

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

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.

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

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

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.

Reference 9

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

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

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

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.

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

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.

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

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

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.

Reference 10

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

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

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.

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

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.

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

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 yellow⁷ oil. Step 4: tert-Butyl (3-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)propoxy)propyl)- (methyl)carbamate

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.

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

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.

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

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.

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

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.

Reference 11

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

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.

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

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.

Reference 12

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

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.

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

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

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.

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

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.

Step 4: l-Benzhydrylazetidin-3-yl methanesulfonate

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

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

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

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.

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.

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

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.

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

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

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.

Reference 13

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-

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

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

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.

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

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.

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

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

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

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.

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

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.

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.

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.

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

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.

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

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.

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-

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

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

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

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.

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

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.

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

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

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

Step 1 : 4- Aminocyclohexanone hydrochloride

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.

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

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.

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

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.

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

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

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

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

N-methylpiperidine-1 -sulfonamide 2,2,2-trifluoroacetate

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.

Reference 16

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

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-

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

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

Reference 17

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

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

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.

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

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

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

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

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.

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

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.

Reference 19

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

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

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

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 Na₂SO₄ and then concentrated. The residue was purified by Prep-HPLC to give the title compound as a yellow solid.

Reference 20

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

Step 1 : Dimethyl 3-iodophthalate

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.

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.

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

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.

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

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

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.

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

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.

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

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

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

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.

Reference 21

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

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.

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

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

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.

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

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.

Reference 22

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

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

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.

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

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.

Reference 23

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

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

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.

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

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.

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

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.

Reference 24

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

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

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.

Reference 25

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

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

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

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.

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

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.

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

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.

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.

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

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

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

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.

Reference 27

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

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 Na₂SO₄ and concentrated. The residue was purified by flash chromatography gave title compound as a yellow solid.

Reference 28

Synthesis of 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

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

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.

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

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

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.

Step 4: tert- Butyl (l-((3-(l-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate

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.

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

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

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 Na₂SO₄ and 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.

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

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.

Reference 29

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

Step 1 : 3-5-Bromo-l-oxoisoindolin-2-ylpiperidine-2, 6-dione

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.

Step 2: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-5.6-dihydropyridine- l(2H)-carboxylate

A mixture of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (1.00 g, 3.11 mmol, 1.00 eq.), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)- carboxylate (1.25 g, 4.04 mmol, 1.30 eq.), K3PO4 (800 mg, 3.73 mmol, 1.20 eq) and Pd(dppf)C12 (114 mg, 0.16 mmol, 0.05 eq) in DMF (10.0 mL) was stirred at 90 °C for 12 h. The mixture was concentrated and purified by silica gel column chromatography eluting with PE/EA (1 :2) to give title compound as yellow solid. Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidine-l-carboxylate

To a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-5,6- dihy dropyri dine- l(2H)-carboxy late (200 mg, 0.47 mmol, l.OOeq.) in THF (2.0 mL) was added Pd/C(40 mg. 20%w/w). The resulting mixture was stirred at 40 °C for 12 h under FL, filtered and concentrated to give the title compound as white solid.

Step 4: 3-(l-Oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2, 6-dione

DCM/TFA=4: 1 (2.5 mL) was added to a stirred solution of tert-butyl 4-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidine-l -carboxylate (100 mg. 0.234 mmol, 1.00 eq.) and the mixture was stirred at RT for 2 h. The mixture was concentrated to give the title compound as brown solid.

Step 5: tert-Butyl (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

To a stirred solution of 3-(l-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (76.60 mg, 0.23 mmol, 1.00 eq) in THF (1.0 mL) was added DMF (1.0 mL), HCOOH(1 drop) and tert-butyl (l-((3-(4-formylpiperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (105.60 mg, 0.23 mmol 1.00 eq). The resulting mixture was stirred at 45 °C for 0.5 h. NaBFLCN (29.40 mg, 0.47 mmol, 2.00 eq) was added at RT and the reaction mixture was stirred at RT for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was w ashed with water and brine and concentrated. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (0-100%), to give the title compound as a white solid. Reference 30

Synthesis of tert-butyl (l-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin- l-yl)-methyl)piperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : Benzyl 4-(dimethoxymethyl)piperidine-l -carboxylate

To a mixture of benzyd 4-formylpiperidine-l-carboxylate (1.00 g, 2.40 mmol, 1.00 eq.) in

MeOH (9.0 mL) was added p-TsOH (38 mg, 0.20 mmol, 0.05 eq.) and trimethoxymethane (2. 14 g, 20.22 mmol, 5.00 eq.). The mixture was stirred at RT for 12 h and then extracted with EtOAc. Purification of the crude product by silica gel column chromatography eluting with PE/EtOAc (10: 1) gave the title compound as a colorless oil.

Step 2: 4-(Dimethoxymethyl)piperidine

To a mixture of benzyl 4-(dimethoxymethyl) piperidine-1 -carboxylate (948 mg, 3.23 mmol, 1.00 eq.) in MeOH (10.0 mL) was added Pd/C (400 mg) and the reaction mixture was stirred at RT under H2 for overnight. The resulting mixture was filtered through C₆lite and the filtrate was concentrated to give the title compound as a colorless oil.

Step 3: tert-Butyl (l-((3-(4-(dimethoxymethyl) piperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate

A mixture of 4-(dimethoxymethyl) piperidine (100 mg, 0.63 mmol, 1.20 eq.), K2CO3 (215 mg, 1.56 mmol, 3.00 eq.), Cui (20 mg, 0.104 mmol, 0.20 eq.), L-proline (18 mg, 0.16 mmol, 0.30 eq.) and tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (219 mg, 0.52 mmol, 1.00 eq.) in DMSO (4.0 mL) was stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water and brine and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1: 1) to give the title compound as white solid.

Step 4: tert-Butyl (l-((3-(4-formylpiperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

To a mixture of tert-butyl (l-((3-(4-(dimethoxymethyl)piperidin-l-yl)phenyl)sulfonyl) piperidin-4-yl)carbamate (640 mg, 1.29 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (4.0 mL) and the mixture was stirred at 45 °C overnight. The reaction mixture was concentrated and dissolved in DCM (5.0 mL) followed by addition of TEA (261 mg. 2.58 mmol, 2.00 eq.) and (BOC)₂O (562 mg, 2.58 mmol, 2.00 eq.). The solution was stirred at RT for 4 h, and concentrated and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (3: 1) to give title compound as yellow solid.

Step 5: tert-Butyl (l-((3-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)- methyl)piperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

The compound was prepared analogously as described in Reference 29, Step 5.

Reference 31

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

To a mixture of Zn dust (300 mg, 4.59 mmol, 1.30 eq.) in DMA (3.0 mL) was added 1,2-dibromoethene (66 mg, 0.35 mmol, 0. 10 eq.) and the mixture was stirred at 65 °C under N2 for 30 min. The mixture was allowed to cool to RT and TMSC1 (38 mg, 0.35 mmol. 0.10 eq.) was added. After stirring the mixture for 30 min., a solution of tert-butyl 3 -iodoazetidine- 1 -carboxylate (1.00 g, 3.53 mmol, 1.00 eq.) in DMA (1.0 mL) was added dropwise. The mixture was stirred at 65 °C under N2 for 2 h, cooled to RT and used in next step without further purification.

Step 2: tert-Butyl 3-(2-(2,6-di ox opiperidin-3-yl)-l-oxoisoindolin-5-yl)azeti dine- 1 -carboxylate

A solution of ( 1 -(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (600 mg, 1.72 mmol, 3.00 eq.) in DMA was slowly added to a mixture of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine- 2, 6-dione (185 mg, 0.57 mmol, 1.00 eq.), Cui (12 mg, 0.06 mmol, 0.10 eq.), Pd(dppl)C12 (44 mg, 0.06 mmol, 0. 10 eq.) in DMA (2.0 mL). The mixture was stirred at 90 °C under N2 overnight. The mixture was concentrated and purified by column chromatography on silica gel (EA) to give the title compound as a brown solid.

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

To a solution of tert-butyl 3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)azetidine-l- carboxylate (44 mg, 0.11 mmol, 1.00 eq.) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise and the solution was stirred at RT for 3 h. The resulting mixture was concentrated to give the crude product as a brown oil. Reference 32

Synthesis of tert-butyl (1 -((3-(4-(( 1 -(2-(2.6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : Benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazine-l- carboxylate

A mixture of tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5.00 g, 11.96 mmol. 1.00 eq.). K2CO3 (5.78 g, 41.86 mmol, 3.50 eq.), Cui (0.45 g. 2.39 mmol, 0.20 eq.), L-PRO (0.41 g, 3.59 mmol, 0.30 eq.) in DMSO (25.00 mL) and benzyl piperazine- 1 -carboxyl ate (3.43 g, 15.55 mmol, 1.30 eq.) was stirred at 100 °C for 12 h. The mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (3: 1) to give the title compound as white solid.

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

The title compound was prepared analogously as described in Reference 30, Step 2.

Step 3: Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- 1 -yl)methyl)piperi dine- 1 -carboxy late

A mixture of tert-butyl (l-((3-(piperazin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (1.07 g, 2.52 mmol, 1.00 eq.), AcOH (3 drops) and benzyd 4-formylpiperidine-l -carboxylate (933 mg, 3.78 mmol, 1.50 eq.) in MeOH (10.0 mL) was stirred at 45 °C for 1 h. The solution cooled to RT and NaBFECN (475 mg, 7.56 mmol, 3.00 eq.) was added. The mixture was stirred at RT for 12 h and then diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (60: 1) to give the title compound as white solid.

Step 4: tert-Butyl (l-((3-(4-((l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Benzyl 4-((4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- l-yl)methyl)piperidine-l -carboxylate was converted to the title compound using similar procedure as described in Reference 28, Step 4-7.

Reference 33

Synthesis of tert-butyl (l-((3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)-[l,4'-bipiperidin]-T-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : tert-Butyl (l-((3-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)sulfonyl)piperidin-4-yl)- carbamate

A mixture of tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (1.00 g, 2.40 mmol, 1.00 eq.), K2CO3(1.16 g, 8.40 mmol, 3.50 eq.), Cui (91 mg, 0.480 mmol, 0.20 eq.), L-proline (83 mg, 0.72 mmol, 0.30 eq.) and l,4-dioxa-8-azaspiro[4.5]decane (412 mg, 2.88 mmol, 1.20 eq.) in DMSO (10.0 mL) was stirred at 90 °C overnight. The reaction mixutre was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1 : 1) to give the title compound as yellow solid. Step 2: tert-Butyl (l-((3-(4-oxopiperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of tert-butyl (l-((3-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)- sulfonyl)piperidin-4-yl)carbamate (624 mg, 1.30 mmol, 1.00 eq.), TsOH.H₂O (49 mg, 0.26 mmol, 0.20 eq.) in acetone (6.0 mL) and H₂O (12.0 mL) was stirred at 60 °C overnight. The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography eluting PE/EtOAc (1: 1) to give the title compound as yellow solid.

Step 3: tert-Butyl (l-((3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)-[l,4'-bipiperidin]-T-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl (l-((3-(4-oxopiperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (44 mg, 1.02 mmol, 0.90 eq.) and 1 drop of AcOH was added to a mixture of 3-(3-methyl-2-oxo-4- (piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2.6-dione (387 mg, 1.13 mmol. 1.00 eq.) in THF (5.0 mL). The reaction mixture was stirred at 40 °C for 0.5 h. NaBEECN (142 mg, 2.60 mmol, 2.00 eq.) was added at RT and stirred at RT overnight. The reaction mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (10: 1) to give the title compound as a yellow solid.

Reference 34

Synthesis of 3-(4-(azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)piperidine-2, 6-dione Step 1: tert-Butyl 3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]- imidazol-4-yl)azetidine-l -carboxylate

A solution of (l-(tert-butoxycarbonyl)azetidin-3-yl)zinc (II) iodide (600 mg, 1.72 mmol, 3.00 eq.) in DMA was slowly added to a mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2.6-dione (193 mg. 0.57 mmol, 1.00 eq.) in DMA (2.0 mL) Cui

(12 mg, 0.06 mmol, 0.10 eq.) and Pd(dppf)C12 (44 mg, 0.06 mmol, 0.10 eq.). The mixture was stirred at 90 °C under N2 overnight. The mixture was concentrated and purified by column chromatography on silica gel (EA) to the title compound as a yellow solid.

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

2,6-dione

To a solution of tert-butyl 3-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)azetidine-l-carboxylate (23 mg, 0.055 mmol, 1.00 eq.) in DCM (1.0 mL) was added TFA (0.2 mL) dropwise and the solution was stirred at RT for 3 h. The resulting mixture was concentrated to give the crude product as a brown oil, which was used in next step without further purification.

Reference 35

Synthesis of tert-butyl (l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-5- yl)piperazin-l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1: tert-Butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-l-carboxylate A mixture of methyl 2-bromo-4,5-difluorobenzoate (2.00 g. 8.00 mmol, 1.00 eq.) and tertbutyl piperazine- 1 -carboxylate (2.23 g, 12.00 mmol, 1.50 eq.), K.2CO3 (1.65 g. 12.00 mmol, 1.50 eq.) in DMA (6.0 mL) was stirred at 80 °C overnight. The mixture was diluted with water and extracted EA. The combined organic layer was washed with brine, dried over N 3286)4. concentrated. The residue was purified by flash chromatography (PE:EA=3: 1) to give the title compound as a colorless oil.

Step 2: tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-l-carboxylate

A mixture of tert-butyl 4-(5-bromo-2-fluoro-4-(methoxycarbonyl)phenyl)-piperazine-l- carboxylate (1.50 g, 3.60 mmol, 1.00 eq.) and CuCN (484 mg, 5.40 mmol, 1.50 eq.) in DMF (6.0 mL was stirred at 100 °C overnight. The mixture was extracted with EA and washed with NH₃.H₂O. The organic layer was washed with water and brine, dried over Na₂SO₄ . concentrated and purified by flash chromatography (PE:EA=3: 1) to give the title compound as a white solid.

Step 3: tert-Buty l 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-5-yl)piperazine-l- carboxylate tert-Butyl 4-(5-cyano-2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-l -carboxylate was converted to the title compound by proceeding analogously as described in Reference 28, Step 6-7.

Step 4: 3-(6-Fluoro-l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione

To a stirred solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin- 5-yl)piperazine-l -carboxylate (95 mg, 0.21 mmol, 1.00 eq.) in DCM (2.0 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil. Step 5: tert-Butyl (l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l-oxoisoindolin-5-yl)piperazin- l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of 3-(6-fluoro-l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione (74 mg, 0.33 mmol, 1.00 eq.), tert-butyl (l-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4- yl)carbamate (138 mg, 0.32 mmol, 1.50 eq.), TEA (127 mg, 1.26 mmol, 6.00 eq.) in THF (5.0 mL) was stirred at 55 °C overnight. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried over Na₂SO₄ . concentrated, and the residue was purified by flash chromatography (DCM:MeOH=20: 1) to give the title compound as a yellow solid.

Reference 36

Synthesis of tert-butyl (l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperazine-l- carboxylate

A mixture of tert-butyl piperazine- 1 -carboxylate (950 mg, 5. 10 mmol, 1 .00 eq.) and 2-(2,6- dioxopiperidin-3-yl)-5,6-difluoroisoindoline- 1,3-dione (1.50 g, 5.10 mmol, 1.00 eq.), DIEA (1.97 g, 15.30 mmol, 3.00 eq.) in NMP (15.0 mL) was stirred at 110 °C overnight. The mixture was diluted with water and extracted EA. The organic layer was washed with brine, dried over Na₂SO₄ , concentrated and the residue was purified by flash chromatography (PE:EA=1:2) to give the title compound as a yellow solid. Step 2: 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-l-yl)isoindoline-L3-dione

To a stirred solution of tert-butyl 4-(2-(2.6-dioxopiperidin-3-yl)-6-fluoro-L3- dioxoisoindolin-5-yl)piperazine-l -carboxylate (800 mg, 1.74 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (1.0 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give the title compound as a yellow oil.

Step 3: 3-(Bromomethyl)benzenesulfonyl chloride

A mixture of 3-methylbenzenesulfonyl chloride (8.00 g, 41.96 mol, 1.00 eq.) NBS (8.22 g, 46.16 mol, 1.10 eq.) and benzoyl peroxide (1.46 g, 4.20 mol, 0.01 eq.) in CCI4 (80.00 mL) was stirred at 80 °C for 12 h. The solution was filtered and the filtrate was concentrated to give crude product as white oil.

Step 4: tert-Butyl (l-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl piperidin-4-ylcarbamate (5.64 g, 21.05 mol, 1.00 eq.) in THF (20.00 mL) was added to a stirred solution of 3-(bromomethyl)benzenesulfonyl chloride (3.79 g, 18.95 mol, 0.90 eq.) in THF (40.00 mL) and TEA (4.25 g, 42.10 mmol, 2.00 eq.) at 0 °C. The resulting mixture was stirred at RT for 12 h, quenched with H2O 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 PE/EA (3: 1), to afford the title compound as white solid.

Step 5: tert-Butyl (l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-l-yl)isoindoline-l, 3-dione (509 mg. 1.41 mmol, 1.00 eq.), tert-butyl (l-((3-(bromomethyl)phenyl)sulfonyl)-piperidin-4- yl)carbamate (916 mg, 2.12 mmol, 1.50 eq.) TEA (854 mg, 8.46 mmol, 6.00 eq.) in THF (10.0 mL) was stirred at 55 °C overnight. The mixture was extracted DCM and water. The organic layer was washed with brine, dried overNa₂SO₄ , filtered and concentrated. The residue was purified by flash chromatography (DCM:MeOH=20: 1) to give the title compound as a yellow solid.

Reference 37

Synthesis of tert-butyl (l-((3-((8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)-

3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : tert-Butyl 8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindohn-5-yl)-3.8-di- azabicyclo [3.2.1 ] octane-3 -carboxylate

A mixture of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-l, 3-dione (200 mg, 0.68 mmol, 1.00 eq.), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (144 mg, 0.68 mmol, 1.00 eq.) and DIEA (263 mg, 2.04 mmol. 3.00 eq.) in NMP (3.0 mL) was stirred at 110 °C overnight. The reaction mixture was quenched with H2O 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 eluting with PE/EtOAc (1 : 1) to give title compound as yellow solid.

Step 2: tert-Butyl (l-((3-((8-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)-3.8- diazabicyclo[3.2.1]octan-3-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl 8-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate was converted to the title compound proceeding analogously as described in Reference 36, Step 2-5. Reference 38

Synthesis of tert-buty l (l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l- yl)-methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : tert-Butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-l-carboxylate

To a stirred solution of methyl 2-cyano-4-fluorobenzoate (10.00 g, 55.80 mmol, 1.00 eq.) in DMSO (150.0 mL) was added tert-butyl piperazine- 1 -carboxylate (1 1.40 g, 61.38 mmol, 1.10 eq.) and DIEA (34.70 g, 268.96 mmol, 4.80 eq.). The resulting mixture was stirred at 110 °C for 12 h. The mixture was extracted with EtOAc washed with brine, concentrated and purified by silica gel column chromatography eluting with PE/EtOAc (3: 1) to give the title compound as yellow solid.

Step 2: tert-Butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-l -carboxylate

A mixture of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-l -carboxylate (8.00 g, 23.20 mmol, 1.00 eq.) NaH₂PO₂.H₂O (5.20 g, 48.70 mmol, 2.10 eq.) and Raney-Ni (5.10 g) in pyridine:H₂O:AcOH=2: l: l (80.0 mL) was stirred at 70 °C for 12 h. The mixture was adjusted pH=7~8 with aq.NaHCCE, filtered, and extracted with EtOAc. The organic layer was washed with brine, concentrated and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (3: 1) to give the title compound as yellow solid. Step 3: tert-Butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine-l -carboxylate A mixture of 3-aminopiperidine-2.6-dione hydrochloride (2.60 g, 15.50 mmol, 1.20 eq.) D1EA (4.03 g, 31.22 mmol, 2.42 eq.). AcOH (10.63 g, 188.76 mmol. 13.78 eq.) and tert-butyl 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-l-carboxylate (4.50 g, 12.90 mmol, 1.00 eq.) in DCM (50.0 mL) was stirred at 35 °C for 4 h and then NaBH(OAc)3 (8.20 g, 38.70 mmol, 3.00 eq.) was added at RT. The mixture was stirred at 40 °C for 12 h and diluted with water and extracted with EtOAc. The organic layer was washed with brine, concentrated, and the residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:2) to give the title compound as white solid.

Step 4: 3-( 1 -Oxo-5-(piperazin- 1 -yl)isoindolin-2-yl)piperidine-2, 6-dione

To a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazine- 1-carboxylate (72 mg. 0. 17 mmol. 1.00 eq.) in DCM (4.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at RT for 2 h and then concentrated to give the title compound as yellow⁷ oil.

Step 5: tert-Butyl (l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)- methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

To a stirred solution of 3-(l-oxo-5 -(piperazin- l-yl)isoindolin-2-yl)piperidine-2,6-di one (55 mg, 0.17 mmol, 1.00 eq.) in THF (2.0 mL) were added TEA (52 mg, 0.51 mmol, 3.00 eq.) and tert-butyl (l-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (95 mg, 0.22 mmol, 1.30 eq.). The reaction mixture was stirred at 55 °C overnight. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with DCM/MeOH (20: 1) to give the title compound as a yellow⁷ solid. Reference 39

Synthesis of tert-butyl (l-((3-((7-(2-(2.6-dioxopiperidin-3-yl)-l-oxoisoindolm-5-yl)-2,7- diazaspiro-[3.5]nonan-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : tert-Butyl 7-(3-cyano-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2- carboxvlate

A mixture of methyl 2-cyano-4-fluorobenzoate (1.00 g, 5.58 mmol. 1.00 eq.) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.39 g, 6.14 mmol. 1.10 eq.) DIEA (719 mg, 16.74 mmol, 3.00 eq.) in DMSO (10.0 mL) was stirred at 110 °C overnight. The mixture was diluted with water and extracted EA. The organic layer was washed with brine, dried over ISfeSCE, and concentrated. The residue was purified by flash chromatography (PE:EA=3: 1) to give the title compound as a white solid.

Step 2: tert-Butyl 7-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane- 2-carboxvlate tert-buty l 7-(3-Cyano-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2- carboxylate was converted to the title compound by proceeding analogously as described in Reference 28, Step 6-7.

Step 3: 3-(l-Oxo-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindolin-2-yl)piperidine-2, 6-dione

To a stirred solution of tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (220 mg, 0.32 mmol, 1.00 eq.) in DCM (2.0 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated to give title compound as a yellow oil.

Step 4: tert-Butyl (l-((3-((7-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)-2,7-diazaspiro-

[3.5]nonan-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of 3-(l-oxo-5-(2,7-diazaspiro[3.5]nonan-7-yl)isoindolin-2-yl)piperidine-2,6- dione (173 mg, 0.47 mmol, 1.00 eq.) and tert-butyl (l-((3-(bromomethyl)phenyl)sulfonyl)- piperidin-4-yl)carbamate (264 mg, 0.61 mmol, 1.30 eq.) TEA (285 mg. 2.82 mmol, 6.00 eq.) in THF (5.0 mL) was stirred at 55 °C overnight. The mixture was diluted with water and extracted DCM. The organic layer was washed with brine, dried over Na₂SO₄ , and concentrated. The residue was purified by flash chromatography (DCM: MeOH=20: l) to give the title compound as a yellow solid.

Reference 40

Synthesis of rac-tert-butyl ((3R,4S)-l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate

Step 1 : rac-tert-Butyl ((3R,4S)-l-((3-(bromomethyl)phenyl)sulfonyl)-3-fluoropiperidin-4- yl)carbamate

3-(Bromomethyl)-benzene-l-sulfonyl chloride (122 mg, 0.46 mmol, 1.00 eq.) in THF(1.0 mL was added to a solution of rac-tert-butyl ((3R,4S)-3-fluoropiperidin-4-yl)carbamate (100 mg, 0.46 mmol, 1.00 eq.) and TEA (93 mg, 0.92 mmol, 2.00 eq.) in THF (2.0 mL) slowly at -10 °C for 3 h. The mixture was diluted with water and extracted EA. The organic layer was washed with brine, dried over Na₂SO₄ , and concentrated. The residue was purified by flash chromatography

(PE:EA=4:1) to give the title compound as a white solid.

Step 2: rac-tert-Butyl ((3R,4S)-l-((3-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate

To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(piperazin-l-yl)isoindoline-l,3- dione (94 mg, 0.26 mmol. 1.00 eq.) and rac-tert-butyl ((3R.4S)-l-((3-(bromomethyl)phenyl)- sulfonyl)-3-fluoropiperidin-4-yl)carbamate (141 mg, 0.31 mmol, 1.20 eq.) in THF (4.0 mL) was added TEA (131 mg, 1.30 mmol, 5.00 eq.) and the mixture was stirred at 55 °C overnight. The mixture was diluted with water and extracted DCM. The organic layer was washed with brine, dried over Na₂SO₄ , and concentrated. The residue was purified by flash chromatography (DCM:MeOH=20: 1) to give the title compound as a yellow' solid.

Reference 41

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

Step 1 : 2-(2,6-Dioxopiperidin-3-yl)-l-oxoisoindoline-5-carbonitrile

A mixture of 3-(5-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (2.00 g, 6.21 mmol, 1.00 eq.) and Zn(CN)2 (438 mg, 3.73 mmol. 0.60 eq.) Pd(pphs)4 (714 mg) in DMF (30.0 mL) was stirred at 100 °C overnight. The mixture was extracted with DCM and purified by silica gel column chromatography eluting with PE/EtOAc (1 :2) to give the title compound as yellow solid. Step 2: 2-(2,6-Dioxopiperidin-3-yl)-l-oxoisoindoline-5-carbaldehyde

A mixture of 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindoline-5-carbonitrile (1.20 g, 4.46 mmol, 1.00 eq.), NaH₂PO₂.H₂0 (993 mg, 9.37 mmol, 2.10 eq.) and Raney-Ni (500 mg) in pyridine: H₂O: AcOH (40.0 mL, 2:2: 1) was stirred at 70 °C overnight. The reaction mixture was filtered and washed with aq. NaHCOs. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting PE/EtOAc (1:2) to give the title compound as yellow solid.

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

A mixture of tert-butyl (l-((3-((tert-butoxycarbonyl)oxy)phenyl)sulfonyl)piperidin-4- yl)carbamate (7.30 g, 16.0 mmol, 1.00 eq.), benzyl 4-((methylsulfonyl)oxy)piperidine-l- carboxylate (7.52 g, 24 mmol, 1.50 eq.) and CS₂CO₃ (10.4 g, 32 mmol, 2.00 eq.) in DMSO (70.0 mL) was stirred at 90 °C for 4 h and then extracted with EtOAc. The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting PE/EtOAc (3: 1) to give the title compound as a yellow solid.

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

A mixture of benzyl 4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)- phenoxy)piperidine-l -carboxylate ( 6.0 g. 10.47 mmol. 1.00 eq.). HCOONH4 ( 3.3 g, 52.35 mmol, 5.00 eq.), and Pd(OH)2 (1.2 g) in EtOH (60.0 mL) was stirred at 70 °C for 4 h. The mixture was filtered and concentrated to give the title compound as a white solid.

Step 5: tert-Butyl (l-((3-((l-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)piperidin-

4-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)carbamate

To a mixture of 2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindoline-5-carbaldehyde (100 mg, 0.37 mmol, 1.00 eq.) in THF (3.0 mL) were added tert-butyl (l-((3-(piperidin-4-yloxy)phenyl)- sulfonyl)piperidin-4-yl)carbamate (169 mg, 0.39 mmol, 1.05 eq.) and 1 drop of AcOH. The mixture was stirred at 40 °C for 0.5 h. NaBH₃CN (47 mg, 0.74 mmol, 2.00 eq.) was added and stirred at RT for 16 h. The reaction mixture was diluted with water and extracted DCM. The organic layer was washed with brine, dried over Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting with DCM/MeOH (20: 1) to give the title compound as a yellow solid.

Reference 42

Synthesis of tert-butyl (l-((3-(4-(l-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)azetidin-3- vl )pi perazin- 1 -yl)phenyl)sulfonyl)piperidin-4-y l)carbamate

Step 1 : Benzyl 3-(4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenyl)piperazin- 1 -yl)azetidine- 1 -carboxylate

To a mixture of tert-butyl (l-((3-(piperazin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (740 mg, 1.75 mmol, 1.00 eq.) in THF (10.0 mL) were added AcOH (3 drops) and benzy l 3-oxoazetidine-l -carboxylate (718 mg, 3.50 mmol, 2.00 eq.). The solution was stirred at 45 °C for 0.5 h. The solution was cooled to RT and NaBHsCN (220 mg, 3.50 mmol, 2.00 eq.) was added. The solution was stirred at RT overnight and then extracted with EtOAc. The mixture was diluted with water and extracted DCM. The organic layer was washed with brine, dried over Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting DCM/MeOH (20: 1) to give the title compound as a white oil.

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

Benzyl 3-(4-(3-((4-((tert-butoxycarbonyl)amino)piperidin-l-yl)sulfonyl)phenyl)-piperazin- 1 -yl)azetidine- 1 -carboxylate was converted to the title compound using similar procedure as described in Reference 28, Step 4-7.

Reference 43

Synthesis of tert-butyl ( 1 -((3 -(3-(4-(2-(2,6-dioxopiperi din-3 -y 1)- 1 -oxoisoindolin-5 -y l)piperazin- 1 - yl)-azetidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Step 1 : 3-Hydroxyazetidine

To a stirred solution of 1-benzhy dry lazeti din-3 -ol (5.00 g. 20.92 mmol. 1.00 eq.) and

Pd(OH)2_? (3.50 g) in MeOH (130.00 mL) was added AcOH (18.50 mL). The resulting mixture was stirred at 50 °C under H2 (50 psi) for 12 h. HC1 (aq) was added to adjust the pH of the solution to pH 3. The solution was concentrated to give crude product as white oil.

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

A mixture of tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5.83 g, 13.95 mmol, 1.00 eq.), K2CO3 (6.74 g, 48.83 mmol, 3.50 eq.), Cui (0.53 g, 2.79 mmol, 0.20 eq.), L-PRO (481 mg, 4.19 mmol, 0.30 eq.) and 3-hydroxyazetidine (2.28 g, 20.92 mmol, 1.50 eq.) in DMSO (50.00 mL) was stirred at 90 °C for 12 h. The mixture was quenched with H2O and extracted with EtOAc. The organic layer was concentrated and purified by silica gel column chromatography eluting with PE/EtOAc (2: 1) to give the title compound as white solid. Step 3: tert-Butyl (l-((3-(3-oxoazetidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

To a stirred solution of tert-butyl (l-((3-(3-hydroxyazetidin-l-yl)phenyl)sulfonyl)- piperidin-4-yl)carbamate (0.50 g, 1.22 mmol, 1.00 eq.) in DCM (5.00 mL) was added Dess-Martin (1.03 g, 2.44 mmol, 2.00 eq.) and the mixture was stirred at 0 °C for 3 h. The mixture was diluted with sodium thiosulfate (aq) and extracted with DCM. The organic layer was concentrated and the residue was purified by silica gel column chromatography, eluted with EtOAc/PE (3: 1), to give the title compound as a white solid.

Step 4: tert-Butyl (l-((3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)piperazin-l-yl)- azetidin- 1 -yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

To a solution of tert-butyl (l-((3-(3-oxoazetidin-l-yl)phenyl)sulfonyl)piperidin-4- yl)carbamate (40.00 mg, O. lOmmol, 1.00 eq.) in THF(1.00 mL) and DMF (0.50 mL) were added AcOH (3 drops) and 3-(l-oxo-5-(piperazin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione (39.00 mg, 0.12 mmol, 1.20 eq.). The solution was stirred at 45 °C for 45 min. The solution cooled to RT and NaBEfiCN (13.00 mg, 0.20 mmol, 2.00 eq.) was added. The mixture was stirred at RT for 12 h and then diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by TLC, eluted with DCM/MeOH (20: 1 ), to afford the title compound as a white solid.

Reference 44

Synthesis of tert-butyl (l-((3-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-4-yl)piperidin-l-yl)azetidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a solution of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol- l-yl)piperidine-2, 6-dione (41.00 mg, 0.12mmol, 1.00 eq) in THF (2.00 mL) and DMF (0.50 mL) were added AcOH (3 drops) and tert-butyl (l-((3-(3-oxoazetidin-l-yl)phenyl)sulfonyl)piperidin-4- yl)carbamate (98.00 mg, 0.24 mmol, 2.00 eq.). The solution was stirred at 45 °C for 0.5 h. Then the solution cooled to RT and NaBH₃CN (15.08 mg, 0.24 mmol, 2.00 eq.) was added. The mixture was stirred at RT for 12 h and then diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by TLC, eluted with DCM/MeOH (20:1), to afford the title compound as a white solid.

Reference 45

Synthesis of rac-l-(6-(l-(3-(((3R,4S)-4-amino-3-fluoropiperidin-l-yl)sulfonyl)benzyl)piperidin-4- yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

Step 1 : 6-Bromo-l -methyl- lH-indazol-3 -amine

To a stirred solution of 4-bromo-2-fluorobenzonitrile (10 g, 0.05 mol, 1.00 eq.) in EtOH (50.0 mL) was added methylhydrazine (57 g, 0.50 mol, 10.00 eq.) and the mixture was stirred at 100°C 30h in sealed tube. Then the mixture was concentrated, and added water. The mixture was filtered to give title compound as pale yellow solid.

Step 2: Methyl 3-((6-bromo-l-methyl-lH-indazol-3-yl)amino)propanoate

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

Step 3: Methyl 3-(l-(6-bromo-l-methyl-lH-indazol-3-yl)ureido)propanoate

NaOCN (26.00 g, 0.32 mol, 2.00 eq.) was added to a solution of methyl 3-((6-bromo-l- methyl-lH-indazol-3-yl)amino)propanoate (50.00 g, 0.16 mol, 1.00 eq.) in AcOH (500.0 mL), and the mixture was stirred at 80°C 20 h under N2. The mixture was diluted with water and extracted with EA, and the organic layer was washed with sat. NaHCCfi aq., water, brine, dried over Na₂SO₄ , concentrated to give the title compound as yellow solid.

Step 4: l-(6-Bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

To a solution of methyl 3-(l-(6-bromo-l-methyl-lH-indazol-3-yl)ureido)propanoate (56.00 g, 0.16 mol, 1.00 eq.) in MeCN (500.0 mL) was added Tirton-B (7.90 g, 0.05 mol, 0.30 eq.) and stirred at r.t. for 20 h under N2. The mixture was concentrated, then diluted with water. The mixture was filtered and solid was washed with water, air dried to give the title compound as pale yellow solid.

Step 5: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-5,6- dihydropyridine- 1 (2H)-carboxy late

To a mixture of l-(6-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- dione (1.10 g, 3.41 mmol, 1.00 eq.) in l,4-dioxane/H2O (10 mL/1 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (1.60 g, 5. 11 mmol, 1.50 eq.), K?PO₄ (2.20 g, 10.22 mmol, 3.00 eq.) and X-Phos-Pd G3 (289 mg, 0.34 mmol, 0. 10 eq. ). and the mixture was stirred at 60 °C under N2 for 3 h. The mixture was diluted with DCM, and the organic layer was washed with water and brine, dried over Na2SO₄, concentrated and purified by column chromatography on silica gel (DCM:MeOH = 20 : 1) to give the title compound as yellow solid.

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

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

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

Step 8 : rac-tert-Buty 1 ((3R,4S)- 1 -((3-((4-(3 -(2,4-dioxotetrahy dropyrimidin- 1 (2H)-yl)- 1 -methyl- lH-indazol-6-yl)piperidin-l-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate A mixture of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(1 H,3H)-di one (82 mg. 0.25 mmol. 1.00 eq.), rac-tert-butyl ((3R,4S)-l-((3- (bromomethyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate (115 mg, 0.25 mmol, 1.00 eq.) in DCM (4.0 mL), and TEA (76 mg, 0.75 mmol, 3.00 eq.) was stirred at 50 °C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (DCM:MeOH = 15 : 1) to give the title compound as white solid. Step 9: rac-1 -(6-(l -(3-(((3R,4S)-4-amino-3-fluoropiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)- l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

A mixture of tert-butyl ((3R,4S)-l-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l- methyl-lH-indazol-6-yl)piperidin-l-yl)methyl)phenyl)sulfonyl)-3-fluoropiperidin-4-yl)carbamate (45 mg, 0.07 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as its TFA salt as brown oil.

The following intermediates were synthesized by proceeding analogously as described in Reference 45.

Reference 46

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

A mixture of l-bromo-4-nitrobenzene (1.0 g, 4.95 mmol. 1.00 eq), tert-butyl 4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-5.6-dihydropyridine-l(2H)-carboxylate (2.30 g, 7.43 mmol, 1.50 eq), K2CO3 (1.37 g, 9.90 mmol, 2.00 eq), and Pd(dppf)C12 (724 mg, 0.99 mmol, 0.20 eq) in dioxane/H2O (15 mL, 5/1 ) was stirred at 100 °C for 4 h. The mixture was filtered and extracted with EA. The combined organic layers were dried over anhydrous Na₂SO₄ . filtered, and concentrated. The residue was purified by silica flash column PE/EtOAc (10: 1) to give product as yellow solid.

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

A mixture of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-l(2H)-carboxylate (1.20 g, 3.95 mmol, 1.00 eq). Pd/C (360 mg) in MeOH/THF (30 mL, 1: 1) was stirred at 45 °C under H2 overnight. The mixture was filtered and concentrated, and the residue was purified by silica flash column PE/EtOAc (3: 1) to give product as yellow solid.

Step 3: tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l-carboxylate

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

TFA (0.5 mL) was added to a mixture of tert-butyl 4-(4-((2.6-dioxopiperidin-3- yl)amino)phenyl)piperidine-l -carboxylate (100 mg, 0.26 mmol, 1.00 eq.) in DCM (2.0 mL) and the mixture was stirred at rt for 2 h. The solution was concentrated to give the title compound as a yellow solid.

Reference 47

Synthesis of 3-(4-(piperazin-l-yl)phenyl)piperidine-2.6-dione

To a stirred solution of phenylmethanol (14.60 g, 135.14 mmol, 2.00 eq.) in THF (250.0 mL) were added t-BuOK (38.00 g, 337.84 mmol, 5.00 eq.) and 2,6-dichloropyridine (10.00 g, 67.57 mmol, 1.00 eq.). The mixture was stirred at 75 °C for 20 h under N2. The mixture was diluted with water and extracted with EA, and the combined organic layers was washed with brine, dried over Na₂SO₄ , concentrated to give the title compound as pale yellow solid.

Step 2: 2,6-Bis(benzyloxy)-3-bromopyridine

NBS (8.70 g, 0.05 mol, 0.95 eq.) was added to a stirred solution of 2,6-bis(benzyloxy)- pyridine (15.00 g, 0.05 mol, 1.00 eq.) in MeCN (100.0 mL) and the mixture was stirred at 80 °C for 4 h under N2. The mixture was diluted with water and extracted with EA. The combined organic layers was washed with brine, dried over Na₂SO₄ , concentrated to give the title compound as yellow solid.

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

A mixture of 2.6-bis(benzyloxy)-3-bromopyridine (19.00 g. 0.05 mol, 1.00 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1.3.2-dioxaborolane) (19.60 g, 0.08 mol. 1.50 eq.), KOAc (10.00 g, 0.10 mol, 2.00 eq ), and Pd(dppf)C12 (3.7 g, 5.00 mmol, 0.10 eq.) in 1,4-dioxane (200.0 mL) was stirred at 100 °C for 25 h under N2. The mixture was diluted with water and extracted with EA, and the combined organic layer was washed with brine, dried over Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting with EA:PE= 0 to 100% to give title compound as yellow solid.

Step 4: 2,6-Bis(benzyloxy)-3-(4-bromophenyl)pyridine

A mixture of 2.6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3.2-dioxaborolan-2-yl)pyridine (4.42 g, 10.60 mmol, 1.20 eq.), 1 -bromo-4-iodobenzene (2.50 g, 8.83 mol, 1.00 eq.). K.3PO4 (5.63 g, 26.50 mmol, 3.00 eq ), and Pd(PPhs)4 (510 mg, 0.44 mmol, 0.05 eq.) in l,4-dioxane/H2O=10: 1 (40.0 mL) was stirred at 100 °C for 16 h under N2. The mixture was diluted with water and extracted with EA, and the combined organic layer was washed with brine, dried over Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting with EA:PE= 0 to 100% to give the title compound as yellow solid.

Step 5: tert-Butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l-carboxylate

A mixture of 2.6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (500 mg, 1.12 mmol, 1.00 eq.), tert-butyl piperazine- 1 -carboxylate (417 mg, 2.24 mmol, 2.00 eq.), CS2CO3 (730 mg, 2.24 mmol, 2.00 eq.), Pd2(dba)s (51 mg, 0.06 mmol, 0.05 eq.), and Ruphos (52 mg, 0.11 mmol, 0.10 eq.) in toluene (15.0 mL) was stirred at 110 °C for 20 h under N2. The mixture was diluted with water and extracted with EA, and the combined organic layer was washed with brine, dried over Na^SOi. concentrated. The residue was purified by silica gel column chromatography eluting with EA:PE= 0 to 100% to give the title compound as yellow solid.

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

A mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-l- carboxylate (260 mg, 0.47 mmol, 1.00 eq.), 10% Pd/C (260 mg) in EA (5.0 mL) and 1,4-dioxane (5.0 mL) was stirred at r.t for 20 h under H2. The mixture was filtered and the filtrate was concentrated to give the title compound as yellow oil.

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

TFA (0.5 mL) was added to a stirred solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperazine-l-carboxylate (160 mg, 0.43 mmol, 1.00 eq.) in DCM (2.0 mL) and the mixture was stirred at r.t for 2 h under N2. The mixture was concentrated to give the title compound as its TFA salt as yellow oil.

Reference 48

Synthesis of 1 -(6-( 1 -(4-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2-methylbut-3-yn-2- yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione hydrochloride Step 1 : l-(l-Methyl-6-(l-(2-methylbut-3-yn-2-yl)piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2.4(lH.3H)-dione

To a solution of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydro pyrimidine- 2,4(lH,3H)-dione (720 mg, 2.2 mmol, 1.0 eq.) in DMSO (5 mL) was added 3-chloro-3-methylbut- 1-yne (451 mg, 4.4 mmol, 2.0 eq.), CuCl (21 mg, 22 mmol. 10.0 eq.) and TEA (0.92 mL, 6.6 mmol, 3.0 eq.), and the resulting mixture was stirred at r.t. for 20 min. The mixture was diluted with water, and the precipitated solid was collected by filtration. The solid was redissolved in DCM, and the organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in next step without further purification. Step 2: tert-Butyl (l-((3-(3-(4-(3-(2.4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol- 6-yl)piperidin-l-yl)-3-methylbut-l-yn-l-yl)phenyl) sulfonyl) piperidin-4-yl)carbamate

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

Step 3: l-(6-(l-(4-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2-methylbut-3-yn-2-yl)piperidin- 4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione hydrochloride A mixture of tert-butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)piperidin-l-yl)-3-methylbut-l-yn-l-yl)phenyl) sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.41 mmol) in ethyl acetate (1 mL) and HCl/EtOAc (4 M, 1 mL) was stirred at r.t. for 2 hrs. The mixture was concentrated under reduced pressure to afford the title compound.

Reference 49

Synthesis of 4-((4-Aminopiperidin-l-yl)sulfonyl)-2-(3-(4-(3-(2.4-dioxotetrahydropyrimidin- l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)but-l-yn-l-yl)benzonitrile hydrochloride

Step 1 : l-(6-(l-(But-3-yn-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydro pyrimidine- 2,4(1 H,3H)-dione

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

Step 2: tert-Butyl (l-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)piperidin- 1 -y l)but- 1 -yn- 1 -y l)phenyl)sulfony l)piperidin-4-y l)carbamate To a solution of l-(6-(l-(but-3-yn-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3- yl)dihydropyrimidine-2.4(lH.3H)-dione (175 mg. 0.46 mmol, 1.0 eq.). Cui (7.98 mg, 0.04 mmol, 0.1 eq ), tert-butyl(l-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (225.41 mg, 0.51 mmol, 1.1 eq.) and triethylamine (212.12 mg, 2.1 mmol, 4.0 eq.) in DMF (3 rnL) was added Pd(dppf)2Ch (30.68 mg, 0.04 mmol, 0.1 eq.) under argon atmosphere, then the resulting mixture was stirred at 100 °C for 2 hrs. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound.

Step 3: 4-((4-Aminopiperidin-l-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- 1 -methyl- 1 H-indazol-6-y l)piperidin- 1 -y l)but- 1 -yn- 1 -y l)benzonitrile hydrochloride

To a solution of tert-butyl (l-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- l-methyl-lH-indazol-6-yl)piperidin-l-yl)but-l-yn-l-yl)phenyl)sulfonyl)pipendin-4-yl)carbamate (116.26 mg, 0. 16 mmol) in DCM (3 mL) was added 4.0M HC1 in dioxane (1.5 mL, 6 mmol), then the resulting mixture was stirred at r.t for 1 h. The mixture was concentrated under reduced pressure to afford the title compound.

Reference 50

Synthesis of 1 -(6-(piperidin-4-yl)-l -(2,2,2-trifluoroethyl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione

Step 1 : 6-Bromo-l-(2,2,2-trifluoroethyl)-lH-indazol-3-amine NaH (2.10 g, 52.83 mmol, 2.00 eq.) was added to a stirred solution of 6-bromo-lH- indazol-3-amine (5.60 g. 26.42 mmol. 1.00 eq.) in DMF (20.0 mL) at 0 °C and the mixture was stirred at 0 °C for Ih. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.7 g, 29.06 mmol, 1.10 eq.) was added and the mixture was stirred at r.t. for 3 h under N2. The mixture was poured into cold water and filtered. The solid was washed with water and dried to give the title compound as yellow solid.

Step 2: l-(6-(Piperidin-4-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione

The title compound was synthesized by proceeding analogously as described in Reference 45, Steps 2-7 with 6-bromo-l-(2,2,2-trifluoroethyl)-lH-indazol-3-amine replacing 6-bromo-l- methyl-lH-indazol-3 -amine.

Reference 51

Synthesis of l-(l -methyl-6-(piperazin-l -yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-

Step 1 : Benzyd 4-(4-cyano-3-fluorophenyl)piperazine-l -carboxylate

A mixture of 2,4-difluorobenzonitrile (18.95 g, 136.20 mmol, 1.50 eq ), benzyd piperazine- 1-carboxylate (20 g, 90.80 mmol, 1.00 eq.) and potassium carbonate (25.10 g, 181.6 mmol, 2.00 eq.) in ACN (200.0 mL) was stirred at 80 °C under N2 for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3: 1) to give the title compound as white solid. Step 2: Benzyl 4-(3-amino-lH-indazol-6-yl)piperazine-l -carboxylate

A mixture of benzyl 4-(4-cyano-3-fluorophenyl)piperazine-l-carboxylate (11.00 g. 32.40 mmol, 1.00 eq.) and N2H4/H2O (10.14g. 161.99 mmol, 5.00 eq) in BuOH (100.0 mL) was stirred at 100 °C under N2 for 16 h. The mixture was concentrated and purified by flash chromatography to give the title compound as yellow solid.

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

To a solution of benzyl 4-(3-amino-lH-indazol-6-yl)piperazine-l-carboxylate (4.00 g, 11.40 mmol. 1.00 eq.) in dry DMF (50.0 mL) at 0 °C was added NaH (0.91 g, 22.80 mmol, 2.00 eq.) under N2, and the mixture was stirred at rt for 30 min. The mixture was cooled to 0 °C, CH3I (1.78 g, 12.54 mmol, 1.10 eq.) in dry DMF (10.0 mL) was added dropwise, and the mixture was stirred for 3 h. The mixture was quenched with water, extracted with EA. The combined organic layers were washed with brine, dried with Na₂SO₄ , and concentrated. The residue was purified by silica gel column chromatography eluting with DCM/MeOH = (50: 1) to give the title compound as yellow solid.

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

The title compound was synthesized by proceeding analogously as described in Reference 45, Steps 2-4 with benzyl 4-(3-amino-l-methyl-lH-indazol-6-yl)piperazine-l-carboxylate replacing 6-bromo-l -methvl-lH-indazol-3-amine. Step 5: l-(l-Methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

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

Reference 52

Synthesis of 1 -(6-(piperazin- 1 -y 1)- 1 -(2,2,2-trifluoroethy 1)- 1 H-indazol-3 -y 1)- dihydropyrimidine-2,4(lH,3H)-dione

Step 1 : Benzyl 4-(3-amino-l-(2,2,2-trifluoroethyl)-lH-indazol-6-yl)piperazine-l-carboxylate

The title compound was prepared by proceeding analogously as described in 51, with 2,2,2-trifluoroethyl trifluoromethanesulfonate replacing Mel in Step 3.

Step 2: 3-((6-(4-((Benzyloxy)carbonyl)piperazin-l-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)- amino)propanoic acid

A mixture of benzyl 4-(3-amino-l-(2,2,2-trifluoroethyl)-lH-indazol-6-yl)piperazine-l- carboxylate (950 mg, 2.20 mmol, 1.00 eq.) and acrylic acid (237.6 mg, 3.30 mmol, 1.50 eq.) in toluene (10.0 mL) was stirred at 130 °C under N2 for 12h. The mixture was concentrated and the residue was punfied by column chromatography (DCM:MeOH=80: l) to give the title compound as a yellow solid.

Step 3: Benzyd 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol- 6-y l)piperazine- 1 -carboxylate

A mixture of 3-((6-(4-((benzyloxy)carbonyl)piperazin-l-yl)-l-(2,2,2-trifluoroethyl)-lH- indazol-3-yl)amino)propanoic acid (620 mg, 1.23 mmol, 1.00 eq.) and urea (369 mg, 6.15 mmol, 5.00 eq.) in AcOH (10.0 mL) was stirred at 120 °C under N2 overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄ , filtered and concentrated. The residue was purified by column chromatography (DCM:MeOH=100: 1) to give the title compound as a yellow solid.

Step 4: l-(6-(Piperazin-l-yl)-l-(2.2.2-trifluoroethyl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione

A mixture of benzy l 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l -(2,2,2- trifluoroethyl)-lH-indazol-6-yl)piperazine-l-carboxylate (280 mg, 0.52 mmol, 1.00 eq.), HCOONH4 (312 mg, 5.20 mmol, 10.0 eq.) and 10% Pd/C (100 mg) in THF/MeOH (5.0 mL/5.0 mL) was stirred at 60 °C under N2 overnight. The mixture was concentrated and the residue was purified by column chromatography (DCM:MeOH = 12 : 1) to give the title compound as a yellow solid. Reference 53

Synthesis of l-(6-(3,3-difluoropipendm-4-yl)-l-methyl-lH-mdazol-3-yl)dihydropynmidine- 2,4(lH,3H)-dione 2,2,2-trifluoroacetate

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

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

Step 2: tert-Butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l(2H)- carboxylate

'IT2O (3.03 g. 10.77 mmol. 1.50 eq.) was added to a mixture of tert-butyl 3.3-difluoro-4- oxopiperidine- 1 -carboxylate (1.68 g, 7.18 mmol, 1.00 eq.) and DIEA (5.56 g, 43.08 mmol, 6.00 eq.) in DCM (20.0 mL). The mixture was stirred at -10 °C under N2 and then stirred at r.t. overnight. The mixture was concentrated in vacuo and purified by column chromatography on silica gel (PE:EA = 10 : 1) to give the title compound as a brown oil. Step 3: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3.3- difluoro-3.6-dihydropyridine-l(2H)-carboxylate

A mixture of l-(l-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione (800 mg, 2.00 mmol, 1.00 eq.), tert-butyl 3,3-difluoro-4- (((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l(2H)-carboxylate (1.10 g, 3.00 mmol, 1.50 eq.), Na2CO? (636 mg. 6.00 mmol, 3.00 eq.), Pd(dppf)C12 (146 mg. 0.20 mmol, 0. 1 eq.) and H2O (2.5 mL) in 1,4-dioxane (10.0 mL) was stirred at 55 °C under N2 overnight. The mixture was concentrated and the residue was purified by column chromatography on silica gel (DCM:MeOH = 120 : 1) to give the title compound as a yellow solid.

Step 4: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-3.3- difluoropiperidine-1 -carboxylate

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

Step 5: l-(6-(3,3-Difluoropiperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione 2,2,2-trifluoroacetate

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

Reference 54

Synthesis of l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH- indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2,2,2-trifluoroacetate

NBS (8.22 g, 46.16 mol, 1.10 eq.) and benzoyl peroxide (1.46 g, 4.20 mol, 0.01 eq.) were added to a stirred solution of 3-methylbenzenesulfonyl chloride (8.00 g, 41.96 mol, 1.00 eq.) in CCU (80.0 mL) and the mixture was stirred at 80°C for 12h. The mixture was filtered, and the filtrate was concentrated to give title compound as white oil, which was used to next step without further purification.

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

3-(Bromomethyl)benzenesulfonyl chloride (5.64 g, 21.25 mol, 1.00 eq.) in THF (20.0 mL) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (3.83 g, 19.13 mol, 0.90 eq.), TEA (4.30 g, 42.50 mmol, 2.00 eq.) in THF (40.0 mL) at 0°C and the mixture was stirred at RT for 12h. The mixture was quenched with H2O and extracted with DCM. 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/EA (3: 1). to afford the title compound as white solid. Step 3: tert-Butyl (l-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6- yl)pipendin-l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)- dione 2,2,2-trifluoroacetate (50 mg, 0.15 mmol, 1.00 eq.) and tert-butyl (l-((3-(bromomethyl)- phenyl)sulfonyl)piperidin-4-yl)carbamate (99 mg, 0.23 mmol, 1.50 eq.), TEA (45 mg, 0.45 mmol, 3.00 eq.) in THF (5.0 mL) was stirred at 55 °C overnight. The mixture was diluted with water and extracted with DCM, and the combined organic layer was washed with brine, dried over Na₂SO₄ , concentrated. The residue was purified by flash chromatography (DCM:MeOH=20: 1) to give title compound as a yellow solid.

Step 4: l-(6-(l-(3-((4-Aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH-indazol-

3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2,2,2-trifluoroacetate

A mixture of tert-butyl (l-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl- lH-indazol-6-yl)piperidin-l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (50 mg, 0.07 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at r.t. for 2h. The mixture was concentrated to give the title compound as brown oil.

The following intermediates were prepared by proceeding analogously to Reference 54.

Reference 55

Synthesis of l-(6-(l-((l-((4-aminopiperidin-l-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-l- methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2,2,2-trifluoroacetate

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

A mixture of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)- di one (500 mg. 1.40mmol, 1.00 eq.), AcOH (3 drops), tert-butyl 4-formylpiperidine-l -carboxylate

(300 mg, 1.40 mmol, 1.00 eq.) in THF (5.0 mL) and DMF (2.5 mb) was stirred at 45 °C for 45 min. The solution was cooled to r.t, NaBHsCN (168 mg, 2.80 mmol, 2.00 eq.) was added and the mixture was stirred at r.t for 2 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography, eluted with DCM/MeOH (20: 1). to afford the title compound as a white solid.

Step 2: l-(l-Methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione

A mixture of tert-butyl 4-((4-(3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- 1H- indazol-6-yl)piperidin-l-yl)methyl)piperidine-l -carboxylate (200 mg, 0.38 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as brown oil.

Step 3: tert-Butyl (l-((4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6- yl)piperidin-l-yl)methyl)piperidin-l-yl)sulfonyl)piperidin-4-yl)carbamate tert-Butyl (l-(chlorosulfonyl)piperidin-4-yl)carbamate (59 mg, 0.20 mmol, 1.05 eq.) in DCM (2.0 mL) was added to a mixture of l-(l-methyl-6-(l-(piperidin-4-ylmethyl)piperidin-4-yl)- lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione (80 mg, 0.19 mmol. 1.00 eq.), TEA (38 mg, 0.38 mmol, 2.00 eq.) in DCM (2.0 mL) at 0 °C, and the mixture was stirred at RT for 12 h. The mixture was quenched with H2O and then extracted with DCM. 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 DCM/MeOH (20: 1), to afford the title compound as white solid.

Step 4: l-(6-(l-((l-((4-Aminopiperidin-l-yl)sulfonyl)piperidin-4-yl)methyl)piperidin-4-yl)-l- methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH.3H)-dione 2,2,2-trifluoroacetate

A mixture of tert-butyl (l-((4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl- lH-indazol-6-yl)piperidin-l-yl)methyl)piperidin-l-yl)sulfonyl)piperidin-4-yl)carbamate (27 mg, 0.039 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as yellow oil.

Reference 56

Synthesis of l-(6-(l-((l-(3-((4-aminopiperidin-l-yl)sulfonyl)phenyl)piperidin-4- yl)methyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione

2,2,2-tri fluoroacetate

Step 1 : tert-Butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate

3-Bromobenzene-l-sulfonyl chloride (5.0 g, 19.57 mmol, 1.00 eq.) in THF (50.0 mL) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (4. 12 g, 20.55 mmol, 1.05 eq.) in THF (50 mL) and TEA (2.18 g, 21.53 mmol, 1.10 eq.) dropwise at -10 °C, and the mixture was stirred at rt for 2 h. The mixture was concentrated and the residue was taken into water/acetonitrile=l :l and stirred for 1 h. The mixture was filtered, and the cake was washed with water and acetonitrile and dried to give the title compound a white solid.

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

A mixture of tert-buty l (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (3.00 g, 7.18 mmol, 1.00 eq.), K2CO3 (3.47 g, 25.1 mmol, 3.50 eq.). L-proline (248 mg, 2.15 mmol, 0.3 eq.), Cui (273 mg, 1.44 mmol. 0.2 eq.) and piperidin-4-ylmethanol (1.07 g. 9.33 mmol, 1.30 eq.) in DMSO (100.0 mL) was stirred at 100 °C for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA=1: 1, to afford the title compound as white solid.

Step 3: tert-Butyl (l-((3-(4-formylpiperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Dess-Martin (2.53 g, 5.96 mmol, 2.00 eq.) was added to a stirred solution of tert-butyl (1- ((3-(4-(hydroxymethyl)piperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (1.35 g. 2.98 mmol, 1.00 eq.) in DCM (15.0 mL) at 0 °C, and the mixture was stirred at RT for 2 h. The mixture was quenched with H2O and then extracted with DCM. 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/EA (1: 1), to afford the title compound as white solid.

Step 4: tert-Butyl (1 -((3-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-l (2H)-yl)-l -methyl- IH-indazol-

6-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of tert-butyl (l-((3-(4-formylpipen din-1 -yl)phenyl)sulfony l)piperidin-4- yl)carbamate (264 mg, 0.585 mmol, 1.00 eq.), CH3COOH (1 drops) and l-(l-methyl-6-(piperidin- 4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (191.5 mg, 0.585 mmol, 1.00 eq.) in THF (2.0 mL)/DMF (2.0 mL) was stirred at 45 °C for 0.5 h. The mixture was cooled to 0 °C and NaBEECN (73.5 mg. 1.17 mmol, 2.00 eq.) was added. After stirring at RT for 12 h, the mixture was quenched with H₂O and extracted with DCM. 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 DCM/MeOH=20: l to give the title compound as yellow solid. Step 5: l-(6-(l-((l-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4- yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2.2.2-trifluoroacetate

A mixture of tert-butyl (l-((3-(4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l- methyl-lH-indazol-6-yl)piperidin-l-yl)methyl)piperidin-l-yl)phenyl)sulfonyl)piperi din-4- yl)carbamate (170 mg. 0.223 mmol. 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound as yellow solid.

The following intermediates were prepared by proceeding analogously as described in

Reference 56.

Reference 57

Synthesis of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-

2,6-diazaspiro[3.3]heptane-2-carboxylate

Step 1 : tert-Butyl 6-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-6-yl)-2.6- diazaspiro[3.3]heptane-2-carboxylate

A mixture of l-(6-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (300 mg, 0.93mmol, 1.00 eq.), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (570 mg, 2.32 mmol, 2.50 eq.), t-BuOK(627 mg. 5.6mmol, 6.00 eq.),t-BuBrettphos Pd G3 (81mg, 0.093 mmol, 0. 10 eq. ) and t-BuXphos (76mg, 0.186 mmol, 0.20 eq.) in 1.4-dioxane (6 mL) was stirred at 100 °C under N2 for 3 h. The mixture was diluted with DCM and the organic layer was washed with w ater and brine, dried over Na₂SO₄ , and concentrated. Purification of the residue by column chromatography on silica gel (DCM:MeOH = 20 : 1) to give the title compound as yellow solid. Step 2: l-(l-Methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(1 H,3H)-di one 2,2,2-trifluoroacetate

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

Reference 58

Synthesis of l-(6-(l-(3-(((ls,4s)-4-aminocyclohexyl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl- lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione 2,2,2-tnfluoroacetate

L1AIH 1 (38.92 mL, 38.92 mmol, 3.0 eq) was added to a suspension of 3 -sulfanylbenzoic acid (2g, 12.97 mmol, 1.0 eq) in anhydrous THF (50 mL). The reaction mixture was stirred at rt for 1 h and then refluxed for 6 h. The suspension was allowed to cool to rt and stirred overnight before being quenched at 0 °C by the slow addition of water, IN aq. NaOH and water. The solid was removed by filtration. The solid was dissolved in IN aq. HC1 and the resulting solution was extracted with EA. The combined organic extracts w ere concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a yellow oil.

Step 2: tert-Butyl ((lr,4r)-4-((3-(hydroxymethyl)phenyl)thio)cyclohexyl)carbamate

A mixture of [4-(tert-butoxycarbonylamino)cyclohexyl] 4-methylbenzenesulfonate (2.9 g, 7.85 mmol, 1.0 eq) and (3-mercaptophenyl)methanol (1.1 g, 7.85 mmol, 1.0 eq), potassium carbonate (2.17 g, 15.7 mmol. 2.0 eq) in MeCN (100 mL) was degassed and refilled with N2 and stirred at 80 °C for 16 h. The mixture was filtered through C₆lite and the filter cake was washed with MeCN. The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-25%) to afford the title compound as a white solid.

Step 3: tert-Butyl ((lr,4r)-4-((3-formylphenyl)thio)cyclohexyl)carbamate

To a stirred mixture of tert-butyl ((lr,4r)-4-((3-(hydroxymethyl)phenyl) thio)cyclohexyl)- carbamate (260 mg, 0.77 mmol, 1.0 eq) in anhydrous DCM (15 mL) at 0 °C, was added DMP (653.5 mg. 1.54 mmol, 2.0 eq) in portions. The resulting mixture was stirred for 2 h at 25 °C. The resulting mixture was diluted with water, quenched with saturated NaeSeCf and saturated NaHCCL at 0 °C. The resulting mixture was stirred at rt for 10 min and extracted with DCM, and dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-25%) to afford the title compound as a white solid. Step 4: tert-Butyl ((lr,4r)-4-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)piperidin-l-yl)methyl)phenyl)thio)cyclohexyl)carbamate

To a stirred mixture of tert-butyl ((lr,4r)-4-((3-formylphenyl)thio) cyclohexyl)carbamate (200 mg, 0.6 mmol, 1.0 eq) and l-[l-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine- 2, 4-dione (hydrochloride salt, 216.9 mg, 0.6 mmol, 1.0 eq) in anhydrous DCE (20 mL) at 0 °C was added sodium triacetoxyborohydride (379.1 mg, 1.8 mmol, 1.0 eq) in portions and the resulting mixture was stirred for 16 h at 25 °C. The mixture was diluted with water, quenched with saturated NaHCCL at 0 °C. and stirred at rt for 10 min. The mixture was extracted with DCM, and the organic layer was washed with brine, dried over anhydrous ISfeSCh. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-5%) to afford title compound as a white solid.

Step 5: l-(6-(l -(3-(((lr,4r)-4-Aminocy cl ohexyl)thio)benzyl)piperidin-4-yl)-l -methyl- IH-indazol- 3-yl)dihydropyrimidine-2,4( lH,3H)-dione 2,2,2-trifluoroacetate

To a stirred mixture of tert-butyl ((lr,4r)-4-((3-((4-(3-(2,4-dioxotetrahydropynmidin- l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)methyl)phenyl)thio)cyclohexyl)carbamate (100 mg, 0.15 mmol, 1.0 eq) in anhydrous DCM (10 mL) at 0 °C was added TFA (0.24 mL) dropwise. The resulting mixture was stirred for 2 h at 25 °C and was concentrated under reduced pressure to afford the title compound as a yellow oil. Step 6: l-(6-(l-(3-(((ls,4s)-4-Aminocyclohexyl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH- indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione 2,2,2-trifluoroacetate

To a stirred mixture of l-(6-(l-(3-(((lr,4r)-4-aminocyclohexyl)thio)benzyl)piperidin-4-yl)- l-methyl-lH-indazol-3-yl)dihydro pyrimidine-2,4(lH,3H)-dione 2,2,2-trifluoroacetate (0.15 mmol, 1.0 eq) in anhydrous DCM (10 mL) at 0 °C was added m-CPBA (78.4 mg, 0.45 mmol, 3.0 eq) and the resulting mixture was stirred for 16 h at 25 °C. The mixture was concentrated under reduced pressure to afford the title compound as a white solid.

Reference 59

Synthesis of (2S .4R)- 1 -((R)-3-((( 1 -(3 -((4-aminopiperidin- 1 -yl)sulfonyl)benzyl)piperidin-4-yl)- methyl)thio)-2-(l-fluorocyclopropane-l-carboxamido)-3-methylbutanoyl)-4-hydroxy-N-((S)-l-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

Step 1 : tert-Butyl (2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoy l)py rrolidine- 1 -carboxyl ate

A mixture of (l S)-l-[4-(4-methylthiazol-5-yl)phenyl]ethanamine (2480. mg, 11.36 mmol) and (2S,4R)-l-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (2889.57 mg, 12.5 mmol), HATU (5183.19mg, 13.63mmol) and TEA (7.92mL, 56.8mmol) in DCM (25 mL) was stirred at 25 °C for 2 h. The mixture was diluted with water and extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to give the title compound.

Step 2: (2S,4R)-4-Hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2- carboxamide

To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[(lS)-l-[4-(4-methylthiazol-5-yl)- phenyl] ethyl] carbamoyl] pyrrolidine- 1 -carboxy late (3.77 g, 8.74 mmol) in DCM (20 mL) was added 4M HCl-dioxane (20 mL. 80 mmol) and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure to afford the title compound.

Step 3: (9H-Fluoren-9-yl)methyl ((R)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-3-methyl-l-oxo-3-(tritylthio)butan-2-yl)carbamate

To a solution of (2R)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-methyl-3-trityl- sulfanyl-butanoic acid (1576.6 mg, 2.57 mmol), (2S,4R)-4-hydroxy-N-[(lS)-l-[4-(4-methyl- thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide hydrochloride (1350 mg, 3.67mmmol) in DMF (10 mL) was added TEA (1.53 mL, 11.01 mmol), and HATU (2790.6 mg, 7.34 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to afford the title compound.

Step 4: (2S,4R)-l-((R)-2-Amino-3-methyl-3-(trity lthio)butanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

To a solution of 9H-fluoren-9-ylmethyl N-[(lR)-l-[(2S,4R)-4-hydroxy-2-[[(lS)-l-[4-(4- methy lthiazol-5 -y l)pheny 1] ethyl] carbamoyl] pyrrolidine- 1 -carbonyl] -2-methy 1-2-tritylsulfany 1- propyl]carbamate (1360 mg. 1.47 mmol) in DCM (10 mL) was added piperidine (0.29 mL, 2.93 mmol) at room temperature, and the solution was stirred at 25 °C for 3 h. The reaction mixture was diluted with water, extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to afford the title compound.

Step 5 : (2S,4R)- 1 -((R)-2-(l -Fluorocyclopropane- 1 -carboxamido)-3-methy l-3-(trity Ithio)- butanoyl)-4-hydroxy-N-((S)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide

To a solution of (2S,4R)-l-[(2R)-2-amino-3-methyl-3-tritylsulfanyl-butanoyl]-4-hydroxy- N-[(lS)-l-[4-(4-methylthiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (2.1 g, 2.98 mmol) and HATU (2265.4 mg, 5.96 mmol) in DCM (1 mL) was added TEA (1155.0 mg, 8.94 mmol). The reaction mixture was purged with Argon and then HATU (2265.4 mg, 5.96 mmol) was added, an the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with DCM, and the organic phase was dried over anhydrous sodium sulfate. The organic layer was concentrated to afford the title compound.

Step 6: (2S,4R)-1 -((R)-2-(l -fluorocyclopropane-1 -carboxamido)-3-mercapto-3-methylbutanoyl)- 4-hy droxy-N-((S)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl) pyrrolidine-2-carboxamide

To a solution of (2S,4R)-l-((R)-2-(l-fluorocyclopropane-l-carboxamido)-3-methyl-3- (tritylthio)butanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide (1.2 g, 1.52 mmol) in DCM (10 mL) was added TFA (10 mL, 129.8 mmol) and triisopropylsilane (1.03 mL, 5.01 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with water and extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford the title compound. Step 7: tert-Butyl 4-((((R)-3-(l-fluorocyclopropane-l-carboxamido)-4-((2S,4R)-4-hydroxy-2- (((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-l-yl)-2-methyl-4-oxobutan-2- yl)thio)methyl)piperidine- 1 -carboxylate

DBU (2433.9 mg, 16.0 mmol) was added to a solution of (2R,4R)-l-[(2R)-2-[(l- fluorocyclopropanecarbonyl)amino]-3-methyl-3-sulfanyl-butanoyl]-4-hydroxy-N-[(lS)-l-[4-(4- methylthiazol-5-yl)phenyl]ethyl] pyrrolidine-2-carboxamide (1.7 g, 2.66 mmol) and tert-butyl 4- (bromomethyl)piperidine-l -carboxylate (1.04 mg, 3.73 mmol) in THF (20 mL) at room temperature, and the reaction was stirred at room temperature overnight. The mixture was diluted with water and extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography to obtain the title compound.

Step 8: (2S,4R)-l-((R)-2-(l -fluorocyclopropane-1 -carboxamido)-3-methyl-3-((piperidin-4-yl- methyl)thio)butanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2- carboxamide

To a solution of tert-butyl 4-[[(2R)-2-[(l-fluorocyclopropanecarbonyl)amino]-3-[(2S,4R)- 4-hydroxy-2-[t(lS)-l-t4-(4-methylthi azol -5-yl)phenylJethyl]carbamoyl]pyrrolidin-l-ylJ- 1,1- dimethyl-3-oxo-propyl]sulfanylmethyl]piperidine-l-carboxylate (1.1 g, 1.47 mmol) in DCM (10 mL) was added 4M HCl-Dioxane (5.mL, 1.47 mmol) at room temperature. The reaction mixture w as stirred at room temperature for 1 h and then concentrated to afford the title compound. Step 9: tert-Butyl (l-((3-((4-((((R)-3-(l-fluorocyclopropane-l-carboxamido)-4-((2S,4R)-4- hydroxy-2-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbarnoyl) pyrrolidin- 1 -yl)-2-methyl-4- oxobutan-2-yl)thio)methyl)piperidin-l-yl)methyl)phenyl) sulfonyl)piperidin-4-yl)carbamate

A mixture of (2S,4R)-l-((R)-2-(l-fluorocyclopropane-l-carboxamido)-3-methyl-3- ((piperidin-4-ylmethyl)thio)butanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl)- ethyl)pyrrolidine-2-carboxamide (300 mg, 0.46 mmol) and tert-butyl N-[l-[3-(bromomethyl)- phenyl]sulfonyl-4-piperidyl]carbamate (221.43 mg, 0.51 mmol), TEA (0.39 mL, 2.79 mmol) in DMF (2 mL) was stirred at 55 °C for 3 h. The mixture was cooled to room temperature and diluted with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate and concentrated and the residue was purified by flash column chromatography to give the title compound.

Step 10: (2S,4R)-l-((R)-3-(((l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)methyl)- thio)-2-(l -fluorocyclopropane-1 -carboxamido)-3-methylbutanoyl)-4-hy droxy -N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

To a solution of tert-butyl (l-((3-((4-((((R)-3-(l-fluorocyclopropane-l-carboxamido)-4- ((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5-yl)phenyl)ethyl) carbamoyl)pyrrolidin-l-yl)- 2-methyl-4-oxobutan-2-yl)thio)methyl)piperidin-l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)- carbamate (450 mg, 0.45 mmol) in DCM (4 mL) was added 4M HCLDioxane (2 mL, 0.45 mmol) at 25 °C, and the mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to afford the title compound. Reference 60

Synthesis of l-(6-(l -(3-((4-armnopiperidin-l-yl)sulfonyl)phenethyl)piperidin-4-yl)-l -methyl- 1H- indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride

Step 1 : l-(l-Methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride

To a stirred solution of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl- lH-indazol-6-yl)piperidine-l -carboxylate (7.2 g, 16.84 mmol) in dichloromethane (72 mL) was added 4 M HC1 in 1.4-di oxane (36 mL) at 0 °C and stirred for 1 h. The mixture was concentrated to afford the title compound as an off-white solid.

Step 2: tert-Butyl (l-((3-vinylphenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5 g, 11.92 mmol), potassium vinyltrifluoroborate (2.4 g, 17.89 mmol). Pd(dppf)C12 (872.48 mg, 1.19 mmol) and potassium carbonate (4.9 g, 35.77 mmol) in dioxane/acetonitrile/water (60 mL, 5:5:2, v/v) was purged with argon five times and stirred at 85 °C 6 h. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography, eluted with ethyl acetate/petroleum ether (0-50%) to afford the title compound as a yellow solid. Step 3: tert-Butyl (l-((3-(2-hydroxyethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

To a stirred solution of tert-butyl (l-((3-vinylphenyl)sulfonyl)piperidin-4-yl)carbamate (4.05 g. 11.05 mmol) in anhydrous tetrahydrofuran (40 mL) was added borane-tetrahydrofuran complex (16.58 mL, 16.58 mmol) dropwise at 25 °C under argon atmosphere and the mixture was stirred for 2.5 h. 10% sodium hydroxide aq (8840.86 mg, 22.1 mmol) was added slowly, followed by hydrogen peroxide (2.26 mL. 22. 1 mmol, 30%). The resulting mixture was stirred at 25 °C for 3.5 h. The reaction mixture was quenched with ammonium chloride (aq.) and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate. After filtration, the filtrated was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluted with ethyl acetate/petroleum ether (0-50%) to afford the title compound and its isomer as white solid.

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

To a stirred solution of tert-butyl (l-((3-(2-hydroxyethyl)phenyl)sulfonyl) piperidin-4-yl)- carbamate (200 mg, 0.52 mmol) in anhydrous di chloromethane (5 mL) was added Dess-Martin Periodinane (441.25 mg, 1.04 mmol) at 0 °C and the mixture was stirred for 1 h. The mixture was diluted with ethyl acetate, washed with sodium sulfite (aq.), sodium bicarbonate (aq.), water, brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate w as concentrated under reduced pressure to afford the title compound as a white solid.

Step 5: tert-Butyl (l-((3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-

6-yl)piperidin-l-yl)ethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(1 H,3H)-di one hydrochloride (95.13 mg, 0.26 mmol) and tert-butyl (l-((3-(2-oxoethyl)- phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.26 mmol) in anhydrous di chloromethane (2 mL) was stirred at 25 °C for 1 h. Sodium triacetoxyborohydride (110.82 mg, 0.52 mmol) was added and the mixture was stirred for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate and the combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluted with methanol/dichloromethane (0~5%) to afford title compound as a yellow solid.

Step 6: l-(6-(l-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenethyl)piperidin-4-yl)-l-methyl-lH- indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride

To a stirred solution of tert-butyl (l-((3-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- l-methyl-lH-indazol-6-yl)piperidin-l-yl)ethyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 0.14 mmol) in dichloromethane (3 mL) was added 4 M hydrogen chi oride/l,4-di oxane (1.5 mL) at 0 °C and stirred for 1 h. The solvent was removed under reduced pressure to afford the title compound as a white solid. Reference 61

Synthesis of l-(6-(l-(3-(3-((4-Aminopipendin-l-yl)sulfonyl)phenyl)-2-methylpropyl) piperidin-4- yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride

Step 1 : tert-Butyl (l-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of palladium (II) acetate (53.54 mg, 0.24 mmol) and tetrabutylammonium bromide (4.0 g, 12.41 mmol) was heated to 130 °C under argon atmosphere, and then tert-butyl (l-((3- bromophenyl)sulfonyl)piperidin-4-yl)carbamate (1.0 g, 2.38mmol), 2-methylprop-2-en-l-ol (515.89 mg, 7. 15 mmol) and sodium bicarbonate (400.69 mg, 4.77 mmol) were added. The mixture was stirred at 130 °C for 4 h. After cooling the mixture to rt, the mixture was diluted with water and ethyl acetate. After filtration, the mixture was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography, eluted with ethyl acetate/petroleum ether (0-21% with 5% dichloromethane) to afford the title compound as an off- white solid.

Step 2: tert-Butyl ( l-((3-(3-(4-(3-(2.4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- IH-indazol-

6-yl)piperidin-l-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of tert-butyl (l-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)- carbamate (100 mg, 0.24 mmol) and l -(l-methyl-6-(piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride (88.63 mg, 0.24 mmol) in anhydrous di chloromethane (2 ml) was stirred at 25 °C for 3 h. Sodium triacetoxyborohydride (154.88 mg, 0.73 mmol) was added and the mixture was stirred 16 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography, eluted with methanol/dichloromethane (0—5%) to afford the title compound as a white solid.

Step 3: l-(6-(l-(3-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2-methylpropyl) piperidin-4-yl)- l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride

To a stirred solution of tert-butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- l-methyl-lH-indazol-6-yl)piperidin-l-yl)-2-methylpropyl)phenyl)sulfonyl) piperidin-4-yl)- carbamate (62 mg, 0.086 mmol) in di chloromethane (2 mL) was added 4 M hydrogen chloride in dioxane (1.0 mL) at 0 °C and the mixture was stirred for 1 h. The mixture was concentrated to afford the title compound as a white solid.

Reference 62

Synthesis of l-(6-(l-(3-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2,2-dimethylpropyl) piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride

Step 1 : tert-Butyl (l-((3-(2,2-dimethyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of tert-butyl N-[l-[3-(bromomethyl)phenyl]sulfonyl-4-piperidyl]carbamate (1.0 g, 2.31 mmol), 2-methylpropanal (416 mg, 5.77 mmol), tetrabutylammonium iodide (85.24 mg, 0.23 mmol) and sodium hydroxide (323.06 mg, 8.08 mmol) in 1,4-dioxane (10 mL) was heated to 70 °C and stirred for 3 h under Argon atmosphere. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography, eluted with ethyl acetate/petroleum ether (0-20% with 5% dichloromethane) to afford the title compound as a white solid. Step 2: tert-Butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol-

6-yl)piperidin-l-yl)-2.2-dimethylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate

Titanium tetraisopropanolate (1241.82 mg, 4.37 mmol) was added to a mixture of tertbutyl (l-((3-(2.2-dimethyl-3-oxopropyl)phenyl)sulfonyl) piperidin-4-yl)carbamate (530 mg. 1.25 mmol) and l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride (408.7 mg, 1.25 mmol) in anhydrous N-methyl-2-pyrrolidone (5.3 mL), and the mixture was heated to 90 °C for 3 h under Argon atmosphere. The mixture was cooled to rt and sodium cyanoborohydride (274.56 mg, 4.37 mmol) was added, and the mixture was stirred at 25 °C for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluted with methanol/dichloromethane (0~5%) to afford the title compound as a white solid.

Step 3: l-(6-(l-(3-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2,2-dimethylpropyl) piperidin-4- yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride

To a stirred solution of tert-butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)- l-methyl-lH-indazol-6-yl)piperidin-l-yl)-2,2-dimethylpropyl)phenyl) sulfonyl)piperidin-4- yl)carbamate (280 mg, 0.38 mmol) in dichloromethane (3 mL) was added 4 M hydrogen chloride in dioxane (1.5 mL) at 0 °C and stirred for 1 h. The solvent was removed under reduced pressure to afford title compound as a white solid.

Reference 63

Synthesis of l-(6-(l-(4-(3-((4-aminopipendin-l-yl)sulfonyl)phenyl)-2-methylbut-3-yn-2- yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride Step 1 : l-(l-Methyl-6-(l-(2-methylbut-3-yn-2-yl)piperidin-4-yl)-lH-indazol-3-yl)dihydro- pyrimidine-2,4(lH,3H)-dione

To a solution of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione (720 mg, 2.2 mmol, 1.0 eq.) in DMSO (5 mL) was added 3-chloro-3-methylbut- 1-yne (451 mg, 4.4 mmol, 2.0 eq.), CuCl (21 mg, 22 mmol. 10.0 eq.) and TEA (0.92 mL, 6.6 mmol, 3.0 eq.), and the resulting mixture was stirred at r.t. for 20 min. The mixture was diluted with water and the precipitated solid was collected by filtration. The solid was redissolved in DCM, and the organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. Step 2: tert-Butyl (l-((3-(3-(4-(3-(2.4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH-indazol- 6-yl)piperidin-l-yl)-3-methylbut-l-yn-l-yl)phenyl) sulfonyl) piperidin-4-yl)carbamate

To a solution of tert-butyl (l-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (211 mg, 0.5 mmol, 1.1 eq.) in DMF (1 mL) was added l-(l-methyl-6-(l-(2-methylbut-3-yn-2-yl)piperidin- 4-yl)-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione (180 mg, 0.46 mmol, 1.0 eq.), Pd(dppf)Ch (37 mg, 0.05 mmol, 0.1 eq.) and Cui (8 mg, 0.05 mmol, 0.1 eq.). The resulting mixture was stirred at 70 °C for 2 h. The mixture was diluted with water and extracted with

EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column, eluted with MeOH/DCM = 0 - 5% to give the title compound as yellow solid.

Step 3: l-(6-(l-(4-(3-((4-Aminopiperidin-l-yl)sulfonyl)phenyl)-2-methylbut-3-yn-2-yl)piperidin- 4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH.3H)-dione hydrochloride A mixture of tert-butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl- lH-indazol-6-yl)piperidin-l-yl)-3-methylbut-l-yn-l-yl)phenyl) sulfonyl)piperidin-4-yl)carbamate (300 mg, 0.41 mmol) in ethyl acetate (1 mL) and HCl/EtOAc (4 M, 1 mL) was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure to afford the title compound.

Reference 64

Synthesis of 4-((4-Aminopiperidin-l-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-l-methyl-lH-indazol-6-yl)piperidin-l-yl)but-l-yn-l-yl)benzonitrile hydrochloride

Step 1 : l-(6-(l-(But-3-yn-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydro pyrimidine- 2,4(lH,3H)-dione

To a solution of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydro pyrimidine- 2,4(1 H,3H)-dione (500 mg, 1.53 mmol, 1.0 eq ), copper (I) chloride (45.36 mg, 0.46 mmol, 0.3 eq.) and tri ethylamine (772.7 mg, 7.64 mmol, 5.0 eq.) in DMSO (5 mL) was added 3-chlorobut-l- yne (270.41 mg, 3.05 mmol, 2.0 eq.) in DMSO (2 mL) dropwise and the reaction mixture was stirred at r.t for 30 min. The mixture was diluted with water and filtered. The filtrate was extracted with EtOAc and the combined organic layers were washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to afford the title compound.

Step 2: tert-Butyl (l-((4-cyano-3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)piperidin-l-yl)but-l-yn-l-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate To a solution of l-(6-(l-(but-3-yn-2-yl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydro- pyrimidine-2,4(lH,3H)-dione (175 mg, 0.46 mmol. 1.0 eq.), Cui (7.98 mg. 0.04 mmol, 0.1 eq.). tert-butyl(l-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)carbamate (225.41 mg, 0.51 mmol, 1.1 eq.) and triethylamine (212.12 mg, 2.1 mmol, 4.0 eq.) in DMF (3 mL) was added Pd(dppf)2Ch (30.68 mg, 0.04 mmol, 0.1 eq.) under argon atmosphere and the resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography to afford the title compound.

Step 3: 4-((4-Aminopiperidin-l-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-

1 -methyl- 1 H-indazol-6-y l)piperidin- 1 -y l)but- 1 -yn- 1 -y l)benzonitrile hydrochloride

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

Example 1

Synthesis of l-(6-(l-(3-((4-((4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)- sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

Step 1 : 4-Methoxy-2-(methylthio)-5-(trifluoromethyl)pyrimidine

To a stirred solution of 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (500 mg,

2.19 mmol, 1.00 eq.) in MeOH (10.0 mL) was added NaOMe (237 mg. 4.39 mmol, 2.00 eq.) at r.t. and the mixture was stirred for 5 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE, to afford the title compound as a yellow oil.

Step 2: 4-Methoxy-2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine

To a stirred solution of 4-methoxy-2-(methylthio)-5-(trifluoromethyl)pyrimidine (290 mg, 1.29 mmol, 1.00 eq.) in DCM (10.0 mL) was added m-CPBA (526 mg, 2.59 mmol, 2.00 eq.) at r.t. and the mixture was stirred for 20 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with w ater, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue w as purified by silica gel column chromatography, eluting with EtOAc:PE=0 to 100%, to afford the title compound as a yellow solid.

Step 3: l-(6-(l-(3-((4-((4-Methoxy-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)- sulfonyl)benzyl)piperidin-4-yl)-l -methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-di one

To a stirred solution of l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-l- methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH.3H)-dione 2,2,2-trifluoroacetic acid (40 mg, 0.07 mmol, 1.00 eq., Int. of Reference 54) in DMSO (2.0 mL) was added 4-methoxy-2- (methylsulfonyl)-5-(trifluoromethyl)pyrimidine (23 mg, 0.09 mmol, 1.30 eq.), and DIEA (27 mg, 0.21 mmol, 3.00 eq.) and the resulting mixture was stirred at 65 °C for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc:PE = 0 to 100%, to afford the title compound as a white solid. MS (ES, m/z): [M+l]⁺ = 756.2. The following compounds were synthesized by proceeding analogously as described in

Example 1. Example 8

Synthesis of l-(l-methyl-6-(l-(3-((4-((4-(methylamino)-5-(trifluoromethyl)pyrimi din-2 -yl)- amino)piperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine-

2,4(lH,3H)-dione

Step 1 : 2-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine

A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (300 mg, 1.39 mmol, 1.00 eq.), methylamine hydrochloride (102 mg, 1.53 mmol, 1.10 eq.) and K2CO3 (386 mg, 2.79 mmol, 2.00 eq.) in THF (3.0 mL) was stirred for 16 h at rt. The mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc=5: 1, to afford the title compound as a white solid.

Step 2: l-(l-Methyl-6-(l-(3-((4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2- yl)amino)piperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(1 H,3H)-dione

A mixture of l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl- lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione 2,2,2-trifluoroacetic acid (254 mg, 0.44 mmol, 3.00 eq.), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (31 mg, 0.15 mmol, 1.00 eq.) in DMSO (2.0 mL) and DIEA (55 mg, 0.44 mmol, 3.00 eq.) was stirred at 90 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM/MeOH= 20: 1, to afford the title compound as a white solid. MS (ES. m/z): [M+l]⁺ = 755.1.

The following compounds were synthesized by proceeding analogously as described in Example 8.

Example 10

Synthesis of l-(6-(l-(3-((4-((5-chloro-4-methylpyrimidin-2-yl)amino)piperidin-l- yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-

Step 1 : l-(6-(l-(3-((4-((5-Chloro-4-methylpyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)benzyl)- piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

To a stirred solution of l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)- l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2,2,2-trifluoroacetic acid (100 mg, 0.15 mmol, l.OOeq.) in DMSO (3.0 mL) was added DIEA (58 mg, 0.45 mmol, 3.00 eq.) and 2,5-dichloro-4-methylpyrimidine (32 mg, 0.20 mmol, 1.30 eq.) and the resulting mixture was stirred at 90 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous ISfeSCE. After filtration, the filtrate was concentrated under reduced pressure, the residue was purified by prep-TLC eluting with DCM/MeOH = 20: 1 to afford the title compound as yellow solid. MS (ES, m/z): [M+l]⁺ = 706.0. Example 11

Synthesis of l-(6-(l-(3-((4-((5-chloro-4-methoxypyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione

Step 1 : 2,5-Dichloro-4-methoxypyrimidine

To a solution of 2,4,5-trichloropyrimidine (1.0 g, 5.45 mmol, 1.00 eq.) in THF (15.0 rnL) was added CH₃ONa (294.5 mg, 5.45 mmol, 1.00 eq.) at 0 °C, and the resulting mixture was stirred at r.t for 12 h. The mixture was poured into water, extracted with EtOAc, washed with water and brine, dried over Na₂SO₄ After filtration, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE to give title compound as white oil.

Step 2: l-(6-(l-(3-((4-((5-Chloro-4-methoxypyrimidin-2-yl)amino)piperidin-l-yl)sulfonyl)- benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2.4(lH.3H)-dione

To a stirred solution of l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)- l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2,2,2-trifluoroacetic acid (85.3 mg, 0.14 mmol, 1.00 eq.) in DMSO (2.0 mL) was added DIEA (56.9 mg. 0.42 mmol, 3.00 eq.) and 2,5-dichloro-4-methoxypyrimidine (23 mg, 0. 14 mmol. 1.00 eq.), and the resulting solution was stirred at 90 °C for 12 h. The mixture was poured into water, extracted with EtOAc, the combined organic layer was washed with water and brine, dried over NaiSOi. The mixture was filtered and concentrated and the residue was purified by prep-TLC to give the title compound as white solid. MS (ES. m/z): [M+l]⁺= 722.3. The following compounds were synthesized by proceeding analogously as described in Example 11.

Example 14 Synthesis of l-(6-(l-(3-((4-((5-chloro-4-(methoxymethyl)pyrimidin-2-yl)amino)piperidin-l- yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lE[-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- dione

Step 1 : (5-Chloro-2-(methylthio)pyrimidin-4-yl)methanol

A mixture of methyl 5-chloro-2-(methylthio)pyrimidine-4-carboxylate (1.29 g, 5.92 mmol, 1.00 eq.) and DIBAL-H (12 mL, 11.84 mmol, 2.00 eq.) in DCM (10 mL) was stirred at 60 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc, to give the title compound as a yellow solid. Step 2: 5-Chloro-4-(methoxymethyl)-2-(methylthio)pyrimidine

To a stirred solution of (5-chloro-2-(methylthio)pyrimidin-4-yl)methanol (100 mg, 0.53 mmol, 1.00 eq.) in DCM (2 mL) was added trimethyl oxonium tetrafluoroborate (79 mg, 0.79 mmol, 1.50 eq.) and N, N, N’, N’-tetramethylnaphthalene-l,8-diamine (169 mg, 0.53 mmol. 1.00 eq.) at r.t. and the mixture was stirred for 1 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM solvent, to give the title compound as a yellow oil.

Step 3: 5-Chloro-4-(methoxymethyl)-2-(methylsulfonyl)pyrimidine

To a stirred solution of 5-chloro-4-(methoxymethyl)-2-(methylthio)pyrimidine (40 mg, 0.20 mmol, 1.00 eq.) in DCM (2 mL) was added m-CPBA (68 mg, 0.40 mmol, 2.00 eq.) at r.t. and the mixture was stirred for 1 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc=5: 1 to give the title compound as a yellow oil.

Step 4: 1 -(6-(l -(3-((4-((5-Chloro-4-(methoxymethyl)pyrimidin-2-yl)amino)piperidin-l - yl)sulfimyl)benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- di one

A mixture of l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione 2,2,2-trifluoroacetic acid (90 mg, 0.16 mmol, 1.00 eq.) and 5-chloro-4-(methoxymethyl)-2-(methylsulfonyl)pyrimidine (35 mg, 0.15 mmol, 1.00 eq.) in DMSO (2 mL) and DIEA (62 mg, 0.48 mmol, 3.00 eq.) was stirred at 65 °C for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=20: l) to give the title compound as a yellow oil. MS (ES, m/z): [M+l]⁺ =736.0.

Example 15

Synthesis of l-(6-(l-(3-((4-((5-chloro-4-(difluoromethoxy)pyrimi din-2 -yl)amino)piperidin-l- yl)sulfonyl)benzjd)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-

Step 1 : tert-Butyl 4-((4,5-dichloropyrimidin-2-yl)amino)piperidine-l-carboxylate

To a stirred solution of 2,4, 5-trichloropyrimi dine (5.00 g, 27.32 mmol, 1.00 eq.) in DCE/t- BuOH (1: 1, 150.0 mL) was added ZnCh (1 M in THF, 39.06 mL, 1.43 eq.) at 0 °C and the resulting mixture was stirred for 1 h. Then tert-butyl 4-aminopiperidine-l -carboxylate (5.20 g, 26.00 mmol. 0.95 eq.) was added, followed by dropwise addition of a solution of TEA (3.13 g, 30.99 mmol, 1.14 eq.) in DCE/t-BuOH (1 : 1 , 50.0 mL). The ice-bath was removed, and the resulting mixture was stirred at 60 °C for 12 h. The mixture was diluted with water and extracted with DCM. The combined organic layer w as washed with brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE:EtOAc (0-20 %), to afford the title compound as a white solid.

Step 2: tert-Butyl 4-((5-chloro-4-hydroxypyrimidin-2-yl)amino)piperidine-l-carboxylate

To a stirred solution of tert-butyl 4-((4, 5-dichloropyrimi din-2 -yl)amino)piperidine-l- carboxylate (500 mg, 1.44 mmol, 1.00 eq.) in 1,4-dioxane (7.0 mL) was added a solution of NaOH (691 mg, 17.28 mmol, 12.00 eq.) in H2O (7.0 mL). This mixture was stirred at 100 °C for 12 h. The mixture was cooled to r.t.. and the mixture pH was adjusted to 6~7 with IN HC1. The resulting mixture was extracted with EtOAc. The combined organic layers was washed with bnne, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM:MeOH (0-5 %) to afford the title compound as a white solid. Step 3: tert-Butyl 4-((5-chloro-4-(difluoromethoxy)pyrimidin-2-yl)amino)piperidine-l- carboxylate

To a stirred solution of tert-butyl 4-((5-chloro-4-hydroxypyrimidin-2-yl)amino)piperidine- 1-carboxylate (330 mg, 1.00 mmol, 1.00 eq.) in DMF (5.0 mL) was added CS2CO3 (652 mg, 2.00 mmol, 2.00 eq.) and ethyl 2-chloro-2,2-difluoroacetate (476 mg, 3.00 mmol, 3.00 eq ), and the mixture was stirred at 100 °C in a sealed tube for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers was washed with brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE:EtOAc (0~20 %), to afford the title compound as a pale yellow solid.

Step 4: 5-Chloro-4-(difluoromethoxy)-N-(piperidin-4-yl)pyrimidin-2-amine tri fluoroacetate

To a stirred solution of tert-butyl 4-((5-chloro-4-(difluoromethoxy)pyrimidin-2- yl)amino)piperidine-l -carboxylate (100 mg, 0.26 mmol, 1.00 eq.) in DCM (4.0 mL) was added TFA (1.0 mL). This mixture was stirred at r.t. for 2 h. The mixture was concentrated to give the title compound as a yellow solid.

Step 5: N-(l-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)-5-chloro-4-(difluoromethoxy)- pyrimidin-2-amine

To a stirred solution of 5-chloro-4-(difluoromethoxy)-N-(piperidin-4-yl)pyrimidin-2-amine trifluoroacetate (50 mg, 0.13 mmol, 1.00 eq.) in THF (2.0 mL) was added TEA (39 mg, 0.39 mmol, 3.00 eq.) and 3-(bromomethyl)benzenesulfonyl chloride (34 mg, 0.13 mmol, 1.00 eq.) at 0 °C and the resulting mixture was stirred for 3h. The mixture was concentrated to afford the title compound as a yellow solid.

Step 6: l-(6-(l-(3-((4-((5-Chloro-4-(difluoromethoxy)pyrimidin-2-yl)amino)piperidin-l- yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- di one

To a stirred solution of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(1 EI,3H)-di one hydrochloride (48 mg, 0.13 mmol, 1.00 eq.) in DMF (2.0 mL) was added TEA (66 mg, 0.65 mmol, 5.00 eq.) and N-(l-((3-(bromomethyl)phenyl)sulfonyl)piperidin-4-yl)-5- chloro-4-(difluoromethoxy)pyrimidin-2-amine (67 mg, 0.13 mmol, 1.00 eq.) and the resulting mixture was stirred at 55 °C for 12 h. The mixture was diluted with water and extracted with

EtOAc. The combined organic layer was washed with brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-TLC eluting with DCM: MeOH (15: 1) to afford the title compound as a white solid MS (ES. m/z): | M+l | = 758.3.

Example 16

Synthesis of l-(6-(l-((l-(3-((4-((5-(difluoromethoxy)-4-methoxypyrimidin-2-yl)amino)piperidin-

1 -yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-l -methyl- lH-indazol-3- yl)dihydropyrimidine-2.4(lH.3H)-dione

Step 1 : (l-(3-Nitrophenyl)piperidin-4-yl)methanol A mixture of l-fluoro-3-nitrobenzene (10.00 g, 70.9 mmol, 1.00 eq.) in DMSO (40.0 mL) was added piperidin-4-ylmethanol (16.31 g. 142.0 mmol. 2.00 eq.) and K.2CO3 (29.36 g. 212.76 mmol, 3.00 eq.) was stirred at 110 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc = 1: 1, to afford the title compound as a yellow oil.

Step 2: (l-(3-Aminophenyl)piperidin-4-yl)methanol

To a stirred solution of (l-(3-nitrophenyl)piperidin-4-yl)methanol (7.40 g, 31.36 mmol, 1.00 eq.) in MeOH (70.0 mL) was added Pd/C (10% w/w 1.50 g) and the resulting mixture was stirred at 110 °C under EI2 for 16 h. The mixture was filtration, the filtrate w as concentrated under reduced pressure, to afford the title compound as a yellow' solid.

Step 3: 3-(4-(Hydroxymethyl)piperidin-l-yl)benzenesulfonyl chloride

To a stirred solution of (l-(3-aminophenyl)piperidin-4-yl)methanol (1.00 g, 4.85 mmol, 1.00 eq.) in H2O (9.0 mL) was added con. HC1 (9.0 mL) and NaNO2 (1.00 g, 14.56 mmol, 3.00 eq.), CUSO4.5H2O (126 mg, 0.49 mmol, 0.10 eq.), NaHSOs (5.04 g, 48.5 mmol, 10.00 eq.) at 0°C and the resulting mixture was stirred for 30 min. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue w as purified by silica gel column chromatography, eluting with (PE/EtOAc = 10:1), to afford the title compound as a yellow- solid.

Step 4: 2-Chloro-4-methoxypyrimidin-5-yl methanesulfonate

To a stirred solution of 2-chloro-4-methoxypyrimidine (2.64 g, 18.24 mmol, 1.00 eq.) in MeCN (40.0 mL) was added bis(methanesulfonyl) peroxide (4.51 g, 23.71mmol, 1.30 eq.) and [Ru(bpy)3](PF6)2 (392 mg. 0.46 mmol, 0.03 eq.) at 25 °C under N2 and the resulting mixture was stirred for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/ EtOAc = 10: 1, to afford the title compound as a white solid.

Step 5: tert-Butyl 4-((4-methoxy-5-((methylsulfonyl)oxy)pyrimidin-2-yl)amino)piperidine-l- carboxylate

To a stirred solution of 2-chloro-4-methoxypyrimidin-5-yl methanesulfonate (930 mg, 3.91 mmol, 1.00 eq.) in DMSO (20.0 mL) was added tert-butyl 4-aminopiperidine-l -carboxylate (940 mg, 4.70 mmol, 1.20 eq.) and DIEA (1.51 g, 11.72 mmol, 3.00 eq.) and the resulting mixture was stirred at 50 °C under N2 for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc = 3: 1, to afford the title compound as a white solid.

Step 6: tert-Butyl 4-((5-hydroxy-4-methoxypyrimidin-2-yl)amino)piperidine-l-carboxylate

To a stirred solution of tert-butyl 4-((4-methoxy-5-((methylsulfonyl)oxy)pyrimidin-2- yl)amino)piperidine-l -carboxylate (1.00 g, 2.50 mmol, 1.00 eq.) in MeOH (10.0 mL) was added a solution of NaOH (500 mg, 12.50 mmol, 5.00 eq.) in H2O (3.0 mL) at 25 °C and the resulting mixture was stirred for 3 h. The mixture was neutralized with IN HC1 to adjust pH to 6 and the mixture was extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc = 1: 1, to afford the title compound as a yellow solid. Step 7: tert-Butyl 4-((5-(difluoromethoxy)-4-methoxypyrimidin-2-yl)amino)piperidine-l- carboxylate To a stirred solution of tert-butyl 4-((5-hydroxy-4-methoxypyrimidin-2- yl)amino)piperidine-l -carboxylate (340 mg. 1.05 mmol, 1.00 eq.) in DMF (10.0 mL) was added ethyl 2-chloro-2,2-difluoroacetate (333 mg, 2.10 mmol, 2.00 eq.) and CS2CO3 (1.03 g, 3.15 mmol, 3.00 eq.) and the resulting mixture was stirred at 100 °C for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous NazSCk After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EA = 10: 1, to afford the title compound as a white oil.

Step 8: 5-(Difluoromethoxy)-4-methoxy-N-(piperidin-4-yl)pyrimidin-2-amine hydrochloride

To a stirred solution of tert-butyl 4-((5-(difluoromethoxy)-4-methoxypyrimidin-2- yl)amino)piperidine-l -carboxylate (130 mg. 0.36 mmol, 1.00 eq.) in EtOAc (2.0 mL) was added 2M HC1 in EtOAc (2.0 mL) at 0 °C and the resulting mixture was stirred for 2 h. The mixture was concentrated under reduced pressure to afford the title compound as a white solid.

Step 9: (l-(3-((4-((5-(Difluoromethoxy)-4-methoxypyrimidin-2-yl)amino)piperidin-l- yl)sulfonyl)phenyl)piperidin-4-yl)methanol

To a stirred solution of 5-(difluoromethoxy)-4-methoxy-N-(piperidin-4-yl)pyrimidin-2- amine hydrochloride (62 mg, 0.20 mmol, 1.00 eq.) in DCM (2.0 mL) was added 3-(4- (hydroxymethyl)piperidin-l-yl)benzenesulfonyl chloride (70 mg, 0.24 mmol, 1.20 eq.) and TEA (61 mg, 0.60 mmol, 3.00 eq.) at 25 °C and the mixture was stirred for 3 h. The mixture was diluted wi th water and extracted wi th DCM. The combined organic layers was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM/MeOH = 30: 1, to afford the title compound as a white oil. Step 10: l-(3-((4-((5-(Difluoromethoxy)-4-methoxypyrimidin-2-yl)amino)piperidin-l- yl)sulfonyl)phenyl)piperidine-4-carbaldehyde

To a stirred solution of (l-(3-((4-((5-(difluoromethoxy)-4-methoxypyrimidin-2- yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidin-4-yl)methanol (40 mg, 0.08 mmol, 1.00 eq.) in DCM (2.0 mL) was added Dess-Martin (64 mg, 0.15 mmol, 2.00 eq.) at 25 °C and the resulting mixture was stirred for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM/MeOH = 30: 1, to afford the title compound as a yellow solid.

Step 11 : l-(6-(l-((l-(3-((4-((5-(Difluoromethoxy)-4-methoxypyrimi din-2 -yl)amino)piperidin-l- yl)sulfonyl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)-l-methyl-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione

To a stirred solution of l-(3-((4-((5-(difluoromethoxy)-4-methoxypyrimidin-2- yl)amino)piperidin-l-yl)sulfonyl)phenyl)piperidine-4-carbaldehyde (40 mg, 0.08 mmol, 1.00 eq.) in DMA (1.0 mL) was added l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimidine- 2,4(lH,3H)-dione hydrochloride (28 mg, 0.08 mmol, 1.00 eq.) and TEA (23 mg, 0.23 mmol, 3.00 eq.). After 5 min, to the resulting mixture was added a mixture of NaBH(OAc)s (39 mg, 0. 18 mmol, 2.42 eq.) in DMA (0.5 mL) at 25 °C and the resulting mixture was stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with water, brine, and the organic layer was dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC eluting with DCM/MeOH = 15: 1, to afford the title compound as ayellow solid. MS (ES, m/z): [M+l]⁺ = 837.1. Example 17

Synthesis of 4-((5-chloro-4-methoxypyrimidin-2-yl)amino)-N-(2-(4-(3-(2.6-dioxopiperidin-3-yl)- l-methyl-lH-indazol-6-yl)piperidin-l-yl)ethyl)-N-methylpiperidine-l -sulfonamide 2,2,2- tri fluoroacetate

Step 1 : tert-Butyl (l-(N-(2-chloroethyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate tert-Butyl (l-(chlorosulfonyl)piperidin-4-yl)carbamate (1.00 g, 3.36 mmol, 1.00 eq.) was added to a mixture of 2-chloro-N-methylethan-l -amine (480 mg.3.69 mmoLl.10 eq.) and TEA(1.02 g, 10.06 mmol, 3.00 eq.) in DCM (10.0 ml) at 0 °C, and the mixture was allowed to stir at rt for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ . After filtration, the filtrate was concentrated under reduced pressure to afford the title compound as a yellow oil.

Step 2: tert-Butyl (l -(N-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-l -methyl- lH-indazol-6-yl)piperidin-l- yl)-ethyl)N-methylsulfamoyl)piperidin-4-yl)carbamate

To a stirred solution of tert-butyl (l-(N-(2-chloroethyl)-N-methylsulfamoyl)piperidin-4- yl)carbamate (500 mg, 1.41 mmol, 1.00 eq.) in ACN (6.0 mb) was added 3-(l-methyl-6- (piperidin-4-yl)-114-indazol-3-yl)piperidine-2, 6-dione hydrochloride (614 mg, 1.69 mmol. 1.20 eq ), DIEA (900 mg, 7.05 mmol, 5.00 eq.) and KI (1.12 g, 7.05 mmol, 5.00 eq.), and the mixture w as stirred at 100 °C for 3h. The mixture was diluted with w ater and extracted with EA. The combined organic layer was washed with brine, dried over anhvdrous Na₂SO₄ . After filtration, the filtrate was concentrated, and the residue was purified by flash chromatography (DCM: MeOH=15: 1) to afford the title compound as a white solid.

Step 3: 4-Amino-N-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-l- yl)ethyl)-N-methylpiperidine-l -sulfonamide hydrochloride

To a stirred solution of tert-butyl (l-(N-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-l -methyl- 1H- indazol-6-yl)piperidin-l-yl)ethyl)-N-methylsulfamoyl)piperidin-4-yl)carbamate (261 mg, 0.40 mmol, 1.00 eq.) in EA (2.0 mL) was added 2 M HC1 in EA (2.0 mL) at rt, and the mixture was stirred for 2 h. The resulting mixture was concentrated under reduced pressure to afford the title compound as a yellow oil.

Step 4: 4-((5-Chloro-4-methoxypyrimidin-2-yl)amino)-N-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-l- methyl-lH-indazol-6-yl)piperidin-l-yl)ethyl)-N-methylpiperidine-l-sulfonamide 2,2,2- trifluoroacetate

The title compound was synthesized by proceeding analogously as described in Example 11 Step 2, with 4-amino-N-(2-(4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6- yl)piperidin-l-yl)ethyl)-N-methylpipendine-l-sulfonamide hydrochloride replacing l-(6-(l-(3- ((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3- yl)dihydropyrimidine-2,4(1H,,3H )-dione 2,2,2-trifluoroacetic acid. MS (ES, m/z): [M+l]⁺ = 688.1. Example 18

Synthesis of 3-(6-(l-(3-((4-((4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)- sulfonyl)propyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)piperidine-2,6-dione

Step 1 : tert-Butyl (l-((3-chloropropyl)sulfonyl)piperidin-4-yl)carbamate

3 -Chloropropane- 1 -sulfonyl chloride (0.91 g, 5.18 mmol. 1.0 eq.) was added to a stirred solution of tert-butyl piperidin-4-ylcarbamate (1.00 g, 4.71 mmol, 1.00 eq.) and TEA (1.43 g, 14.13 mmol, 3.00 eq.) in DCM (30 mL) at 0 °C, and the mixture was stirred at rt for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, and the organic layer was dried over anhydrous ISfeSCfi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE:EA = 6: 1 to afford the title compound as a yellow solid. Step 2: tert-Butyl (l-((3-(4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperidin-l- yl)propyl)sulfonyl)piperidin-4-yl)carbamate

A mixture of tert-buty l (l-((3-chloropropyl)sulfonyl)piperidin-4-yl)carbamate (900 mg, 2.55 mmol, 1.00 eq.), 3-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)piperidine-2, 6-dione (831 mg, 2.55 mmol, 1.00 eq.), KJ (423 mg, 2.55 mmol, 1.00 eq.). DIEA (986 mg, 7.65 mmol, 3.00 eq.) in MeCN (30.0 mL) was stirred at 80 °C for 16 h. After cooling to rt. the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM/MeOH = 20: 1 to afford the title compound as a yellow solid. Step 3: 3-(6-(l-(3-((4-Aminopiperidin-l-yl)sulfonyl)propyl)piperidin-4-yl)-l-methyl-lH-indazol- 3-yl)piperidine-2, 6-dione hydrochloride

2 M HC1 in EA (5.0 mL) was added to a stirred solution of tert-butyl (l-((3-(4-(3-(2,6- dioxopiperidin-3-yl)-l -methyl- lH-indazol-6-yl)piperi din- l-yl)propyl)sulfonyl)piperi din-4- yl)carbamate (100 mg. 0. 15 mmol) in EA (2.0 mL). The mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure to afford the title compound as a yellow solid. Step 4: 3-(6-(l-(3-((4-((4-Methoxy-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-l-yl)- sulfonyl)propyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione

The title compound was synthesized by proceeding analogously as described in Example 1 Step 3, with 3-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)propyl)piperidin-4-yl)-l-methyl-lH- indazol-3-yl)piperidine-2, 6-dione hydrochloride replacing l-(6-(l-(3-((4-aminopiperidin-l- yl)sulfonyl)benzyl)piperidin-4-yl)-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)- dione 2,2,2-trifluoroacetic acid.

The following compounds were synthesized by proceeding analogously as described in Example 18.

Biological Examples Biological Example 1

Inhibition of CDK2 and CDK4: Phospho-Rb Measurement in C₆lls Phospho-Rb Measurement in C₆lls

Phosphorylation of RB protein at S807/811 were measured using HTRF phospho-RB cellular kits (Cat# 64RBS807PEG) from Cisbio.

On Day 1, 0VCAR3 (CDK2 dependent cell line) and T47D (CDK4-dependent) cells were seeded into 96-well tissue-culture treated plates at 20,000 cells/well in 200 pL and incubated overnight at 37 °C in CO2 atmosphere. On Day 2, the cells were treated with test compounds at concentrations from 0.3 to 10,000 nM using HP D300 digital dispenser. Twenty-four hours after compound treatment, cell culture media was removed by flicking the plate and tapping the plate against clean paper towel. 30 pL IX lysis buffer was supplemented from the kit was added to each well and the plate was then incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 pL cell lysate from 96-well cell culture plate was transferred to 384-well small volume white detection plate. 2 pL premixed detection solution was added and the plate was covered with sealer. To prepare the detection solution. d2 conjugated- phospho-RB antibody and Eu-cryptate conjugated phosphor-RB antibody were diluted into detection buffer following manufacturer’s instruction. Detection plates were incubated for 4 h at room temperature and read on ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM/620 nM) was plotted against the compound concentration and normalized to DMSO controls. Half maximal inhibition concentration (IC50) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA).

In the table below; A indicates an IC50 of greater than or equal to 1 nM but less than or equal to 100 nM; B indicates an IC50 of greater than 100 nM but less than or equal to 500 nM; C indicates an IC50 of greater than 500 nM but less than or equal to 2.5 pM; D indicates a IC50 of greater than 2.5 pM. Biological Example 2

High-throughput Measurement of C₆llular Endogenous CDK2/4

Effects of compounds on cellular CDK2 and CDK4 levels were monitored by a high- throughput HTRF assay.

To determine half maximal degradation concentration (DC50) and maximum degradation level (Dmax) values of compounds, cellular CDK level was measured in 96-well format using HTRF total CDK cellular kit (CDK2 Cat# 64CDK2TPEG; CDK4 Cat# 64CDK4TPEH) from Cisbio/Revvity.

On Day 1, cells were seeded into 96-well tissue-culture treated plates at 20.000 cells/well in 200 LIL and incubated overnight at 37°C in CO2 atmosphere. On Day 2 cells were treated with compounds at concentration ranging from 0.1 to 1,000 nM using Tecan D300e digital dispenser (HP Inc., CA, USA). 6 or 24 hours after compound treatment, cell culture media was removed by flicking the plate and tapping the plate against clean paper towel. Immediately 30 pL IX lysis buffer was supplemented from the kit and added to each well and the plate is incubated at room temperature on shaker for 30 min. After homogenization by pipetting up and down, 8 pL cell lysate from 96-well cell culture plate was transferred to 384-well small volume white detection plate. 2 pL premixed detection solution was added and the plate is covered with sealer. To prepare the detection solution, d2 conjugated-CDK antibody and Eu-cryptate conjugated CDK antibody were diluted into detection buffer following manufacturer’s instruction. Detection plates were incubated overnight at room temperature and read on ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM/620 nM) was normalized to DMSO controls (0% degradation) and lysis buffer controls (100% degradation) to calculate the relative CDK level (%CDK relative to DMSO), which was then plotted against the compound concentration.JTalf maximal degradation concentration (DCso) and maximal degradation (Dmax) values were calculated with a four-parameter logistic fit using GraphPad Prism (version 9; La Jolla, CA).

In the table below, A indicates a DC50 of greater than or equal to 1 nM but less than or equal to 10 nM; B indicates a DC50 of greater than 10 nM but less than or equal to 100 nM; C indicates a DC50 of greater than 100 nM but less than or equal to 1 pM; and D indicates a DC50 of greater than 1 pM nM but less than or equal to 5 pM. NT means not tested. Table B

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

Tablet Formulation

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

Ingredient Quantity per tablet (mg) compound Formula (I) or (IB) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation

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

Ingredient Quantity per capsule (mg)

Compound Formula (I) or (IB) 200 lactose spray dried 148 magnesium stearate 2

Injectable Formulation

Compound of the disclosure in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery', 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxy propyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution Composition

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

Nasal spray solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 LIL of spray for each application.

Claims

What is Claimed:

1. A compound of Formula (I):

Degron wherein

R¹ is cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, or cycloalky l substituted with one to three halo;

R² is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, or dialkylamino;

R³ are independently hydrogen or deuterium; and

Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene. where each of the aforementioned rings is substituted with R^a, R^b, and R^c independently 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:

Y^a is CH or N;

Z^a is a bond, -CH2-, -NH-, -O-. or -NHC(O)- where NH of -NHC(O)- is attached to Y^a; ring A is a group of formula (a), (b), or (c):

(a) R^aa where: e independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;

R⁴ and R⁵ are independently hydrogen or alkyl; or R⁴ and R⁵ together with the carbon to which they are attached form >C=O;

M is -O- or -NR⁶-; and

R⁶ is hydrogen or alkyl; and

R⁶ is 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 R^ee and R^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and X¹, X², X³, and X⁴ are independently a bond, -alkylene-, -O-, -(O-alkylene)-, -(alkylene-O)-, -(NR^gg-alkylene)-, -(alkyl ene-NR^hh)-, -N(alkyl)-, -C(=O)-, are independently hydrogen, alkyl, or cycloalkyl and each alkylene, itself or as part of another group, is optionally substituted with one or two fluoro;

R^y, R^yl, and R^y2 are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with R^d and R^f selected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino; and

W^a is bond. O, S, or alkylene; and

L is -Z'-Z²-Z -Z⁴-Z⁵-Z⁶- where:

Z¹ is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O)2NR-, -NR’S(O)2-, -(O-alkylene)a-, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with R^h and R' independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z² is 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 R^k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z³ is 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 R^m and Rⁿ independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialky lamino;

Z⁴ is 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 R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z³ is 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 R^q and R^r independently selected from hydrogen, deuterium, alkyl, alkoxy , halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino; and

Z⁶ is 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 R^s, R\ and R^u where R^s is hydrogen, deuterium, or halo, R^l is 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 R⁷ and R⁸ independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxy, alkylcarbonyl, alkyloxy carbonyl, amino, alkylamino, dialkylamino, and cyano), and R^u is hydrogen or halo; or when R^l and R^u are attached to the same carbon or to adjacent carbon atoms of the linear portion of the alky dene or heteroalkydene, R^l and R^u together with the carbon atom(s) to which they are attached can form cycloalkylene or heterocyclylene (where the cycloalkylene and heterocyclylene formed by R^l and R^u are substituted with R⁹ and R¹⁰ independently 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 R^v selected from hydrogen, fluoro, and cyano, and alkynylene of -Z³- and -Z⁴- are substituted with R^w and R^x independently selected from hydrogen, halo, haloalkyl. alkoxy, hydroxy, and cyano; or yvhen R" and R^x are 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 R¹¹ and R¹² independently 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 R¹ is halo, haloalkyl. or haloalkoxy.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is 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 R² is alkoxy.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R² is 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 R^a. R^b, and R^c where R^a and R^b are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano, and R^c is hydrogen.

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 Z⁶ is -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 Z² are each a bond;

Z³ is cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ;

Z⁴ is a bond, alkylene, -O-, cycloalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, fused heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and R^p independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r: and

Z⁶ is -S(O)2-; and wherein alkylene in Z⁴ is substituted with R^s, R\ and R^u.

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:

X¹, X², X³, X⁴, and Z¹ are each a bond;

Z² is heterocyclylene substituted with R^J and R^k independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z³ is heterocyclylene substituted with R^m and Rⁿ independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy;

Z⁴ is a bond, alkylene, or -O-;

Z³ is phenylene or monocyclic heteroarylene, each ring substituted with R^q and R^r independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and

Z⁶ is -S(O)2-; and wherein alkylene in Z⁴ is substituted with R^s, R\ and R^u.

15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:

X¹, X², X³, X⁴, and Z¹ are each a bond; Z² is heterocyclylene substituted with R' and R^k are independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z³ is a bond, alkylene, or -O-;

Z⁴ is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R° and R^p;

Z⁵ is phenylene or monocyclic heteroarylene, each ring substituted with R^q and R^r; and

Z⁶ is -S(O)2-; and wherein alkylene in Z³ is substituted with R^s, R\ and R^u.

16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:

Z³ is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R^m and Rⁿ;

Z⁴ is alkylene, -O-, heterocyclylene, -(alkylene)-heterocyclylene-, -(alkylene)-bridged heterocyclylene-, where each ring, by itself or as part of another group, is substituted with R° and R^p;

Z⁵ is phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R^q and R^r; and

Z⁶ is -S(O)2; and each alkylene in Z⁴, itself or as part of another group, is substituted with R^s and R^l.

17. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein:

X¹, X², X³, X⁴, Z¹, and Z² are each a bond;

Z³ 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 R^m and Rⁿ;

Z⁴ is alky lene, alkenylene, alkynylene, heteroalkylene, where alkylene and heteroalkylene are substituted with R^s, R‘, and R^u and alkenylene is substituted with R^v;

Z⁵ is phenylene, monocyclic heteroarylene, heterocycylene. bridged heterocyclylene. or spiro heterocyclylene, where each ring is substituted with R^q and R^r; and

Z⁶ is -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 R^m, Rⁿ. and R^q are 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 Z⁵ is and 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 Z⁴ is -(alkylene)-heterocyclylene-, where heterocyclylene is substituted with R° and R^p.

22. The compound of any one of claims 1 to 14, and 16 to 20, or a pharmaceutically acceptable salt thereof, wherein Z⁴ is C₃ to C₆ alkydene substituted with R^s, R\ and R^u where R^s, R‘, and R^u are 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 R^m and Rⁿ are independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano; and

Z⁴ is C₃ to C₆ alkylene substituted with R^s, R\ and R^u.

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 ligand where R^ee is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl.

25. A pharmaceutical composition comprising a compound of any one of claims 1 to

24. 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.