WRN degraders and methods of use thereof

Abstract

The disclosure provides compounds, e.g., compounds of Formula I, and their use in treating medical diseases or disorders, such as cancer. The compounds are contemplated to be bifunctional degraders of Werner syndrome RecQ like helicase (WRN).

Description

WRN DEGRADERS AND METHODS OF USE THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 738,595 filed on December 24, 2024; the content of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Werner syndrome RecQ like helicase (WRN) is a member of the RecQ helicase family whose general function is to unwind and separate double-stranded DNA, activities which are required before DNA can be copied for DNA replication and cell division.Werner protein also plays an important role in repairing damaged DNA. for example, in the repair of double strand breaks or single nucleotide damage.

[0003] WRN has been identified as a synthetic lethality target in cancers displaying high levels of microsatellite instability (MSI-H), which occurs due to loss of DNA mismatch repair (MMR). Types of microsatellite instability -high cancers include, for example, colorectal, endometrial, gastric, and ovarian cancers, but MSI-H status may occur in other types of cancer. MSI-H cancers are strongly dependent on WRN expression, as WRN is critical for maintaining genomic integrity. As such, inhibition of WRN has become an area of high interest for targeted therapies of MSI-H cancers.

[0004] WRN helicase domain inhibitors (WRNi) are currently in clinical trials against MSI-H tumors. However, WRNi efficacy in pre-clinical models for several MSI-H cancers (for example, endometrial, gastric, & ovarian) has been poor compared to colorectal cancers. Further, MSI-H cancers are associated with a high likelihood of developing mutational resistance to first line WRNi therapies, necessitating the development of next generation WRN therapies to overcome resistance mechanisms.

[0005] For example, due to the allosteric mechanism of action of existing WRN inhibitors, mutational resistance could arise w here loss of allostery' necessitates an alternative approach to WRN therapy. To this end. the development of a WRN degrader mechanism represents an attractive approach to treat MSI-H cancers, and to overcome mutational resistance to WRN inhibitors.

[0006] Thus, an unmet need exists to develop new therapies, for example WRN degraders, for treating cancers with high microsatellite instability’ and / or resistance to allosteric inhibition of WRN.SUMMARY

[0007] The disclosure is directed, in part, to compounds that may function as degraders of Werner syndrome RecQ like helicase (WRN). Also disclosed herein are pharmaceutical compositions comprising at least one disclosed compound and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure provides a method of treating a disease or disorder that may benefit from degradation of WRN protein. In some embodiments, the disease or disorder is a cancer. In other embodiments, for example, the cancer is a microsatellite stability high (MSI-H) cancer. In additional embodiments, the cancer is resistant to allosteric inhibition of WRN. In certain embodiments, the cancer is, for example, colorectal, endometrial, gastric, or ovarian cancer.

[0008] For example, disclosed herein is a method of treating a microsatellite instability- high (MSI-H) cancer in a patient in need thereof, wherein the cancer is insensitive to WRN allosteric inhibition, comprising administering to the patient a therapeutically effective amount of a bifunctional conjugate represented by Formula (I):W-L-E(I);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:W is a Werner syndrome RecQ like helicase (WRN) binding compound;L is a linking moiety covalently linking W and E; andE is a E3 ubiquitin ligase complex binding moiety.

[0009] Also disclosed herein is a method of treating a microsatellite instability-high (MSI-H) cancer in a patient in need thereof, wherein the cancer is insensitive to WRN allosteric inhibition, comprising administering to the patient a therapeutically effective amount of a bifunctional conjugate represented by Formula (II):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cgalkoxy;Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cgalkyl, C2-Cgalkenyl, C2-C6alkynyl, Ci-Cgalkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and'm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C1-C6alkylene. C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:two to ten bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(O)-, -C(O)NRa-. -NRaC(O)O-, -OC(O)NRa-, -NRaC(O)NRb-, (-OCH2CH2-)1-5, (-CH2CH2O-)1-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and Ci-C’ealkyl. wherein C i-Cgalk l optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cgalkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;m is 1, 2, or 3;n is 1, 2, or 3;p is 0, 1, 2, 3, 4, or 5; andE is a E3 ubiquitin ligase complex binding moiety capable of covalently binding to a cereblon or VHL protein of the E3 ubiquitin ligase complex.

[0010] Further disclosed herein is a bifunctional conjugate represented by Formula (I):W-L-E(I);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:W is a Werner syndrome RecQ like helicase (WRN) binding compound;L is a linking moiety covalently linking W and E; andE is a E3 ubiquitin ligase complex binding moiety.

[0011] Also disclosed herein is a bifunctional conjugate represented by Formula (II):Y1oor a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O- -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O- RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C60ycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealk yl,Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -0(C=0)0Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- andm: wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C1-C6alkylene. C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:two to ten bivalent units each represented by -(CRL1RL2) and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(O)-, -C(O)NRa-, -NRaC(0)0-, -OC(O)NRa-, -NRaC(0)NRb-, (-OCH2CH2-)I-5, (-CH2CH2O-)I-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen. Ci-C3alkyl, and Ci-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl optionally substituted with one or moresubstituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cealkoxy: orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;m is 1, 2, or 3;n is 1, 2, or 3;p is 0, 1, 2, 3, 4, or 5; andE is a E3 ubiquitin ligase complex binding moiety capable of covalently binding to a cereblon or VEIL protein of the E3 ubiquitin ligase complex.

[0012] In addition, disclosed herein is a compound represented by Formula (III):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O- -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one. two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=0)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(0)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- andm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C1-C6alkylene. C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is selected from the group consisting of hydrogen, -(C=0)0Ci-C6alkyl, and -(C=O)Ci-C6alkyl;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or moresubstituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb. C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, C1-C3alkyl, and C1-C3alkoxy;m is 1, 2, or 3;n is 1, 2, or 3; andp is 0, 1, 2, 3, 4, or 5.

[0013] Also disclosed herein are pharmaceutical compositions comprising at least one compound of the disclosure and at least one pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions comprise at least one additional therapeutic agent.

[0014] Also disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from degradation of WRN protein, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. In some embodiments, the methods described herein may be useful to treat a cancer, for example, colorectal, endometrial, gastric, or ovarian cancer.DETAILED DESCRIPTION

[0015] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherw ise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0016] The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.

[0017] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary' alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as Ci-ealkyl, Cwalkyl, andCi-3alkyl, respectively. Exemplary alky l groups include, but are not limited to, methyl, ethyl, propyl, isopropyl. 2-methyl-l -butyl, 3-methyl-2-butyl, 2-methyl-l -pentyl. 3-methyl-l-pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1 -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyd, isopenty l, neopentyl, hexyl, etc.

[0018] The term “alkenyl” as used herein refers to an unsaturated straight or branched hy drocarbon having at least one carbon-carbon double bond. Exemplary' alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as Ci-Csalkenyl, C2-C6alkenyl, and C?-C4alkenyl, respectively.Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0019] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and Cs-ealkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyL butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0020] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C i-Csalkoxy, Ci-Cealkoxy, and C2-Cealkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[0021] The term "aryl” refers to a radical of a monocyclic or polycyclic (e.g, bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 p electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g.. phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the ary l ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene. phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl. and tetrahydronaphthyl. Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R37is each independently selected from Ci-Cs alkyd, Ci-Cs haloalkyl, 4-10 membered heterocyclyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR38R59, SO2NR58R59, S-alkyl, SOalkyl, SChalkyl, Saiyl, SOaryl, SO2aryl: or R56and R57may' be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61are each independently hydrogen, Ci-Cs alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, Cg-Cw aryl, substituted Ce-Cio aryl. 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[0022] The term “carbonyl’’ as used herein refers to the radical -C(O)-.

[0023] The term “cyano” as used herein refers to the radical -CN.

[0024] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-6, or 4-6 carbons, referred to herein as Cs-Ciocycloalkyl, Cs ecycloalkyl or C4-6Cycloalkyl, respectively.Exemplary7cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[0025] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[0026] The terms “haloalkyl” as used herein refers to an alky l radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl (i.e., CF3), difluoromethyl, fluoromethyl, chloromethyl, di chloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like. Exemplary7haloalkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6,1-4, or 1-3 carbon atoms substituted with a halogen (i.e., Cl, F, Br and I), referred to herein as Cuehaloalkyl, Ci-4 haloalkyl. and Ci-shaloalkyl, respectively.

[0027] The term "hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alky l, e.g., heteroalkyd, cycloalky l, e.g., heterocyclyl, ary l, e g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms, such as nitrogen, oxygen, or sulfur.

[0028] The terms “heteroaryl” or “heteroaromatic group’' as used herein refers to an aromatic 5-10 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. The term may also be used to refer to a 5-7 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, pyrrolopyridine, indole, thiazole, oxazole, isothiazole, isoxazole, imidazole, benzoimidazole, imidazopyridine, pyrazole, triazole, pyridine or pyrimidine, etc.

[0029] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic group” are art-recognized and refer to saturated or partially unsaturated 3-12 membered ring structures, for example, 4-10 membered ring structures, for example, 4-8 membered ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur, wherein the sulfur atom may be oxidized to SO or SO2.. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. The term may also be used to refer to 4-10 membered saturated or partially unsaturated ring structures that are bridged, fused or spirocyclic ring structures, whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran, dihydrofuran, dihydropyran, tetrahydropyran, etc. Further examples include Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyL tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyL pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyi, piperidonyl, 4-piperidinonyl, quinudidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl,oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro- 1 H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1 H,3'H- spiro [cyclopropane- 1,2'-pyrrolizine], hexahy dro- 1 H-pyrroliziny 1, hexahy dro- 1 H-pyrrolo [2,1- c][l]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyI 1 -oxide and tetrahydro-2H-thiopyranyl 1.1 -dioxide. In some embodiments, the heterocycle is a spiro heterocycle (e.g..2,8-diazaspiro[4.5]decane). In some embodiments, the heterocycle is a bridged heterocycle (e.g., octahydro- lH-4,7-methanoisoindole). " Spiro heterocyclyl," or “spiro heterocycle'’ refers to a polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of N, O, and S(0)m(wherein m is an integer of 0 to 2) as ring atoms.

[0030] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[0031] The term “oxo” as used herein refers to the radical =0.

[0032] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0033] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0034] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0035] “Individual,” “patient.” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the disclosure can be administered to a mammal, such as a human, but can also be administeredto other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g. cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). '‘Modulation” includes antagonism (e.g., inhibition), inverse agonism, agonism, biased agonism, biased signal transduction, functionally selective agonism, partial antagonism and / or partial agonism.

[0036] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity7required to achieve a desired therapeutic and / or prophylactic effect.

[0037] The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions.Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l, T-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety7may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0038] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term "‘stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(-),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0039] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol — denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carboncarbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0040] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or " E” configuration wherein the terms “Z” and ‘E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic rings may also be referred to as “cis” or “trans,” where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0041] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed byresolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim. 2009.

[0042] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

[0043] The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N.18O,170,31P,32P,35S,18F, and36C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0044] Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) mayafford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0045] The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, el al, Nature Reviews Drug Discovery 2008, 7, 255). For example, if a compound of the disclosure or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-s)alkyl, (C2-i2)alky lcarbonyloxy methyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-l-(alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxy carbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxy carbonyloxy )ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1 -(alkoxy carbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-(Ci-2)alkylamino(C2-3)alkyl (such as [3-dimethylaminoethyl), carbamoyl-(Ci-2)alkyl, N, N-di(Ci-2)alkylcarbamoyl-(Ci-2)alkyl and piperidino-, pyrrolidino- or morpholino(C'2-3 (alkyl.

[0046] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-6)alkylcarbonyloxy methyl, l-((Ci-6)alkylcarbonyloxy)ethyl,l-methyl-l-((Ci-6)alkylcarbonyloxy)ethyl (Ci-e)alkoxy carbonyloxymethyl, N-(Cu 6)alkoxycarbonylaminomethyl, succinoyl, (Ci-6)alkylcarbonyl, a-amino(C i-4)alkylcarbonyl, arylalkylcarbonyl and a-aminoalkylcarbonyl, or a-aminoalkylcarbonyl-a-aminoalkylcarbonyl, where each a -aminoalkylcarbonyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(Ci-6)alkyl)2 or glycosyl(the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[0047] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an N- alkylcarbonyloxyalkyl derivative, an (oxodioxolenyl)methyl derivative, an N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. For examples, see Simplicio, et al., Molecules 2008, 13, 519 and references therein.I. Compounds

[0048] The present disclosure is directed, in part, to compounds that may function as degraders of Werner syndrome RecQ like helicase (WRN). In some embodiments, the present disclosure provides a method of treating a disease or disorder that may benefit from degradation of WRN protein. In some embodiments, the disease or disorder is, for example, a cancer.

[0049] For example, disclosed herein is a method of treating a microsatellite instability- high (MSI-H) cancer in a patient in need thereof, wherein the cancer is insensitive to WRN allosteric inhibition, comprising administering to the patient a therapeutically effective amount of a bifunctional conjugate represented by Formula (I):W-L-E(I);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:W is a Werner syndrome RecQ like helicase (WRN) binding compound;L is a linking moiety covalently linking W and E; andE is a E3 ubiquitin ligase complex binding moiety.

[0050] In some embodiments, for example, E is capable of binding or recruiting E3 ubiquitin ligase complex directly or indirectly. In other embodiments, E is capable of binding to, for example, an associated cofactor, adaptor protein, or substrate recognition domain of E3 ubiquitin ligase, thereby enabling the recruitment of the E3 ligase ubiquitin ligase complex. In still other embodiments, E may be selected from the group consisting of, for example, an antibody, a protein, a peptide, an aptamer, a nanobody, or a small moleculebinding moiety. For example, in certain embodiments E recognizes and binds to a E3 ligase target substrate. In further embodiments. E binds to a cofactor or adaptor protein that facilitates the interaction between E3 ligase and the cofactor or adaptor protein. In additional embodiments, for example, E binds to a recognition domain or a substrate receptor of E3 ubiquitin ligase complex. In additional embodiments, E is capable of binding to, for example, VHL ligase, CRBN, MDM2 ligase, an IAP (e.g., cIAP1 or CIAP2), and / or KEAP1 protein. In other embodiments, E is capable of binding to. for example, a cereblon or VHL protein of the E3 ubiquitin ligase complex.

[0051] In some embodiments, W is capable of binding covalently or non-covalently to the Werner syndrome RecQ like helicase (WRN). For example, in some embodiments W is capable of covalently binding to cysteine residue 727 of the Werner syndrome RecQ like helicase (WRN). In certain embodiments, for example, the WRN binding compound includes a Michael acceptor covalent binding moiety.

[0052] For example, in some embodiments the WRN binding compound is represented by:wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NR'11-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and R'12are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one. two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, Cz-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C( O)NRaRb. -NRa(C O)Rb. -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;p is 0, 1, 2, 3, 4, or 5; and* denotes the point of attachment to L.

[0053] In other embodiments, a contemplated bifunctional conjugate of the present disclosure is conjugate is represented by Formula (IA):wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O- -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-C6alkoxy, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy, C3-Cecycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2C1-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and.,4^m; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond. C1-C6alkylene. C2-Cealkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:one to twelve bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(O)-, -C(O)NRa-. -NRaC(O)O-, -OC(O)NRa-, -NRaC(0)NRb-, (-OCH2CH2-)I-5. (-CH2CH2O-)I-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cgalkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;m is 1, 2, or 3;n is 1, 2, or 3; andp is 0, 1, 2, 3, 4, or 5.

[0054] In some embodiments, Y1and Y2are, for example, each -NH-. In other embodiments, X1and X2are, for example, each N. In still other embodiments, R1is - (CRcRd)-C3-C4cycloalkyl: wherein Rcand Rdare each independently selected from the groupconsisting of hydrogen and halogen. In further embodiments, for example, Z is

[0055] It can be appreciated that L, L1or L2as disclosed herein may include a chemical moiety inserted before or as a replacement of e.g., a -CH2- moiety, or one or more glycol units, e g., L may include an alkylene, an alkynylene, or alkenylene moiety, a PEG moiety (e g., (-CH2CH2-O-CH2CH2-O-CH2CH2-O-)qqor (-O-CH2CH2-O-CH2CH2-O-CH2CH2-)qqwhereqqis 1-10, e.g., 2, 3, 4), and / or an optionally substituted triazolyl, and / or a saturated, optionally substituted heterocyclyl such as piperazine and piperidine. For example, L, L1and L2taken together or alone may be a combination of PEG and alkyl, alkenyl, or alkynyl motifs (each optionally including heteroaryl, heterocyclyl, or aryl) as described herein.

[0056] In certain embodiments, for example, a bifunctional conjugate disclosed herein may be represented by Formula (IB):wherein:q is 1 or 2; andL1is selected from the group consisting of a bond, C i-6alkylene, and Ci-Ceheteroalkylene. In other embodiments, L1is selected from the group consisting of, for example, a bond, -CH2-O-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, -CH2-O-CH2-CH2-CH2-, heterocyclyl, and heteroaryl.

[0057] In other embodiments, Z is -NH-. For example, in some embodiments a bifunctional conjugate disclosed herein may be represented by Formula (IC):NH Owherein L1is selected from the group consisting of Ci-Ceheteroalkylene and C1-C6alkylene.

[0058] In some embodiments, L1is selected from the group consisting of, for example, - CH2-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, and -CH2-O-CH2-CH2-CH2-.

[0059] In additional embodiments, R2is independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, -NRaRb, Ci-C6alkyl. and Ci- Cealkoxy. In further embodiments, p is 0, 1, or 2. For example, in certain embodiments p is0. In other embodiments, R3is selected from the group consisting of, for example, -CH3, -CH2CH3, and -CH2-CH2-CH3. For example, in some embodiments R3is -CH3.

[0060] In some embodiments, L2is selected from the group consisting of -C(O)-Ci-Cioalkylene-C(O)-, -C(O)-C1-C10alkylene-(O)-, and -Ci-Cioalkylene-C(O)-.

[0061] In some embodiments, L2is selected from the group consisting of, for example, -C(O)-(CH2)-C(O)-, -C(O)-(CH2)2-C(O)-. -C(O)-(CH2)3-C(O)-. -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -C(O)-(CH2)7-C(O)-, -C(O)-(CH2)8-C(O)-, -C(O)-(CH2)9-C(O)-, -C(O)-(CH2)10-C(O)-, -C(O)-(CH2)-(O)-, -C(O)-(CH2)2-(O)-, -C(O)-(CH2)3-(O)-, -C(O)-(CH2)4-(O)-, -C(O)-(CH2)5-(O)-, -C(O)-(CH2)6-(O)-. -C(O)-(CH2)7-(O)-, -C(O)-(CH2)8-(O)-, -C(O)-(CH2)9-(O)-, -C(O)-(CH2)10-(O)-, -(CH2)-C(O)-. and -(CH2)2-C(O)-.

[0062] For example, in certain embodiments L2is selected from the group consisting of -C(O)-(CH2)2-C(O)-_ -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)6-C(O)-, -C(O)-(CH2)8-C(O)-, and -C(O)-(CH2)10-C(O)-, -C(O)-(CH2)2-(O)-, -C(O)-(CH2)4-(O)-, -C(O)-(CH2)6-(O)-, -C(O)-(CH2)S-(O)-, and -C(0)-(CH2)io-(0)-. In still other embodiments, m is 1 and n is 1. In some embodiments, for example, m is 2 and n is 2.

[0063] In further embodiments, E is selected from the group consisting of, for example,o

[0064] Also disclosed herein is a method of treating a microsatellite instability-high (MSI-H) cancer in a patient in need thereof, wherein the cancer is insensitive to WRN allosteric inhibition, comprising administering to the patient a therapeutically effective amount of a bifunctional conjugate represented by Formula (II):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;Y1is selected from the group consisting of -NRY1-, -O- -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O- RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one. two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=0)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(0)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- andm; w herein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond. C1-C6alkylene. C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:two to ten bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(O)-. -C(O)NRa-. -NRaC(O)O-, -OC(O)NRa-, -NRaC(O)NRb-, (-OCH2CH2-)i.5. (-CH2CH2O-)i.5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, C1-C3alkyl, and C1-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein Ci-Cgalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl. -NRaRb. C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-C3alkoxy;m is 1, 2, or 3;n is 1, 2, or 3;p is 0, 1, 2, 3, 4, or 5; andE is a E3 ubiquitin ligase complex binding moiety capable of covalently binding to a cereblon or VHL protein of the E3 ubiquitin ligase complex.

[0065] For example, in some embodiments a contemplated bifunctional conjugate of the present disclosure is conjugate is represented by Formula (IIA):(IIA);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and Ci-C6alkoxy;R3is C1-C6alkyl optionally substituted with one, two, or three halogens;R4and R5are each independently selected from the group consisting of halogen and hydrogen;Z is selected from the group consisting of-CH2NH-, -CH2-O-CH2-CH2-NH-,Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;E is selected from the group consisting ofp is 0, 1, or 2;q is 1 or 2; andt is 2. 3, 4, 5, 6. 7, 8, 9 or 10.

[0066] In some embodiments, for example, p is 0, 1, or 2. In other embodiments, q is 1. In still other embodiments, R4and R5are each, for example, fluoro. In further embodiments, R3is selected from the group consisting of, for example, -CH3, -CH2CH3, and -CH2-CH2- CH3. For example, in certain embodiments R3is -CH3. In additional embodiments, t is, for example, 4, 6, or 8.

[0067] Further disclosed herein is a bifunctional conjugate represented by Formula (I):W-L-E(I);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:W is a Werner syndrome RecQ like helicase (WRN) binding compound;L is a linking moiety covalently linking W and E; andE is a E3 ubiquitin ligase complex binding moiety.

[0068] In some embodiments, for example, E is capable of binding or recruiting E3 ubiquitin ligase complex directly or indirectly. In other embodiments, E is capable of binding to, for example, an associated cofactor, adaptor protein, or substrate recognition domain of E3 ubiquitin ligase, thereby enabling the recruitment of the E3 ligase ubiquitin ligase complex. In still other embodiments, E may be selected from the group consisting of, for example, an antibody, a protein, a peptide, an aptamer, a nanobody, or a small molecule binding moiety. For example, in certain embodiments E recognizes and binds to a E3 ligase target substrate. In further embodiments, E binds to a cofactor or adaptor protein that facilitates the interaction between E3 ligase and the cofactor or adaptor protein. In additional embodiments, for example, E binds to a recognition domain or a substrate receptor of E3 ubiquitin ligase complex. In additional embodiments, E is capable of binding to, for example, VHL ligase, CRBN, MDM2 ligase, an IAP (e.g., cIAP1 or CIAP2), and / or KEAP1 protein. In other embodiments, E is capable of binding to, for example, a cereblon or VHL protein of the E3 ubiquitin ligase complex.

[0069] In some embodiments, W is capable of binding covalently or non-covalently to the Werner syndrome RecQ like helicase (WRN). For example, in some embodiments W is capable of covalently binding to cysteine residue 727 of the Werner syndrome RecQ like helicase (WRN). In certain embodiments, for example, the WRN binding compound includes a Michael acceptor covalent binding moiety.

[0070] For example, in some embodiments the WRN binding compound is represented by:wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one. two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=0)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, Cz-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=0)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;p is 0, 1, 2, 3, 4, or 5; and* denotes the point of attachment to L.

[0071] In other embodiments, a contemplated bifunctional conjugate of the present disclosure is conjugate is represented by Formula (IA):wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, Ci-C6alkyl, and Ci-C6alkoxy;Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and'm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C1-C6alkylene, C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:one to twelve bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(O)-, -C(O)NRa-. -NRaC(0)0-, -OC(O)NRa-, -NRaC(0)NRb-, (-OCH2CH2-)1-5, (-CH2CH2O-)1-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein Ci-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cgalkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;m is 1, 2, or 3;n is 1, 2, or 3; andp is 0, 1, 2, 3, 4, or 5.

[0072] In some embodiments, Y1and Y2are, for example, each -NH-. In other embodiments, X1and X2are, for example, each N. In still other embodiments, R1is -(CRcRd)-C3-C4cycloalkyl; wherein Rcand Rdare each independently selected from the group* consisting of hydrogen and halogen. In further embodiments, for example, Z is

[0073] It can be appreciated that L, L1or L2as disclosed herein may include a chemical moiety inserted before or as a replacement of e.g., a -CH2- moiety, or one or more glycol units, e.g., L may include an alky lene, an alkynylene, or alkenylene moiety, a PEG moiety' (e.g., (-CH2CH2-O-CH2CH2-O-CH2CH2-O-)qqor (-O-CH2CH2-O-CH2CH2-O-CH2CH2-)qqwhereqqis 1-10. e.g., 2. 3, 4). and / or an optionally substituted triazolyl, and / or a saturated, optionally substituted heterocyclyl such as piperazine and piperidine. For example, L, L1and L2taken together or alone may be a combination of PEG and alkyl, alkenyl, or alkynyl motifs (each optionally including heteroaryl, heterocyclyl, or aryl) as described herein.

[0074] In certain embodiments, for example, a bifunctional conjugate disclosed herein may be represented by Formula (IB):wherein:q is 1 or 2; andL1is selected from the group consisting of a bond, Ci-6alkylene, and Ci-Ceheteroalkylene. In other embodiments, L1is selected from the group consisting of, for example, a bond, -CH2-O-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, -CH2-O-CH2-CH2-CH2-, heterocyclyl, and heteroaryl.

[0075] In other embodiments, Z is -NH-. For example, in some embodiments a bifunctional conjugate disclosed herein may be represented by Formula (IC):wherein L1is selected from the group consisting of Ci-Ceheteroalkylene and C1-C6alkylene.

[0076] In some embodiments, L1is selected from the group consisting of, for example, -CH2-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, and -CH2-O-CH2-CH2-CH2-.

[0077] In additional embodiments, R2is independently selected for each occurrence from the group consisting of, for example, halogen, hydroxyl, -NRaRb, C1-C6alkyl, and Ci- Cealkoxy. In further embodiments, p is 0, 1, or 2. For example, in certain embodiments p is 0. In other embodiments. R3is selected from the group consisting of, for example, -CH3, - CH2CH3, and -CH2-CH2-CH3. For example, in some embodiments R3is -CH3.

[0078] In some embodiments, L2is selected from the group consisting of --C(O)-Ci- Cioalkylene-C(O)-, -C(0)-Ci-Cioalkylene-(0)-, and -Ci-Cioalkylene-C(O)-.

[0079] In some embodiments, L2is selected from the group consisting of, for example, - C(O)-(CH2)-C(O)-, -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)- (CH2)3-C(O)-, -C(O)-(CH2)6-C(O)-, -C(O)-(CH2)7-C(O)-, -C(O)-(CH2)8-C(O)-, -C(O)- (CH2)9-C(O)-, -C(O)-(CH2)10-C(O)-, -C(O)-(CH2)-(O)-, -C(O)-(CH2)2-(O)-, -C(O)-(CH2)3- (O)-, -C(O)-(CH2)4-(O)-, -C(O)-(CH2)5-(O)-, -C(O)-(CH2)6-(O)-. -C(O)-(CH2)7-(O)-, -C(O)- (CH2)8-(O)-, -C(O)-(CH2)9-(O)-, -C(O)-(CH2)10-(O)-, -(CH2)-C(O)-, and -(CH2)2-C(O)-.

[0080] For example, in certain embodiments L2is selected from the group consisting of - C(O)-(CH2)2-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)6-C(O)-, -C(O)-(CH2)8-C(O)-, and - C(0)-(CH2)IO-C(0)-, C(O)-(CH2)2-(O)-, -C(O)-(CH2)4-(O)-, -C(O)-(CH2)6-(O)-, -C(O)- (CH2)8-(O)-, and -C(O)-(CH2)10-(O)-. In still other embodiments, m is 1 and n is 1. In some embodiments, for example, m is 2 and n is 2.

[0081] In further embodiments. E is selected from the group consisting of. for example,or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cealkoxy, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Csalkyl, and Ci-C6alkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- andm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, Ci-C6alkylene, C2-C6alkenylene, and Ci-C6heteroalkylene;L2is a linking moiety comprising:two to ten bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(O)-, -C(O)NRa-. -NRaC(O)O-, -OC(O)NRa-, -NRaC(O)NRb-, (-OCH2CH2-)1-5, (-CH2CH2O-)1-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein Ci-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cgalkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;m is 1, 2, or 3;n is 1, 2, or 3;p is 0, 1, 2, 3, 4, or 5; andE is a E3 ubiquitin ligase complex binding moiety capable of covalently binding to a cereblon or VHL protein of the E3 ubiquitin ligase complex.

[0083] For example, in some embodiments a contemplated bifunctional conjugate of the present disclosure is conjugate is represented by Formula (IIA):NH ORo (IIA);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one, two, or three halogens;R4and R5are each independently selected from the group consisting of halogen and hydrogen;Z is selected from the group consisting ofRaand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;E is selected from the group consisting ofp is 0, 1, or 2;q is 1 or 2; andt is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0084] In some embodiments, for example, p is 0, 1, or 2. In other embodiments, q is 1. In still other embodiments, R4and R5are each, for example, fluoro. In further embodiments, R3is selected from the group consisting of, for example, -CH?, -CH2CH3, and -CH2-CH2- CH?. For example, in certain embodiments R3is -CH3. In additional embodiments, t is, for example, 4, 6, or 8.

[0085] In addition, disclosed herein is a compound represented by Formula (III):R3"S\\RO (III):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, Ci-Cgalkyl, and Ci-Cgalkoxy:Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6cycloalkyl; wherein cycloalkyl may optionally be substituted with one. two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-Cgalkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Cgalkyl, and Ci-Cgalkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl. C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and'm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C1-C6alkylene, C2-Cealkenylene, and Ci-Ceheteroalkylene;L2is selected from the group consisting of hydrogen, -(C=O)OCi-C6alkyl, and -(C=O)Ci-C6alkyl;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C1-C6alkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, C1-C3alkyl, and C1-C3alkoxy;m is 1, 2, or 3;n is 1, 2, or 3; andp is 0, 1, 2, 3, 4, or 5.

[0086] For example, in some embodiments a compound disclosed herein may be represented by Formula (III A):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one, two, or three halogens;R4and R5are each independently selected from the group consisting of halogen and hydrogen;R6is selected from the group consisting of hydrogen and -(C=O)OCi-C6alkyl;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;p is 0, 1, or 2; andq is 1 or 2.

[0087] In some embodiments, for example, p is 0, 1, or 2. In other embodiments, q is 1. In still other embodiments, R4and R5are each, for example, fluoro. In further embodiments, R3is selected from the group consisting of. for example, -CH3. -CH2CH3, and -CH2-CH2- CH3. For example, in certain embodiments R3is -CH3. In additional embodiments, R6is,for example,0or hydrogen.

[0088] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds.

[0089] In other embodiments, the compound is a compound identified in Table 2 below or a pharmaceutically acceptable salt thereof.Table 2. Exemplary compounds.No Structure201 O kA A k N X OHo"F F6p,ISk202 O I A^A A k XO oHd' NF F6 IZo?v 203204^. A OX f^° P N s. A 7< A N X oHoF F6205o r°A<^ A N X^ 'P A k N X OHoF F61oA k XHd'N OF F6Q y\W A P H X i \7 W ’O 2 o o II< Z01d bo o { yL iicr NH° A y o1bSk^°Nb^ oJS o-W^N H^A b ^N 1 AAO N 7C6F F

[0090] In some embodiments, for example, a contemplated WRN binding compound may be a compound or a derivative of a compound represented by Formula (A):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:ring A is aryl, heteroaryl, or (C3-C11)cycloalkyl;each R1is independently halogen, (Ci-Cs)alkyl, halo(Ci-C6)alkyl. hydroxy(Ci- Ce)alkyl, amino(Ci-C6)alkyl, (C3-C6)cycloalkyl, hydroxyl, (Ci-Ce)alkoxy, halo(Ci- Ce)alkoxy, (C3-C6 )cycloalkoxy, (Ci-Ce)alkylsulfanyl, amino, ((Ci-C6)alkyl)amino-, ((C 1- Ce)alkyl)(( Ci-C6)alkyl)amino-, CN, COOH, CONH2, SF5, heterocycloalkyl, aryl, aryloxy, (Ci-C6)cycloalkyl-(Ci-C4)alkyl-O-, aryl-( Ci-C4)alkyl-0-, heterocycloalkyl-( Ci-C4)alkyl-0-, heteroaryl-( Ci-C4)alkyl-0-, (Ci-C6)cycloalkyl-( Ci-C4)alkyl-NH-, aryl-( Ci-C4)alkyl-NH-, heterocycloalkyl-( Ci-C4)alkyl-NH-, heteroaryl-(Cl-C4)alkyl-NH-, (Ci-C6)cycloalkyl-( Ci- C4)alkyl-, aryl-( Ci-C4)alkyl-, heterocycloalkyl-( Ci-C4)alkyl-, and heteroaryl-( Ci-C4)alkyl-; wherein each of aryl, cycloalkyl, heterocycloalkyl, and heteroaryl moieties in R1is substituted with 0-3 Rla;or two adjacent R1groups taken together with the ring atoms to which they are attached form a 5- or 6-membered non-aromatic ring, wherein the 5- or 6-memberednonaromatic ring includes 0-2 heteroatoms selected from N and O and is substituted with 0- 3 Rla;each R2 is independently halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxyl, (C1-C6)alkoxy, amino, ((C1-C6)alkyl)amino-, ((C1-C6)alkyl)((C1-C6)alkyl)amino-, or CN;R3is hydrogen or (Ci-Ce)alkyl;each R4 is independently halogen, (C1-C6)alkyl, or halo(C1-C6)alkyl;each R1a is independently halogen, CN, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, hydroxyl, or (C1-C6)alkoxy;m is 0, 1, 2, or 3; n is 0, 1, or 2; p is 1 or 2: and q is 0, 1, or 2;

[0091] In other embodiments, for example, a contemplated WRN binding compound may be a compound or a derivative of a compound represented by Formula (B):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:Ring A is a bivalent cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclylene; phenylene; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently- selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroarylene ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclylene having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclylene that is optionally bridged or spirocyclic, and a 5-12 membered saturated or partially unsaturated bicyclic heterocyclylene that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R1is hydrogen, halogen, -CN, or an optionally substituted Ci-6 aliphatic group;R2is a Ci-6 aliphatic group, a Ci-6 aliphatic-Cy’ group, or a cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bi cyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic, and a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein R2 is substituted with y instances of RA;R3and R4are each independently selected at each occurrence from hydrogen, halogen, CN, -NO2, -OR, -SR, -NR2, -NRC(O)R, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2. -N(R)S(O)2R, a C1-6aliphatic group optionally substituted with -C(O)NR2or NR2, a Ci-6 aliphatic-C” group, or C”; wherein when mis 2 or 3, two adjacent instances of CR3R4are optionally combined to form a carbon-carbon double bond of the formula -C(R4)=C(R4)-;each instance of R5is independently selected from hydrogen, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, C(O)NR2, C(O)N(R)OR. -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, a Ci-6 aliphatic group substituted with z instances of RB, a Cl -6 aliphatic-Cy’” group substituted with z instances of RB, and Cy’” substituted with z instances of RB; or two instances of R5on the same atom together form oxo; or two instances of R5on adjacent atoms of Ring A, taken together with said adjacent atoms, form a phenyl ring fused to Ring A, wherein said phenyl ring is substituted with 0-4 independently selected halogens;R6is hydrogen, halogen, a Ci-6 aliphatic group, -SF5, -OR, -SR, -S(O)2NR2, -NR2, -S(O)2R, -SiR3, or a cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bi cyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the Ci-6 aliphatic group and cyclic group are substituted with z instances of RB;each instance of RAis independently selected from hydrogen; a Ci-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; two instances of RAon the same atom together form oxo; and a cyclic group selected from: 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group is optionally substituted with 1, 2, or 3 groups independently selected from -OR, -CR2OR, and halogen;each instance of RBis independently selected from hydrogen; a Ci-6 aliphatic group optionally substituted with 1, 2. or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; -N(R)S(O)2R; phenyl; and two instances of RBon the same atom together form oxo;each of Cy', Cy", and Cy”' is independently an optionally substituted cyclic group selected from: a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bi cyclic heteroaromatic ring having1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bi cyclic aromatic carbocyclic ring;

[0092] each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3, - C(O)2C(CH3)3, - C(O)2CH(CH3)2, -S(O)2CH3, an optionally substituted Ci-6 aliphatic group, an optionally substituted cyclic group selected from: phenyl; an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on the same atom are taken together with the same atom to form a cyclic group selected from: an optionally substituted 4-7 membered saturated or partially unsaturated carbocycyl; an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;x is 0, 1, 2, 3, or 4; mis 0, 1, 2, or 3; n is 1 or 2; y is 0, 1, 2, or 3; and z is 0, 1, 2, or 3.

[0093] In further embodiments, for example, a contemplated WRN binding compound may be a compound or a derivative of a compound represented by Formula (C) or Formula (D):0(C) or0 0(D); or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:L1is is C 1-4 alkylene;L2is O, S, OC(O), OSO2, OC(O)O, or OC(O)NH;L3is is C1-8 alkylene;R1, R2, R4, and R5are each independently H, halogen, C1-4 alkyl, or Ci-4haloalkyl; and R3is is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 hydroxyalkyd, C1-6 haloalk 1, C6-12 aryl, or C6-12 aryl-Ci-4 alkyl, each of which is optionally substituted with halogen, C1-4 alkyl, or C1-4 haloalkyl.

[0094] In additional embodiments, for example, a contemplated WRN binding compound may be a compound or a derivative of a compound represented by Formula (E):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X is CR2orN;Y is CR4orN;Z is CR5orN;or Y and Z taken together form an optionally’ substituted five- to six-membered heteroaryl, or an optionally substituted five- to six-membered heterocyclyl;R1is H, -O-(optionally substituted Cs-Cs cycloalkyl), -O-(optionally substituted Ci-Ce alkyl), -O-(optionally substituted Ce-Cio aryl), -O-(optionally substituted five- to sixmembered heteroaryl), -O-(optionally substituted five- to six-membered heteroeyclyl), or optionally substituted C3-C8 cycloalky l;or R1together with the carbon atoms to which it is shown attached and X form an optionally substituted five- to six-membered heterocyclyl;R2is H, optionally substituted Ci-Ce alky l, or halo;R3is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 cycloalkenyl, optionally substituted Cs-Cio aryl, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, -NR2, -N(R)(optionally substituted C3-C8 cycloalkyl), - S-(optionally substituted Ci-Ce alkyd), -O-(optionally substituted Ci-Ce alkyl), -O- (optionally substituted C3-C8 cycloalkyl), optionally substituted four- to six-membered heterocyclyl or heterocyclenyl, optionally substituted five- to six-membered heteroaryl, or - □-(optionally substituted Cs-Cs cycloalkyl);or R3taken together with the carbon atom to which it is shown attached and Y form an optionally substituted Ce-Cio aryl, an optionally substituted Cb-C's cycloalkyl or cycloalkenyl, or an optionally substituted five- to six-membered heterocyclyl or heterocyclenyl;R4is H, Ci-Ce alkyl, cyano, or halo;or R4together with the carbon atom to which it is shown attached and Z form an optionally substituted five- to six -membered heteroaryl;or R3and R4taken together with the carbon atoms to which they are show n attached and R3taken from an optionally substituted Ce-Cio aryl, an optionally substituted C4-C8 cycloalkyl or cycloalkeny l, or an optionally substituted five- to six-membered heterocyclyl or heterocyclenyl;R5is H, Ci-C6alkyl, -NR2, or -N(R)-C(=O)-( Ci-C6alkyl);each R is independently H, or optionally substituted Ci-Ce alkyl; andV is selected from the group consisting of a vinylsulfone, an alkynylsulfone, a vinylsulfonamide, a vinylsulfoxide, an alkynylsulfoxide, a vinylsulfoximine, an alkynylsulfoximine. an acrylamide, an acrylonitrile, an alkynenitrile, an enone, a ynone. an enoate, and a ynoate.

[0095] In some embodiments, for example, a contemplated WRN binding compound may be a compound or a derivative of a compound represented by Formula (F):R’or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R1is an optionally substituted Cg-Cio aryl, or an optionally substituted five- to sixmembered cycloalkyl or cycloalkenyl;R2is H, halo, hydroxy, optionally substituted Ci-Ce alkyl, optionally substituted Cs-C12 aryl, optionally substituted C3-C8 cycloalkyl, or -O-Ci-Ce alkyl;R2ais H or Ci-Ce alkyl;or R2and R2atogether with the carbon atom to which they are shown attached form an optionally substituted Cs-Cs cycloalkyl;n is 1 or 2;m is 0 or 1;R3and R3aare each independently H, halo or Ci-Ce alkyl;or C(R2)(R2a) and the adjacent C(R3)(R3a) when n is 2 are taken together to form an optionally substituted Ce-Cio aryl; andV is selected from the group consisting of a vinylsulfone, an alkynylsulfone, a vinylsulfonamide, a vinylsulfoxide, an alkynylsulfoxide, a vinylsulfoximine, an alkynylsulfoximine, an acrylamide, an acrylonitrile, an alkynenitrile, an enone, a ynone, an enoate, and a ynoate.

[0096] In some embodiments, a contemplated WRN binding compound may be a compound or a derivative of a compound selected from the group consisting of:F, CCH3or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

[0097] In some embodiments, a contemplated WRN binding compound may bind covalently or non-covalently to WRN. In some embodiments, a contemplated small molecule capable of binding, for example, covalently binding, to Werner syndrome RecQ like helicase (WRN) may be selected from a compound, or a derivative of a compound, disclosed in, for example. WO / 2024 / 215923. WO / 2024 / 010782, WO / 2024 / 010784, WO / 2023 / 062575, WO / 2019 / 241802, and WO / 2024 / 246863, the content of each of which is incorporated herein by reference in its entirety.

[0098] In some embodiments, contemplated E3 ligase ligands of the present disclosure for CRBN may include, for example:

[0099] For example, in some embodiments contemplated E3 ligase ligands of the present disclosure for CRBN may include:

[0100] In some embodiments, contemplated E3 ligase ligands of the present disclosure for VHL may include, for example:

[0101] Additional E3 ligase ligands of the present disclosure for MDM2 may include, for example:

[0102] Additional E3 ligase ligands of the present disclosure for IAP may include, for example:

[0103] For example, contemplated general structures of E3 ligase ligands of the present disclosure may include, e.g.,:wherein X is CH2 or C=O; R is the point of attachment to L; R1is alky l or a point of attachment to L; R2is H or an alternative point of attachment to L; R3is H or CH3; R5is alkyl or a point of attachment to L; R6is alkyl or an alternative point of attachment to L; and R7is alkyl or an alternative point of attachment to L.

[0104] Procedures for making compounds described herein are provided in the examples below. In the reactions described below, it may be necessary to protect reactive functional groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, see Greene, Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds as disclosed herein. Starting materials used in the following scheme can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0105] Compounds disclosed herein, or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify disclosed compounds or any preceding intermediates by modifying, introducing or removing appropriate functional groups.

[0106] Where it is desired to obtain a particular enantiomer of a disclosed compound, this may be produced from a corresponding mixture of enantiomers by employing any suitable conventional procedure for resolving enantiomers known to those skilled in the art. For example, diastereomeric derivatives (such as salts) can be produced by reaction of a mixture of enantiomers of a disclosed compound (such a racemate) and an appropriate chiralcompound (such as a chiral base). The diastereomers can then be separated by any conventional means such as crystallization or chromatography, and the desired enantiomer recovered (such as by treatment with an acid in the instance where the diastereomer is a salt). Alternatively, a racemic mixture of esters can be resolved by kinetic hydrolysis using a variety7of biocatalysts (for example, see Patel Stereoselective Biocatalysts, Marcel Decker; New York 2000).

[0107] In another resolution process a racemate of disclosed compounds can be separated using chiral High Performance Liquid Chromatography. Alternatively, a particular enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the disclosure.

[0108] In an alternative embodiment, disclosed compounds may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may' be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%. at least 80%. at least 85%. at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.II. Methods

[0109] Further disclosed herein are methods of treating a patient suffering from a condition, disease, or disorder that is affected by, associated with, or would benefit from degradation of WRN, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof. For example, disclosed herein are methods of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutical composition thereof.

[0110] In some embodiments, for example, the compounds and compositions disclosed herein may be used to treat a cancer. For example, disclosed herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effectiveamount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0111] In some embodiments, the cancer may be selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, renal cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, thymic cancer, skin cancer, and brain cancer. In some embodiments, the cancer may be selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer. For example, disclosed herein is a method of treating a cancer selected from the group consisting of gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer, in a patient need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also disclosed herein is a method of treating a cancer selected from the group consisting of gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer, in a patient need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0112] In some embodiments, the cancer to be treated is, for example, gastric cancer. Provided herein, for example, is a method of treating gastric cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating gastric cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula 1, Formula 11, or Formula III, and a pharmaceutically acceptable excipient.

[0113] In some embodiments, the cancer to be treated is, for example, colorectal cancer. Provided herein, for example, is a method of treating colorectal cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also providedherein is a method of treating colorectal cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0114] In some embodiments, the cancer to be treated is, for example, endometrial cancer. Provided herein, for example, is a method of treating endometrial cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating endometrial cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0115] In some embodiments, the cancer to be treated is, for example, esophageal cancer. Provided herein, for example, is a method of treating esophageal cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating esophageal cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0116] In some embodiments, the cancer to be treated is, for example, ovarian cancer. Provided herein, for example, is a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating ovarian cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0117] In some embodiments, the cancer to be treated is, for example, renal cancer. Provided herein, for example, is a method of treating renal cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also providedherein is a method of treating renal cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0118] In some embodiments, the cancer to be treated is, for example, bladder cancer. Provided herein, for example, is a method of treating bladder cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating bladder cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0119] In some embodiments, the cancer to be treated is, for example, thymic cancer. Provided herein, for example, is a method of treating thymic cancer in a patent in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating thymic cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0120] In some embodiments, the cancer to be treated is, for example, prostate cancer. Provided herein, for example, is a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating prostate cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0121] In some embodiments, the cancer to be treated is, for example, skin cancer. Provided herein, for example, is a method of treating skin cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a methodof treating skin cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0122] In some embodiments, the cancer to be treated in the patient is a microsatellite instability-high (MSI-H) cancer. For example, disclosed herein is a method of treating a microsatellite instability -high (MSI-H) cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also provided herein is a method of treating a microsatellite instability -high (MSI-H) cancer in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. and a pharmaceutically acceptable excipient. In some embodiments, the microsatellite instability -high (MSI-H) cancer is selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, renal cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, thymic cancer, skin cancer, and brain cancer. In some embodiments, the microsatellite instability-high (MSI-H) cancer may be selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer.

[0123] MSI-H status of a cancer may be determined using any suitable method now known or later developed. Methods for identifying MSI-H status of a cancer are well known in the art. Non-limiting examples of assessing MSI-H status include polymerase chain reaction (PCR)-based microsatellite instability testing, next-generation sequencing (NGS)-based analysis of microsatellite loci, or immunohistochemical (IHC) evaluation of mismatch repair (MMR) protein expression. In certain PCR-based assays, a cancer may be classified as MSI-H when instability’ is detected in at least about 30% of tested microsatellite loci, for example, instability at two or more loci in a standard five-marker panel. In certain NGS-based assays, MSI-H status may be identified based on a validated instability score or a threshold proportion of unstable microsatellite loci, such as approximately 10% or greater, depending on the assay. In certain IHC-based assays, MSI-H status may be inferred from loss of expression of one or more MMR proteins selected from MLH1, MSH2, MSH6, and PMS2, indicating mismatch repair deficiency. Any patient whose cancer meets one or moreclinically accepted criteria indicative of MSI-H status may be treated according to the methods disclosed herein.

[0124] In other embodiments, the cancer to be treated in the patient is insensitive, for example, resistant, to allosteric inhibition of WRN protein. For example, disclosed herein is a method of treating a cancer insensitive (e.g., resistant) to allosteric inhibition of WRN protein in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also disclosed herein is a method of treating a cancer insensitive (e.g.. resistant) to allosteric inhibition of WRN protein in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient. In some embodiments, the cancer that is resistant to allosteric inhibition of WRN is selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, renal cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, thymic cancer, skin cancer, and brain cancer. In some embodiments, the cancer that is resistant to allosteric inhibition of WRN may be selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer.

[0125] In further embodiments, for example, the cancer to be treated in the patient is a microsatellite instability -high (MSI-H) cancer that is resistant to allosteric inhibition of WRN. For example, disclosed herein is a method of treating a microsatellite instability-high (MSI-H) cancer that is resistant to allosteric inhibition of WRN in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also disclosed herein is a method of treating a microsatellite instability -high (MSI-H) cancer that is resistant to allosteric inhibition of WRN in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient. In some embodiments, the microsatellite instability-high (MSI-H) cancer that is resistant to allosteric inhibition of WRN is selected from the group consisting of. for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, renal cancer, breast cancer, prostate cancer, lung cancer,bladder cancer, pancreatic cancer, liver cancer, thymic cancer, skin cancer, and brain cancer. In some embodiments, the microsatellite instability-high (MSI-H) cancer that is resistant to allosteric inhibition of WRN may be selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer.

[0126] Further disclosed herein is a method of degrading WRN protein in a patient in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Further disclosed herein is a method of degrading WRN protein in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0127] In some embodiments, degrading WRN protein is associated with treating a cancer selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, renal cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, thymic cancer, skin cancer, and brain cancer. In other embodiments, degrading WRN protein is associated with treating, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, or renal cancer.

[0128] For example, disclosed herein is a method of degrading WRN protein in a patient suffering from cancer, and in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also disclosed herein is a method of degrading WRN protein in a patient suffering from cancer, and in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0129] In addition, disclosed herein is a method of degrading WRN protein in a patient suffering from a microsatellite instability -high (MSI-H) cancer, and in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g.. a compound of Formula I, Formula II. or Formula III. Also disclosed herein is a method of degrading WRN protein in a patient suffering from microsatellite instability -high(MSI-H) cancer, and in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g.. a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0130] Further disclosed herein is a method of degrading WRN protein in a patient suffering from a cancer resistant to allosteric inhibition of WRN, and in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also disclosed herein is a method of degrading WRN protein in a patient suffering from a cancer resistant to allosteric inhibition of WRN, and in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient.

[0131] Also disclosed herein is a method of degrading WRN protein in a patient suffering from a microsatellite instability -high (MSI-H) cancer that is resistant to allosteric inhibition of WRN, and in need thereof, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III. Also disclosed herein is a method of degrading WRN protein in a patient suffering from a microsatellite instability -high (MSI-H) cancer that is resistant to allosteric inhibition of WRN, and in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound of Formula I, Formula II, or Formula III, and a pharmaceutically acceptable excipient. In some embodiments, the cancer selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, renal cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, pancreatic cancer, liver cancer, thymic cancer, skin cancer, and brain cancer. In other embodiments, the cancer is selected from the group consisting of, for example, gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, or renal cancer.

[0132] The compounds described herein can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein. For clarity, contemplated herein are both a fixed composition comprising a disclosed compound and another therapeutic agent such as disclosed herein, and methods of administering, separately a disclosed compound and a disclosed therapeutic. For example, provided in the presentdisclosure is a pharmaceutical composition comprising a compound described herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a disclosed compound and one additional therapeutic agent is administered. In some embodiments, a disclosed compound as defined herein and two additional therapeutic agents are administered. In some embodiments, a disclosed compound as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a disclosed compound and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a disclosed compound as one therapeutic agent and one or more additional therapeutic agents. For example, a disclosed compound and an additional therapeutic agent can be administered in a single formulation.

[0133] In some embodiments, the benefit experienced by a patient is increased by administering a compound described herein with a second therapeutic agent that also has therapeutic benefit. In one specific embodiment, a compound described herein is coadministered with a second therapeutic agent wherein the compound described herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. The overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[0134] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0135] The compounds and compositions describe herein are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compositions described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compositions are administered to a subjectduring or as soon as possible after the onset of the symptoms. In specific embodiments, a composition described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.

[0136] In particular, in certain embodiments, the disclosure provides a method of treating the above medical indications comprising administering a subject in need thereof a therapeutically effective amount of a compound described herein. The methods described herein also include administering to the patient a therapeutically effective amount of at least one compound as described herein, which is optionally formulated in a pharmaceutical composition.III. Pharmaceutical Compositions and Kits

[0137] Another aspect of the disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, intranasal, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and / or may be formulated for oral or subcutaneous administration.

[0138] Exemplary pharmaceutical compositions of this disclosure may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the disclosure, as an active ingredient, in admixture with an organic or inorganic earner or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0139] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the disclosure, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0140] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0141] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, mayoptionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0142] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0143] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0144] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.

[0145] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0146] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0147] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0148] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0149] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0150] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0151] In another aspect, the disclosure provides enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4. of about 8.6. of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e. g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of the present disclosure.

[0152] The disclosure also provides kits for use by a e.g., a consumer in need of treatment of a disease or disorder described herein. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administrationmodes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0153] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows '‘First Week, Monday, Tuesday,... etc.... Second Week, Monday, Tuesday,... “ etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.EXAMPLES

[0154] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods aretherefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.Example 1: Synthesis of Intermediates

[0155] Preparation of 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylic acid (Int-1)step 5 step 6Step 1. Synthesis of ethyl 2-(methylsulfanyl)-4-phenoxypyrimidine-5-carboxylate

[0156] To a stirred mixture of phenol (245 g, 2.60 mol) in DMF (5000 mL) were added K2CO3 (490 g, 3.55 mol) and ethyl 4-chloro-2-(methylsulfanyl) pyrimidine-5-carboxylate (550 g, 2.36 mol) in portions at 5 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (4000 mL * 3). The filtrate was washed with brine (800 mL * 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (2500 mL). The resulting mixture was filtered, and the filter cake was washed with PE (300 mL * 4). The filtrate was concentrated under reduced pressure to afford ethyl 2-(methylsulfanyl)-4-phenoxypyrimidine-5-carboxylate (570 g, 83.1%) as a yellow solid, m / z ES+ [M+H]+291. Step 2. Synthesis of ethyl 2-chloro-4-phenoxypyrimidine-5-carboxylate

[0157] To a stirred mixture of ethyl 2-(methylsulfanyl)-4-phenoxypyrimidine-5-carboxylate (570 g, 1.96 mol) in DCM (300 mL) and ACN (300 mL) was added sulfuroyl dichloride (397 g, 2.94 mol) in portions at 12 °C under nitrogen atmosphere. The resultingmixture was stirred at 20 °C for 0.5 h under nitrogen atmosphere. The reaction was quenched with ice water at 10 °C. The resulting mixture was extracted with DCM (900 mL * 3). The combined organic layer was washed with brine (400 mL * 3), and sat. NaHCO₃ (aq.) (400 mL * 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (300 mL * 4) to obtain ethyl 2-chloro-4-phenoxypyrimidine-5-carboxylate (490 g, 89.6%) as an off-white solid, m / z ES+ [M+H]+279.Step 3. Synthesis of ethyl 2-(l-cyclopropylethenyl)-4-phenoxypyrimidine-5-carboxylate

[0158] To a stirred mixture of ethyl 2-chloro-4-phenoxypyrimidine-5-carboxylate (380 g, 1.36 mol) in dioxane (3800 mL) and H2O (380 mL) was added 2-(l-cyclopropylethenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (316 g, 1.64 mol), K2CO3 (415 g, 3.00 mol) and PdC12[P(tBu)2Ph]2 (76.6 g, 123 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2.5 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (900 mL * 3). The filtrate w as washed with brine (500 mL * 3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (8: 1) to afford ethyl 2-(l-cyclopropylethenyl)-4-phenoxypyrimidine-5 -carboxylate (180 g, 42.5%) as a yellow oil. m / z ES+ [M+H]⁺ 311. Step 4. Synthesis of ethyl 2-cyclopropanecarbonyl-4-phenoxypyrimidine-5-carboxylate

[0159] To a stirred mixture of ethyl 2-(1-cyclopropylethenyl)-4-phenoxypyrimidine-5-carboxylate (21 g, 67.7 mmol) and Potassium osmate(VI) dihydrate (2.49 g, 6.76 mmol) in THF (100 mL) and H2O (100 mL) was added NaIO4 (57.9 g, 271 mmol) in portions at 10 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The mixture was filtered and the precipitate solid was washed with EtOAc (900 mL * 3). Then the filtrate was washed with sat. sodium hyposulfite (aq.) (300 mL * 3) and brine (300 mL * 3), dried over anhydrous Na2SO4 to afford ethyl 2-cyclopropanecarbonyl-4-phenoxypyrimidine-5-carboxylate (16 g, crude) as a black oil which was used in the next step directly without further purification, m / z ES+ [M+H]+313. Step 5. Synthesis of ethyl 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylate

[0160] A mixture of ethyl 2-cyclopropanecarbonyl-4-phenoxypyrimidine-5-carboxylate (16 g, 51.2 mmol) in DAST (80 mL) was stirred at 45 °C for 7 h under nitrogen atmosphere.The reaction w as quenched by the addition of ice w ater (500 mL) at 10 °C. The resulting mixture was extracted with DCM (500 mL * 3). The combined organic layer was washed with brine (300 mL * 3), sat. NaHCCL (400 mL * 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (8:1) to afford ethyl 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylate (10 g, 58.4%) as a y ellow oil. m / z ES+ [M+H]+335.Step 6. Synthesis of 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylic acid

[0161] A mixture of ethyl 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylate (10 g. 29.9 mmol) in DCE (100 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction was quenched by the addition of ice water (200 mL) at 10 °C. The resulting mixture was extracted with EtOAc (500 mL * 3). The residue was acidified to pH 5 with cone. HC1. The aqueous layer was extracted with DCM (300 mL * 3). The combined organic layer was washed with brine (30 mL * 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylic acid (6.1 g, 65.6%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H), 9.19 (s, 1H), 7.50 - 7.46 (m, 2H), 7.33 - 7.25 (m, 3H), 1.66 - 1.53 (m. 1H), 0.69 - 0.52 (m, 4H); m / z ES+ [M+H]+307.Preparation of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Int-3)Step 1. Synthesis of 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

[0162] A solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (25 g, 73.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (34.3 g, 111 mmol) and K3PO4(31.4 g, 148 mmol) in 1,4-dioxane (500 mL) and H2O (50 mL) was added XPhos Pd G2 (8.72 g, 11.1 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. After completion of reaction, the mixture was allowed to cool down to room temperature. The reaction was quenched with EtOAc (500 mL). The combined organic layer was washed with brine (500 mL * 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (40% to 70%) to afford 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 (22 g, 67.6%) as a brown yellow’ solid, m / z ES+ [M+H]+441.Step 2. Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate

[0163] To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (22 g, 49.9 mmol) in 2,2,2-trifluoroethan-l-ol (440 mL) was added wet Pd / C (55 g, 10%) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for overnight. The mixture was filtered through a celite pad and concentrated under reduced pressure to afford 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 (14 g, 63.5%) as an off-white solid.NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.11 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.91 (dd, J= 8.2, 1.6 Hz, 1H), 4.19 - 3.98 (m, 2H), 3.87 (d, J= 8.9 Hz, 1H), 3.33 (s, 3H), 3.00 - 2.55 (m, 6H), 1.99 (d, J= 11.4 Hz, 1H), 1.75 (d, J= 12.7 Hz, 2H), 1.65 - 1.46 (m, 2H). 1.42 (s, 9H); m / z ES+ [M+H]+443.Step 3. Synthesis of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0164] To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (4.5 g, 10.1 mmol) in DCM (50 mL) were added HC1 in 1,4-dioxane (10 mL). The resulting solution was stirred 4 h at 25 °C. The mixture w as concentrated to give 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (3.6 g, 93.7%) as yellow solid, m / z ES+ [M+H]+343.Preparation of 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Int-4)Step 1. Synthesis of tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d ]imidazol-5-yl) -3, 6-dihydropyridine- 1 ( 2H) -carboxylate

[0165] A solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (23.5 g, 73.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (34.3 g, 111 mmol) and K₃PO₄ (31.4 g, 148 mmol) in 1,4-dioxane (500 mL) and H2O (50 mL) was added XPhos Pd G2 (8.72 g, 11.1 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. After completion of reaction, the mixture was allowed to cool down to room temperature. The reaction was quenched with EtOAc (500 mL). The combined organic layer was washed with brine (400 mL * 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (50% to 80%) to afford tert-butyl 4-[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-l -carboxylate (23 g, 70.6%) as a brown yellow solid, m / z ES+ [M+H]+441.Step 2. Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

[0166] To a solution of tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (23 g, 52.2 mmol) in 2,2,2-trifluoroethan-l-ol (460 mL) was added wet Pd / C (34.5 g, 10%) in a pressure tank. The mixture was hydrogenated at room temperature under30 psi of hydrogen pressure for 2 h. The mixture was filtered through a celite pad and concentrated under reduced pressure to afford tert-butyl 4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidine-l -carboxylate (15 g, 65.1%) as an off-white solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.03-6.95 (m, 3H), 5.38 (dd, J= 12.6, 5.4 Hz, 1H), 4.08 (d, J= 12.9 Hz, 2H), 3.60 (s, 3H), 3.49 - 3.29 (m, 2H), 3.02 - 2.79 (m, 2H), 2.78 - 2.55 (m. 2H), 2.06 - 1.92 (m, 1H), 1.81 (d, J= 12.8 Hz, 2H). 1.58 (q, J= 12.5, 11.4 Hz. 2H), 1.42 (s, 9H); m / z ES+ [M+H]+443.Step 3. Synthesis of 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0167] To a solution of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (5.0 g, 11.3 mmol) in DCM (60 mL) were added HC1 in 1,4-di oxane (12 mL). The resulting solution was stirred for 5 h at 25 °C. The mixture was concentrated to give 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (3.6 g, 92.9%) as yellow solid, m / z ES+ [M+H]+343.Preparation of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (Int-5)lnt-5Step 1. Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l-carboxylate

[0168] A mixture of tert-butyl 4-(4-aminophenyl)piperidine-l -carboxylate (10 g, 36.2 mmol), NaHCO₃ (9.1 g, 109 mmol) and 3 -bromopiperidine-2, 6-dione (10.4 g. 54.3 mmol) in DMF (200 mL) was stirred at 80 °C for 12 h. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (300 mL * 3). The combined organic layer was washed with brine (300 mL * 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l -carboxylate (8 g, 57.1%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 6.95 (d, J= 8.4 Hz, 2H), 6.61 (d, J= 8.4 Hz, 2H). 5.67 (d, J= 7.5 Hz, 1H), 4.34 - 4.18 (m, 1H), 4.05 (d. J= 12.9 Hz, 2H), 2.85 - 2.67 (m,4H), 2.65 - 2.51 (m, 2H), 2.22 - 2.04 (m, 1H), 1.96 - 1.80 (m, 1H), 1.69 (d, J= 12.9 Hz, 2H). 1.42 (s, 9H); m / z ES+[M+H]+388.Step 2. Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione

[0169] To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l-carboxylate (8 g. 20.6 mmol) in DCM (160 mL) was treated with TFA (30 mL, 263 mmol) at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure to afford 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (5.8 g, 97.8%) as a colorless oil. m / z ES+ [M+H]+288.Preparation of 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (Int-6)Int-6Step 1. Synthesis of tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l-carboxylate

[0170] A mixture of tert-butyl 4-(3-aminophenyl)piperidine-l-carboxylate (10 g, 36.2 mmol), NaHCO₃ (9.1 g, 109 mmol) and 3-bromopiperidine-2.6-dione (10.4 g, 54.3 mmol) in DMF (200 mL) was stirred at 80 °C for 12 h. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (300 mL * 3). The combined organic layer was washed with brine (300 mL * 2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford tert-butyl 4-(3-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-l-carboxylate (8 g, 57.1%) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 6.99 (t, J= 7.8 Hz, 1H), 6.59 - 6.46 (m, 1H). 6.51 - 6.31 (m, 2H), 5.74 (d, J= 7.6 Hz, 1H), 4.40 - 4.26 (m. 1H), 4.05 (d, J= 12.9 Hz, 2H), 2.84 - 2.66 (m, 1H). 2.65 - 2.52 (m, 1H), 2.21 - 2.04 (m. 1H), 1.96 - 1.77 (m. 1H), 1.74 - 1.64 (m, 4H), 1.49 - 1.40 (m, 2H), 1.41 (s, 9H); m / z ES+ [M+H]+388.Step 2. Synthesis of 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2.6-dione

[0171] To a solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidine-1-carboxylate (8 g, 20.6 mmol) in DCM (160 mL) was treated with TFA (30 mL, 263.1 mmol) at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure to afford 3-((3-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (5.8 g, 97.8%) as a colorless oil. m / z ES+ [M+H]+288.Preparation of (S, E)-2-(cyclopropyldifluoromethyl)-N-(3-(methylsulfonyl)-l-(piperidin-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide (Int-Al)lnt-A1Step 1. Synthesis of tert-butyl 4-(l-amino-2-hydroxyethyl)piperidine-l -car boxy late

[0172] A solution of tert-butyl 4-(l-amino-2-methoxy-2-oxoethyl) piperidine-1-carboxylate (10 g, 36.7 mmol) in methanol (100 mL) at 0 °C under nitrogen atmosphere followed by the addition of NaBH₄ (6.98 g, 184 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (500 mL * 2). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The tert-butyl 4-(1-amino-2-hydroxyethyl)piperidine-1 -carboxylate (8 g, crude) was used in the next step directly without further purification, m / z ES+ [M+H]+245.Step 2. Synthesis of tert-butyl 4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-hydroxyethyl)piperidine-l -carboxylate

[0173] A solution of 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylic acid (Int-1) (10 g. 37.7 mmol), HATU (18.7 g, 49.1 mmol), Et3N (9.93 g, 98.2 mmol) in DCM (80 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 20 min under nitrogen atmosphere, followed by the addition of tert-butyl 4-(l-amino-2-hydroxyethyl)piperidine-l-carboxylate (8 g, 32.7 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 20 min under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL). The residue was washed with brine (100 mL * 5). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (1: 1) to afford tert-butyl 4-(l-(2-(cyclopropyldifhioromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-hydroxyethyl)piperidine-l-carboxylate (8.0 g, 45.9%) as a white solid, m / z ES+ [M+H]+533.Step 3. Synthesis of tert-butyl 4-(l -(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-oxoethyl)piperidine-l-carboxylate

[0174] A solution of tert-butyl 4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-hydroxyethyl)piperidine-l-carboxylate (7.0 g, 13.1 mmol) in DCM (140 mL) at 0 °C under nitrogen atmosphere followed by the addition of DMP (11.2 g, 26.3 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with PE (400 mL). The resulting mixture was filtered, and the filter cake was washed with PE (100 mL * 2). The filtrate w as washed with sat. NaHCO3 (aq.) (300 mL). The organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product tert-butyl 4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-oxoethyl)piperidine-l-carboxylate (6.5 g, 93.2%) was used in the next step directly without further purification, m / z ES+ [M+H]+531.Step 4. Synthesis of tert-butyl (E)-4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)piperidine-l-carboxylate

[0175] A solution of tert-butyl 4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-oxoethyl)piperidine-l-carboxylate (6.5 g, 12.3 mmol) in THF (65 mL) at 0 °C under nitrogen atmosphere followed by the addition of NaH (588 mg, 14.7 mmol, 60%) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere, followed by the addition of diethyl methanesulfonylmethylphosphonate (3.38 g, 14.7 mmol) in portions al 0 °C. The resulting mixture was stirred at 0 °C for 20 min under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (100 mL * 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5: 1) to afford tert-butyl (E)-4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)piperidine-l-carboxylate (4.5 g) as a yellow oil. [M+H]+607.Step 5. Synthesis of tert-butyl (S, E)-4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)piperidine-l-carboxylate

[0176] The product of tert-butyl (E)-4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)piperidine-l-carboxylate (4.5 g, 7.43 mmol) was separated by chiral SFC with the following conditions (Column: XA-CHIRAL ART Cellulose-SC, 3 * 25 cm 5um; Mobile Phase A: CO2, Mobile Phase B: 1PA: Hexane = 1: 1 (0.2% ca. 4% in Isopropyl Alcohol, ca. 2.0 mol / L); Flow rate: 80 mL / min; Gradient (B%): isocratic 50% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1 (min): 3.1; RT2 (min): 4.2; Sample Solvent: ACN; Injection Volume: 2.5 mL) to afford (the later peak) tert-butyl (S, E)-4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl) allyl)piperidine-l -carboxylate (2.0 g, 26.9%) as a white solid. 'H NMR (300 MHz, DMSO-d6) 59.00 (s, 1H), 8.78 (d, J= 8.9 Hz, 1H), 7.49 (dd, J= 8.9. 6.9 Hz. 2H), 7.37 - 7.26 (m, 3H). 6.97 - 6.61 (m, 2H). 4.82 - 4.70 (m. 1H), 3.95 (d. J= 13.0 Hz, 2H), 2.98 (s, 3H), 2.80 -2.57 (m, 1H), 1.93 - 1.81 (m, 1H), 1.70 - 1.57 (m, 3H), 1.35 (s, 9H), 1.26 - 1.12 (m, 3H), 0.68 - 0.51 (m, 4H); m / z ES+ [M+H]+607.Step 6. Synthesis of (S, E)-2-(cyclopropyldifluoromethyl)-N-(3-(methylsulfonyl)-l-(piperidin-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide

[0177] A solution of tert-butyl (S, E)-4-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)piperidine-l-carboxylate (1 g, 1.65 mmol) in DCM / TFA (3 / 1) (20 mL) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (50 mL) to afford (S, E)-2-(cyclopropyldifluoromethyl)-N-(3-(methylsulfonyl)-l-(piperidin-4-yl)allyl)-4-phenoxypyrimidine-5-carboxamide (600 mg, 71.9%) as a yellow oil. m / z ES+ [M+H]+507.Preparation of (R, E)-N-(l-(2-aminoethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide (Int-A2)Step 1. Synthesis of methyl N-((benzyloxy)carbonyl)-O-(2-((tert-butoxycarbonyl)amino)ethyl)-L-serinate

[0178] A solution of 1-benzyl 2-methyl (2S)-aziridine-l,2-dicarboxylate (5.0 g, 21.3 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (2.91 g, 18.1 mmol) in CHCls (50 mL) under nitrogen atmosphere followed by the addition of boron trifluoride diethyl etherate (0.77 g. 2.55 mmol, 46.5%) in portions at 0 °C for 1 h. The resulting mixture was stirred at room temperature for additional 6 h. After completion of reaction, the reaction wasquenched with saturated sodium bicarbonate solution at 0 °C. The resulting mixture was extracted with DCM (500 mL * 2). The combined organic layer was washed with brine (200 mL * 2), dried over anhydrous Na2SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (5% to 40%) to afford methyl N-((benzyloxy)carbonyl)-O-(2-((tert-butoxycarbonyl)amino)ethyl)-L-serinate (2.5 g, 29.7%) as a yellow oil. m / z ES+ [M+H]+397.Step 2. Synthesis of benzyl (R)-(l-(2-((tert-butoxycarbonyl)amino)ethoxy)-3-hydroxypropan-2-yl)carbamate

[0179] A solution of methyl N-((benzyloxy)carbonyl)-O-(2-((tert-butoxycarbonyl)amino)ethyl)-L-serinate (2.5 g, 6.31 mmol) in MeOH (25 mL) was added NaBH4 (1.43 g, 37.8 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 3 h under nitrogen atmosphere. After completion of reaction, the reaction was quenched with sat. NH4CI (aq.) (150 mL) at 0 °C. The resulting mixture was extracted with DCM (300 mL * 3). The combined organic layer was washed with brine (100 mL * 2), dried over anhydrous Na2SO4 After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.8 g) was used in the next step directly without further purification, m / z ES+ [M+H]+369.Step 3. Synthesis of tert-butyl (R)-(2-(2-amino-3-hydroxypropoxy)ethyl)carbamate

[0180] To a solution of benzy l (R)-(l-(2-((tert-butoxycarbonyl)amino)ethoxy)-3-hydroxypropan-2-yl)carbamate (1.8 g, 4.89 mmol) in ethyl acetate (36 mL) was added wet Pd / C (0.54 g, 10%) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 1 h, filtered through a celite pad and concentrated under reduced pressure. The crude product (1.2 g) was used in the next step directly without further purification, m / z ES+ [M+H]+235.Step 4. Synthesis of tert-butyl (R)-(2-(2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-hydroxypropoxy)ethyl)carbamate

[0181] A solution of 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylic acid (Int-1) (1.25 g, 4.10 mmol), TEA (1.55 g, 15.4 mmol) andHATU (2.92 g.7.68 mmol) in DCM (12 mL) was stirred at room temperature for 15 min under nitrogen atmosphere, followed by the addition of tert-butyl (R)-(2-(2-amino-3-hydroxypropoxy)ethyl)carbamate (1.2 g, 5.12 mmol) in portions at room temperature. Theresulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. After completion of reaction, the reaction was quenched with DCM (20 mL). The combined organic layer was washed with brine (20 mL * 3), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE / THF (25% to 60%) to afford tert-butyl (R)-(2-(2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-hydroxypropoxy)ethyl)carbamate (1.6 g, 59.7%) as an off-white solid, m / z ES+ [M+H]+523.Step 5. Synthesis of tert-butyl (S)-(2-(2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-oxopropoxy)ethyl)carbamate

[0182] To a stirred solution of tert-butyl (R)-(2-(2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-hydroxypropoxy)ethyl)carbamate (1.6 g, 3.06 mmol) in DCM (32 mL) was added Dess-Martin periodinane (2.60 g, 6.12 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h under nitrogen atmosphere. After completion of reaction, the resulting mixture was diluted with PE (96 mL). The resulting mixture was filtered; the filter cake was washed with DCM / PE = 1 / 3. The filtrate was quenched by the addition of saturated sodium bicarbonate solution (150 mL) at 0 °C and washed with brine (150 mL * 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (S)-(2-(2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-oxopropoxy)ethyl)carbamate (1 g, crude) as a brown yellow oil, which was used in the next step directly without further purification, m / z ES+ [M+H]+521.Step 6. Synthesis of tert-butyl (E)-(2-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)ethyl)carbamate

[0183] A solution of diethyl methanesulfonylmethylphosphonate (0.44 g, 1.92 mmol) in THF (20 mL) was treated with NaH (0.08 g, 1.92 mmol) at 0 °C for 1 h under nitrogen atmosphere followed by the addition of tert-butyl (S)-(2-(2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-oxopropoxy)ethyl)carbamate (1 g, 1.92 mmol) THF (20 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. After completion of reaction, the reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (160 mL * 2). The combined organic layer was washed with brine (100 mL * 2), dried over anhydrous Na2SO4. After filtration,the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (35% to 60%) to afford tert-butyl (E)-(2-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)ethyl)carbamate (500 mg, 43.6%) as an off-white semisolid. m / z ES+ [M+H]+597.Step 7. Synthesis of tert-butyl (R, E)-(2-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)ethyl)carbamate

[0184] The tert-butyl (E)-(2-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)ethyl)carbamate (500 mg, 0.84 mmol) was purified by prep-chiral-HPLC with the following conditions (Column: XA-(R, R)-WHELK-O, 3 * 25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA: DCM = 2: 1 (0.2% ca. 4% in Isopropyl Alcohol, ca. 2.0 mol / L); Flow rate: 80 mL / min; Gradient (B%): isocratic 50% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wave Length: 220 nm; RT1 (min): 3.14; RT2 (min): 4.53; Sample Solvent: ACN; Injection Volume: 2 mL) to afford (the earlier peak) tert-butyl (R, E)-(2-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)ethyl)carbamate (170 mg) as an off-white oil.1H NMR (300 MHz, Chloroform-d) 59.45 (s, 1H), 8.21 (d, J= 7.6 Hz, 1H). 7.55 - 7.43 (m, 2H), 7.42 - 7.28 (m. 1H), 7.26 - 7.18 (m, 1H), 6.99 (dd, J= 15.1, 5.4 Hz, 1H). 6.64 (dd. J= 15.2, 1.6 Hz. 2H), 5.18 - 4.99 (m, 1H), 3.74 (d, J = 4.0 Hz, 2H), 3.59 - 3.53 (m, 2H), 3.54 - 3.48 (m, 2H), 2.95 (s, 3H), 1.40 (s, 9H), 0.93 - 0.83 (m, 1H), 0.77 - 0.66 (m, 2H), 0.61- 0.51 (m, 2H); m / z ES+ [M+H]+597.Step 8. Synthesis of (R, E)-N-(1-(2-aminoethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide

[0185] A solution of tert-butyl (R, E)-(2-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)ethyl)carbamate (170 mg, 0.285 mmol) in DCM (2.4 mL) under nitrogen atmosphere followed by the addition of TFA (0.6 mL) dropwise at 0 °C. The resulting mixture was stirred for additional for 1 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford (R, E)-N-(l-(2-aminoethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide (140 mg, 98.9%) as a light yellow oil. m / z ES+ [M+H]+497.Preparation of (R, E)-2-(cyclopropyldifluoromethyl)-N-(4-(methylsulfonyl)-l-(piperidin-4-ylmethoxy)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Int-A3)Step 1. Synthesis of tert-butyl (S)-4-((2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropoxy)methyl)piperidine-l-carboxylate

[0186] A solution of 1-benzyl 2-methyl (S)-aziridine-l,2-dicarboxylate (5 g. 21.3 mmol) and tert-butyl 4-(hydroxymethyl)piperidine-l -carboxylate (3.89 g, 18.1 mmol) in CHCh (50 mL) under nitrogen atmosphere followed by the addition of boron trifluoride diethyl etherate (0.77 g, 2.55 mmol, 46.5%) in portions at 0 °C for 1 h. The resulting mixture was stirred at room temperature for additional 6 h. After completion of reaction, the reaction was quenched with saturated sodium bicarbonate solution at 0 °C. The resulting mixture was extracted with DCM (400 mL * 4). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (30% to 50%) to afford tert-butyl (S)-4-((2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropoxy)methyl)piperidine-l-carboxylate (2.7 g, 28.2%) as ayellow oil. m / z ES+ [M+H]+451.Step 2. Synthesis of tert-butyl (R)-4-((2-(((benzyloxy)carbonyl)amino)-3-hydroxypropoxy)methyl)piperidine-l -carboxylate

[0187] A solution of tert-butyl (S)-4-((2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropoxy )methyl)pi peri dine- 1 -carboxylate (2.7 g, 5.99 mmol) in MeOH (27 mL) was added NABH4 (1.51 g, 35.9 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 3 h under nitrogen atmosphere. After completion of reaction, the reaction was quenched with sat. NH4CI (aq.) (150 mL) at 0 °C. The resulting mixture was extracted with DCM (300 mL * 3). The combined organic layer was washed with brine (200 mL * 2), dried over anhydrous Na2SO4L. After filtration, the filtrate was concentrated under reduced pressure. The crude product (2.5 g) was used in the next step directly without further purification, m / z ES+ [M+H]+423.Step 3. Synthesis of tert-butyl (R)-4-((2-amino-3-hydroxypropoxy)methyl)piperidine-l-carboxylate

[0188] To a solution of tert-butyl (R)-4-((2-(((benzyloxy)carbonyl)amino)-3-hydroxypropoxy)methyl)piperidine-l-carboxylate (2.5 g. 5.92 mmol) in ethyl acetate (50 mL) was added wet Pd / C (0.75 g, 10%) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 1 h, filtered through a celite pad and concentrated under reduced pressure. The crude product (1.9 g) was used in the next step directly without further purification, m 'z ES+ [M+H]+489.Step 4. Synthesis of tert-butyl (R)-4-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-hydroxypropoxy)methyl)piperidine-l-carboxylate

[0189] A solution of 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylic acid (Int-1) (1.61 g, 5.27 mmol), TEA (1.20 g, 19.8 mmol) and HATU (3.75 g, 9.88 mmol) in DCM (19 mL) was stirred at room temperature for 15 min under nitrogen atmosphere, followed by the addition of tert-butyl (R)-4-((2-amino-3-hydroxypropoxy)methyl)piperidine-l-carboxylate (1.9 g, 6.59 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. After completion of reaction, the reaction was quenchedwith DCM (30 mL). The combined organic layer was washed with brine (150 mL * 3), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE / THF (25% to 60%) to afford tert-butyl (R)-4-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-hydroxypropoxy)methyl)piperidine-l-carboxylate (3.2 g, 84.2%) as an off-white solid, m / 'z ES+ [M+H]+577.Step 5. Synthesis of tert-butyl (S)-4-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-oxopropoxy)methyl)piperidine-l-carboxylate

[0190] To a stirred solution of tert-butyl (R)-4-((2-(2-(cyclopropyldifhioromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-hydroxypropoxy)methyl)piperidine-l-carboxylate (3.2 g, 5.55 mmol) in DCM (64 mL) was added Dess-Martin periodinane (4.70 g, 11.1 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h under nitrogen atmosphere. After completion of reaction, the resulting mixture was diluted with PE. The resulting mixture was fdtered, and the filter cake was washed with DCM / PE = 1 / 3. The filtrate was quenched by the addition of saturated sodium bicarbonate solution (200 mL) at 0 °C and washed with brine (150 mL * 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (S)-4-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-oxopropoxy)methyl)piperidine-l -carboxylate (2.2 g, crude) as a brown yellow^ oil. The crude product was used in the next step directly without further purification. m / z ES+ [M+H]+575.Step 6. Synthesis of tert-butyl (E)-4-(((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)methyl)piperidine- 1 -carboxylate

[0191] A solution of diethyl methanesulfonylmethylphosphonate (0.88 g, 3.82 mmol) in THF (44 mL) was treated with NaH (0.16 g, 3.83 mmol, 60%) at 0 °C for 1 h under nitrogen atmosphere followed by the addition of tert-butyl (S)-4-((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-oxopropoxy)methyl)piperidine-l -carboxylate (2.2 g, 3.83 mmol) in THF (44 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for30 min under nitrogen atmosphere. After completion of reaction, the reaction was quenched by the addition of sat. NH4CI (aq.) (150 mL) at 0 °C. The resulting mixture was extracted with EtOAc (80 mL * 3). The combined organic layer was washed with brine (100 mL * 2), dried over anhydrous Na2SO4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (0% to 55%) to afford tert-butyl (E)-4-(((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)methyl)piperidine-l -carboxylate (1.2 g, 48.2%) as an off-white semi-solid, m / z ES+ [M+H]+651.Step 7. Synthesis of tert-butyl 4-[[(E,2R)-2-[[2-[cyclopropyl(difluoro)methyl]-4-phenoxy-pyrimidine-5-carbonyl ]amino ]-4-methylsulfonyl-but-3-enoxy Jmethyl ] piperidine- 1 -carboxylate

[0192] The tert-butyl (E)-4-(((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)methyl)piperidine-l-carboxylate (1.2 g, 1.85 mmol) was purified by Chiral HPLC with the following conditions (Column: XA-CHIRALPAK IG. 3 * 25 cm, 5 pm: Mobile Phase A: CO2. Mobile Phase B: EtOH: ACN = 3: 1 (0.2% ca. 4% in Isopropyl Alcohol, ca. 2.0 mol / L): Flow rate: 80 mL / min; Gradient (B%): isocratic 40% B; Column Temperature (°C): 35; Back Pressure (bar): 100; Wave Length: 220 nm; RT1 (min): 3.6; RT2 (min): 4.8; Sample Solvent: EtOH; Injection Volume: 2 mL) to afford (the later peak) tert-butyl (R, E)-4-(((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)methyl) piperidine- 1 -carboxyl ate (750 mg) as an yellow oil. 'H NMR (300 MHz, DMSO-t / e) δ 9.07 (s, 1H), 8.80 (d, J= 8.3 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.39 - 7.27 (m, 3H), 7.15 - 6.57 (m, 2H), 5.01 (dd, J= 8.3, 4.2 Hz, 1H), 3.82 (d, J= 12.5 Hz, 2H), 3.66 - 3.58 (m, 2H), 3.27 (d, J = 6.3 Hz, 2H). 2.98 (s, 3H). 2.63 - 2.53 (m, 2H), 1.71 - 1.67 (m. 2H), 1.52 (d. J= 13.8 Hz, 2H), 1.38 (s, 9H), 1.00 - 0.86 (m, 2H), 0.68 - 0.50 (m, 4H); m / z ES+ [M+H]+651.Step 8. Synthesis of (R, E)-2-(cyclopropyldifluoromethyl)-N-(4-(methylsulfonyl)-l-(piperidin-4-ylmethoxy)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide

[0193] A solution of tert-butyl (R, E)-4-(((2-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-4-(methylsulfonyl)but-3-en-l-yl)oxy)methyl)piperidine-l -carboxylate (750 mg, 1.15 mmol) in DCM (3.2 mL) under nitrogen atmosphere followed by the addition of TFA (0.8 mL) dropwise at 0°C. The resulting mixture was stirred for additional for 1 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford (R, E)-2-(cyclopropyldifluoromethyl)-N-(4-(methylsulfonyl)-l-(piperidin-4-ylmethoxy)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (620 mg, 97.7%) as a light yellow oil. m / z ES+ [M+H]+551.Preparation of (S, E)-N-(l-(azetidin-3-yl)-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide (Int-A4)Step 1. Synthesis of tert-butyl 3-(l-amino-2-hydroxyethyl)azetidine-l-carboxylate

[0194] A solution of tert-butyl 3-(l-amino-2-methoxy-2-oxoethyl)azetidine-l-carboxylate (4.9 g, 20.1 mmol) in MeOH (25 mL) was added NaBH4i (4.21 g, 100 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 3h under nitrogen atmosphere. After completion of reaction, the reaction was quenched with sat. NH4CI (aq.) (250 mL) at 0 °C. The resulting mixture was extractedwith DCM (400 mL * 3). The combined organic layer was washed with brine (200 mL * 2). dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (3.4 g) was used in the next step directly without further purification, m / z ES+ [M+H]+217.Step 2. Synthesis of tert-butyl 3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-hydroxyethyl)azetidine-l -carboxylate

[0195] A solution of 2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxylic acid (Int-1) (4.67 g, 10.7 mmol), TEA (4.62 g, 45.8 mmol) and HATU (5.80 g, 15.3 mmol) in DCM (33 mL) was stirred at room temperature for 15 min under nitrogenatmosphere, followed by the addition of tert-butyl 3-(l-amino-2-hydroxyethyl)azetidine-l-carboxylate (3.3 g, 15.3 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. After completion of reaction, the reaction was quenched with DCM (150 mL * 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4U. The residue was purified by silica gel column chromatography, eluted with PE / THF (0% to 55%) to afford tert-butyl 3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-hydroxyethyl)a / etidine-l -carboxylate (4.0 g, 52%) as an off-white solid, m / z ES+ [M+H]+ 505.Step 3. Synthesis of tert-butyl 3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-oxoethyl)azetidine-l-carboxylate

[0196] To a stirred solution of tert-butyl 3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-hydroxyethyl)azetidine-l-carboxylate (4.0 g, 7.93 mmol) in DCM (80 mL) was added Dess-Martin periodinane (6.72 g, 15.9 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h under nitrogen atmosphere. After completion of reaction, the resulting mixture was diluted with PE. The resulting mixture w as filtered, and the filter cake w as washed with DCM / PE = 1 / 3. The filtrate was quenched by the addition of saturated sodium bicarbonate solution (300 mL * 2) at 0 °C and washed with brine (150 mL * 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-oxoethyl)azetidine-l-carboxylate (3.5 g) as a brown yellow oil, which was used in the next step directly without further purification, m / z ES+ [M+H]+503.Step 4. Synthesis of terl-bulyl (E)-3-(l-(2-(cyclopropyldlfluoromelhyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)azetidine-l -carboxylate

[0197] A solution of l-[ethoxy(methylsulfonylmethyl)phosphoryl]oxyethane (1.47 g, 6.37 mmol) in THF (64 mL) was treated with NaH (0.268 g, 6.37 mmol) at 0 °C for 1 h under nitrogen atmosphere followed by the addition of tert-butyl 3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-2-oxoethyl)azetidine-l-carboxylate (3.2 g, 6.37 mmol) THF (30 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. After completion of reaction, the reaction w as quenched by the addition of sat. NH4CI (aq.) (200 mL) at 0 °C. The resultingmixture was extracted with EtOAc (250 mL * 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (30% to 70%) to afford tert-butyl (E)-3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)azetidine-l -carboxylate (2.5 g, 67.8%) as an off-white semi-solid, m / z ES+ [M+H]+579.Step 5. Synthesis of tert-butyl (S, E)-3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)azetidine-l-carboxylate

[0198] The tert-butyl (E)-3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)azetidine-l -carboxylate (2.5 g, 4.33 mmol) was purified by prep-chiral-HPLC with the following conditions (Column: XA-CHIRALPAK IF, 3 * 25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: EtOH: Hexane = 1: 1; Flow rate: 100 mL / min; Gradient (B%): isocratic 30% B; Column Temperature (°C): 25; Back Pressure(bar): 100; Wave Length: 220 nm; RT1 (min): 6.6; RT2 (min): 8.0; Sample Solvent: EtOH: DCM = 1: 1; Injection Volume: 2.5 mL) to afford (the later peak) tert-butyl (S, E)-3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)azetidine-l -carboxylate (600 mg) as an off-white solid. 'H NMR (300 MHz, DMSO-c / g) 58.98 (d. J= 16.1 Hz, 2H), 7.47 (dd. J= 8.9, 6.9 Hz, 2H). 7.40 - 7.22 (m, 3H), 6.94 (dd,. / = 15.3, 1.5 Hz, 1H), 6.72 (dd, J= 15.2, 4.9 Hz, 1H), 5.02 (q, J= 8.0 Hz, 1H), 3.94 - 3.81 (m, 2H), 3.77 - 3.65 (m, 2H), 2.97 (s, 3H), 2.92 - 2.80 (m, 1H), 1.72 - 1.52 (m, 1H), 1.32 (s, 9H), 0.67- 0.49 (m, 4H); m / z ES+ [M+H]+579.Step 6. Synthesis of (S, E)-N-(l-(azetidin-3-yl)-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide

[0199] A solution of tert-butyl (S, E)-3-(l-(2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamido)-3-(methylsulfonyl)allyl)azetidine-l-carboxylate (700 mg, 1.15 mmol) in DCM (3.2 mL) under nitrogen atmosphere followed by the addition of TFA (0.8 mL) dropwise at 0 °C. The resulting mixture was stirred for additional for 1 h at room temperature. After completion of the reaction, the reaction mixture w as concentrated under reduced pressure to afford (S, E)-N-(l-(azetidin-3-yl)-3-(methylsulfonyl)allyl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5-carboxamide (550 mg, 94.1%) as a light yellow oil. m / z ES+ [M+H]+479.Preparation of 6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-6-oxohexanoic acid (Int-Bl)Step 1. Synthesis of tert-butyl 6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-6-oxohexanoate

[0200] 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 (1.2 g, 3.1 mmol) in DCM (20 mL) were added 6-(tert-butoxy)-6-oxohexanoic acid (747 mg, 3.7 mmol), HATU (1.4 g, 3.7 mmol) and DIEA (800 mg, 6.2 mmol). The resulting solution was stirred 3 h at 25 °C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 20% to 65%) to give tert-butyl 6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-6-oxohexanoate (1.2 g, 71.8%) as light yellow solid, m / z ES+ [M+H]+527.Step 2. Synthesis of 6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-6-oxohexanoic acid

[0201] A solution of tert-butyl 6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-6-oxohexanoate (1.5 g, 2.85 mmol) in DCM (16 mL) under nitrogen atmosphere followed by the addition of TFA (4 mL) dropwise at 0 °C. The resulting mixture w as stirred for additional for 1 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted with diethyl ether (10 mL). The precipitated solids were collected by filtration and washed with diethyl ether (20 mL * 2) to afford 6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-6-oxohexanoic acid (1.2 g, 89.5%) as an off-white solid, m / z ES+ [M+H]+471.

[0202] The following intermediates were made according to the procedure described for Int-Bl.Precursor Analytical Stmcture Precursor 21 dataHU\^ OLCMS: m / z Q ° Int-3 ES+ [M+H]+6" / X 499.Int-B2 Ot-Bu0HOr" o> Hd OLCMS: m / z Int-3 ES+ [M+H] Q w o+527.Int-B3 Ot-BuOor <)H LCMS: m / z Int-4 ES+ [M+H]+\ N. H 471.Ot-BuInt-B4u0TX^0LCMS: m / z Int-4 ES+ [M+H]+499.Int-B5 Ot-BuPreparation of 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro- 1H- benzo [d] imidazol-4-yl)piperidin- 1-yl)- 10-oxodecanoic acid (Int-B7)Step 1. Synthesis of tert-butyl 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo- 2.3-dihydro- lH-benzo[dJimidazol-4-yl)piperidin-l -yl)- 10-oxodecanoate

[0203] To a solution of tert-butyl 10-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2.3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-10-oxodecanoate (The compound was an intermediate in the synthesis of Int-B3, utilizing a procedure analogous to that of Int- Bl.) (100 mg, 0.17 mmol) in DMF (2 mL) was treated with CS2CO3 (168 mg, 0.52 mmol) at 0 °C for 5 min under nitrogen atmosphere followed by the addition of Mel (0.03 g, 0.21 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for1 h under nitrogen atmosphere. After completion of reaction, the resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions to afford tert-butyl 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-10-oxodecanoate (50 mg, 48.8%) as a white solid, m / z ES+ [M+H]+597. Step 2. Synthesis of 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-10-oxodecanoic acid

[0204] A solution of tert-butyl 10-(4-(3-methyl-l-(l-methyl-2.6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-10-oxodecanoate (50 mg, 0.08 mmol) in DCM (1 mL) under nitrogen atmosphere followed by the addition of TFA (0.25 mL) dropwise at 0 °C. The resulting mixture was stirred for additional for 1 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted with diethyl ether (5 mL). The precipitated solids were collected by filtration and washed with diethyl ether (5 mL *2) to afford 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-10-oxodecanoic acid (35 mg, 77.26%) as an off-white solid, m / z ES+ [M+H]+541.Preparation of 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H- benzo [d] imidazol-5-yl)piperidin- 1-yl)- 10-oxodecanoic acid (Int-B8)Step 1. Synthesis of tert-butyl 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidm-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-10-oxodecanoate

[0205] A solution of tert-butyl 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-10-oxodecanoate (The compound was an intermediate in the synthesis of Int-B7, utilizing a procedure analogous to that of Int-Bl.) (100 mg, 0.17 mmol) in DMF (2 mL) was treated with CS2CO3 (168 mg, 0.52 mmol) at 0 °C for 5 min under nitrogen atmosphere followed by the addition of MeI (0.03 g, 0.21 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. After completion of reaction, the resultingmixture was diluted with water (5 mL). The resulting mixture was extractedwith EtOAc (20 mL * 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4L. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions to afford tert-butyl 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-10-oxodecanoate (50 mg, 48.8%) as a white solid, m / z ES+ [M+H]+597.Step 2. Synthesis of 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-10-oxodecanoic acid

[0206] A solution of tert-butyl 10-(4-(3-methyl-l-(l-methyl-2.6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-10-oxodecanoate (50 mg, 0.08 mmol) in DCM (1 mL) under nitrogen atmosphere followed by the addition of TFA (0.25 mL) dropwise at 0 °C. The resulting mixture was stirred for additional for 1 h at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting mixture was diluted with diethyl ether (5 mL). The precipitated solids were collected by filtration and washed with diethyl ether (5 mL * 2) to afford 10-(4-(3-methyl-l-(l-methyl-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-10-oxodecanoic acid (35 mg, 77.3%) as an off-white solid, m / z ES+ [M+H]+ 541.Preparation of 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-4-oxobutanoic acid (Int-B9)oolnt-B9HStep 1. Synthesis of tert-butyl 4-(4-(4-((2,6-dioxopiperidin-3-yl)ammo)phenyl)piperidin-l-yl)-4-oxobutanoate

[0207] Into a 100 mL round-bottom flask w ere added 3-((4-(piperidin-4-yl)phenyl)amino)piperidine-2, 6-dione (Int-5) (1 g, 3.50 mmol), HATU (2.0 g, 5.22 mmol)and DIEA (1.4 g, 10.4 mmol) at 25 °C in DCM (20 mL). The resulting solution was stirred 3 h at 25 °C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4 to obtain a crude product. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford tert-butyl 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-4-oxobutanoate (1.1 g, 71.4%) as a white solid, m / 'z ES+ [M+H]+444.Step 2. Synthesis of 4-(4-(4-((2,6-dioxopiperidin-3-yl)ammo)phenyl)piperidin-l-yl)-4-oxobutanoic acid

[0208] To a solution of tert-butyl 4-(4-(4-((2.6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-4-oxobutanoate (1.1 g, 2.4 mmol) in DCM (20 mL) was added TFA (30 mL) at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure to afford 4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-l-yl)-4-oxobutanoic acid (600 mg, 62.5%) as a colorless oil. m / z ES+ [M+H]+388.

[0209] The following intermediates were made according to the procedure described for Int-B9.Structure Precursor Analytical data O II 1 H0°^N^0LCMS: m / z ES+hit- 5T 1 T J [M+H]+416.HInt-BlOOn i H LCMS:0°VNV° Int-5 m2 ES+ [M+H]+H 444.Int-BllOn i H LCMS:hit- 5 m / z ES+ [M+H] L l I J1H 472.Int-B12oHOS / \A,'Xn? IH0\TxX\zNx / \ LCMS: m / z ES+Int-6TJ T X [M+H]+388.CT NI' X)HInt-B13On iO <^x<^x N x^ LCMS: w z ES+TJ T I Int-6[M+H]+416.CT N X)HInt-B140n i0XX LCMS: m,'z ES+Int- 6[M+H]+444.CT N' X)HInt-B15oHOx x-x^ / ^^n i iO ^ LCMS: m / z ES+T j T 1 Int-6cr 'N X) [M+H]+472.HInt-B16Preparation of 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)-5-oxopentanoic acid (Int-B17)lnt-B17Step 1. Synthesis of methyl l-(5-(tert-butoxy)-5-oxopentanoyl)piperidine-4-carboxylate

[0210] To a solution of methyl piperidine-4-carboxylate (2.0 g, 13.9 mmol) in DCM (50 mL) were added 5-(tert-butoxy)-5-oxopentanoic acid (2.9 g, 15.3 mmol), HATU (6.3 g, 16.6 mmol) and DIEA (3.6 g, 27.8 mmol). The resulting solution was stirred 3 h at 25 °C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 10% to 45%) to give methyl l-(5-(tert-butoxy)-5-oxopentanoyl)piperidine-4-carboxylate (3.2 g, 73.2%) as colorless oil. m / z ES+ [M+H]+314. Step 2. Synthesis of l-(5-(tert-butoxy)-5-oxopentanoyl)piperidine-4-carboxylic acid

[0211] To a solution of methyl l-(5-(tert-butoxy)-5-oxopentanoyl)piperidine-4-carboxylate (1.0 g, 3.2 mmol) in MeOH (10 mL) were added LiOH (161 mg, 6.7 mmol) in H2O (50 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude product by 1 -(5 -(tert-butoxy)-5 -oxopentanoy l)piperidine-4-carboxy lie acid (1.1 g) as light yellow oil. m / z ES+ [M+H]+300.Step 3. Synthesis of tert-butyl 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)-5-oxopentanoate

[0212] To a solution of l-(5-(tert-butoxy)-5-oxopentanoyl)piperidine-4-carboxylic acid (500 mg, 1.7 mmol) in DCM (10 mL) were added 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (485 mg, 1.4 mmol), HATU (638 mg, 1.7 mmol) and DIEA (542 g, 27.8 mmol). The resulting solution was stirred 3 h at 25 °C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4L, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 30% to 70%) to give tert-butyl 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)-5-oxopentanoate (314 mg, 30.1%) as yellow solid, m / z ES+ [M+H]+624.Step 4. Synthesis of 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzoldJimidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)-5-oxopentanoic acid

[0213] To a solution of tert-butyl 5-(4-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)-5-oxopentanoate (100 mg, 0.16 mmol) in DCM (10 mL) were added TFA (2 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude product by 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)-5-oxopentanoic acid (110 mg) as brown solid, m / z ES+ [M+H]+568.

[0214] The following intermediates w ere made according to the procedure described for Int-B17.Structure Precursor Analytical dataO HN^\0=^7LCMS: »? / zES+ Int-4A A XXN>0[M+H]+568.0Int-B18Preparation of 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-inethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)pentanoic acid (Int-B19)Step 1. Synthesis of methyl l-(5-(tert-butoxy)-5-oxopentyl)piperidine-4-carboxylate

[0215] To a solution of methyl piperidine-4-carboxylate (2.0 g, 13.9 mmol) in ACN (50 mL) were added tert-butyl 5-bromopentanoate (3.6 g, 15.3 mmol), K2CO3 (3.8 g, 27.8mmol). The resulting solution was stirred 16 h at 60 °C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4 filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 20% to 45%) to give methyl l-(5-(tert-butoxy)-5-oxopentyl)piperidine-4-carboxylate (3.1 g, 74.1%) as colorless oil. m / z ES+ [M+H]+300.Step 2. Synthesis of l-(5-(tert-butoxy)-5-oxopentyl)piperidine-4-carboxylic acid

[0216] To a solution of methyl l-(5-(tert-butoxy)-5-oxopentyl)piperidine-4-carboxylate (1.0 g, 3.3 mmol) in MeOH (10 mL) were added LiOH (161 mg, 6.7 mmol) in H2O (50 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude product by l-(5-(tert-butoxy)-5-oxopentyl)piperidine-4-carboxylic acid (1.1 g) as light yellow oil. m / z ES+ [M+H]+286.Step 3. Synthesis of tert-butyl 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)pentanoate

[0217] To a solution of l-(5-(tert-butoxy)-5-oxopentyl)piperidine-4-carboxylic acid (500 mg, 1.7 mmol) in DCM (10 mL) were added 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (485 mg, 1.4 mmol), HATU (638 mg, 1.7 mmol) and DIEA (542 g, 27.8 mmol). The resulting solution was stirred 3 h at 25 °C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 40% to 70%) to give tert-butyl 5-(4-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)pentanoate (313.5 mg, 30.1%) as yellow solid, m / z ES+ [M+H]+610.Step 4. Synthesis of 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)pentanoic acid

[0218] To a solution of tert-butyl 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)pentanoate (100.0 mg, 0.16 mmol) in DCM (10 mL) were added TFA (2 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude product by 5-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidine-l-carbonyl)piperidin-l-yl)pentanoic acid (110 mg) as brown solid, m / z ES+ [M+H]+554.

[0219] The following intermediates were made according to the procedure described for Int-B19.Structure Precursor 1 Analytical data O HNA OAA II jf 'T LCMS: m / z ES+ > O Int-4A'l i [M+H]+554.OInt-B20O OxHH r H VNHO N > l | \NA_A LCMS: m / z ES+ A-\ n< NA Int-3o [M+H]+526.0Int-B21O HN" \n °AA X JZ LCMS: m / z ES+ Int-4[M+H]+526.Oy 0A 'Int-B22Preparation of l-(5-(4-(l-(2,6-dioxopiperidin-3-yI)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylic acid (Int-B23)Step 1. Synthesis of methyl l-(5-(tert-butoxy)-5-oxopentanoyl)piperidine-4-carboxylate

[0220] To a solution of tert-butyl piperidine-4-carboxylate (2.0 g, 13.9 mmol) in DCM (50 mL) were added 5-methoxy-5-oxopentanoic acid (2.9 g, 15.3 mmol), HATU (6.3 g, 16.6 mmol) and DIEA (3.6 g, 27.8 mmol). The resulting solution was stirred 3 h at 25 °C. The residue was treated with water (300 mL) and extracted with DCM (500 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 35% to 45%) to give tert-butyl l-(5-methoxy-5-oxopentanoyl)piperidine-4-carboxylate (3.2 g, 73.2%) as colorless oil. m / z ES+ [M+H]+314. Step 2. Synthesis of 5-(4-(tert-butoxycarbonyl)piperidin-l-yl)-5-oxopentanoic acid

[0221] To a solution of tert-butyl l-(5-methoxy-5-oxopentanoyl)piperidine-4-carboxylate (1.0 g, 3.2 mmol) in MeOH (10 mL) were added LiOH (161 mg, 6.7 mmol) in H2O (50 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude product by 5-(4-(tert-butoxycarbonyl)piperidin-l-yl)-5-oxopentanoic acid (1.1 g) as light yellow oil. m / z ES+ [M+H]+300.Step 3. Synthesis of tert-butyl l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylate

[0222] To a solution of 5-(4-(tert-butoxycarbonyl)piperidin-l-yl)-5-oxopentanoic acid (500 mg, 1.7 mmol) in DCM (10 mL) were added 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (485 mg, 1.4 mmol), HATU (638 mg, 2.55 mmol) and DIEA (542 mg, 5.1 mmol). The resulting solution was stirred 3 h at 25 °C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered andconcentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtO Ac = 40% to 60%) to give tert-butyl l-(5-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylate (314.5 mg, 31.1%) as yellow solid, m / z ES+ [M+H]+624.Step 4. Synthesis of l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylic acid

[0223] To a solution of tert-butyl l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylate (100 mg, 0.16 mmol) in DCM (10 mL) were added TFA (2 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude product by l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylic acid (99 mg) as brown solid, m / z ES+ [M+H]+568.

[0224] The following intermediates were made according to the procedure described for Int-B23.Preparation of l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentyl)piperidine-4-carboxylic acid (Int-B25)Step 1. Synthesis of tert-butyl l-(5-methoxy-3-oxopentyl)piperidine-4-carboxylate

[0225] To a solution of methyl 5-bromopentanoate (1.0 g, 5.15 mmol) in ACN (10 mL) were added tert-butyl piperidine-4-carboxylate (795 mg. 4.3 mmol) and K.2CO3 (1.19 g, 8.6 mmol). The resulting solution was stirred 3 h at 60 °C. The mixture was cooled to room temperature. The residue was treated with water (30 mL) and extracted with EtOAc (100 mL * 3). The organic extracts were washed with brine, dried over anhy drous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 0 ~ 3 / 1) to give tert-butyl l-(5-methoxy-5-oxopentyl)piperidine-4-carboxylate (1.1 g, 85.9%) as light yellow oil. m / z ES+ [M+H]+300.Step 2. Synthesis of 5-(4-(tert-butoxycarbonyl)piperidin-l-yl)pentanoic acid

[0226] To a solution of tert-butyl l-(5-methoxy-5-oxopentyl)piperidine-4-carboxylate (1.0 g, 3.3 mmol) in MeOH (10 mL) were added LiOH (161 mg, 6.7 mmol) in H2O (50 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated down to obtain a crude product by 5-(4-(tert-butoxycarbonyl)piperidin-l-yl)pentanoic acid (1.1 g) as light yellow oil. m / z ES+ [M+H]+286.Step 3. Synthesis of tert-butyl l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentyl)piperidine-4-carboxylate

[0227] To a solution of 5-(4-(tert-butoxycarbonyl)piperidin-l-yl)pentanoic acid (500 mg, 1.75 mmol) in DCM (10 mL) were added 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (499 mg, 1.46 mmol), HATU (664 mg, 2.63 mmol) and DIEA (677 mg, 5.25 mmol). The resulting solution was stirred 3 h at 25°C. The residue was treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 0-70%) to give tert-butyl l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylate (304 mg, 0.49 mmol, 28.6%) as yellow solid, m / z ES+ [M+H]+610.Step 4. Synthesis of l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentyl)piperidine-4-carboxylic acid

[0228] To a solution of tert-butyl l-(5-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentanoyl)piperidine-4-carboxylate (100 mg, 0.16 mmol) in DCM (10 mL) were added TFA (2 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude product by l-(5-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-5-oxopentyl)piperidine-4-carboxylic acid (102 mg) as brown solid, m / z ES+ [M+H]+554.

[0229] The following intermediates were made according to the procedure described for Int-B25.Preparation of 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoic acid (Int-B29)step 1Step 1. Synthesis of tert-butyl 4-(4-(2-methoxy-2-oxoethyl)piperidin-l-yl)-4-oxobutanoate

[0230] To a stirred mixture of methyl 2-(piperidin-4-yl)acetate (1.08 g, 6.89 mmol) and DIEA (2.23 g, 17.2 mmol) in DMF (10 mL) was added HATU (2.62 g, 6.89 mmol) in portions at 25 °C. To the above mixture was added 4-(tert-butoxy)-4-oxobutanoic acid (1 g, 5.74 mmol) in portions at 25 °C. The resulting mixture was stirred at 25 °C for additional 1 h. After the reaction was completed. The resulting mixture was extracted with EtOAc (300 mL * 3). The combined organic layer was washed with water (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford tert-butyl 4-[4-(2-methoxy-2-oxoethyl)piperidin-l-yl]-4-oxobutanoate (1.5 g, 83.4%) as a colorless oil. m / z ES+ [M+H]+314.Step 2. Synthesis of 2-(l-(4-(tert-butoxy)-4-oxobutanoyl)piperidin-4-yl)acetic acid

[0231] To a stirred solution of tert-butyl 4-[4-(2-methoxy-2-oxoethyl)piperidin-l-yl]-4-oxobutanoate (300 mg, 0.96 mmol) in THF : H2O (2 mL: 0.2 mL) was added LiOH.H2O (80.3 mg, 1.91 mmol) in portions at 25 °C. The resulting mixture was stirred at 60 °C for 3 h. The crude product was used in the next step directly without further purification, m / z ES+ [M+H]+300.Step 3. Synthesis of tert-butyl 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoate

[0232] To a stirred solution of 2-(l-(4-(tert-butoxy)-4-oxobutanoyl)piperidin-4-yl)acetic acid (94.4 mg. 0.32 mmol), HATU (120 mg, 0.32 mmol) and DIEA (84.9 mg, 0.66 mmol) in DMF (2 mL) was added 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (90 mg, 0.26 mmol) in portions at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford tert-butyl 4-(4-(2-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoate (100 mg, 89%) as a white solid, m / z ES+ [M+H]+624.Step 4. Synthesis of 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoic acid

[0233] To a stirred mixture of tert-butyl 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoate (70 mg, 0.11 mmol) in ethyl acetate (0.71 mL, 7.25 mmol) was added HC1 in 1,4-dioxane (0.5 mL, 0.014 mmol, 4.0 mol / L) dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to obtained the crude product. The crude product was used in the next step directly without further purification, m / z ES+ [M+H]+568.

[0234] The following intermediates were made according to the procedure described for Int-B29.Preparation of 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)butanoic acid (Int-B31)Step 1. Synthesis of tert-butyl 4-(4-(2-methoxy-2-oxoethyl)piperidin-l-yl)butanoate

[0235] To a solution of methyl 2-(piperidin-4-yl)acetate (2.0 g, 12.7 mmol) in ACN (50 mL) were added tert-butyl 4-bromobutanoate (3.4 g, 15.3 mmol), K2CO3 (3.8 g, 27.8 mmol) at 25 °C. The resulting solution was heated to 60 °C and stirred for 16 h. Then the residue was cooled to 25 °C and treated with water (50 mL) and extracted with DCM (50 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 0% to 45%) to give tert-butyl 4-(4-(2-methoxy-2-oxoethyl)piperidin-l-yl)butanoate (2.9 g. 76.3%) as colorless oil. m / z ES+ [M+H]+300.Step 2. Synthesis of 2-(l-(4-(tert-butoxy)-4-oxobutyl)piperidin-4-yl)acetic acid

[0236] To a solution of tert-butyl 4-(4-(2-methoxy-2-oxoethyl)piperidin-l-yl)butanoate (1.0 g, 3.3 mmol) in MeOH (10 mL) were added LiOH (161 mg, 6.7 mmol) in H2O (50 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated down to obtain a crude product by 2-(l-(4-(tert-butoxy)-4-oxobutyl)piperidin-4-yl)acetic acid (1.0 g) as light yellow oil. m / z ES+ [M+H]+286.Step 3. Synthesis of tert-butyl 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)butanoate

[0237] To a solution of 2-(l-(4-(tert-butoxy)-4-oxobutyl)piperidin-4-yl)acetic acid (500 mg, 1.7 mmol) in DCM (10 mL) were added 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (485 mg, 1.4 mmol), HATU (638 mg, 1.7 mmol) and DIEA (542 g, 27.8 mmol). The resulting solution was stirred for 3 h at 25 °C. The residue was treated with water (50 mL) and extracted with DCM (100 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated down to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 45% to 70%) to give tert-butyl 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)butanoate (313.5 mg, 30.1%) as yellow solid. m / z ES+ [M+H]+610.Step 4. Synthesis of 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)butanoic acid

[0238] To a solution of tert-butyl 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)butanoate (100 mg, 0.16 mmol) in DCM (10 mL) were added TFA (2 mL). The resulting solution was stirred 3 h at 25 °C. The mixture was concentrated to obtain a crude 4-(4-(2-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-2-oxoethyl)piperidin-l-yl)butanoic acid (115 mg) as brown solid, m / z ES+ [M+H]+554.

[0239] The following intermediates were made according to the procedure described for Int-B31.Structure Precursor Analytical data I O T" O)O=LCMS: m / z ES+ Int-4[M+H]+554.2rS >Z W w o Z=^ \.\ W w / ( \ 2 t too — >OxH4 # O1 T \N\\ A / \ \ O / T J LCMS: m / z ES+ Int-3H0J<. N^J O [M+H]+526.JInt-B32LCMS: m / z ES+ Int-4[M+H]+526.Preparation of 2-(l-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutanoyl)piperidin-4-yl)acetic acid (Int-B35)Step 1. Synthesis of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoate

[0240] To a solution of 4-methoxy-4-oxobutanoic acid (500 mg, 3.79 mmol) in DMF (5 mL) were added HATU (1.73 g, 4.54 mmol), DIEA (1.47 g, 11.4 mmol) and tert-butyl 2-(piperidin-4-yl)acetate (792 mg, 3.97 mmol). The resulting solution was stirred 2 h at 25 °C. The residue was treated with water (5 mL) and extracted with DCM (80 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4L, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtO Ac = 0 to 3 / 1) to give methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoate (700 mg, 59.0%) as light yellow solid, m / z ES+ [M+H]+314.Step 2. Synthesis of 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoic acid

[0241] A solution of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoate (700 mg, 2.23 mmol) and LiOI L I I2O (187 mg, 4.47 mmol) in THF (8 mL), Water (2 mL) was stirred at 60 °C for 2 h. The resulting mixture was concentrated under reduced pressure to afford crude 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoic acid (532 mg) as a yellow' solid, m / z ES+ [M+H]+300.Step 3. tert-butyl 2-(l-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutanoyl)piperidin-4-yl)acetate

[0242] To a solution of 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)-4-oxobutanoic acid (160 mg, 0.52 mmol) in DMF (5 mL) were added HATU (239 mg, 0.63 mmol), DIEA (203 mg, 1.57 mmol) and 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (188 mg, 0.55 mmol). The resulting solutionwas stirred 2 h at 25 °C. The residue was treated with water (10 mL) and extracted with DCM (30 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 0 to 3 / 1) to give tertbutyl 2-(l-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutanoyl)piperidin-4-yl)acetate (180 mg, 55.1%) as a yellow solid, m / z ES+ [M+H]+624.Step 4. Synthesis of 2-(1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-4-oxobutanoyl)piperidin-4-yl)acetic acid

[0243] A solution of tert-butyl 2-(l-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutanoyl)piperidin-4-yl)acetate ^5 °x(80 mg, 0.13 mmol) in HCl / EtOAc (4.0 M) (1 mL) was stirred at room temp for 30 min. The resulting mixture was concentrated under reduced pressure to afford 2-(l-(4-(4-(l-(2,6- OZ ' ^dioxopiperidin-3-yl)-3-methyl > mo-=2-oxo-2.3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutanoyl)piperidin-4-yl)acetic acid (66 mg, 90.7%) as a yellow solid, m / z ES+ [M+H]+568.

[0244] The following intermediates were made according to the procedure described for Int-B35. 9z oStructure Precursor Analytical dataLCMS: m / z ES+ Int-4[M+H]+568.Preparation of 2-(l-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutyl)piperidin-4-yl)acetic acid (Int-B37)Step 1. Synthesis of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)butanoate

[0245] A mixture of tert-butyl 2-(piperidin-4-yl)acetate (500 mg, 2.51 mmol), K2CO3 (693 mg, 5.02 mmol) and methyl 4-bromobutanoate (545 mg, 3.01 mmol) in ACN (5 mL) was stirred at 60 °C for 16 h under nitrogen atmosphere. The residue was treated with water (10 mL) and extracted with DCM (60 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 0 to 3 / 1) to give methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)butanoate (650 mg, 86.5%) as light yellow oil. m / z ES+ [M+H]+300.Step 2. Synthesis of 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-1-yl)butanoic acid

[0246] A solution of methyl 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)butanoate (300 mg, 1.00 mmol) and LiOH. ELO (84.1 mg, 2.00 mmol) in THF (4 mL) and Water (1 mL) w as stirred at 60 °C for 2 h. The resulting mixture w as concentrated under reduced pressure to afford crude 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)butanoic acid (245 mg, 83.9%) as a yellow solid, m / z ES+ [M+H]+286.Step 3. Synthesis of tert-butyl 2-(1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)-4-oxobutyl)piperidin-4-yl)acetate

[0247] To a solution of 4-(4-(2-(tert-butoxy)-2-oxoethyl)piperidin-l-yl)butanoic acid (150 mg, 0.52 mmol) in DMF (5 mL) were added HATU (235 mg, 0.62 mmol), DIEA (200 mg, 1.55 mmol) and 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (188 mg, 0.55 mmol). The resulting solution was stirred 2 h at 25 °C. The residue was treated with water (5 mL) and extracted with DCM (30 mL * 3). The organic extracts were washed with brine, dried over anhydrous Na2SO4.filtered and concentrated down to obtain a crude product. The residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc = 0 to 3 / 1) to give tert-butyl 2-(l-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutyl)piperidin-4-yl)acetate (170 mg, 54.2%) as ayellow solid, m / z ES+ [M+H]+610.Step 4. Synthesis of 2-(l-(4-(4-(l-(2, 6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutyl)piperidin-4-yl)acetic acid

[0248] A solution of tert-butyl 2-(l-(4-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutyl)piperidin-4-yl)acetate (80. img, 0.13 mmol) in EICl / EtOAc (4.0 M) (1 mL X) / zz z was stirred at room temp for 30 min. The resulting mixture was concentrated under reduced pressure to afford 2-(l -(4-(4-(l -(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperidin-l-yl)-4-oxobutyl)piperidin-4-yl)acetic 00 Z a ' -cid (66 mg, 90.7%) as ayellow- solid, m / z ES+ [M+H]+554.

[0249] The following intermediates were made according to the procedure described for Int-B37.Structure Precursor Analytical data X oLCMS: m / z ES+ Int-4[M+H]+554.LCMS: m / z ES+ Int-3[M+H]+526.0Int-B39Example 1. Preparation of 2-(cyclopropyldifluoromethyl)-N-((2R, E)-l-(2-(6-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-6-oxohexanamido)ethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (Compound 123)

[0250] A solution of 6-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-l-yl)-6-oxohexanoic acid (Int-B5) (19 mg, 0.04 mmol), TEA (16.3 mg, 0.16 mmol) and HATU (23 mg, 0.06 mmol) in DCM (0.5 mL) was stirred at room temperature for 15 min under nitrogen atmosphere, followed by the addition of (R, E)-N-(l-(2-aminoethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-2-(cyclopropyldifluoromethyl)-4-phenoxypyrimidine-5 -carboxamide (Int-A2) (20 mg, 0.04 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crudeproduct (50 mg) was purified by Prep-HPLC (Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Column: XBridge C18 30 * 150 mm, 5 μm; Flow rate: 35 mL / min; Gradient (B%): isocratic 35%-68% 7 min; Wave Length: 254 nm / 220 nm; RT1 (min): 7) to afford 2-(cyclopropyldifluoromethyl)-N-((2R,E)-1-(2-(6-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)-6-oxohexanamido)ethoxy)-4-(methylsulfonyl)but-3-en-2-yl)-4-phenoxypyrimidine-5-carboxamide (6.9 mg, 17.7%) as a white solid.1H NMR (300 MHz, DMSO-dg) 5 11.07 (s, 1H), 9.04 (s, 1H), 8.88 (d,.7= 8.2 Hz, 1H), 7.84 (dd,.7= 13.4, 6.5 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.35 - 7.25 (m, 3H), 7.09 (s, 1H), 6.99 (d, J= 8.1 Hz, 1H), 6.94 - 6.77 (m, 2H), 5.54 -4.98 (m, 2H), 4.54 (d, J = 12.7 Hz, 1H), 4.28 (s, 1H), 3.97 (t, J= 10.0 Hz, 2H), 3.62 (d, J = 5.7 Hz, 1H). 3.43 (d, J= 7.3 Hz, 2H). 3.17 (t. J= 5.7 Hz. 2H), 3.06 (t, J = 12.4 Hz, 1H).2.92 (d, J= 16.7 Hz, 4H), 2.80 - 2.64 (m, 2H), 2.62 - 2.52 (m, 3H), 2.34 - 2.23 (m, 2H), 2.11 -1.91 (m, 3H), 1.83 - 1.69 (m, 2H), 1.67 - 1.36 (m, 8H), 0.63 - 0.51 (m, 4H); m / z ES+ [M+H]+949.

[0251] The following compounds were prepared using the procedure from Example 1.Cmpd No ’HNMR LCMS Purification Conditions ’H NMR (300 MHz, DMSO-Je) 811.08 Mobile Phase A: Water (s, 1H).9.04 (s, 1H), 8.88 (d, J= 8.2 Hz, (0.1%FA), Mobile Phase B: 1H), 7.87 - 7.73 (m, 1H), 7.47 (t, J = ACN; Column: Xselect CSH 7.8 Hz. 2H), 7.35 - 7.25 (m, 3H), 7.12 C18 19*250 mm, 5 μm; Flow - 6.77 (m, 5H), 5.61 - 4.91 (m, 2H), rate: 20 mL / min; Gradient 4.54 (d, J = 12.8 Hz, 1H), 4.35 - 3.87 m / z (B%): isocratic 35%-65% 9 (m, 2H), 3.62 (d, J = 5.7 Hz, 2H). 3.49 ES+ min; Wave Length: 254 nm / 107- 3.35 (m. 2H), 3.33 - 3.30 (m, 2H), [M+H] 220 nm; RT1 (min): 9 3.24 - 3.00 (m. 3H), 2.95 (s, 3H). 2.93+977.- 2.52 (m, 5H), 2.29 (t, J= 7.6 Hz, 2H),2.09 - 1.91 (m. 3H), 1.79 - 1.69 (m,2H), 1.67 - 1.52 (m, 2H), 1.52 - 1.37(m. 5H), 1.29 - 1.19 (m, 4H), 0.63 - 0.48 (m, 4H).’H NMR (300 MHz, DMSO-t / e) 511.07 Mobile Phase A: Water (10 (s, 1H).9.04 (s, 1H), 8.87 (d, J= 8.2 Hz, mmol / L NH4HCO3), Mobile 1H), 7.84 - 7.72 (m, 1H), 7.47 (dd, J = Phase B: ACN; Column: 8.4, 7.2 Hz, 2H), 7.35 - 7.25 (m, 3H), XBridge C18 30*150 mm, 5 7.13 - 6.75 (m, 5H), 5.60 - 5.26 (m, μm; Flow rate: 35 mL / min;m / z1H), 5.05 - 4.92 (m, 1H), 4.54 (d, J = Gradient (B%): isocratic 40%- ES+12.8 Hz, 1H). 4.33 - 3.87 (m, 2H), 3.68 70% 7 min; Wave Length: 254[M+H]-3.36 (m, 3H), 3.31 (s, 3H), 3.21 -2.99 nm / 220 nm; RT1 (min): 7+1005.(m, 3H), 2.95 (s, 2H), 2.92 - 2.52 (m,6H), 2.35 - 2.22 (m, 2H), 2.09 - 1.94(m, 3H). 1.84 - 1.69 (m. 2H), 1.68 - 1.35 (m, 7H). 1.27- 1.18 (m, 8H). 0.66-0.51 (m, 4H).’H NMR (300 MHz, DMSO-A) 511.09 Mobile Phase A: Water (s, 1H), 9.04 (s, 1H), 8.88 (d,.7 = 8.2 Hz. (0.1%FA). Mobile Phase B: 1H), 7.81 (t, J = 5.6 Hz. 1H), 7.47 (dd. ACN; Column: Xselect CSH J = 8.5, 7.2 Hz, 2H), 7.35 - 7.24 (m. C18 19*250 mm, 5 gm; Flow 3H), 7.07 - 6.74 (m, 5H), 5.36 (dd, J = rate: 20 mL / min; Gradient 12.7, 5.4 Hz, 1H). 5.03 - 4.94 (m, 1H). m / z (B%): isocratic 38%-68% 9 4.54 (d, J= 12.8 Hz, 1H). 3.95 (d, J = ES+ min; Wave Length: 254 nm / 13.4 Hz, 1H), 3.68- 2.58 (m, 5H), 3.56 [M+H] 220 nm; RTl(min): 9- 3.40 (m, 3H), 3.22 - 3.08 (m, 3H),+949.2.95 (s, 3H), 2.95 - 2.79 (m, 1H), 2.77- 2.53 (m, 3H), 2.36 - 2.22 (m, 2H),2.11 - 1.90 (m, 3H), 1.89 - 1.71 (m,2H), 1.73 - 1.55 (m, 2H), 1.50 - 1.42(m, 5H), 0.64- 0.50 (m, 4H).’H NMR (300 MHz, DMSO-t / e) 811.09 Mobile Phase A: Water (s, 1H).9.04 (s, 1H), 8.87 (d. J = 8.3 Hz, (0.1%FA), Mobile Phase B: 1H), 7.85 - 7.73 (m, 1H), 7.53 - 7.42 ACN; Column: Xselect CSH m / z(m, 2H), 7.35 - 7.25 (m. 3H), 7.01 - C18 19*250 mm, 5 μm; Flow ES+6.77 (m, 5H). 5.42 - 5.30 (m, 1H). 5.03 rate: 20 mL / min; Gradient [M+H]- 4.93 (m. 1H), 4.55 (d, J = 12.7 Hz, (B%): isocratic 35%-65% 9+947.1H). 4.02 - 3.91 (m. 1H), 3.66 - 3.55 min; Wave Length: 254 nm / (m, 5H), 3.52 - 3.39 (m, 3H), 3.24 - 220 nm; RTl(min): 93.08 (m, 3H), 2.95 (s, 3H), 2.93 - 2.78(m, 1H), 2.78 - 2.51 (m, 3H), 2.36 - 2.22 (m, 2H), 2.09 - 1.95 (m, 3H), 1.89- 1.76 (m, 2H), 1.69 - 1.54 (m, 2H),1.51 - 1.40 (m, 5H), 1.26 - 1.20 (m,4H), 0.66 -0.51 (m, 4H).’H NMR (300 MHz, DMSO-rfe) 511.08 Mobile Phase A: Water (s, 1H), 9.04 (s, 1H), 8.87 (d, J = 8.3 Hz. (lOmmol / L NH4HCO3), Mobile 1H), 7.86 - 7.72 (m, 1H). 7.52 - 7.41 Phase B: ACN; Column: (m. 2H), 7.35 - 7.25 (m, 3H), 7.11 - XBridge C18 30*150 mm, 6.59 (m, 5H), 5.61 - 4.92 (m, 2H), 4.55 5|.un; Flow rate: 35 mL / min; (d, J= 12.9 Hz, 1H), 4.28 (s, 1H), 4.05 m / z Gradient (B%): isocratic 40%- - 3.89 (m, 2H), 3.66 - 3.58 (m, 4H). ES+ 70% 7 min; Wave Length: 254 3.56 - 3.38 (m, 3H), 3.21 - 3.09 (m, [M+H] nm / 220 nm; RTl(min): 7 3H), 2.98 - 2.80 (m, 4H), 2.74 - 2.57+1005.(m, 2H), 2.37 - 2.23 (m, 2H), 2.09 - 1.90 (m, 3H), 1.89 - 1.76 (m, 2H), 1.71- 1.51 (m, 2H), 1.48 - 1.39 (m, 5H),1.27 - 1.13 (m, 8H), 0.66 - 0.51 (m,4H).’H NMR (300 MHz, DMSO-Je) 811.08 Mobile Phase A: Water (10 (s, 1H), 9.04 (d, J = 9.3 Hz, 1H), 8.80 mmol / L NH4HCO3), Mobile (d, J= 8.3 Hz, 1H), 7.54-7.42(m, 2H), Phase B: ACN; Column: 7.37- 7.25 (m,3H). 7.09 (d, J = 1.5 Hz, XBridge C1830*150 mm, 5 gm; 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.96 - Flow rate: 35 mL / min: Gradient 6.76 (m, 3H). 5.58 - 4.91 (m, 2H), 4.55 (B%): isocratic 35%-65% 7 m / z(d, J = 12.7 Hz, 1H), 4.38 - 3.91 (m, min; Wave Length: 254 nm / ES+3H), 3.78 - 3.52 (m, 2H). 3.31 (s, 3H), 220 nm; RTl(min): 7[M+H]3.29 - 3.15 (m, 2H), 3.07 (t, J = 12.7+1003.Hz, 1H), 2.99 - 2.85 (m, 3H), 2.90 - 2.51 (m, 6H), 2.40 - 2.27 (m, 3H), 2.26- 2.18 (m, 2H). 2.04 - 1.92 (m, 1H),1.84 - 1.66 (m. 2H), 1.70 - 1.39 (m.10H), 1.04 - 0.76 (m, 2H), 0.66 - 0.48(m. 4H).¹H NMR (300 MHz, DMSO-d₆) δ 9.24 Mobile Phase A: Water - 10.86 (m, 1H), 9.04 (d, J = 9.5 Hz, (10mmol / L NH₄HCO₃), Mobile 1H), 8.79 (d, J = 8.4 Hz, 1H), 7.54 - Phase B: ACN; Column: 7.42 (m, 2H), 7.36 - 7.25 (m, 4H), 7.08 XBridge C18 30*150 mm, 5 μm; Flow rate: 35 mL / min; 5.59 - 4.90 (m, 2H), 4.55 (d, J = 12.8 m / z Gradient (B%): isocratic 35%- Hz, 1H), 4.33 - 4.21 (m. 2H), 4.03 - ES+ 70% 7 min; Wave Length: 254 3.92 (m, 2H). 3.74 - 3.57 (m, 2H). 3.29 [M+H] nm / 220 nm; RT1 (min): 7 - 3.17 (m, 2H), 3.07 (t, J = 12.9 Hz,+1031.1H), 2.93 (d. J = 14.6 Hz, 3H), 2.85 - 2.53 (m, 7H). 2.43 - 2.11 (m, 6H). 2.02- 1.93 (m, 2H), 1.85 - 1.36 (m, 11H),1.27 (s, 4H), 1.02 - 0.79 (m, 2H), 0.56(t, J = 9.3 Hz. 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.06 Mobile Phase A: Water (10 (s, 1H). 9.04 (d. J = 9.7 Hz. 1H), 8.80 mmol / L NH₄HCO₃), Mobile (d, J= 8.3 Hz. 1H), 7.54-7.42 (m, 2H). Phase B: ACN; Column: 7.36 -7.25 (m, 3H), 7.08 (d, J= 1.6 Hz. XBridge C18 30*150 mm. 5 μm; Flow rate: 35 mL / min; (m. 2H), 4.55 (d, J= 12.7 Hz, 1H), 4.36 m / z Gradient (B%): isocratic 40%- - 3.88 (m, 2H), 3.70 - 3.52 (m, 3H), ES+ 75% 7 min; Wave Length: 254 3.31 (s, 3H), 3.29 - 3.18 (m, 2H), 3.14 [M+H] nm / 220 nm; RT1 (min): 7 - 2.99 (m, 1H), 2.93 (d, J = 14.6 Hz,+1059.3H), 2.95 - 2.70 (m, 3H), 2.71 - 2.53(m, 3H), 2.42 - 2.22 (m, 2H), 2.18 (t, J= 7.4 Hz, 2H), 2.02- 1.92(m, 1H), 1.87- 1.35 (m, 12H), 1.25 (s. 9H), 1.01 - 0.77 (m, 2H), 0.66 - 0.50 (m, 4H).’H NMR (300 MHz, DMSO-t / e) 811.09 Mobile Phase A: Water (s, 1H), 9.04 (d, J = 9.4 Hz, 1H), 8.80 (lOmmol / L NH4HCO3), Mobile (d, J = 8.3 Hz, 1H). 7.49 (t, J = 7.9 Hz, m / z Phase B: ACN: Column: 2H), 7.37 - 7.25 (m, 3H), 7.05 - 6.78 ES+ XBridge C1830*150 mm, 5 gm; (m, 5H), 5.75 - 4.89 (m. 2H), 4.55 (d, J [M+H] Flow rate: 35 mL / min: Gradient = 12.8 Hz. 1H), 4.37 - 3.90 (m, 2H),+1003. (B%): isocratic 35%-65% 7min; 3.77 - 3.63 (m, 1H), 3.60 (s, 4H), 3.56 Wave Length: 254 nm / 220 nm; - 3.43 (m, 1H), 3.29 - 3.20 (m, 1H). RTl(min): 73.23 - 3.07 (m, 3H), 2.96 (s, 3H), 2.92- 2.50 (m, 5H), 2.40 - 2.31 (m, 3H),2.29 - 2.18 (m, 2H), 2.02 - 1.92 (m,1H), 1.89 - 1.76 (m, 2H), 1.76 - 1.57(m, 3H), 1.55 - 1.34 (m. 7H), 1.06 - 0.71 (m, 2H). 0.63 - 0.51 (m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.09 Mobile Phase A: Water (10 (s, 1H), 9.04 (d, J= 10.0 Hz, 1H), 8.80 mmol / L NH₄HCO₃), Mobile (d, J= 8.3 Hz, 1H), 7.54-7.43 (m, 2H), Phase B: ACN; Column: 7.35 - 7.25 (m, 3H), 7.05 - 6.77 (m, XBridge C18 30*150 mm, 5 5H), 5.71 - 4.87 (m, 2H), 4.55 (d, J = μm; Flow rate: 35 mL / min; 12.8 Hz, 1H), 4.37 - 3.91 (m, 2H), 3.72 m / z Gradient (B%): isocratic 35%- - 3.58 (m, 6H), 3.56 - 3.43 (m, 1H), ES+ 70% 7 min; Wave Length: 254 3.28 - 3.09 (m, 3H), 2.93 (d, J= 14.7 [M+H] nm / 220 nm; RT1(min): 7Hz, 3H), 2.89 - 2.52 (m. 5H), 2.41 - ⁺ 1031.2.27 (m, 2H). 2.22 - 2.13 (m, 2H). 2.06- 1.92 (m, 1H), 1.91 - 1.76 (m, 2H),1.76 - 1.36 (m, 10H), 1.35 - 1.10 (m,5H), 1.06 - 0.69 (m, 2H), 0.63 - 0.51(m, 4H).’H NMR (300 MHz, DMSO-t / e) 611.09 Mobile Phase A: Water (10 (s, 1H). 9.04 (d. J = 9.9 Hz. 1H), 8.80 mmol / L NH4HCO3), Mobile (d, J= 8.3 Hz. 1H), 7.54-7.42 (m, 2H). Phase B: ACN; Column: 7.36 - 7.25 (m, 3H), 7.05 - 6.71 (m. XBridge C18 30*150 mm. 5 5H), 5.58 - 4.94 (m, 2H), 4.55 (d. J = |im; Flow rate: 35 mL / min; 13.0 Hz, 1H), 4.39 - 3.87 (m, 3H), 3.72 m / z Gradient (B%): isocratic 40%- - 3.63 (m, 1H), 3.61 - 3.42 (m, 5H). ES+ 75% 7 min; Wave Length: 254 3.29 - 3.09 (m, 3H), 2.94 (d, J= 14.6 [M+H] nm / 220 nm; RT1(min): 7Hz, 3H), 2.90 - 2.53 (m, 6H), 2.41 - ⁺ 1059.2.23 (m, 2H), 2.24 - 2.10 (m, 2H), 2.05- 1.91 (m, 1H), 1.89 - 1.79 (m, 2H),1.75 - 1.36 (m, 10H), 1.34 - 1.17 (m,8H), 1.04 - 0.73 (m, 2H), 0.66 - 0.48(m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.07 Mobile Phase A: Water (10 (s, 1H), 9.17 - 8.89 (m, 2H), 7.47 (t, J = mmol / L NH₄HCO₃), Mobile 7.8 Hz. 2H), 7.35 - 7.23 (m, 3H), 7.13 Phase B: ACN; Column: - 6.68 (m, 5H). 5.32 (dd, J= 12.9, 5.5 XBridge C18 30*150 mm, 5 Hz, 1H), 5.06 (s, 1H). 4.54 (d. J= 12.7 μm; Flow rate: 35 mL / min; Hz, 1H), 4.15 (dt, J = 17.3, 8.6 Hz, 1H), m / z Gradient (B%): isocratic 30%- 4.05 - 3.76 (m. 3H), 3.70 (dt, J = 15.8, ES+ 63% 7 min; Wave Length: 254 7.7 Hz. 1H), 3.15 - 2.99 (m, 1H), 2.97 [M+H] nm / 220 nm; RT1 (min): 7 (d. J= 2.9 Hz, 3H), 2.96-2.68 (m.3H),+931.2.69 - 2.52 (m. 4H), 2.27 (dd, J = 8.1,4.3 Hz. 3H), 2.08 - 1.84 (m, 3H). 1.74(dd, J= 18.0. 4.5 Hz. 1H), 1.70 - 1.34(m. 8H), 1.28 - 1.18 (m, 1H), 0.66 - 0.50 (m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.01 Mobile Phase A: Water (10 (s, 1H), 9.25 - 8.88 (m, 2H), 7.76 - 6.67 mmol / L NH₄HCO₃), Mobile (m. 10H). 5.58 - 4.98 (m, 2H). 4.57 (d. Phase B: ACN; Column: J= 12.7 Hz, 1H), 4.33 - 3.62 (m, 6H). XBridge C18 30*150 mm. 5 3.09 (t, J = 12.2 Hz, 1H), 3.03 - 2.55 μm; Flow rate: 35 mL / min; (m. 10H). 2.32 (t, J = 7.6 Hz, 2H), 2.11 m / z Gradient (B%): isocratic 35%- - 1.72 (m, 5H). 1.72 - 1.12 (m. 12H), ES+ 70% 8 min; Wave Length: 254 0.68 - 0.50 (m, 4H). [M+H] nm / 220 nm; RT1 (min): 8+959.¹H NMR (300 MHz, DMSO-d₆) δ 11.07 Mobile Phase A: Water (10 (s, 1H), 9.00 (q, J = 8.7, 8.1 Hz, 2H), mmol / L NH₄HCO₃), Mobile 7.53 - 7.41 (m, 2H), 7.36 - 7.23 (m, Phase B: ACN; Column: 3H), 7.12 - 6.66 (m, 5H), 5.32 (dd, J = XBridge C18 30*150 mm, 5 12.8, 5.4 Hz, 1H), 5.05 (d. J= 11.5 Hz, μm; Flow rate: 35 mL / min;m / zlH),4.55 (d, J= 12.7 Hz, 1H). 4.12 (dt, Gradient (B%): isocratic 38%- ES+J= 16.8. 8.4 Hz, 1H), 4.03 - 3.60 (m, 72% 8 min; Wave Length: 254[M+H]5H), 3.07 (t, J = 12.8 Hz, 1H), 2.97 (d, nm / 220 nm; RT 1 (min): 8 ⁺ 987.J = 2.9 Hz, 3H), 2.96 - 2.53 (m, 6H),2.45 - 2.37 (m, 1H). 2.36 - 2.23 (m,2H), 2.04 - 1.70 (m, 5H), 1.70 - 1.53(m, 2H), 1.53 - 1.30 (m. 6H), 1.21 (d, J= 12.0 Hz, 9H), 0.65 - 0.50 (m, 4H).’H NMR (300 MHz, DMSO-A) 511.09 Mobile Phase A: Water (10 (s, 1H), 9.11 - 8.95 (m, 2H), 7.47 (t, J = mmol / L NH4HCO3), Mobile 7.8 Hz. 2H), 7.29 (tt, J = 1.3. 2.5 Hz. Phase B: ACN; Column: 3H), 6.97 (s, 4H), 6.74 (dt, J= 15.4, 3.6 XBridge C18 30*150 mm. 5 Hz. 1H), 5.36 (dd, J= 12.5, 5.3 Hz, 1H). pm; Flow rate: 35 mL / min; 5.06 (s, 1H), 4.55 (d, J = 12.7 Hz, 1H). Gradient (B%): isocratic 30%- m / z4.15 (dt, J = 16.8, 8.5 Hz, 1H), 4.05 - 63% 7 min; Wave Length: 254ES+3.62 (m, 4H), 3.60 (s, 3H), 3.56 - 3.42 nm / 220 nm; RT1 (min): 7[M+H](m, 1H), 3.16 (t, J= 12.5 Hz, 1H), 2.97+931.(d, J= 3.1 Hz, 3H), 2.96 - 2.80 (m, 2H),2.77 - 2.54 (m, 3H), 2.30 (s, 2H), 2.05- 1.88 (m, 3H), 1.83 (ddd, J= 10.2, 5.5,2.1 Hz, 2H), 1.74 - 1.48 (m, 3H), 1.41(dd, J = 13.0, 5.6 Hz, 4H), 0.65 - 0.50(m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.08 Mobile Phase A: Water (10 (s, 1H), 9.13 - 8.89 (m, 2H), 7.47 (t, J = mmol / L NH₄HCO₃), Mobile 7.8 Hz, 2H), 7.29 (dt, J = 7.4, 5.6 Hz, Phase B: ACN; Column: 3H), 6.95 (d, J= 11.7 Hz, 4H), 6.74 (dt, XBridge C18 30*150 mm, 5 J= 15.2, 3.6 Hz, 1H), 5.36 (dd, J= 12.5, μm; Flow rate: 35 mL / min; 5.3 Hz, 1H), 5.06 (s, 1H), 4.55 (d, J = m / z Gradient (B%): isocratic 35%- 13.1 Hz, 1H), 4.13 (dt, J= 16.5, 8.3 Hz, ES+ 70% 8 min; Wave Length: 254 1H), 4.03 - 3.63 (m, 4H), 3.60 (s, 3H), [M+H] nm / 220 nm; RT 1 (min): 83.56 - 3.42 (m, 1H), 3.16 (t, J = 12.7 ⁺ 959.Hz, 1H), 2.97 (d, J = 2.8 Hz, 3H), 2.95- 2.79 (m, 2H), 2.76 - 2.55 (m, 2H),2.30 (q, J= 7.7 Hz, 2H), 2.04 - 1.76 (m,5H), 1.74 - 1.30 (m, 8H), 1.26 - 1.18(m. 4H), 0.68 - 0.49 (m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.09 Mobile Phase A: Water (10 (s, 1H). 9.00 (q, J = 8.6 Hz. 2H), 7.47 mmol / L NH₄HCO₃), Mobile (t, J= 7.7 Hz, 2H), 7.36 - 7.23 (m, 3H). Phase B: ACN; Column: 6.96 (d. J= 3.9 Hz, 4H), 6.81 - 6.68 (m. XBridge C18 30*150 mm. 5 1H), 5.42 - 5.30 (m, 1H), 5.05 (s, 1H). μm; Flow rate: 35 mL / min; 4.55 (d, J= 12.7 Hz, 1H), 4.13 (dt, J = Gradient (B%): isocratic 38%- 16.7, 8.4 Hz, 1H). 4.04 - 3.75 (m, 3H), m / z 72% 8 min; Wave Length: 254 3.77 - 3.61 (m, 1H), 3.60 (s, 3H), 3.56 ES+ nm / 220 nm; RT1 (min): 8 - 3.42 (m, 1H), 3.16 (t, J = 12.8 Hz, [M+H]1H), 2.97 (d, J = 3.0 Hz, 3H), 2.95 -+987.2.79 (m, 2H), 2.78 - 2.55 (m, 3H), 2.30(q, J = 10.5, 9.0 Hz, 2H), 2.02 - 1.94(m, 1H), 1.84 (d, J= 12.0 Hz, 3H), 1.72- 1.54 (m, 2H), 1.55 - 1.42 (m, 3H),1.42 - 1.30 (m, 2H), 1.21 (d, J = 12.7Hz, 9H), 0.57 (t, J= 9.6 Hz, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.08 Mobile Phase A: Water (10 (s, 1H).9.00 (s, 1H), 8.85 (d, J= 9.0 Hz, mmol / L NH₄HCO₃), Mobile 1H), 7.54 - 7.43 (m, 2H), 7.31 (t, J = Phase B: ACN; Column: 7.4 Hz, 3H), 7.11 (d, J = 1.4 Hz, 1H), XBridge C18 30*150 mm, 5 7.03 (d, J = 8.1 Hz, 1H), 6.96- 6.84 (m, μm; Flow rate: 35 mL / min; 2H), 6.88 - 6.75 (m, 1H), 5.41 - 5.29 Gradient (B%): isocratic 32%- m / z(m, 1H), 4.80 (s, 1H). 4.57 (d. J = 12.8 64% 7 min; Wave Length: 254ES+Hz, 1H), 4.43 (d, J= 12.8 Hz, 1H).3.99 nm / 220 nm; RT1 (min): 7[M+H](d. J= 13.4 Hz, 1H), 3.88 (d. J= 13.1+959.Hz, 1H), 3.33 (s, 3H), 3.15 - 3.09 (m,1H), 2.99 (s, 3H). 2.97 - 2.77 (m. 3H),2.64-2.50 (m, 2H), 2.58- 2.25 (m. 5H),2.07 - 1.95 (m, 2H), 1.79 - 1.57 (m,6H), 1.49 - 1.41 (m, 5H). 1.23 - 1.17(m. 2H), 0.68- 0.51 (m, 4H).’HNMR(300MHz, DMSO-< / 6) 811.08 Mobile Phase A: Water (s, 1H), 9.00 (s, 1H), 8.83 (d, J= 8.8 Hz, (lOmmol / L NH4HCO3), Mobile 1H), 7.54 - 7.43 (m, 2H), 7.37 - 7.26 Phase B: ACN; Column: (m, 3H), 7.10 (d, J= 1.4 Hz, 1H), 7.07 XBridge C18 30*150 mm, 5 - 6.98 (m, 1H), 6.96 - 6.84 (m, 2H), |im; Flow rate: 35 mL / min; 6.87 - 6.75 (m, 1H), 5.35 (dd, J= 12.8, Gradient (B%): isocratic 35%- 5.3 Hz, 1H), 4.80 (s, 1H), 4.57 (d, J = m / z 68% 7 min; Wave Length: 254 12.7 Hz, 1H), 4.42 (d, J= 12.8 Hz, 1H), ES+ nm / 220 nm; RT1(min): 7 3.99 (d, J= 13.1 Hz, 1H), 3.86 (d, J = [M+H]13.2 Hz, 1H), 3.33 (s. 3H), 3.17 - 3.01+987.(m, 1H), 2.99 (s, 3H), 2.93 - 2.73 (m,4H), 2.72-2.62 (m, 2H), 2.61 -2.55 (m,1H), 2.38 - 2.30 (m, 2H), 2.24 - 2.05(m, 2H). 2.05 - 1.95 (m, 2H).1.95 - 1.82 (m, 2H). 1.82 - 1.37 (m, 9H). 1.30- 1.21 (m, 6H). 0.68 - 0.51 (m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.08 Mobile Phase A: Water (10 (s, 1H), 9.00 (d. J= 2.1 Hz, 1H), 8.84 - mmol / L NH₄HCO₃), Mobile 8.69 (m, 1H), 7.54 - 7.40 (m, 2H), 7.35 Phase B: ACN; Column: - 7.22 (m, 3H), 7.10 (d, J = 1.4 Hz, 1H), XBridge C18 30*150 mm, 5 μm; 7.02 (d, J= 8.1 Hz, 1H), 6.95 - 6.77 (m, Flow rate: 35 mL / min; Gradient 3H), 5.47 - 5.20 (m, 1H), 4.80 (s, 1H), (B%): isocratic 38%-72% 7 m / z4.57 (d, J = 12.9 Hz, 1H), 4.42 (d, J = min; Wave Length: 254 nm / ES+13.0 Hz, 1H). 3.99 (d, J= 13.3 Hz, 1H), 220 mn; RT1 (min): 7[M+H]3.85 (d, J= 13.1 Hz, 1H). 3.33 (s, 3H),+1015.3.09 (t. J= 12.4 Hz, 1H). 2.99 (s, 3H),2.95 - 2.59 (m, 6H). 2.42 - 2.27 (m,3H). 2.24 - 2.07 (m, 2H), 1.99 (d, J =11.7 Hz, 2H), 1.77 (d, J = 12.9 Hz, 2H).1.71 - 1.37 (m. 9H), 1.35 - 1.17 (m.10H). 0.66 - 0.52 (m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.07 Mobile Phase A: Water (s, 1H). 8.98 (s, 1H), 8.79 - 8.71 (m. (10mmol / L NH₄HCO₃), Mobile 1H), 7.50 - 7.42 (m, 2H). 7.34 - 7.24 Phase B: ACN; Column: (m. 3H), 6.96 (s, 3H), 6.94 - 6.74 (m. XBridge C18 30*150 mm. 5 2H), 5.35 (dd, J = 12.6, 5.4 Hz, 1H), μm; Flow rate: 35 mL / min; 4.78 (s, 1H), 4.55 (d, J= 12.9 Hz, 1H), Gradient (B%): isocratic 32%- m / z4.41 (d, J = 12.9 Hz, 1H), 3.97 (d, J = 64% 7 min; Wave Length: 254ES+13.4 Hz, 1H), 3.86 (d, J = 13.6 Hz, 1H), nm / 220 nm; RTl(min): 7[M+H]3.60 (s, 3H), 3.51 - 3.44 (m, 1H), 3.21+959.- 3.10 (m, 1H), 2.99 - 2.81 (m, 4H),2.32 (s, 3H), 2.25 - 2.21 (m, 1H), 2.20- 2.11 (m, 1H), 1.96 (s, 2H), 1.81 (d, J= 12.3 Hz, 2H), 1.65 (s, 4H), 1.46 (s,5H), 1.19 - 1.05 (m, 6H), 0.64 - 0.50(m, 4H).¹H NMR (300 MHz, DMSO-d₆) δ 11.09 Mobile Phase A: Water (10 (s, 1H). 8.98 (s, 1H), 8.80 (d, J= 8.1 Hz, mmol / L NH₄HCO₃), Mobile 1H), 7.53 - 7.42 (m, 2H), 7.32 (d, J = Phase B: ACN; Column: 7.5 Hz, 1H), 6.98 (s, 3H), 6.90 - 6.74 XBridge C18 30*150 mm, 5 (m, 2H), 5.37 (dd, J = 12.7, 5.5 Hz, 1H), μm; Flow rate: 35 mL / min; 4.79 (s, 1H), 4.56 (d, J= 12.5 Hz, 1H), Gradient (B%): isocratic 35%- m / z4.42 (d, J = 12.8 Hz, 1H), 3.99 (d, J = 68% 7 min; Wave Length: 254ES+106 13.2 Hz, 1H). 3.87 - 3.81 (m, 1H). 3.61 nm / 220 nm; RT1 (min): 7[M+H](s, 3H), 2.98 (s. 3H), 2.90 (s, 3H), 2.80+987.- 2.65 (m. 3H), 2.45 - 2.39 (m, 2H),2.38 - 2.30 (m, 3H). 2.21 - 2.15 (m,3H). 2.00 - 1.94 (m. 2H), 1.87 - 1.71(m, 5H), 1.69 - 1.41 (m, 4H), 1.40 - 1.05 (m, 6H), 0.65 - 0.52 (m. 4H).’HNMR(300MHz, DMSO-Je) 511.10 Mobile Phase A: Water (10 (s, 1H), 9.00 (s, 1H). 8.84 - 8.73 (m, mmol / L NH4HCO3), Mobile 1H), 7.54 - 7.43 (m, 2H), 7.37 - 7.24 Phase B: ACN; Column: (m, 3H), 6.99 (d, J = 2.0 Hz, 3H), 6.94 XBridge C18 30*150 mm, 5 - 6.83 (m, 1H), 6.87 - 6.75 (m, 1H), μm; Flow rate: 35 mL / min; 5.38 (dd, J= 12.4, 5.3 Hz. 1H), 4.80 (s, Gradient (B%): isocratic 38%- 1H), 4.57 (d, J = 12.9 Hz. 1H), 4.43 (d, 72% 8 min; Wave Length: 254 m / zJ = 12.7 Hz, 1H). 4.00 (d. J = 13.4 Hz, nm / 220 nm; RT1 (min): 8 ES+105 1H). 3.86 (d. J = 13.3 Hz. 1H), 3.62 (s,[M+H]3H), 3.51 (t, J = 11.7 Hz, 1H), 3.27 -+1015.3.09 (m, 2H), 2.99 (s, 3H). 2.98 - 2.82(m. 2H), 2.81 - 2.52 (m, 4H), 2.48 - 2.29 (m, 2H), 2.26 - 2.05 (m, 2H), 2.05- 1.95 (m, 2H), 1.88 - 1.82 (m, 2H).1.81 -1.45 (m, 7H), 1.43 - 1.31 (m.2H), 1.30 - 1.21 (m, 9H). 0.69 - 0.54(m. 4H).Example 2: WRN degradation Assay

[0252] Compounds of the present disclosure were evaluated for target engagement with WRN protein, as well as their ability to function as degraders of WRN (HiBit assay.Promega). Nano-Gio® HiBiT Lytic Reagent was added in equal amounts to the culture medium present in each well, and mixed. Lumiscence was read out using a biotek Neo2 plate reader. The results are shown in Table 3. For target engagement TEso (pM) and degradation DC50 (pM): A is < 1 pM; B is > 1 pM and < 10 pM; and C is > 10 pM and < 100 pM. For maxTE (%) and maximal degradation Dmax (%): A is < 25%; B is > 25 % and < 50%; C is > 50% and < 75%; and D is > 75%. For TD AUC (Targeted Degradation Area Under the Curve): A is < 1000; B is > 1000 and < 2000; and C is > 2000.Table 3.TEso TD AUCNo maxTE (%) DCso (pM) Dmax (%)(PM)101 A C A C102 A B B B103 A A B A104 C B B A C105 C A A B A106 A A B107 B A B108 B B B109 B A C110 B B B111 B B A112 B B B113 A B A114 B B B115 A B A116 A B A117 B A A118 B B A119 B A C120 B B B121 C B B122 B A C123 B A C124 A A C201 A202 C B203 C C204 c C205 c C206 c B207 A208 B C209 C B210 A211 C C212 A213 C BExample 3

[0253] The efficacy of disclosed compounds in a microsatellite instabilit -high, RKO colon carcinoma cell model was evaluated (CTG luminescence assay, Promega). The results are shown in Table 4. For IC50(pM) and DC50(nM): A is < 1; B is > 1 and < 10; and C is > 10. For inhibition max Imax (%) and Dmax by Jess Western Blot (%): A is < 25; B is > 25 and < 50; C is > 50 and < 75; and D is > 75.Table 4.No IC50(μM) Imax (%) DC50(nM) Dmax (%) 101 C A B102 c A B C103 B D C C104 C A A105 B D C D106 C DExample 4:

[0254] Antibodies used for WRN degradation ELISA: Capture Antibody: WRN Rabbit anti WRN (1 / 250); Detection Antibody: mouse anti WRN (1 / 250); Secondary HRP Antibody: Goat anti mouse-HRP antibody (1 / 1000).

[0255] Buffers: Coat buffer #1: PBS; Coat buffer #2: ELISA Carbonate Coating Buffer; Wash buffer #1: PBS; Blocking buffer: PBS, 0.05% Tween-20, 5% skimmed milk; Wash buffer #2: PBS + 0.05% tween-20.

[0256] Maxisorp 384-well white plates were coated with 25 uL of primary antibody per well diluted (1:250) in PBS (or carbonate coating buffer). The plate was spun at 1000 g for 2 seconds, then incubated overnight at 4 deg C. The coating liquid was removed by shaking out the plate into a sink, blotting on paper, and dispensing 100 uL of PBS into wells. This process was repeated 3 times for a total of 4 washes. After the final wash, 100 pL per well of blocking reagent was added (PBS, 0.05% Tween-20, 5% skimmed milk), and the plates were incubated for a minimum of 1 h at room temperature. The blocking buffer was removed and the plate was washed once with 100 uL of PBST. 20-25 pL of treated lysates (0.1-1 mg / mL in Pierce IP Lysis buffer + HALT) was added and the plate was spun at 1000 g for 2 seconds. The plate was then incubated for 1-2 h at room temperature. The plate was washed 4X with PBST (100 uL / well, 3 min incubation), followed by the addition detection antibody diluted (1:250) in blocking buffer (25 uL / well). The plate was spun at 1000 g for 2 seconds and then incubated at room temp, for 1-2 h. The plate was then washed 4X with PBST (100 uL / well, 3 min incubation), followed by the addition secondary antibody diluted (1:1000) in blocking buffer (25 uL / well). The plate was spun at 1000 g for 2 seconds and then incubated at room temp, for 1-2 h. The plate was washed 4X with PBST (100 uL / well, 3 min incubation) followed by the addition SuperSignal ELISA PICO reagent (25 uL / well). The plate was spun at 1000 g for 2 seconds and then immediately read on plate reader for chemiluminescence.

[0257] The efficacy of disclosed compounds was evaluated using the above WRN degradation ELISA in a 22RV1 cell line, which is a microsatellite instability-high, human prostate cancer model and an WRN inhibitor insensitive cell line. The results are shown in Table 5. For DC50 (pM): A is < 1; B is > 1 and < 5; C is > 5 and < 10; and C is > 10. For Dmax (%): A is < 25; B is > 25 and < 50; C is > 50 and < 75; and D is > 75.Table 5.No DC50(μM) Dmax (%) 101 D B 102 B C 103 B C 104 D B 105 A C 106 B C 107 B C 108 D B 109 D A 110 C C 111 C C 112A113 B C 114 B C 115 B c 116 C c 117A118B119A120 B C 121 A D 122A123 D B 124 D BB C125B C126B D127B D128B129 B C130B C131B132 CA D133A D134A D135A D136B D137A D138B D139A D140D A141D B142D A143B D144D A145Example 5

[0258] The efficacy of disclosed compounds in a 22RV1 cell line was evaluated (CTG luminescence assay). The results are shown in Table 6. For IC50(μM): A is < 1; B is > 1 and < 10; and C is > 10.Table 6.No IC50(μM)103 B105 B115 B126 B127 B131 BINCORPORATION BY REFERENCE

[0259] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS AND SCOPE

[0260] In the claims articles such as “a,” ‘an,” and '‘the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in. employed in. or otherwise relevant to a given product or process.

[0261] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g.. in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, w here the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the low er limit of the range, unless the context clearly dictates otherwise.

[0262] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the presentinvention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0263] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

1. CLAIMSWhat is claimed is:

1. A method of treating a microsatellite instabi li ty-high (MSI-H) cancer in a patient in need thereof, wherein the cancer is insensitive to WRN allosteric inhibition, comprising administering to the patient a therapeutically effective amount of a bifunctional conjugate represented by Formula (I):W-L-E(I);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:W is a Werner syndrome RecQ like helicase (WRN) binding compound;L is a linking moiety covalently linking W and E; andE is a E3 ubiquitin ligase complex binding moiety.

2. The method of claim 1, wherein E is capable of binding or recruiting E3 ubiquitin ligase complex directly or indirectly.

3. The method of claim 1, wherein E is capable of binding to an associated cofactor, adaptor protein, or substrate recognition domain of E3 ubiquitin ligase, thereby enabling the recruitment of the E3 ligase ubiquitin ligase complex.

4. The method of claim 1, wherein E recognizes and binds to a E3 ligase target substrate.

5. The method of claim 1. wherein E binds to a cofactor or adaptor protein that facilitates the interaction between E3 ligase and the cofactor or adaptor protein.

6. The method of claim 1, wherein E binds to a recognition domain or a substrate receptor of E3 ubiquitin ligase complex.

7. The method of claim 6, where E is capable of binding to VHL ligase, CRBN, MDM2 ligase, an IAP (e.g., cIAP1 or CIAP2), and / or KEAP1 protein.

8. The method of claim 6 or 7, wherein E is capable of binding to a cereblon or VEIL protein of the E3 ubiquitin ligase complex.

9. The method of any one of claims 1-8, wherein E is selected from the group consisting of an antibody, a protein, a peptide, an aptamer, a nanobody, or a small molecule binding moiety.

10. The method of any one of claims 1-9, wherein W is capable of binding covalently or non-covalently to the Werner syndrome RecQ like helicase (WRN).

11. The method of any one of claims 1-10, wherein W is capable of covalently binding to cysteine residue 727 of the Werner syndrome RecQ like helicase (WRN).

12. The method of any one of claims 1-11, wherein the WRN binding compound includes a Michael acceptor covalent binding moiety.

13. The method of claims 1-12, wherein the WRN binding compound is represented by:wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O-. -S-. -S(O)-. and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-:RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl. C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=0)0Rb, -NRa(C=0)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(0)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;p is 0, 1, 2, 3, 4, or 5; and* denotes the point of attachment to L.

14. The method of any one of claims 1-13, wherein the bifunctional conjugate is represented by Formula (I A):wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O- -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one. two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=0)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(0)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;n^N^'Z is selected from the group consisting of -NR - andm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C1-C6alkylene. C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:one to twelve bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(0)-, -C(0)NRa-. -NRaC(0)0-, -OC(O)NRa-, -NRaC(0)NRb-, (-OCH2CH2-)1-5. (-CH2CH2O-)1-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, C1-C3alkyl, and C1-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein Ci-Cgalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cealkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl. -NRaRb. C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-C3alkoxy;m is 1, 2, or 3;n is 1, 2, or 3; andp is 0, 1, 2, 3, 4, or 5.

15. The method of any one of claims 1-14, wherein Y1and Y2are each -NH-.

16. The method of any one of claims 1-15, wherein X1and X2are each N.

17. The method of any one of claims 1-16, wherein R1is -(CRcRd)-C3-C4cycloalkyl; wherein Rcand Rdare each independently selected from the group consisting of hydrogen and halogen.

18. The method of any one of claims 1-17, wherein Z is19. The method of any one of claims 1-18, wherein the bifun ctional conjugate is represented by Formula (IB):wherein:q is 1 or 2; andL1is selected from the group consisting of a bond and Ci-Ceheteroalkylene.

20. The method of claim 19, wherein L1is selected from the group consisting of a bond, -CH2-O-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, and -CH2-O-CH2-CH2-CH2-.

21. The method of any one of claims 1-18, wherein Z is -NH-.

22. The method of any one of claims 1-18 and 21, wherein the bifunctional conjugate is represented by Formula (IC);wherein L1is selected from the group consisting of Ci-Ceheteroalkylene and C1-C6alkylene.

23. The method of claim 22, wherein L1is selected from the group consisting of -CH2-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, and -CH2-O-CH2-CH2-CH2-.

24. The method of any one of claims 1-23, wherein R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, Ci-C6alkyl, and Ci-Cealkoxy.

25. The method of any one of claims 1-24, wherein p is 0, 1, or 2.

26. The method of any one of claims 1-25, wherein p is 0.

27. The method of any one of claims 1-26, wherein R3is selected from the group consisting of -CH3, -CH2CH3, and -CH2-CH2-CH3.

28. The method of any one of claims 1-27, wherein R3is -CH3.

29. The method of any one of claims 1-28, wherein L2is selected from the group consisting of -C(0)-Ci-Cioalkylene-C(0)-, -C(0)-Ci-Cioalkylene-(0)-, and -Ci-Cioalkylene-C(O)-.

30. The method of any one of claims 1-29, wherein L2is selected from the group consisting of -C(O)-(CH2)-C(O)-, -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -C(O)-(CH2)7-C(O)-, -C(O)-(CH2)8-C(O)-, -C(O)-(CH2)9-C(O)-, -C(O)-(CH2)10-C(O)-, -C(O)-(CH2)-(O)-, -C(O)-(CH2)2-(O)-, -C(O)-(CH2)3-(O)-, -C(O)-(CH2)4-(O)-. -C(O)-(CH2)5-(O)-, -C(O)-(CH2)6-(O)-, -C(O)-(CH2)7-(O)-. -C(O)-(CH2)8-(O)-, -C(O)-(CH2)9-(O)-, -C(O)-(CH2)10-(O)-, -(CH2)-C(O)-, and -(CH2)2-C(O)-.

31. The method of any one of claims 1-30, wherein L2is selected from the group consisting of -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)6-C(O)-, -C(O)-(CH2)8-C(O)-, and -C(O)-(CH2)10-C(O)-, -C(O)-(CH2)2-(O)-, -C(O)-(CH2)4-(O)-, -C(O)-(CH2)6-(O)-, -C(O)-(CH2)8-(O)-, and -C(O)-(CH2)10-(O)-,32. The method of any one of claims 1-31, wherein m is 1 and n is 1.

33. The method of any one of claims 1-32, wherein m is 2 and n is 2.

34. The method of any one of claims 1-33, wherein E is selected from the group consisting of35. A method of treating a microsatellite instability -high (MSI-H) cancer in a patient in need thereof, wherein the cancer is insensitive to WRN allosteric inhibition, comprising administering to the patient a therapeutically effective amount of a bifunctional conjugate represented by Formula (II):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O- -S-, -S(0)-, and -S(0)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one. two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, -C(=O)NRaRb, -NRa(C=0)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(0)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and'm; w herein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C1-C6alkylene. C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:two to ten bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(0)-, -C(0)NRa-. -NRaC(0)0-, -OC(O)NRa-, -NRaC(0)NRb-, (-OCH2CH2-)1-5. (-CH2CH2O-)1-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, C1-C3alkyl, and C1-C3alkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and Ci-Cgalkyl, wherein Ci-Cgalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cgalkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl. -NRaRb. Ci-Csalkyl, and Ci-Cgalkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-C3alkoxy;m is 1, 2, or 3;n is 1, 2, or 3;p is 0, 1, 2, 3, 4, or 5; andE is a E3 ubiquitin ligase complex binding moiety capable of covalently binding to a cereblon or VHL protein of the E3 ubiquitin ligase complex.

36. The method of claim 35, wherein the bifunctional conjugate is represented by Formula (IIA):(IIA);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and Ci-Cgalkoxy;R3is Ci-Cgalkyl optionally substituted with one, two, or three halogens;R4and R5are each independently selected from the group consisting of halogen and hydrogen;Z is selected from the group consisting ofRaand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;E is selected from the group consisting ofp is 0, 1, or 2;q is 1 or 2; andt is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

37. The method of claim 36, wherein p is 0. 1, or 2.

38. The method of claim 36 or 37, wherein q is 1.

39. The method of any one of claims 36-38, wherein R4and R5are each fluoro.

40. The method of any one of claims 36-39, wherein R3is selected from the group consisting of -CH3, -CH2CH3. and -CH2-CH2-CH3.

41. The method of any one of claims 36-40, wherein R3is -CH3.

42. The method of any one of claims 36-41, wherein t is 4, 6, or 8.

43. A bifunctional conjugate represented by Formula (I):W-L-E(I);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:W is a Werner syndrome RecQ like helicase (WRN) binding compound;L is a linking moiety covalently linking W and E; andE is a E3 ubiquitin ligase complex binding moiety.

44. The bifunctional conjugate of claim 43, wherein E is capable of binding or recruiting E3 ubiquitin ligase complex directly or indirectly.

45. The bifunctional conjugate of claim 43, wherein E is capable of binding to an associated cofactor, adaptor protein, or substrate recognition domain of E3 ubiquitin ligase, thereby enabling the recruitment of the E3 ligase ubiquitin ligase complex.

46. The bifunctional conjugate of claim 43, wherein E recognizes and binds to a E3 ligase target substrate.

47. The bifunctional conjugate of claim 43, wherein E binds to a cofactor or adaptor protein that facilitates the interaction between E3 ligase and the cofactor or adaptor protein.

48. The bifunctional conjugate of claim 43, wherein E binds to a recognition domain or a substrate receptor of E3 ubiquitin ligase complex.

49. The bifunctional conjugate of claim 48, where E is capable of binding to VHL ligase, CRBN, MDM2 ligase, an IAP (e.g„ clAPl or CIAP2), and / or KEAP1 protein.

50. The bifunctional conjugate of claim 48 or 49, wherein E is capable of binding to a cereblon or VHL protein of the E3 ubiquitin ligase complex.

51. The bifunctional conjugate of any one of claims 43-50, wherein E is selected from the group consisting of an antibody, a protein, a peptide, an aptamer, a nanobody, or a small molecule binding moiety.

52. The bifunctional conjugate of any one of claims 43-51, wherein W is capable of binding covalently or non-covalently to the Werner syndrome RecQ like helicase (WRN).

53. The bifunctional conjugate of any one of claims 43-52, wherein W is capable of covalently binding to cysteine residue 727 of the Werner syndrome RecQ like helicase (WRN).

54. The bifunctional conjugate of any one of claims 43-53, wherein the WRN binding compound includes a Michael acceptor covalent binding moiety’.

55. The bifunctional conjugate of claims 43-54, wherein the WRN binding compound is represented by:wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl. -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -0-, -S-. -S(0)-. and -S(0)2-; Y2is selected from the group consisting of -NRY2-, and -0-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein Ci-Cgalkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted wi th one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=O)ORb, -NRa(C=0)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OC1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=0)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=0)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(0)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;p is 0, 1, 2, 3, 4, or 5; and* denotes the point of attachment to L.

56. The bifunctional conjugate of any one of claims 43-55, wherein the bifunctional conjugate is represented by Formula (I A):wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)0-3-C3-C6cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy. -C(=O)NRaRb. -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -0(C=0)0Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Csalkyl, and Ci-C6alkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cealkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, -SH. -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2C1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Cgalkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and"m; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond, C i-Cealkylene, C2-Cealkenylene, and Ci-Cgheteroalkylene;L2is a linking moiety comprising:one to twelve bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(0)-, -C(O)NRa-. -NRaC(0)0-, -OC(O)NRa-, -NRaC(0)NRb-, (-OCH2CH2-)1-5, (-CH2CH2O-)1-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein Ci-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cgalkoxy: orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;m is 1, 2, or 3;n is 1, 2, or 3; andp is 0, 1, 2, 3, 4, or 5.

57. The bifunctional conjugate of any one of claims 43-56, wherein Y1and Y2are each -NH-.

58. The bifunctional conjugate of any one of claims 43-57, wherein X1and X2are each N.

59. The bifunctional conjugate of any one of claims 43-58, wherein R1is -(CRcRd)-C3-C4cycloalkyl; wherein Rcand Rdare each independently selected from the group consisting of hydrogen and halogen.

60. The bifunctional conjugate of any one of claims 43-59, wherein Z ism.

61. The bifunctional conjugate of any one of claims 43-60, wherein the bifunctional conjugate is represented by Formula (IB):wherein:q is 1 or 2; andL1is selected from the group consisting of a bond and Ci-Ceheteroalkylene.

62. The bifunctional conjugate of claim 61, wherein L1is selected from the group consisting of a bond, -CH2-O-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, and -CH2-O-CH2-CH2-CH2-.

63. The bifunctional conjugate of any one of claims 43-59, wherein Z is -NH-.

64. The bifunctional conjugate of any one of claims 43-59 and 63, wherein the bifunctional conjugate is represented by Formula (IC);wherein L1is selected from the group consisting of Ci-Ceheteroalkylene and C1-C6alkylene.

65. The bifunctional conjugate of claim 64, wherein L1is selected from the group consisting of -CH2-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, and -CH2-O-CH2-CH2-CH2-.

66. The bifunctional conjugate of any one of claims 43-65, wherein R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy.

67. The bifunctional conjugate of any one of claims 43-66, wherein p is 0, 1, or 2.

68. The bifunctional conjugate of any one of claims 43-67, wherein p is 0.

69. The bifunctional conjugate of any one of claims 43-68, wherein R3is selected from the group consisting of -CH3, -CH2CH3, and -CH2-CH2-CH3.

70. The bifunctional conjugate of any one of claims 43-69, wherein R3is -CH3.

71. The bifunctional conjugate of any one of claims 43-70, wherein L2is selected from the group consisting of -C(0)-Ci-Cioalkylene-C(0)-, -C(0)-Ci-Cioalkylene-(0)-, and -Ci-Cioalkylene-C(O)-.

72. The bifunctional conjugate of any one of claims 43-71, wherein L2is selected from the group consisting of -C(O)-(CH2)-C(O)-, -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-. -C(O)-(CH2)7-C(O)-. -C(O)-(CH2)8-C(O)-, -C(O)-(CH2)9-C(O)-, -C(O)-(CH2)10-C(O)-, -C(O)-(CH2)-(O)-, -C(O)-(CH2)2-(O)-, -C(O)-(CH2)3-(O)-, -C(O)-(CH2)4-(O)-, -C(O)-(CH2)5-(O)-, -C(O)-(CH2)6-(O)-, -C(O)-(CH2)7-(O)-, -C(O)-(CH2)8-(O)-, -C(O)-(CH2)9-(O)-, -C(O)-(CH2)10-(O)-, -(CH2)-C(O)-, and -(CH2)2-C(O)-.

73. The bifunctional conjugate of any one of claims 43-72, wherein L2is selected from the group consisting of -C(O)-(CH2)2-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)6-C(O)-, -C(O)-(CH2)8-C(O)-, and -C(O)-(CH2)10-C(O)-, -C(O)-(CH2)2-(O)-, -C(O)-(CH2)4-(O)-, -C(O)-(CH2)6-(O)-, -C(O)-(CH2)8-(O)-, and -C(O)-(CH2)10-(O)-.

74. The bifunctional conjugate of any one of claims 43-73, wherein m is 1 and n is 1.

75. The bifunctional conjugate of any one of claims 43-74, wherein m is 2 and n is 2.

76. The bifunctional conjugate of any one of claims 43-75, wherein E is selected from the group consisting of77. A bifunctional conjugate represented by Formula (II):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cgalkoxy;Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-; Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=O)ORb, -NRa(C=0)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OC1-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, Ci-Cgalkyl, and Ci-Cgalkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, Ci-Cgalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, C3-C6cycloalkyl, phenyl, -C(=O)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(0)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and'm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond. C1-C6alkylene. C2-C6alkenylene, and Ci-Ceheteroalkylene;L2is a linking moiety comprising:two to ten bivalent units each represented by -(CRL1RL2)-; and optionally one, two, three, or four additional bivalent units each independently selected from the group consisting of -0-, -NRa-, -S-, -S(0)-, -S(0)2-, -C(0)0-, -0C(0)-, -NRaC(0)-, -C(0)NRa-, -NRaC(0)0-, -OC(O)NRa-, -NRaC(0)NRb-, (-OCH2CH2-)1-5, (-CH2CH2O-)1-5, alkynylene, alkenylene, 5-6 membered heteroaryl, and 5-6 membered heterocyclyl;RL1and RL2are each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cgalkoxy; orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, C1-C3alkyl, and C1-C3alkoxy;m is 1, 2, or 3;n is 1, 2, or 3;p is 0, 1, 2, 3, 4, or 5; andE is a E3 ubiquitin ligase complex binding moiety capable of covalently binding to a cereblon or VHL protein of the E3 ubiquitin ligase complex.

78. The bifunctional conjugate of claim 77, wherein the bifunctional conjugate is represented by Formula (IIA):(IIA);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;R3is C1-C6alkyl optionally substituted with one, two, or three halogens;R4and R5are each independently selected from the group consisting of halogen and hydrogen;Z is selected from the group consisting ofRaand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;E is selected from the group consisting ofp is 0, 1, or 2;q is 1 or 2; andt is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

79. The bifunctional conjugate of claim 78, wherein p is 0, 1, or 2.

80. The bifunctional conjugate of claim 78 or 79, wherein q is 1.

81. The bifunctional conjugate of any one of claims 78-80, wherein R4and R5are each fluoro.

82. The bifunctional conjugate of any one of claims 78-81, wherein R3is selected from the group consisting of -CHs, -CH2CH3, and -CH2-CH2-CH3.

83. The bifunctional conjugate of any one of claims 78-82, wherein R3is -CH3.

84. The bifunctional conjugate of any one of claims 78-83, wherein t is 4, 6, or 8.

85. A compound represented by Formula (III):or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:X1is selected from the group consisting of N and C(RX1);X2is selected from the group consisting of N and C(RX2);RX1and RX2are each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;Y1is selected from the group consisting of -NRY1-, -O-, -S-, -S(O)-, and -S(O)2-;Y2is selected from the group consisting of -NRY2-, and -O-;RY1and RY2are each independently selected from the group consisting of hydrogen and C1-C6alkyl; wherein C1-C6alkyl may optionally be substituted with one or more halogens;R1is -(CRcRd)o-3-C3-C6Cycloalkyl; wherein cycloalkyl may optionally be substituted with one, two, or three substituents each independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-C6alkoxy, -C(=0)NRaRb, -NRa(C=0)Rb, -0(C=0)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, and -O(C=O)Ci-C6alkyl, -O(C=O)OCi-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -CN, -NO2, -NRaRb, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Csalkoxy, C3-C6cycloalkyl, phenyl, -C(=0)NRaRb, -NRa(C=O)Rb, -O(C=O)NRaRb, -NRa(C=O)ORb, -NRa(C=O)NRaRb, -(C=O)Ci-C6alkyl, -(C=O)OCi-C6alkyl, -O(C=O)C1-C6alkyl, -O(C=O)OCi-C6alkyl, -SH, -SC1-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)2NRaRb, and -NRaS(O)2Ci-C6alkyl, wherein each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and phenyl may optionally be substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, oxo, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one or more halogens;Z is selected from the group consisting of -NRZ- and'm; wherein * denotes the point of attachment to L1;L1is selected from the group consisting of a bond. C1-C6alkylene. C2-Cealkenylene, and Ci-Ceheteroalkylene;L2is selected from the group consisting of hydrogen, -(C=0)0Ci-C6alkyl, and -(C=O)Ci-C6alkyl;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl, wherein C1-C6alkyl optionally substituted with one or moresubstituents each independently selected from the group consisting of halogen, hydroxyl, and Ci-Cealkoxy: orRaand Rb, together with the nitrogen to which they are attached, may be joined together to form a 4-7 membered heterocyclyl optionally substituted by one or more substituents each independently selected from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and C1-C6alkoxy;Rcand Rdare each independently selected for each occurrence from the group consisting of hydrogen, halogen, Ci-Csalkyl, and Ci-Csalkoxy;m is 1, 2, or 3;n is 1, 2, or 3; andp is 0, 1, 2, 3, 4, or 5.

86. The compound of claim 85, wherein the compound is represented by Formula (IIIA):'Z(IIIA);or a pharmaceutically acceptable salt and / or a stereoisomer thereof, wherein:R2is independently selected for each occurrence from the group consisting of halogen, hydroxyl, -NRaRb, C1-C6alkyl, and Ci-Cealkoxy;R3is C1-C6alkyl optionally substituted with one, two, or three halogens;R4and R5are each independently selected from the group consisting of halogen and hydrogen;N.RR6R6R6is selected from the group consisting of hydrogen and -(C=O)OCi-C6alkyl;Raand Rbare independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;p is 0, 1, or 2; andq is 1 or 2.

87. The compound of claim 86, wherein p is 0, 1, or 2.

88. The compound of claim 86 or 87, wherein q is 1.

89. The compound of any one of claims 86-88, wherein R4and R5are each fluoro.

90. The compound of any one of claims 86-89, wherein R3is selected from the group consisting of -CH3, -CH2CH3, and -CH2-CH2-CH3.

91. The compound of any one of claims 86-90, wherein R3is -CH3.

92. The compound of any one of claims 86-91, wherein R6isor hydrogen.

93. A compound selected from the group consisting of:or a pharmaceutically acceptable salt and / or a stereoisomer thereof.

94. A compound selected from the group consisting of:172173174175176O=S=O IO=S=O I180O=S=O Ior a pharmaceutically acceptable salt and / or a stereoisomer thereof.

95. A pharmaceutical composition comprising a compound of any one of claims 43-94, or a pharmaceutically acceptable salt and / or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

96. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 43-94, or the pharmaceutical composition of claim 95.

97. The method of claim 96, wherein the cancer is a microsatellite instability-high (MSI-H) cancer.

98. The method of claim 96, wherein the cancer is insensitive to WRN allosteric inhibition.

99. The method of any one of claims 96-98, wherein the cancer is a microsatellite instability-high (MSI-H) cancer and is insensitive to WRN allosteric inhibition.

100. The method of any one of claims 1-42 and 96-99, wherein the cancer is selected from the group consisting of gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer.

101. A method of treating a microsatellite instability -high (MSI-H) cancer selected from the group consisting of gastric cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and renal cancer in a patient in need thereof, wherein the cancer is insensitive to WRN allosteric inhibition, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 43-94, or the pharmaceutical composition of claim 95.

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